Specific Investigations: • OPG for bone erosion. • USG neck for clinically N0 neck when neck is to be observed or neck evaluation is difficult. • CT scan/ MRI for suspected vascular / maxillary infiltration and extension of tumor in infratemporal fossa. - CT scan is preferred to assess early bone involvement, in midline lesions and in sites as buccal mucosa, upper & lower alveolus, RMT & hard palate - MRI is preferred for tongue and floor of mouth lesions and for extension in oropharynx or parapharyngeal space. • PET(CT) scan for evaluation of post treatment residual/ recurrent disease. • EUA for mapping of lesion.
TNM Staging (UICC, 2002)
Lip & Oral Cavity |
Tx |
Primary tumour cannot be assessed |
T0 |
No evidence of primary tumour |
Tis |
Carcinoma in situ |
T1 |
Tumour 2cm or less in the greatest diameter |
T2 |
Tumour > 2cm but < 4 cm in the greatest diameter |
T3 |
Tumour > 4cm in the greatest diameter |
T4 |
T4 lesions have been divided into T4a (resectable) and T4b unresectable), leading to the division of Stage IV into Stage IVA, Stage IVB, and Stage IVC.
T4a (oral cavity) - Tumor invades adjacent structures (eg, through cortical bone, into deep [extrinsic] muscle of the tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face)
T4b - Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery.
|
|
|
Neck Nodes |
Nx |
Regional LN cannot be assessed
|
N0 |
No regional LN metastasis
|
N1 |
Ipsilateral Single node < 3cm
|
N2a |
Ipsilateral Single node 3-6cm
|
N2b |
Ipsilateral multiple nodes <6cm |
N2c |
Bilateral/Contralateral nodes<6cm |
N3 |
Lymph node > 6cm |
LIP
T1, T2 Tumours: Surgery or RT Primary: Surgery: Wide excision Radiotherapy: Radical Radiotherapy / Brachytherapy.
Nodes N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes MND is required N+: MND / RND
Note: Post op RT as per earlier guidelines.
T3, T4 Tumours: Surgery + Post operative RT/ CT-RT Primary: Surgery: Wide excision with marginal/ segmental / hemimandible resection if required with reconstruction.
Nodes N0: SOHD followed by FS, if positive nodes MND is required N+: MND / RND
Note: Bilateral neck needs to be addressed if the primary disease is in midline or extending across midline (including middle third mandible). Post op RT/CT-RT as per earlier guidelines.
BUCCAL MUCOSA
T1, T2 Tumours: Primary: Surgery: wide excision +/- marginal mandibulectomy or margins. Radiotherapy:Radical RT/ Brachytherapy.
Nodes N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes, MND is required N+: MND / RND Note: Post op RT as per earlier guidelines. T3, T4 Tumours: Surgery + Post operative RT or CT-RT Primary: Surgery: Composite resection of the buccal mucosa with mandible or upper alveolus or overlying skin with reconstruction
Nodes N0: SOHD followed by FS, if positive, nodes MND is required N+: MND / RND Note: Post op RT/ CT-RT as per earlier guidelines.
ORAL TONGUE & FLOOR OF MOUTH
T1, T2 Tumours: Primary: Surgery: Wide Excision Glossectomy / Hemiglossectomy Radiotherapy: Radical RT/ Brachytherapy
Nodes N0** Observe/ Elective MND (criteria listed below)# N+ MND/ RND Note: Post op RT/CT-RT as per earlier guidelines.
T3, T4 Tumours: Surgery + Post operative Radiotherapy Primary: Surgery: Appropriate wide / total glossectomy with mandibular swing or pull through along with lingual plate / segmental / hemimandibular resection, if required (based on extent of involvement)
Nodes N0: SOHD / MND / RND N+: MND / RND Note: Bilateral necks need to be addressed if the primary disease is in midline or extends across midline (including middle third mandible). Post op RT/CT+RT as per guidelines.
** USG neck if decision to observe the N0 neck is made. #Criteria for elective neck dissection ¨ Depth of infiltration > 3-4mm ¨ High grade tumour ¨ Expected poor follow up
LOWER ALVEOLUS & RETRO MOLAR TRIGONE
Mandible uninvolved or minimally involved Primary: Surgery: Wide Excision with marginal mandibulectomy (avoided in RMT disease, edentulous mandible, paramandibular disease, post radiotherapy)
Nodes N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes MND is required N+: MND / RND Note: Post op RT as per earlier guidelines.
Mandible grossly involved Surgery + Post operative/ CT-RT Primary: Surgery: Wide Excision (cheek flap) with segmental/ hemi-mandible resection
Nodes N0: SOHD followed by FS, if positive nodes, MND is required N+: MND / RND. Note: Bilateral necks needs to be addressed if the primary disease is in midline or extends across midline (including middle third mandible). Post op RT/ CT-RT as per earlier guidelines.
UPPER ALVEOLUS & HARD PALATE
Maxillary antrum not involved Upper alveolectomy / Partial maxillectomy Radical RT / Brachytherapy for selected early T1-2 Hard palate lesions
Maxillary antrum involved Orbital floor preserving total maxillectomy
Note: Neck needs to be addressed if the neck is clinically positive, if there is extension of the primary disease to the buccal mucosa or there is soft tissue infiltration or radiological suspicion of metastatic node. Post operative RT/ CT-RT as per guidelines mentioned earlier.
Reconstructive options for oral cavity- |
Objectives: |
Achieve primary healing Maintain oral competence Facilitate swallowing Prevent aspiration Preserve speech |
Based on the size and composition of defect, the options are: Mucosal defects – • Leave raw • Primary closure • Split thickness skin graft (STSG) • Mucosal grafts
Full thickness defects - • Local Flaps- Abbe-Estlander’s flap, Gille’s Flap (for lip) • Regional flaps - Tongue flap, Nasolabial flap, Facial artery myomucosal flap, , Masseter flap, Platysmal flap, , Forehead flap • Distant Flaps- Pectoralis major myocutaneous flap, Deltopectoral flap, Latissimus dorsi myocutaneous flap • Free Flaps- Radial forearm flap, Lateral arm flap, Antero-lateral thigh flap
Mandibular Defects Anterior mandibular defect needs to be reconstructed by- . Free osteocutaneous flaps- Fibular osteocutaneous flap (preferred because of long bone length, easy contouring and dual blood supply), Radial osteo-cutaneous flap, Scapular osteocutaneous flap • Distant flaps- Pectoralis major msteocutaneous Flap, Latissimus dorsi osteocutaneous flap, Trapezius osteocutaneous flap
Lateral mandibular defects may be reconstructed with adequate soft tissue replacement, complemented by proper use of guide bite prosthesis and appropriate post-operative isometric exercises.
Suggested reading: 1. de Visscher JG, Botke G, Schakenraad JA, et al. A comparison of results after radiotherapy and surgery for stage I squamous cell carcinoma of the lower lip.Head Neck 1999;21:526-30 2. Iyer SG, Pradhan SA, Pai PS, Patil S. Surgical treatment outcomes of localized squamous carcinoma of buccal mucosa. Head Neck. 2004 Oct;26(10):897-902. 3. Pathak KA, Agarwal R, Deshpande MS. Marginal mandibulectomy for lateral sulcus tumours. Eur J Surg Oncol. 2004 Sep;30(7):804-6. 4. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for oral tongue cancer. Laryngoscope 2002; 112:616-25 5. Hicks WL Jr, North JH Jr, Loree TR, et al. Surgery as a single modality therapy for squamous cell carcinoma of the oral tongue. Am J Otolaryngol 1998: 19:24-8 6. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for floor-of-mouth cancer. Laryngoscope 2000; 110:1764-72 7. Haddadin KJ, Soutar D, Oliver R, et al. Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection. Head Neck 1999;21:517-25 8. Fakih AR, Rao RS, Borges AM, et al. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 1989;158:309-13 9. Soo K C, Rpiro RH, King W, et al. Squamous carcinoma of the gums. Am J Surg 1998; 156:281-5 10. Totsuka Y, Usui Y, Tei K, et al. Mandibular involvement by squamous cell carcinoma of lower alveolus: analysis and comparative study of the histologic and radiologic features. Head Neck 1991;13:40-50. 11. Hidalgo DA: Fibula Free Flap mandibular reconstruction. Clin. Plast. Surg. 21:25, 1994. 12. Evans JF, Shah JP. Epidermoid carcinoma of the palate. Am J Surg 1981;142:451-5 13. Kunkel M, Forster GJ, Reichert TE, Jeong JH, Benz P, Bartenstein P, Wagner W, Whiteside TL. Detection of recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission tomography: implications for prognosis and patient management. Cancer. 2003 Nov15;98(10):2257-65.
HEAD & NECK CANCERS Oral Cancers |
EBM
|
1. A comparison of results after radiotherapy and surgery for stage I squamous cell carcinoma of the lower lip. de Visscher JG, Botke G, Schakenraad JA, et al. Head Neck 1999;21:526-30 BACKGROUND: Controversy still exists as to whether radiotherapy or surgery is the preferable therapeutic modality for stage I squamous cell carcinoma of the lower lip. Therefore, a retrospective study was undertaken to compare the results of both treatment modalities. METHODS: The results of 90 patients who received radiotherapy and 166 patients who underwent surgery as the primary form of treatment for their stage I primary squamous cell carcinoma of the lower lip were evaluated. Tumor size and histological grade of differentiation were assessed. RESULTS: Local control rates were the same with radiotherapy or surgery. Overall survival rates for both groups of patients were similar as well. Disease-free survival rates in the patients who underwent radiotherapy were significantly lower compared with the surgically treated group. This was due to a higher occurrence of regional metastases in the patients who received radiotherapy. Univariate analysis showed that irradiated patients had a statistically significant greater tumor size. The difference of histological differentiation between the groups was also statistically significant, the analysis showed that only tumor size carried significant independent prognostic information. CONCLUSIONS: The cure rates of stage I squamous cell carcinoma of the lower lip are favorable whether treated by radiotherapy or surgery, and local control rates are similar. The radiotherapeutic treated group showed an increased incidence of cervical metastases, which was due to the more advanced tumor size in these patients.
2. Surgical treatment outcomes of localized squamous carcinoma of buccal mucosa. Iyer SG, Pradhan SA, Pai PS, Patil S. et al. Head Neck. 2004 Oct;26(10):897-902.
BACKGROUND: The purpose of the study was to analyze the outcomes after surgical therapy (peroral wide excision) for early squamous carcinoma of the buccal mucosa. METHODS: This is a retrospective study of localized squamous carcinoma of the buccal mucosa treated with peroral wide excision at a major tertiary-care hospital. RESULTS: A total of 147 consecutive patients were analyzed. One hundred eight patients (73.5%) had no recurrence, whereas 18 (12.2%) had a local recurrence, 11 (7.5%) had regional metastasis, and 10 (6.8%) had locoregional recurrence over a median follow-up of 46 months. Most patients with local recurrences (15 patients, 83.3%) and regional metastases (eight patients, 72%) could be salvaged with treatment. In contrast, only four patients (40%) with locoregional recurrence could be salvaged. Most of the recurrences in this study group occurred within 2 years of primary treatment (29 [74%] of 39 patients). Three-year actuarial overall survival rate and disease-free survival rates were 91% and 77%, respectively. CONCLUSIONS: Peroral wide excision seems to be an adequate procedure for early squamous carcinoma of buccal mucosa. Histologic grade of the tumor emerged as the only prognostic factor of significance for recurrence in this study.
3. Marginal mandibulectomy for lateral sulcus tumours. Pathak KA, Agarwal R, Deshpande MS. Eur J Surg Oncol. 2004 Sep;30(7):804-6.
OBJECTIVE: To report a retrospective series of marginal mandibulectomy for cancers of oral cavity, with special reference to squamous cancers of gingival buccal complex. METHODS: Retrospective record review of 107 patients who underwent marginal mandibulectomy between 1994 and 2001. RESULTS: Eighty-three marginal mandibulectomies were done for gingivo-buccal complex cancers. Local failure rate was 16%. The 2-year and 5-year disease free survival rates were 69 and 60%, respectively. The local recurrence free survival at the end of 2 and 5 years were 79 and 70%, respectively. CONCLUSION: In carefully selected patients, marginal mandibulectomy is an oncologically safe.
4. Influence of bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and oropharynx. O'Brien CJ, Adams JR, McNeil EB, Taylor P, Laniewski P, Clifford A, Parker GD. Int J Oral Maxillofac Surg. 2003 Oct;32(5):492-7. The aim of this paper was to evaluate the influence of bone invasion on treatment outcome among patients with cancers of the oral cavity and oropharynx and to determine whether or not outcome was influenced by the extent of mandibular resection. A review of 127 prospectively documented patients who were treated with marginal or segmental resection for oral (n = 110) and oropharyngeal (n = 17) cancers was undertaken. There were 97 males and 30 females with a median age of 61 years. Clinical T stages were: T1 17 patients, T2 33, T3 22, T4 55. Median followup was 4 years. A total of 94 patients underwent marginal resections and 33 underwent segmental resections. Histological bone invasion was present in 17 patients (16%) in the marginal resection group and 21 patients (64%) in the segmental group (P<0.05). Soft tissue surgical margins were positive in 11 patients (12%) in the marginal group and in seven patients (21%) in the segmental group (P=not significant). Local control did not correlate significantly with T stage, the extent of mandibular resection or the presence of histological bone invasion, but was significantly influenced by positive soft tissue margins (P<0.01). Among patients with bone invasion, the local control rate was higher following segmental resection when compared to marginal resections (87% vs. 75%) but this was not statistically significant. Survival was significantly influenced by positive soft tissue margins but not bone invasion or the type of resection. We conclude that bone invasion alone did not predict for local control or survival rates among patients with oral and oropharyngeal cancers. Involved soft tissue margins were highly predictive of local recurrence and decreased survival. Conservative resection of the mandible is safe as long as marginal mandibulectomy does not lead to compromise of soft tissue margins. Segmental resection should be reserved for patients extensive bone invasion or those with limited invasion in a thin atrophic mandible.
5. Analysis of treatment results for oral tongue cancer. Sessions DG, Spector GJ, Lenox J, et al. Laryngoscope 2002;112:616-25 OBJECTIVE: The study reports the results of treatment of oral tongue cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 332 patients with oral tongue cancer treated in the Departments of Otolaryngology-Head and Neck Surgery and Radiation Therapy at Washington University School of Medicine (St. Louis, MO) from 1957 to 1996. METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral tongue who were previously untreated and were treated with curative intent by one of five modalities and who were eligible for 5-year follow-up were included. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival rate (DSS) was 57% with death due to tumor in 43%. The 5-year cumulative disease-specific survival probability (CDSS) was 0.61 (Kaplan-Meier) with a mean of 17.5 years and a median of 30.1 years. The DSS by treatment modality included local resection (73%), composite resection (61%), radiation therapy (46%), local resection and radiation therapy (65%), and composite resection with radiation therapy (CR/RT) (44%). Overall, local resection had a significantly improved DSS and CR/RT had a decreased DSS that was related to the stage of disease being treated. In treating stage IV disease, CR/RT produced a more significantly improved CDSS than the other treatment modalities. Recurrence at the primary site was as common as recurrence in the neck. Eighty-nine percent of recurrences occurred within the first 60 months. Recurrence significantly decreased survival. DSS was significantly improved in patients with clear margins of resection. Metastasis to a distant site occurred in 9.6% of patients. Twenty-one percent of patients had second primary cancers, and 54% of these patients died of their second primary cancer. CONCLUSIONS: Significant improvement in DSS was seen in patients with clear margins, early stage grouping and clinical (pretreatment) tumor stage, and negative nodes. Significant decrease in DSS was seen in patients with close or involved margins, advanced stage grouping and clinical (pretreatment) tumor staging, positive clinical (pretreatment) node staging, and tumor recurrence. Obtaining clear margins of resection is crucial because it significantly affects survival. A minimum of 5 years of close monitoring is recommended because of the high incidence of second primary cancers.
6. Analysis of treatment results for floor-of-mouth cancer. Sessions DG, Spector GJ, Lenox J, et al. Laryngoscope 2000;110:1764-72 OBJECTIVE: This study reports the results of treating floor-of-mouth cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 280 patients with floor-of-mouth cancer treated in the Department of Otolaryngology-Head and Neck Surgery at Washington University Medical School (St. Louis, MO) from 1960 to 1994. METHODS: Patients with biopsy-proven squamous cell carcinoma of the floor of mouth who were previously untreated were treated with curative intent by one of five modalities and were all eligible for 5-year follow-up. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival (DSS) was 56% with death due to tumor in 44% of patients. The 5-year cumulative disease-specific survival (CDSS) was 0.61 (Kaplan-Meier probability) with a mean of 8.3 years and a median of 9.7 years. The DSS by treatment modality included local resection (76%), composite resection (63%), radiation therapy (43%), local resection with radiation therapy (61%), and composite resection with radiation therapy (55%). Overall, there was no significant difference in DSS by treatment modality. Recurrence at the primary site (41%) was the most common site of treatment failure. Nineteen percent of patients had recurrence in the neck. Eighty-eight percent of initial recurrences occurred within 60 months after the onset of treatment. Metastasis to a distant site occurred in 30% of patients. Twenty percent of these patients had second primary cancers, and 53% of these patients died of their second primary cancers. CONCLUSIONS: Significantly improved 5-year DSS was seen in the patients with clear margins, early clinical tumor stage, and negative nodes. Significantly decreased 5-year survival was seen in the patients with involved margins, advanced clinical tumor stage, positive nodes, and tumor recurrence. Patients with no clinically positive nodes (cNO) can be observed safely for regional nodal disease and subsequent positive nodes can be treated as they occur with no adverse affect on survival. Because of high recurrence rates at the primary site and neck, and an increased rate of both distant metastasis and the development of second primary cancers, patients should be monitored closely for a minimum of at least 5 years.
7. The prognostic implications of the surgical margin in oral squamous cell carcinoma. Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA. Int J Oral Maxillofac Surg. 2003 Feb;32(1):30-4.
The prime objective of tumour ablation in oral squamous cell carcinoma (OSCC) is the removal, with a 'margin' of normal tissue, of the whole tumour. Definition of what constitutes margin involvement varies. This study aims to examine the factors associated with close and involved surgical margins in the management of OSCC. A cohort of 200 consecutive patients with previously untreated OSCC provided the material for the study. Various clinical, operative and pathological parameters were related to the status of the surgical margin, as well as time to recurrence, and survival. Cox regression analysis of the survival was also undertaken. Of the 200 patients 107 (53.5%) had clear margins, 84 (42%) close and 9 (4.5%) involved. Poor correlation was found between the status of the surgical margin and clinical factors, but in contrast high correlation between histological indicators of aggressive disease and close or involved surgical margins. These results imply that close surgical margins in OSCC could be regarded as an indictor of aggressive disease.procedure to achieve good local control.
8. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Kligerman J, Lima RA, Soares JR, et al. Am J Surg 1994;168:391-4 BACKGROUND: Recent studies in patients with previously untreated T1 and T2 squamous cell carcinoma (SCC) of the tongue and floor of the mouth have shown a relationship between tumor thickness, neck metastasis, and survival. Our study was conducted to determine the indication of elective neck dissection in patients with early oral cavity SCC. PATIENTS AND METHODS: Sixty-seven patients were stratified by stage (T1 and T2 NO), and those in each stage were randomized to receive one of two types of treatment; resection alone (RA) or resection plus elective supraomohyoid neck dissection (RSOND). Fifty-two patients (78%) were men and 15 (22%) were women. The median age was 57 years old (range 34 to 95). RESULTS: Twenty-six (39%) patients had tumor in the floor of the mouth and 41 (61%), in the tongue. Using the criteria of the Union Internationale Contre le Cancer (UICC), 1987, we classified 31 tumors (46%) as T1 lesions and 36 (54%) as T2 lesions. Thirty patients had a tumor thickness < or = 4 mm and 37 had a tumor thickness > 4 mm. Thirty-three (49%) patients were treated with RA, and 34 patients (51%) were treated with RSOND. Seven (21%) patients of the RSOND group had occult cervical metastasis. There were recurrences in 14 (42%) patients of the RA group and 8 (24%) patients of the RSOND group. The disease-free survival rates at 3.5 years for RA and RSOND patients were 49%, and 72%, respectively. The impact of sex, age, site, cancer stage, and tumor thickness was assessed by the Mantel-Haenszel chi-square procedure. Later stage (P = 0.05) and increased tumor thickness (P = 0.005) were significantly associated with treatment failures. CONCLUSION: Neck dissection remains mandatory in the early stage of oral SCC, because of better survival rates compared to RA and the poor salvage rate. In particular, patients with tumor thickness > 4 mm treated with RSOND had significant benefit on disease-free survival.
9. Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection. Haddadin KJ, Soutar D, Oliver R, et al. Head Neck 1999;21:517-25 BACKGROUND: Prophylactic surgical treatment of the neck in "early tongue tumors" is a controversial issue. METHODS: From a database of 226 patients with squamous cell carcinoma of the tongue treated at Canniesburn Hospital, Glasgow, U.K., between 1980 and 1996, a total of 137 patients with a minimum follow up of 24 months or until death were clinically identified as being T1/T2, N0 (UICC) when first seen. These patients were divided into three groups according to the management of the neck; 53 patients did not have a neck dissection at any time (NKD0), 47 patients underwent a synchronous neck dissection at the time of treatment of the primary (NKDS), and 37 patients subsequently required a metachronous neck dissection when lymph node metastasis became clinically apparent (NKDM). These three groups were compared with respect to age, sex, site, duration of symptoms, previous treatment (if any), initial treatment protocol, resection margin, type of neck dissection (if any), loco-regional recurrence, systemic escape, number of positive lymph nodes, and presence of extracapsular spread. Disease-related survival was calculated using Kaplan-Meier survival curves with logrank test and chi-square statistical analysis. RESULTS: The pT stage was upgraded to T3/4 in 3/53 patients (6%) of the NKD0 group, 11/47 patients (23%) of the NKDS group, and 2/37 patients (5%) of the NKDM group (p < 0.001). The 5-year determinate survival rates for the three groups were: NKD0 59.7%, NKDS 80.5%, NKDM 44.8%, and (NKD0 + NKDM) 53.6% with a statistically significant improvement in survival for NKDS vs NKDM (logrank 10.58, p = 0.001) and for NKDS vs (NKD0 + NKDM) (logrank 6.06, p = 0.014). The incidences of positive nodes in the NKDS and NKDM groups were 18/47 patients (38%) and 32/37 patients (86%) respectively. Neck positive patients in the NKDM group had a significantly greater number of positive nodes in comparison with N positive patients in the NKDS group (chi trend, p = 0.001), a higher incidence of extracapsular spread, 30/32 vs 9/18 (chi test, p < 0. 0001), and decreased survival. The incidence of occult cervical metastasis for the whole group was 41%. CONCLUSION: Patients with clinical T1/2, N0 tongue tumors who underwent a synchronous neck dissection had an improved survival outcome even though as a group they had a higher incidence of occult metastasis, relatively more T2 lesions, a worse pT stage, and had more posterior third lesions requiring more difficult initial surgery. Tongue tumors have a high incidence of subclinical nodal disease, which is less curable when it presents clinically. The information gleaned from the nodal status allows a more informed plan of adjuvant therapy.
10. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Fakih AR, Rao RS, Borges AM, et al. Am J Surg 1989;158:309-13 A prospective, randomized trial was carried out to assess the value of elective versus therapeutic neck dissection in early squamous cell carcinoma of the oral tongue. Disease-free survival (median follow-up 20 months) was 52 percent versus 63 percent in patients who underwent hemiglossectomy alone and those who underwent hemiglossectomy and radical neck dissection, respectively (difference not statistically significant). Patients with a tumor depth of less than 4 mm did significantly better than those with a tumor depth of greater than 4 mm; they were also more likely to have uninvolved nodes at elective radical neck dissection compared with those with a tumor depth of greater than 4 mm. However, when the survival rates of patients in the two treatment groups were compared with respect to a tumor depth of 4 mm, there was no significant difference between the hemiglossectomy and the hemiglossectomy and radical neck dissection groups. A policy of interval elective radical neck dissection only in those with a tumor depth of greater than 4 mm may optimize cure rates and avoid neck dissection in those unlikely to develop neck recurrence.
11. Controlling advanced neck disease: efficacy of neck dissection and radiotherapy. Richards BL, Spiro JD. Laryngoscope 2000;110:1124-7 OBJECTIVE: Neck dissection remains the standard method of treating cervical metastasis from head and neck squamous cell carcinoma. In light of recent trends to modify the classic radical neck dissection (RND) for early neck disease, we reviewed our experience with radical and modified RND (MRND) plus radiotherapy as treatment for N2/N3 neck disease in head and neck squamous cell carcinoma. METHODS: We retrospectively reviewed our clinical records from July 1989 to June 1996 to identify 43 neck dissections in 39 patients who were found to have pathologically N2 or N3 neck disease treated primarily by neck dissection and postoperative radiotherapy. All patients had head and neck squamous cell carcinoma with a minimum follow-up of 24 months. RESULTS: Nine percent (4/43) of the dissected necks were pathologically N2a, 72% (31/43) were N2b, 7% (3/43) were N2c, and 12% (5/43) were N3. Of these, 28% (12/43) underwent a RND and 72% (31/43) underwent a MRND. The most common modification of RND was preservation of the spinal accessory nerve. All patients underwent postoperative radiotherapy with a mean dose of 55 Gy. Only 4 of 43 dissected necks had isolated treatment failure, for a regional control rate of 91%. CONCLUSIONS: The combination of RND or MRND and radiotherapy is highly effective in controlling neck disease in the absence of persistent or recurrent local disease. Also, in our experience, MRND appears to be as effective as RND in controlling even advanced neck disease, which supports preservation of the spinal accessory nerve whenever oncologically feasible.
12. Detection of recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission tomography: implications for prognosis and patient management. Kunkel M, Forster GJ, Reichert TE, Jeong JH, Benz P, Bartenstein P, Wagner W, Whiteside TL. Cancer. 2003 Nov15;98(10):2257-65. BACKGROUND: Patients with recurrent oral squamous cell carcinoma (OSCC) have a dismal prognosis and represent a therapeutic challenge. A positron emission tomography (PET) scan with [(18)F]-2-fluorodeoxyglucose [(18)F]FDG) can improve early cancer detection. The current study evaluates the prognostic value of [(18)F]FDG-PET scan in patients with recurrent OSCC. METHODS: The authors studied 97 patients with previously resected OSCC who were restaged by PET scanning. Of the 97 patients, 64 had no evidence of clinical disease and 33 were suspected of having disease by imaging, clinical findings, or pathologic evaluation. The median follow-up period was 35.4 months after a PET scan. The end points included disease recurrence, a disease recurrence-free period 6 months after a PET scan, or death. RESULTS: The overall sensitivity of a PET scan did not exceed 90% and its specificity varied from 67% for local disease recurrence/second primaries to 99% for lymph node metastasis. Increased [(18)F]FDG uptake predicted increased hazard of death (hazard ratio: 6.83; P = 0.00034) and proved to be a highly predictive marker of disease status. A significant association was established for incremental standardized uptake values and 3-year patient survival (P=0.0089), indicating that intense glucose metabolism in the tumor is a negative marker of survival in recurrent OSCC. Overall, survival was longer in patients with a negative rather than a positive PET scan (P<0.00001). CONCLUSIONS: PET scanning was found to be highly valuable for diagnosing OSCC recurrence in a postoperative setting. It provided prognostic information and played an important role in patient counseling and management.
Stage I and II are treated with surgery or radiotherapy as a single modality. There no randomized control trials comparing surgery with radiotherapy in early stage disease. Combined modality in the form of surgery with post-operative radiotherapy is used in operable stage III & IV disease. There is a controversy regarding management of N0 neck in oral cancers. |
|
Treatment options: Stage I & II ( T1-2 N0 ) • Radical Radiotherapy : In most cases. • Surgery: In selected cases eg. Lateralised lesion, infiltrative disease. (Criteria: Patient’s preference, institutional practice and complexity of procedure).
Stage III & IV T1-2, N2-3 • Concomitant CT plus RT, followed by neck salvage if residual nodes or as a planned procedure. • Split therapy: (In selected cases of large nodes with small radio-curable primary) Node mass excision followed by RT / CT+RT.
T3-4, N0, N+ • Concomitant CT plus RT : In most cases. • Surgery: (if low peri-op risk & reasonable functional outcome) Composite resection + appropriate neck dissection + Post-operative radiotherapy Note: Post-op RT / CT+RT as per general guidelines.
HEAD & NECK CANCERS Oropharyngeal Carcinoma |
EBM
|
1. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. Denis F, Garaud P, Bardet E, Alfonsi M, et al. J Clin Oncol. 2004 Jan 1;22(1):69-76. PURPOSE: We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A). PATIENTS AND METHODS: A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa. RESULTS: Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant). CONCLUSION: Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.
2. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Olmi P, Crispino S, Fallai C, Torri V, et al. Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):78-92. PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leucopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.
3. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC). Domenge C, Hill C, Lefebvre JL, De Raucourt D, et al. Br J Cancer 2000;83:1594-8 The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2-3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d’Etude des Tumeurs de la Tete Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy.
4. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Calais G, Alfonsi M, Bardet E, et al. J Natl Cancer Inst 1999;91:2081-6 BACKGROUND : We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS : A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS : Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.
5. Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma. Pinto LH, Canary PC, Araujo CM, et al. Int J Radiat Oncol Biol Phys 1991;21:557-62 From April 1986 to May 1989, 112 patients seen at a single institution with previously untreated squamous cell oropharynx carcinoma, Stages III and IV, were randomly assigned to 66 Gy in 33 fractions of 2 Gy each (conventional RT) versus 70.4 Gy in 64 fractions of 1.1 Gy given twice a day with a minimal interfraction interval of 6 hours (hyperfractionated RT). The overall time for both arms was 6 1/2 weeks. Patients were stratified by site (base of the tongue vs others), T stage (T1/T2 vs T3 vs T4), N stage (N0/N1 vs N2 vs N3), and lymphnode size (less than 6 cm vs greater than 6 cm). As of January 1990, an analysis was performed in 98 patients (8 patients in the conventional arm and 6 in the hyperfractionation not included). The groups were balanced by age, performance status, stage, and site of the primary disease. The median follow-up time was 25 months. The probability of complete loco-regional response was 62% in the hyperfractionation arm and 52% for the conventional fractionation (p = 0.28). There was no difference in the control of lymphnodal disease (hyperfractionated = 55%, conventional = 57%; p = 0.92), but the disease control in the oropharynx only was significantly improved in the hyperfractionation arm (84% vs 64%, p = 0.02). Overall survival rate at 42 months was 27% for the hyperfractionation arm and 8% for the conventional (p = 0.03). Survival rates for hyperfractionated versus conventional RT were 40% versus 18% (p = 0.06), respectively, for Stage III patients and 16% versus 0% (p = 0.15), respectively, for Stage IV. There was significant improvement in survival in favor of the hyperfractionation arm in patients with lesions outside the base of the tongue (31% vs 15%, p = 0.02), for those with a 50-70% Karnofsky status (19% vs 0%, p = 0.006) and for patients with N0/N1 disease (38% vs 15%, p = 0.03). Acute toxicities were of similar magnitude, although both skin and mucosal reactions appeared earlier on the hyperfractionation scheme. To date, no differences in late toxicity have been observed. We conclude that in a subset group of patients with locally advanced carcinoma of the oropharynx, hyperfractionated radiotherapy appears to provide improved survival without adding to increased toxicity.
OTHER SELECT PUBLICATIONS : * Tiwari RM, van Ardenne A, Leemans CR, et al. Advanced squamous cell carcinoma of the base of the tongue treated with surgery and post-operative radiotherapy. Eur J Surg Oncol. 2000;26:556-60. * Gourin CG, Johnson JT. Surgical treatment of squamous cell carcinoma of the base of tongue. Head Neck. 2001; 23 (8) : 653-60. * Robertson ML, Gleich LL, Barrett WL, et al. Base-of-tongue cancer: survival, function, and quality of life after external-beam irradiation and brachytherapy. Laryngoscope. 2001;111:1362-5.
The treatment of oropharyngeal carcinoma is aimed at maximizing cure with minimal functional morbidity. Radical radiotherapy is the treatment of choice in early T1, T2 tumors and chemoradiotherapy is the treatment of choice in advanced T3, T4 tumors. Surgery is preferred in select early cases where surgical resection is associated with reasonable functional outcome. It is also preferred with postoperative radiotherapy in select advance cases eg. Infiltrative lesions of base tongue, tonsil and lesions involving the mandible and as a salvage procedure for residual neck nodes following chemoradiotherapy. |
LARYNX AND HYPOPHARYNX Larynx: • Supra-glottis: Epiglottis, Ary-epiglottic folds, Arytenoids, False cords, Ventricles. • Glottis: True vocal cord with anterior & posterior commissure. • Subglottis.
Hypopharynx: • Pyriform sinus • Post-cricoid region • Posterior pharyngeal wall
Specific investigations before definitive treatment: • Indirect laryngoscopy / Hopkins telescopy/flexible laryngoscopy : To access cord mobility and extent of mucosal disease.
• Barium swallow: To map the mucosal extent of disease. Post-cricoid involvement well seen.
• Direct laryngoscopy: To define the exact extent of the disease, assess areas not well seen on IDL/Hopkins namely anterior commissure; pyriform fossa and post-cricoid & obtain a biopsy.
• Microlaryngocsopy: for early cord lesions
• Imaging CT/MRI scan: Mandatory before conservative laryngectomy / laryngeal preservation therapy. Gives information regarding: 1- Extent of disease. 2- Cartilage invasion. 3- Extra-laryngeal spread. 4- Para/Pre-epiglottic spaces. 5- Tumor volume. 6- Nodal disease. * CT scan preferred for cartilage erosion. * MRI preferred for soft tissue invasion.
• PET (CT) for evaluating post treatment residual or recurrent disease.
• Speech counseling.
TNM STAGING (UICC 2002) PRIMARY TUMOR
TX – Primary tumor cannot be assessed. T0 – No evidence of primary tumor. Tis – Carcinoma in situ
Supraglottis
T1 |
Limited to one sub site of supraglottis, normal cord mobility
|
T2 |
Invades mucosa of >1 adjacent sub site of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base tongue, medial wall of PFS) without fixation of the larynx
|
T3 |
Limited to larynx with cord fixation and/or invades any of the following: PC, pre-epiglottis tissues, Paraglottic space, and /or minor thyroid cartilage erosion (e.g. Inner cortex)
|
T4a |
Tumor invades through the thyroid cartilage and/ or invades tissues beyond the larynx. (Trachea, soft tissues of neck including the deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus).
|
T4b |
Tumor invades prevertebral space, encases carotid artery or invades mediastinal structures.
|
|
|
|
Glottis
|
T1 |
Limited to vocal cord(s) (may involve anterior or posterior commissure) with normal mobility.
|
T1a |
Limited to one vocal cord.
|
T1b |
Involving both vocal cords.
|
T2 |
Extends to supraglottis and / subglottis, and / or impaired cord mobility.
|
T3 |
Limited to larynx with vocal cord fixation and / or invades paraglottic space, and or minor thyroid cartilage invasion (e.g . inner cortex).
|
T4a |
Invades through thyroid cartilage, and/or invades tissues beyond larynx, (e.g. trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus)
|
T4b |
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
|
|
|
|
Subglottis
|
T1 |
Limited to subglottis
|
T2 |
Extends to vocal cord(s) with normal or impaired mobility
|
T3 |
Limited to larynx with vocal cord fixation
|
T4 |
Invades through cricoid or thyroid cartilage and/or extends into other tissues beyond the larynx, (e.g. trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus).
|
|
|
|
Hypopharynx
|
T1 |
Limited to one sub site of hypopharynx and 2cm or less in greatest diameter
|
T2 |
Invades more than one sub site of hypopharynx or adjacent site or, measures >2cm but <4cm in the greatest diameter without fixation of the hemilarynx
|
T3 |
>4cm in greatest diameter, or, with fixation of hemilarynx
|
T4 |
Invades adjacent structure e.g., thyroid / cricoid cartilage, carotid artery, soft tissues of the neck, prevertebral fascia/muscles etc
|
|
|
|
Nodes
|
Nx |
Regional LN cannot be assessed
|
N0 |
No regional LN metastasis
|
N1 |
Ipsilateral Single node < 3cm
|
N2a |
Ipsilateral Single node >3cm and <6cm
|
N2b |
Ipsilateral multiple nodes <6cm
|
N2c |
Bilateral / Contra lateral nodes < 6cm
|
N3 |
Lymph node > 6cm
|
SUPRAGLOTTIS : Surgery is preferred over radiotherapy in cases with • large volume disease. • Cartilage erosion. • Bulky nodal disease. • Gross pre epiglottis space involvement • General condition not permitting concurrent chemoradiotherapy
Management of neck nodes |
N0 |
Bilateral neck nodes need to be addressed either with surgery lateral neck dissection (II-IV) or RT
|
N1 |
Bilateral Comprehensive/ anterolateral neck dissection (II-IV) + Post operative RT.
|
N2-3 |
Bilateral MND / RND (on side of greater disease) + Post operative RT.
|
Small primary (radiocurableT1-2) with large resectable disease (N2-3) may be considered for neck dissection with RT to primary and neck.
Note : Post operative RT as per guidelines mentioned earlier
GLOTTIS
GLOTTIS
Stage III – T1-2 N1 / T3N0-1 • Concomitant CT+RT • Surgery : Vertical Partial Laryngectomy/ Near-Total laryngectomy / Total laryngectomy + RT • Radical radiotherapy in patients with low GC/poor performance status who might not tolerate CT+RT
Stage IV – T4a N0-1 / T1-4aN2-3 • Surgery : Near-Total laryngectomy / Total laryngectomy + RT • Concomitant CT+RT • Radical radiotherapy in patients with low GC/poor performance status who might not tolerate CT+RT
N0-1 nodes are managed with RT if the primary is treated with RT. If surgery is the primary treatment modified neck dissection for N1 nodes is recommended.
N2-3 nodes need MND/RND with Post-operative chemoradiotherapy. If radiotherapy is the primary treatment, neck dissection follows radiotherapy 4-6 weeks later if residual nodes persist, or electively irrespective of nodal status.
PYRIFORM FOSSA T1-2 No,1 • Radical Radiotherapy • Partial Laryngo-pharyngectomy • Endoscopic laser resection in select cases.
T1-2 N2-3 • Concurrent CT+RT. • Radical Radiotherapy Salvage surgery (Low GC - unable to tolerate CT+RT). • Split Therapy - Neck dissection + Radical Radiotherapy to primary and neck.
T3-4, Any N • Near-Total Laryngectomy /Total laryngectomy + Partial pharyngectomy + Post operative Radiotherapy. • Reconstruction of defect depends on mucosal defect. If mucosa adequate – primary closure, if mucosa inadequate – patch PMMC or free radial forearm flap. • Concurrent CT + RT. • Radical radiotherapy salvage surgery (Low GC –unable to tolerate CT+RT). Note : • Post operative RT as per guidelines mentioned earlier • Surgery is the treatment of choice in • Large volume disease • Bulky neck nodes • Cartilage erosion • Extensive soft tissue involvement
POST CRICOID & POSTERIOR PHARYNGEAL WALL T1-2 N0-1 : Radical Radiotherapy
T3-4 Any N : Small volume disease • Concurrent CT+RT. • Radical Radiotherapy Salvage surgery (Low GC –unable to tolerate CT+RT T3-4 Any N : Large volume disease • Total laryngo-pharyngo-oesophagectomy with gastric pullup or Free jejunal flap or tube pectoralis myocutaneous flap and Post operative Radiotherapy. Note : 1. Post operative RT as per guidelines mentioned earlier. 2. Surgery is the treatment of choice in • Large volume disease • Bulky neck nodes • Cartilage erosion • Extensive soft tissue involvement
HEAD & NECK CANCERS Laryngeal & Hypopharyngeal Cancer |
EBM
|
1. LARYNGEAL PRESERVATION IN ADVANCED PYRIFORM SINUS CANCERS : Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. Lefebvre JL, Chevalier D, Luboinski B, et al. J Natl Cancer Inst 1996;88:890-9 BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.
Surgery and radiotherapy as a single modality have similar results in Stage I & II disease (level III evidence). However, Radiotherapy is preferred over surgery due to its low morbidity and voice preservation. In stage III & IV disease, Surgery plus Post-operative radiotherapy and Chemo-radiotherapy have shown equal results regarding survival. Due to higher chance of laryngeal preservation, Chemo-radiotherapy should be offered to patients with low volume disease and good follow up. |
HEAD & NECK CANCERS Early Glottic Carcinoma |
EBM
|
1. Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control/complications. Dinshaw KA, Sharma V, Agarwal JP et al. Int J Radiat Oncol Biol Phys 2000;48:723-35 PURPOSE : To evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. METHODS AND MATERIALS : Between 1975 and 1989, 676 patients with early glottic carcinoma (460 T1 and 216 T2) received curative radiation with three different treatment regimens, as follows: Regimen 1-50 Gy/15 Fr/3 weeks (3.33 Gy/daily) for 192 patients; Regimen 2-60-62.5 Gy/24-25 Fr/5 weeks (2.5 Gy/daily) for 352 patients; and Regimen 3-55-60 Gy/25-30 Fr/5-6 weeks (2-2.25 Gy/daily) for 132 patients. RESULTS : The local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p = 0.0). For the T1N0M0 group, field size had significant impact on local control with both univariate (p = 0.05) and multivariate (p = 0.03) analysis. For T2N0M0, group field size (p = 0.03) as well as registration year (p = 0.016) were significant in univariate analysis whereas only field size remained significant on multivariate analysis. Persistent radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p = 0.000) but not related to different treatment regimens. CONCLUSION : The shorter fractionation schedule had comparable local control, without increased complications in comparison to the protracted schedule and is best suited for a busy department.
2. Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer. Dey P, Arnold D, Wight R, et al. Cochrane Database Syst Rev 2002;(2):CD002027 BACKGROUND : Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early stage glottic cancer. Case series suggest that they confer similar survival advantage. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES : To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer SEARCH STRATEGY: Electronic search of MEDLINE (from 1966 to October 2000), EMBASE (from 1980 to October 2000), CINAHL (from 1982 to October 2000) and CancerLit (from 1963 to October 2000) databases and the Cochrane Controlled Trials Register. SELECTION CRITERIA : Randomised controlled trials (RCT) comparing open surgery, endolaryngeal resection and/or radiotherapy DATA COLLECTION AND ANALYSIS : Two reviewers independently assessed RCTs identified from the electronic searches for eligibility and methodological quality. All authors of the review discussed the results of these assessments. MAIN RESULTS : Only one RCT was identified which compared open surgery and radiotherapy among a substantial number of patients with early glottic laryngeal cancer. REVIEWER’S CONCLUSIONS : There is currently insufficient evidence to guide management decisions on the most effective treatment. Interpretation of the only large scale RCT comparing open surgery and radiotherapy in patients with early glottic cancer is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis. Endolaryngeal resection of early glottic tumours is becoming more common and a well designed multicentre RCT is warranted.
Cure rates are similar in early glottic cancers with radiation therapy and surgical modalities like transoral laser surgery and open partial laryngectomy. There is no conclusive evidence to support any particular modality and at this instance the treatment is still based on patient and physician preference. The possibility of running a trial to demonstrate the superiority of a particular modality is difficult. |
HEAD & NECK CANCERS Organ Preservation Protocol |
EBM
|
1. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324 : 1685-90 BACKGROUND : We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. METHODS : Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. RESULTS : After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. CONCLUSIONS : These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.
2. Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. Arlene A. Forastiere, M.D., Helmuth Goepfert, M.D., Moshe Maor, M.D, et al N Engl J Medicine 2003 ;349;2091-2098. BACKGROUND: Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown. METHODS: We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx. RESULTS: A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone).The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy. CONCLUSIONS: In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.
Organ preservation in laryngeal / hypopharynngeal cancers seemed a reality with the landmark VA & EORTC trials. This concept was further strengthened by the Inter-group study findings. As of today chemoradiotherapy should be considered the standard of care for small volume stage III/IV laryngeal and hypopharynngeal cancer. |
NASOPHARYNX
Specific Investigations before definitive treatment • Nasopharyngeal examination, endoscopy & biopsy • Chest X- ray • CT scan/ MRI including entire neck • Bone scan (optional), especially in WHO type III
TNM STAGING (UICC 2002)
|
T1 |
Tumour confined to the nasopharynx
|
T2 |
Tumour extends to soft tissue of oropharynx and or nasal fossa
|
T2a |
without parapharyngeal extension
|
T2b |
with parapharyngeal extension
|
T3 |
Tumour invades bony structure and/or paranasal sinuses
|
T4 |
Tumour with intracranial extension and./or involvement of cranial nerves, infratemporal fossa, hypopharynx, or orbit.
|
Nx |
Regional LN cannot be assessed
|
N0 |
No Regional LN metastasis
|
N1 |
Unilateral metastasis in LN(s), 6 cm or less in greatest dimension above Supraclavicular fossa
|
N2 |
Bilateral Metastasis in LN(s), 6cm or less in greatest dimension above supraclavicular fossa
|
N3 |
Metastasis in LN(s) (a) greater than 6 cm in dimension (b) in the supraclavicular fossa
|
Nasopharyngeal carcinoma differs from other head and neck squamous cell carcinomas in following aspects • Classified into 3 types a) WHO type I – Keratinising Sq. Ca b) WHO type II – Non-keratinising Sq. Ca c) WHO type III – Undiferrentiated carcinoma • Radiosensitive tumours, even with large volume nodal disease respond well to radiotherapy. • WHO type III (Undiferrentiated carcinoma) responds better than keratinising variety. • Surgery has a very limited role as en bloc surgical resection of the primary tumour is difficult and severely morbid. Surgery is usually reserved for elective/ salvage of residual neck nodes.
Treatment options T1 / Selected T2 N0 : • Radical Radiotherapy alone with or without Intraluminal Brachytherapy • IMRT or 3-DCRT maybe used when facilities are available.
T3-4 N0 / Any T N+ • Concurrent chemoradiotherapy • Neo Adjuvant CT x 2 cycles + Concurrent CT + RT
Chemoradiotherapy Schedule for Undiferentiated Ca Nasopharynx: Cisplatinum (33mg / m2 / day x 3 days) + Ifosfamide (2gm /m2 / day x 3 days) + Mesna rescue x 2 cycles followed by Concomitant weekly Cisplatinum (30 mg / m2) during radiotherapy(70Gy) For bulky tumors at presentation, neo-adjuvant chemotherapy, followed by concurrent chemoradiotherapy may be tried though there is no evidence to suggest that it is superior to concurrent chemoradiotherapy.
Note : • Role of surgery is minimal : No neck dissection upfront even for large nodes/ Neck dissection is reserved for palpable nodes persisting 8 weeks after radiotherapy and when the primary is controlled. • Treatment of recurrence : Re-irradiation, surgery in selected cases.
HEAD & NECK CANCERS Nasopharyngeal Carcinoma |
EBM |
1. Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol. 2002 Jun;25(3):219-23. Huncharek M, Kupelnick B It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.
2. Combined radiotherapy and chemotherapy for nasopharyngeal carcinoma. Fu KK. Semin Radiat Oncol 1998; 8 : 247-53 Among squamous cell carcinomas of the head and neck, nasopharyngeal carcinoma is probably the most radiosensitive and chemosensitive. It also has the highest incidence of distant metastasis. This article reviews the results of randomized trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma to date. Induction chemotherapy with bleomycin, epirubicin, and cisplatin was shown to increase disease-free survival but not overall survival in a trial by the International Nasopharyngeal Cancer Study Group. Concurrent radiotherapy and cisplatin followed by adjuvant cisplatin and 5-fluorouracil infusion significantly decreased local, nodal, and distant failures and increased progression-free and overall survival in the Head and Neck Intergroup Trial. The toxicity of combined chemotherapy and radiotherapy, however, primarily acute toxicity, was significantly greater than that of radiotherapy alone. Further clinical trials using novel drugs, altered fractionation radiotherapy and chemotherapy dose schedules, new radiotherapy techniques, and other treatment modifiers are needed to further improve the therapeutic ratio.
3. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 1996; 35 : 463-9 PURPOSE : Our Phase II trial using bleomycin, epirubicin, and cisplatin (BEC) protocol in the treatment of loco-regionally advanced undifferentiated nasopharyngeal carcinoma (UCNT) patients has shown encouraging results with high objective response, disease-free survival, and overall survival rates. To establish the value of this BEC regimen as neoadjuvant chemotherapy, we initiated in 1989 a large international Phase III trial. It compares three cycles of BEC followed by radiotherapy to radiotherapy alone. METHODS AND MATERIALS : From November 1989 to October 1993, 339 patients with negative metastases workup, stratified by accrual center have been randomized, 168 to radiotherapy alone and 171 to chemotherapy plus radiotherapy. All patients characteristics were well balanced in both arms. There was a quality control/data verification by specialist panel (radiology, histology, radiotherapy, chemotherapy) and external policy board expert every 60-80 patients having completed treatment. RESULTS : With a median follow-up of 49 months (range: 23-70), despite an excess of treatment-related deaths in the neoadjuvant chemotherapy arm (8 vs. 1%), there is a significant difference in disease free survival favoring the chemotherapy arm (p < 0.01). The proportion of local and/or regional metastases was comparable in both arms. No difference in overall survival is seen but the numbers of events needed for analysis has not yet been reached. CONCLUSIONS : BEC type neoadjuvant chemotherapy has a significant impact in the natural history of UCNT. Further follow-up is needed to establish an eventual overall survival difference.
4. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngealcancer: phase III randomized Intergroup study 0099. Al-Sarraf M, LeBlanc M, Giri PG,et al. J Clin Oncol 1998; 16 : 1310-7 PURPOSE : The Southwest Oncology Group (SWOG) coordinated an Intergroup studywith the participation of Radiation Therapy Oncology Group (RTOG), and EasternCooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS : Radiotherapy was administered in both arms: 1.8-to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total doseof 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS : Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION : We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.
5. Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two Phase III Trials Daniel T.T. Chua , Jun Ma , Jonathan S.T. Sham *, Hai-Qiang Mai , Damon T.K. Choy, Ming-Huang Hong , Tai-Xiang Lu , and Hua-Qing Min J Clin Oncol 2005;23(6): 1118-1124 Purpose: To evaluate the long-term outcome in patients with nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and radiotherapy (CRT) versus radiotherapy alone (RT). Patients and Methods: The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat. Results: The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms. Conclusion: The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.
6. The Additional Value of Chemotherapy to Radiotherapy in Locally Advanced Nasopharyngeal Carcinoma: A Meta-Analysis of the Published Literature J.A. Langendijk, Ch.R. Leemans, J. Buter, J. Berkhof, B.J. Slotman J Clin Oncol 2004;22(22):4604-4612 PURPOSE: The purpose of this meta-analysis was to determine the additional value of neoadjuvant, concurrent, and/or adjuvant chemotherapy to radiation in the treatment of locally advanced nasopharyngeal carcinoma (NPC) with regard to the overall survival (OS) and the incidence of local-regional recurrences (LRR) and distant metastases (DM). PATIENTS AND METHODS: To be eligible, full published studies had to deal with biopsy-proven NPC and have patients randomly assigned to receive conventional radiotherapy (66 to 70 Gy in 7 weeks) or radiotherapy combined with chemotherapy. RESULTS: Ten randomized clinical studies were identified, including 2,450 patients. The pooled hazard ratio (HR) of death for all studies was 0.82 (95% CI, 0.71 to 0.95; P = .01) corresponding to an absolute survival benefit of 4% after 5 years. Three categories of trials were defined according to the sequence of chemotherapy, including neoadjuvant chemotherapy, at least concomitant chemoradiotherapy, and adjuvant chemotherapy. A significant interaction term (P = .02) was found among these three categories. The largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. Comparable results were found for the incidence of LRR and DM. CONCLUSION: The results of this study indicate that concomitant chemotherapy in addition to radiation is probably the most effective way to improve OS in NPC.
Nasopharyngeal carcinomas are relatively radio and chemosensitive tumours. Radiotherapy forms the mainstay of treatment of nasopharyngeal carcinomas. Surgery has a very limited role to play in management of nasopharyngeal carcinomas. It is shown that chemotherapy plus radiotherapy improves disease free and progression free survival compared to radiotherapy alone in advanced nasopharyngeal carcinomas. But, it is controversial whether addition of chemotherapy to radiotherapy improves overall survival. Recently published meta-analysis has shown that it does improve overall survival. |
NASAL CAVITY & PARANASAL SINUSES
Sites • Nasal Cavity • Maxilla • Ethmoids • Frontal Sinus • Sphenoid
Investigations / Procedures 1. Biopsy Punch / Endoscopic 2. Imaging (mandatory) to asses the extent of disease Computed Tomography (CT) and / or Magnetic Resonance Imaging (MRI) * CT scan - preferred for osseous involvement, floor of anterior cranial fossa and orbital walls
* MRI preferred for - Soft tissue extent - Intracranial extension - Perineural Spread - Differentiation between retained secretions and tumour tissue - Post surgery setting
3. Prosthetic / Dental Workup Pre-operative dental impression for post-op prosthesis Staging: TNM (UICC) 2002
Maxilla
T1 |
Tumour limited to the mucosa with no erosion or destruction of bone.
|
T2 |
Tumour causing bone erosion or destruction, including extension into hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates.
|
T3 |
Tumour invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses.
|
T4a |
Tumour invades any of the following: anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses
|
T4b |
Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, clivus
|
|
|
|
Nasal Cavity and Ethmoid Sinus
|
T1 |
Tumour restricted to one subsite of nasal cavity or ethmoid sinus, with or without bony invasion
|
T2 |
Tumour involves two subsites in a single site or extends to involve an adjacent site within the nasoethmoidal complex, with or without bony invasion.
|
T3 |
Tumour extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
|
T4a |
T4aTumour invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses
|
T4b |
Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of the trigeminal nerve (V2), nasopharynx, clivus
|
|
|
|
Neck
|
Nx |
Regional LN cannot be assessed
|
N0 |
No regional LN metastasis
|
N1 |
Single node < 3cm
|
N2a |
Single node >3cm and <6cm
|
N2b |
Ipsilateral multiple nodes <6cm
|
N2c |
Bilateral/Contralateral nodes < 6cm
|
N3 |
Lymph node > 6cm
|
Treatment Options Nasal Cavity & Ethmoid sinus Treatment of Primary: T1, T2: 1. Surgery ± post-operative radiotherapy • Approaches-Midfacial degloving or Lateral rhinotomy or Endoscopic Transnasal • Medial maxillectomy with ethmoidal clearance may be adequate for localised ethmoidal and nasal cavity tumors. • RT in case of margin positivity or perineural spread 2. Radical Radiotherapy preferred if surgical resection morbid
T3, T4a Surgery + Adjuvant RT • Total Maxillectomy with ethmoidectomy • Combined Craniofacial approach for lesions reaching / involving the cribriform plate. • Orbital exenteration if eye involved.
T4b 1. Palliative - RT or CT Concurrent CTRT may be considered in patient with good performance status.
2. Resection in very select group with favourable histology with low biologically aggressive tumours for eg. Adenoid cystic carcinoma, basal cell carcinoma.
Treatment of Neck: N0 Observe
N+ Appropriate neck dissection and post-operative radiotherapy to both necks.
MAXILLARY SINUS
Treatment of Primary: T1, T2: Surgery + Post-op Radiotherapy • Infrastructure maxillectomy • Maxillectomy with orbital plate preservation • RT in case of margin positivity or perineural spread
T3: Surgery + Post op Radiotherapy • Total Maxillectomy with Ethmoidectomy • Orbital exenteration if eye involved.
T4a: I. Combined craniofacial resection + Post op Radiotherapy
II. CT+RT in unresectable tumours
T4b: I. Palliative - RT or CT Concurrent CTRT may be considered in patient with extremely good performance status.
II. Resection in very select group with favourable histology tumours for eg. Adenoid cystic carcinoma, basal cell carcinoma.
Treatment of Neck: N0 Observe N+ Appropriate neck dissection and post-operative radiotherapy.
Criteria of Unresectibility • Gross infiltration of infratemporal fossa. • Pterygoplatine fissure involvement • Involvement of dura and intra-cerebral extension of squamous carcinoma. • Cavernous sinus involvement • Involvement of sphenoid. • Extensive soft tissue and skin infiltration. • Bilateral orbital involvement
Post- Maxillectomy Reconstruction: • Sling if orbital floor excised, to prevent post-op diplopia. Fascial sling preferred over muscle • Micro vascular Free tissue transfer for 1. Extensive skin and soft tissue defect 2.More than half of palatal loss 3. Orbit resection 4. Skull Base Reconstruction • Temporary obturator for 2 –3 months till complete contracture occurs. • Final maxillary prosthesis after 2-3 months
Follow up Policy : Follow up Imaging indicated when local examination with endoscope insufficient. MRI preferred over CT scan.
Suggested reading • Schantz SP, Harrison LB, Forastiere AA: Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 797-860. • Goldenberg D, Golz A, Fradis M, et al.: Malignant tumors of the nose and paranasal sinuses: a retrospective review of 291 cases. Ear Nose Throat J 80 (4): 272-7, 2001. • Thawley SE, Panje WR, Batsakis JG, et al., eds.: Comprehensive Management of Head and Neck Tumors. 2nd ed. Philadelphia, Pa: WB Saunders, 1999. • Perry C, Levine PA, Williamson BR, Cantrell RW: Preservation of the eye in paranasal sinus cancer surgery. Arch Otolaryngol Head Neck Surg 1988 Jun; 114(6): 632-4 • Som ML: Surgical management of carcinoma of the maxilla. Arch Otolaryngol 1974 Apr; 99(4): 270-3
Abstracts:
HEAD & NECK CANCERS Nasal Cavity & PNS |
EBM
|
1. Malignant tumors of the nasal cavity and paranasal sinuses. Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB. Head Neck 2002 Sep;24(9):821-9 PURPOSE: To evaluate the role of radiation therapy in patients with nasal cavity and paranasal sinus tumors. MATERIALS AND METHODS: Between October 1964 and July 1998, 78 patients with malignant tumors of the nasal cavity (48 patients), ethmoid sinus (24 patients), sphenoid sinus (5 patients), or frontal sinus (1 patient) were treated with curative intent by radiation therapy alone or in the adjuvant setting. There were 25 squamous cell carcinomas, 14 undifferentiated carcinomas, 31 minor salivary gland tumors (adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma), 8 esthesioneuroblastomas, and 1 transitional cell carcinoma. Forty-seven patients were treated with irradiation alone, 25 with surgery and postoperative irradiation, 2 with preoperative irradiation and surgery, and 4 with chemotherapy in combination with irradiation with or without surgery. RESULTS: The 5-year actuarial local control rate for stage I (limited to the site of origin; 22 patients) was 86%; for stage II (extension to adjacent sites (eg, adjacent sinuses, orbit, pterygomaxillary fossa, nasopharynx; 21 patients) was 65%; and for stage III (destruction of skull base or pterygoid plates, or intracranial extension; 35 patients) was 34%. The 5-year actuarial local control rate for patients receiving postoperative irradiation was 79% and for patients receiving irradiation alone was 49% (p=.05). The 5-, 10-, 15-, and 20-year ultimate local control rates for all 78 patients were 60%, 56%, 48%, and 48%, respectively. The 5-, 10-, 15-, and 20-year cause-specific survival rates for all 78 patients were 56%, 45%, 39%, and 39%, respectively. The 5-, 10-, 15-, and 20-year absolute survival rates for all 78 patients were 50%, 31%, 21%, and 16%, respectively. Of the 67 (86%) patients who were initially seen with node-negative disease, 39 (58%) received no elective neck treatment, and 28 (42%) received elective neck irradiation. Of the 39 patients who received no elective neck treatment, 33 (85%) did not experience recurrence in the neck compared with 25 (89%) of 28 patients who received elective neck irradiation. Most patients who received elective neck irradiation (57%) had stage III disease. Twenty-one (27%) of 78 patients had unilateral blindness develop secondary to radiation retinopathy or optic neuropathy; the complication was anticipated in most of these patients, because the ipsilateral eye was irradiated to a high dose. Four patients (5%) unexpectedly had bilateral blindness develop because of optic neuropathy. All four of these patients received irradiation alone. CONCLUSION: Surgery and postoperative radiation therapy may result in improved local control, absolute survival, and complications when compared with radiation therapy alone. Elective neck irradiation is probably unnecessary for patients with early-stage disease.
2. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Cancer 2001 Dec 15;92(12):3012-29 BACKGROUND: The authors reviewed treatment results in patients with nasal and paranasal sinus carcinoma from a large retrospective cohort and conducted a systematic literature review. METHODS: Two hundred twenty patients who were treated between 1975 and 1994 with a minimum follow-up of 4 years were reviewed retrospectively. A systematic review of published articles on patients with malignancies of the nasal and paranasal sinuses during the preceding 40 years was performed. RESULTS: The 5-year survival rate was 40%, and the local control rate was 59%. The 5-year actuarial survival rate was 63%, and the local control rate was 57%. Factors that were associated statistically with a worse prognosis, with results expressed as 5-year actuarial specific survival rates, included the following: 1) histology, with rates of 79% for patients with glandular carcinoma, 78% for patients with adenocarcinoma, 60% for patients with squamous cell carcinoma, and 40% for patients with undifferentiated carcinoma; 2) T classification, with rates of 91%, 64%, 72%, and 49% for patients with T1, T2, T3, and T4 tumors, respectively; 3) localization, with rates of 77% for patients with tumors of the nasal cavity, 62% for patients with tumors of the maxillary sinus, and 48% for patients with tumors of the ethmoid sinus; 4) treatment, with rates of 79% for patients who underwent surgery alone, 66% for patients who were treated with a combination of surgery and radiation, and 57% for patients who were treated exclusively with radiotherapy. Local extension factors that were associated with a worse prognosis included extension to the pterygomaxillary fossa, extension to the frontal and sphenoid sinuses, the erosion of the cribriform plate, and invasion of the dura. In the presence of an intraorbital invasion, enucleation was associated with better survival. In multivariate analysis, tumor histology, extension to the pterygomaxillary fossa, and invasion of the dura remained significant. Systematic review data demonstrated a progressive improvement of results for patients with squamous cell and glandular carcinoma, maxillary and ethmoid sinus primary tumors, and most treatment modalities. CONCLUSIONS: Progress in outcome for patients with nasal and paranasal carcinoma has been made during the last 40 years. These data may be used to make baseline comparisons for evaluating newer treatment strategies.
3. Surgical salvage after failed radiation for paranasal sinus malignancy. Curran AJ, Gullane PJ, Waldron J, Irish J, Brown D, O'Sullivan B, Cummings B. Laryngoscope 1998 Nov;108:1618-22 OBJECTIVE: To comment on the role of surgical salvage following failed initial treatment for paranasal sinus malignancy. DESIGN: A retrospective analysis of one hundred eighty patients treated at The Princess Margaret Hospital, Toronto, from 1976 to 1993. MATERIALS AND METHODS: Thirty-four of 95 patients (36%) who failed initial treatment underwent surgical salvage. Initial therapy in this group was radiation only (n = 27) and combined therapy (n = 7). Patient, tumor, and surgical data were recorded. There were 23 T4, three T3, six T2, and two T1 carcinomas. Survival, recurrence rates, and the influence of a variety of variables on outcome were analyzed. RESULTS: Two- and 5-year overall actuarial survival calculated from the date of diagnosis was 54% and 35%, respectively. Two- and 5-year overall actuarial survival calculated from the date of salvage surgery was 44% and 22%, respectively. Advanced age (P < .004), patients with T4 category disease (P < .04), and squamous cell carcinomas (P < .049) correlated with poorer outcome on univariate analysis. Local failure was the most common cause of death (n = 13; 65%). CONCLUSION: Salvage surgery has a limited role in the management of persistent or progressive disease following failure of initial treatment. Careful postradiation surveillance with endoscopic biopsy under general anesthesia and immediate surgical resection when appropriate may improve the salvage rate.
SALIVARY GLANDS Specific Investigations prior to definitive treatment: • FNAC- Not mandatory, usually recommended when other pathology suspected e.g. granulomatous infection and in cases of malignancy when facial nerve may have to be sacrificed. • CT scan- Whenever bony infiltration or skull base infiltration is suspected • MRI - Investigation of choice for deep lobe involvement, facial nerve involvement, intra-cranial extension and recurrent tumors.
|
Staging: UICC staging (2002) |
|
Primary Tumor (T) |
TX: |
Cannot be assessed |
T0: |
No evidence of primary tumor |
T1: |
Tumor 2 cm or less in greatest dimension without extraparenchymal extension |
T2: |
Tumor more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension |
T3: |
Tumor more than 4 cm and/or tumor having extraparenchymal extension |
T4a: |
Tumor invades skin, mandible, ear canal, and/or facial nerve. |
T4b: |
Tumor invades skull base and/or pterygoid plates and/or encases carotid artery |
|
|
|
Regional Lymph Nodes (pN) |
NX: |
Cannot be assessed |
N0: |
No regional lymph node metastasis |
N1: |
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension |
N2a: |
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension |
N2b: |
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension |
N2c: |
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension |
N3: |
Metastasis in a lymph node, more than 6 cm in greatest dimension |
Treatment :
Primary Tumor : • Parotid: - Superficial parotidectomy is minimal surgical procedure. - Adequate parotidectomy for small adenomas in the tail of the parotid - Total parotidectomy – in cases with - Deep lobe tumors - High grade tumors - Positive margin following a superficial Parotidectomy - Total Parotidectomy with the excision of facial nerve - when the nerve is involved by the tumor. -Radical parotidectomy - when tumor involves - Skin - Infra-temporal fossa - Mandible - Petrous bone.
Note: Facial nerve is spared if there is clearly identifiable plane between it and the tumor, else sacrificed, not to leave behind residual disease
• Submandibular gand - excision of the submandibular gland + MND • Minor salivary gland tumors - excision with a cuff of normal tissue ( adequate margins). • Management of Neck: N0 neck -Level II nodal sampling-FS-MND N+ neck - MND/RND
Adjuvant RT- Indications are as follows [1,2,3] 1. T3/T4 cancers 2. Close or positive margins 3. Lymph node metastasis 4. Adenoid cystic carcinoma 5. High or intermediate grade tumors 6. Deep lobe tumors 7. Pre op facial nerve paralysis 8. Lymphatic or vascular invasion or peri-neural involvement 9. Recurrent tumors • Radical RT for unresectable primary. Fast neutron beam radiation therapy or accelerated hyperfractionated photon beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors. [4, 5,6]
References: 1. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986. 2. Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002. 3. Sessions RB, Harrison LB, Forastiere AA: Tumors of the salivary glands and paragangliomas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 886-906. 4. Buchholz TA, Laramore GE, Griffin BR, et al.: The role of fast neutron radiation therapy in the management of advanced salivary gland malignant neoplasms. Cancer 69 (11): 2779-88, 1992. 5. Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996. 6. Laramore GE, Krall JM, Griffin TW, Duncan W, Richter MP, Saroja KR, Maor MH, Davis LW.Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40.
HEAD & NECK CANCERS Salivary gland |
EBM
|
1. Surgery for major salivary gland cancer Witt RL Oncol Clin N Am. 2004 Jan;13(1):113-127 Major salivary gland cancers are rare, with many histologic types and subtypes.The tumor stage at presentation will dictate the need for imaging,FNA, and facial nerve monitoring. Immunohistochemistry has enhanced diagnosis. In addition, precise attention to surgical landmarks and technique will reduce complications. Tumor stage, histologic type, tumor grade,surgical margin, facial nerve dysfunction, perineural involvement, extra-parenchymal spread, and nodal metastasis are factors influencing the indication for neck dissection, postoperative radiation therapy, and survival rate.
2. Management of malignant sublingual salivary gland tumors. Ferlito A, Rinaldo A, Shaha AR, Pellitteri PK, Bradley PJ,. Oral Oncol. 2004 Jan;40(1):2-5. The majority of tumors of the sublingual gland are malignant, with adenoid cystic carcinoma and mucoepidermoid carcinoma being the most frequent. Many other malignant tumor types have also been reported. The sublingual gland anatomically is not a unit organ and while it is described anatomically as being confined to the anterior floor of the mouth, salivary tissue may be located laterally along the submandibular duct and posterior floor of the mouth. Diagnosis should be suspected when any thickening or raised lesion presents in this area and a biopsy performed to confirm malignancy before planning further treatment. Surgery is the treatment of choice, and should include an en-block resection of the anterior floor of mouth as a minimum, and may include a portion of mandible, as well as a supraomohyoid neck dissection. Adjuvant radiotherapy should be considered in most of the patients after surgical excision.
3. Salivary gland neoplasms. Day TA, Deveikis J, Gillespie MB, Joe JK et al. Curr Treat Options Oncol. 2004 Feb;5(1):11-26 Treatment and cure of salivary gland neoplasms requires surgical intervention in most cases. For parotid neoplasms, the most common surgical procedure performed is the superficial parotidectomy with facial nerve preservation. Postoperative radiation therapy is indicated in high-grade salivary gland malignancies and malignancies with increased risk of locoregional recurrence. Primary radiation, including neutron beam techniques, may play a role in certain histologic types or nonoperative candidates. Chemotherapy has yet to result in improvements in survival or quality of life in the treatment of salivary gland malignancy. Advances in radiation therapy techniques, including intensity-modulated radiation therapy, provide opportunities for reduced morbidity.
4. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Spiro RH. Head and Neck Surgery 1986; 8 : 177-184 We have reviewed a 35-year experience with 2,807 patients treated for salivary tumors which arose in the parotid gland (1,695 patients; 70%), submandibular gland (235 patients; 8%), and seromucinous glands of the upper aerodigestive tract (607 patients; 22%). Pleomorphic adenomas comprised 45% of the total, most of which occurred in the parotid gland. The clinical findings and the distribution of patients according to the histology and the site of origin are summarized. Treatment was surgical and the resection was conservative when possible, depending upon the extent of the tumor. The impact of site, histology, grade, and tumor stage on the results is shown.
5. Malignant parotid tumors: prognostic factors and optimum treatment.. Theriault C, Fitzpatrick PJ American Journal of Clinical Oncology 1986; 9 : 510-516 A retrospective study of 271 patients with parotid carcinoma seen between 1958 and 1980 is reported. Among these were 64 (24%) mucoepidermoid tumors (all degrees of differentiation), 50 (18%) adenocarcinomas, 40 (15%) malignant mixed tumors, 39 (14%) adenoid cystic carcinomas, 37 (14%) undifferentiated, 21 (8%) acinic, and 20 (7%) squamous cell carcinomas. The proportion of advanced (T3T4) to early (T1T2) tumors was 1.7:1. At diagnosis, 42 (15%) patients had regional metastases. An analysis for prognostic factors showed that the histology, tumor stage, regional metastases (No vs. N+), age, and damage to the facial nerve all influence cause-specific survival. After multivariate analysis the tumor size and the presence of regional metastases were the two most significant factors (p less than 0.0001 and 0.004). The prognostic characteristics were similar for the 67 (25%) patients treated by surgery and for the 169 (62%) patients treated with surgery and postoperative radiotherapy. Patients treated with combined therapy had a 10-year relapse-free rate of 62% compared to 22% for those treated by surgery alone (p = 0.0005).
6. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Laramore GE, Krall JM, Griffin TW et al Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40. To compare the efficacy of fast neutron radiotherapy versus conventional photon and/or electron radiotherapy for unresectable, malignant salivary gland tumors a randomized clinical trial comparing was sponsored by the Radiation Therapy Oncology Group in the United States and the Medical Research Council in Great Britain. METHODS AND MATERIALS: Eligibility criteria included either inoperable primary or recurrent major or minor salivary gland tumors. Patients were stratified by surgical status (primary vs. recurrent), tumor size (less than or greater than 5 cm), and histology (squamous or malignant mixed versus other). After a total of 32 patients were entered onto this study, it appeared that the group receiving fast neutron radiotherapy had a significantly improved local/regional control rate and also a borderline improvement in survival and the study was stopped earlier than planned for ethical reasons. Twenty-five patients were study-eligible and analyzable. RESULTS: Ten-year follow-up data for this study is presented. On an actuarial basis, there continues to be a statistically-significant p = 0.009) but there is no improvement in overall survival (15% vs. 25%, p = n.s.). Patterns of failure are analyzed and it is shown that distant metastases account for the majority of failures on the neutron arm and local/regional failures account for the majority of failures on the photon arm. Long-term, treatment-related morbidity is analyzed and while the incidence of morbidity graded "severe" was greater on the neutron arm, there was no significant difference in "life-threatening" complications. This work is placed in the context of other series of malignant salivary gland tumors treated with definitive radiotherapy. CONCLUSIONS: Fast neutron radiotherapy appears to be the treatment-of-choice for patients with inoperable primary of recurrent malignant salivary gland tumors.
Specific Investigations prior to definitive treatment: 1. FNAC 2. Serum Calcitonin (In suspected case of Medullary thyroid carcinoma) 3. USG neck for the initial work-up of a solitary thyroid nodule and in follow-up. 4. CT scan of Neck (if tracheal / vascular infiltration suspected) in differentiated thyroid cancer 5. CT Scan of Neck and Mediastinum- in Medullary carcinoma to assess nodal involvement.. 6. Chest X-Ray 7. PET-CT Scan: - Raised thyroglobulin and disease not located - Raised calcitonin and disease not located.
STAGING (UICC -2002) (Thyroid cancer is the only cancer where age and histology are incorporated in the staging) Primary tumor (T) [Note: All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor (the largest determines the classification).] TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor 2 cm or less in greatest dimension, limited to the thyroid T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid T3: Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues) T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
All anaplastic carcinomas are considered T4 tumors.
T4a: Intrathyroidal anaplastic carcinoma— surgically resectable T4b: Extrathyroidal anaplastic carcinoma— surgically unresectable
Regional lymph nodes ( N ) Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes. NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal / Delphian lymph nodes) N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes
Distant metastases (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis
UICC stage groupings Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic (undifferentiated) carcinoma.
Papillary or follicular thyroid cancer Younger than 45 years • Stage I - Any T, any N, M0 • Stage II - Any T, any N, M1
Age 45 years and older • Stage I T1, N0, M0 • Stage II T2, N0, M0 • Stage III T3, N0, M0, T1, N1a, M0 , T2, N1a, M0, T3, N1a, M0 • Stage IVA T4a, N0, M0, T4a, N1a, M0, T1, N1b, M0, T2, N1b, M0, T3, N1b, M0, T4a, N1b, M0 • Stage IVB T4b, any N, M0 • Stage IVC Any T, any N, M1
Medullary thyroid cancer • Stage I T1, N0, M0 • Stage II T2, N0, M0 • Stage III T3, N0, M0 , T1, N1a, M0 , T2, N1a, M0, T3, N1a, M0 • Stage IVA T4a, N0, M0 , T4a, N1a, M0 , T1, N1b, M0, T2, N1b, M0, T3, N1b, M0, T4a, N1b, M0 • Stage IVB T4b, any N, M0 • Stage IVC Any T, any N, M1
Anaplastic thyroid cancer All anaplastic carcinomas are considered stage IV. • Stage IVA - T4a, any N, M0 • Stage IVB T4b, any N, M0 • Stage IVC Any T, any N, M1
Risk Stratification: There are several risk stratification criteria such as AGES, AMES, MACIS etc. The broad consensus from all of them are as follows-
|
Low Risk |
High Risk |
Patient Factor: |
Age |
<40 |
>40 |
Sex |
Female |
Male |
Tumor Factor: |
Histology: |
--- |
Tall Cell, Diffuse Sclerosing Insular Variant, Hurthle Cell Columnar Cell |
Size |
<4 |
>4 |
Extrathyroidal Extension |
Nil |
+ |
Metastases |
Nil |
+ |
Treatment of Differentiated Thyroid Cancers : Surgery forms the mainstay of treatment in all stages of differentiated thyroid cancers including metastatic cancer. The extent of surgery depends upon the risk categorization of the patient.
Low Risk Patient - Hemithyroidectomy High Risk Patients- Total Thyroidectomy Management of lymph nodes : • Central compartment clearance (removal of glands along the recurrent laryngeal nerve) and ipsilateral nodal sampling ? FS ? MND. • MND (Type II or III) for positive lymph nodes. • RND (rarely required) if large nodes infiltrating surrounding structure Other treatment modalities : • Surgery : For orthopaedic stabilisation / cord compression. • External radiotherapy : Limited role, indications are - Surgically unresectable disease not responding to I 131 - Gross residual disease, - poor uptake on post-op scan. • Chemotherapy – No role. Treatment of Medullary Thyroid Carcinoma (MTC) : There are two types of MTC • Sporadic type • Familial type – associated with Multiple Endocrine Neoplasia (MEN) IIA, IIB and familial non-MEN MTC Indications to investigate for familial MTC : • Young age • Bilateral / multicentric disease • Clinical features of familial MTC • Family history of MTC or other tumours associated with MEN Investigations for suspected familial MTC : • S. Ca, S. phosphate and S. PTH for parathyroid tumours • USG abdomen, Urinary VMA Metastatic work-up for all MTCs : • Chest X-ray • USG abdomen • Bone scan Treatment for MTC : • Surgery : Total thyroidectomy with central compartment clearance (dissection of nodes from Hyoid to Innominate vessels and Laterally from carotid to carotid) +/- MND • Radiotherapy used only for palliation in advanced unresectable disease. Adjuvant RT following an R+ resection is recommended. • No role of chemotherapy.
Treatment of anaplastic thyroid carcinoma : Operable (very uncommon) : Total Thyroidectomy Inoperable : Palliative Adriamycin based CT+ RT
FOLLOW UP POLICY:
Papillary / follicular carcinoma: • Oral thyroxine (T4) supplementation to keep TSH low (0.5-5 mIU/ml if no residual disease and 0.1 mIU/ml if residual disease present); • Oral calcium supplementation if hypo-calcemia present. • S. Thyroglobulin, Chest X-ray, Diagnostic whole body scan according to risk category. Medullary Thyroid cancers: • Serum Calcitonin Serum Calcitonin normal : Observe Serum Calcitonin raised : Imaging to detect recurrence
• Operable recurrence detected : Surgery • Inoperable Recurrence detected : - If patient is symptomatic and debulking not morbid- Palliative surgery - Palliative Radiotherapy - Symptomatic treatment. • No recurrence detected: Observe only
Selected Readings: 1. Sanders LE, Cady B: Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 133 (4): 419-25, 1998. 2. Mazzaferri EL: Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 66 (1): 105-11, 1991. 3. Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994. 4. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994. 5. Shah JP, Loree TR, Dharker D, et al.: Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 164 (6): 658-61, 1992. 6. Andersen PE, Kinsella J, Loree TR, et al.: Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg 170 (5): 467-70, 1995.
HEAD & NECK CANCERS Thyroid Cancers |
EBM
|
1. An expanded view of risk-group definition in differentiated thyroid carcinoma. Cady B, Rossi R. Surgery 1988; 104 : 947-53 There continues to be controversy about every aspect of management of differentiated thyroid carcinoma. In an age-based risk group previously described, low-risk patients made up 62% of cases and had a death rate of only 1%. Recent reports from the Mayo Clinic have expanded the concept of the low-risk group to include 86% of all cases with a 2% death rate by utilizing several anatomic and pathologic criteria of risk. We offer here another multifactorial system for the identification of low-risk patients who made up 89.4% of all patient seen between 1961 and 1980 and who have a death rate of only 1.8%. The resultant high-risk group constitutes 11% of cases but carries a 46% mortality rate. The risk-group definition is completely clinical and is based on age, presence of distant metastases, and the size and extent of primary cancer. It can be used confidently at the operating table to select conservative succeeding decades analyzed, from 1941 to 1980, the effectiveness of this clinical categorization has increased substantially in separating patients at high and low risk, so that a mortality rate ratio of 26:1 now exists between high- and low-risk groups, respectively.
2. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Hay ID, Grant CS, Taylor WF, et al. Surgery 1987; 102 : 1088-95 From a multivariate analysis of more than 14,200 patient-years’ experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system can identify patients at increased risk of PTC mortality and was employed as an adjustment variable for analyzing the role of different types of surgical treatment in 860 PTC patients. Cancer mortality at 25 years in patients with an AGES score of 3.99 or less was 1% after ipsilateral lobectomy (n = 131) and 2% after bilateral resection (n = 603), whether subtotal or total (p = 0.15). Of patients with an AGES score of 4 or more, those who underwent lobectomy alone (n = 30) had a mortality rate from PTC at 25 years of 65%, while those undergoing bilateral resection (n = 86) had a lower rate of 35% (p = 0.06). For patients at minimal risk (score of 3.99 or less) of PTC death, no improvement in survival was demonstrable when patients underwent more than ipsilateral lobectomy. However, in a subgroup (score of 4 or more) identified to be at significant risk of PTC death, the survival after bilateral resection was much higher than after ipsilateral lobectomy alone. In neither the “minimal” nor the “higher” risk subgroup was PTC survival significantly improved by the performance of total thyroidectomy.
3. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Pasieka JL, Zedenius J, Auer G, et al. Surgery 1992; 112 : 1154-9 BACKGROUND : The purpose of this study was to prospectively assess whether nuclear DNA content added prognostic value to existing risk factors in patients with papillary thyroid cancer. METHODS : Nuclear DNA content was measured both on the fine needle aspiration material and the surgical specimen in 73 patients with primary or recurrent papillary thyroid cancer. We modified the existing age of patient, presence of distant metastases, extent and size of the tumor (AMES) risk-group classification to include DNA ploidy with AMES (DAMES). Patients with euploid tumors that were AMES low risk were considered to be DAMES low risk; patients with euploid tumors that were AMES high risk became intermediate risk, and patients with aneuploid tumors that were AMES high risk became DAMES high risk. RESULTS : Forty-eight patients were in the DAMES low-risk group. Recurrences and/or distant metastases developed in only four (8%) of these patients. Twenty-two patients were in the DAMES intermediate-risk group. Twelve (55%) of the intermediate-risk group had residual, recurrent, or distant metastatic disease, with one death from cancer at 120 months. Three patients were in the DAMES high-risk group. Distant metastases developed in all three patients, who died within 24 months from thyroid cancer. A statistically significant difference existed in the development of recurrence/metastases or death from cancer in the DAMES high-risk group compared with the other risk groups combined. CONCLUSIONS : Nuclear DNA content adds prognostic value to the existing AMES risk-group classification. Because DNA analysis on fine needle aspiration correlated well with the surgical specimen DNA analysis, this modified classification can be used perioperatively to further individualize the treatment of patients with papillary thyroid cancer.
4. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Hay ID, Bergstralh EJ, Goellner JR, et al. Surgery 1993; 114 : 1050-7 BACKGROUND : Multivariate analyses in papillary thyroid carcinoma (PTC) have shown that age, tumor size, local invasion and distant metastasis are independent predictive variables. This study attempted to define a reliable prognostic scoring system for predicting PTC mortality rates with 15 candidate variables that included completeness of primary tumor resection but excluded histologic grade and DNA ploidy. METHODS : The study group comprised 1779 patients with PTC (followed up for > 26,000 patient-years), divided by treatment dates into 1940 to 1964 (n = 764) and 1965 to 1989 (n = 1015). Cox model analysis and stepwise variable selection led to a prognostic model initially derived from the training set (n = 764). The initial prognostic score was thereafter validated externally with the later (1965 to 1989) “test” data set. RESULTS : The final model included five variables abbreviated by metastasis, age, completeness of resection, invasion, and size (MACIS). The final prognostic score was defined as MACIS = 3.1 (if aged < or = 39 years) or 0.08 x age (if aged > or = 40 years), + 0.3 x tumor size (in centimeters), +1 (if incompletely resected), +1 (if locally invasive), +3 (if distant metastases present). Twenty-year cause-specific survival rates for patients with MACIS less than 6, 6 to 6.99, 7 to 7.99, and 8+ were 99%, 89%, 56%, and 24%, respectively (p < 0.0001). CONCLUSIONS : Because the five variables needed for MACIS scoring are readily available after primary operation, such a prognostic system could have widespread applicability in assessment of PTC.
5. Low-risk differentiated thyroid cancer: the need for selective treatment. Shaha AR, Shah JP, Loree TR. Ann Surg Oncol 1997; 4 : 328-33 BACKGROUND : The well recognized prognostic factors in differentiated carcinoma of the thyroid are age, grade, extracapsular extension, distant metastasis, and size of the tumor. Based on these prognostic factors, we have divided patients into low-, intermediate-, and high-risk categories. Clearly, there are significant differences in these three groups. This article analyzes in depth our data on low-risk thyroid cancer patients. METHODS: A retrospective review of 1,038 patients with differentiated carcinoma of the thyroid was undertaken. Various prognostic factors and risk groups were analyzed. Univariate and multivariate analyses were performed, and the survival curves were plotted by the Kaplan-Meier method. The inclusion criteria for the low-risk group were age younger than 45 years, tumors < 4 cm in size, low-grade histology, absence of distant metastasis, and absence of extrathyroidal extension. There were 465 patients in the low-risk group. Four hundred three patients had papillary and 62 patients had follicular thyroid cancer. There were 120 male and 354 female patients. Two hundred seventy-eight patients (60%) presented with clinically apparent lymph node metastasis. RESULTS: With a median follow-up of 20 years, the 10- and 20-year survival in this select group was 99%. The local, regional, and distant recurrence rates were 5, 9, and 2% in this series. The analysis of the data showed statistical difference in local recurrence rate between partial lobectomy and total lobectomy (27 vs. 4%; p = 0.005). There was no statistical difference in local recurrence rate between total lobectomy compared with total thyroidectomy (4 vs. 1%; p = 0.10). The overall failure rate between partial lobectomy and total thyroidectomy (27 vs. 8%) was statistically significant (p = 0.04). There was no statistical difference in the overall failure rate between total lobectomy and total thyroidectomy (13 vs. 8%; p = 0.06). There was no survival difference between various histologies or nodal status. CONCLUSIONS: Patients with low-risk tumors have excellent long-term survival. Nodulectomy or partial lobectomy should be avoided. The intraoperative decisions regarding the extent of thyroidectomy should be based on gross clinical findings and risk group analysis.
6. Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Vitale G, Caraglia M, Ciccarelli A, et al. Cancer 2001; 91 : 1797-808 BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells. At present, surgery is the most important treatment for MTC. METHODS : We describe the current approaches of MTC treatment (surgery, chemotherapy, radiation therapy, and biologic therapy). RESULTS: MTC is currently approached surgically in the main part through total thyroidectomy and compartment-oriented microdissection of cervicomediastinal lymph nodes. Substitutive l-thyroxine administration together with close clinical monitoring and the measurement of basal and stimulated serum calcitonin are subsequently performed. Radiotherapy and chemotherapy play a marginal role in advanced MTC. Recently, it has been found that somatostatin analogs and type I interferon are able to control the neuroendocrine symptoms induced by advanced MTC and that they provide clinical benefit by improving the lifestyle of these patients. CONCLUSION : Although these agents are poorly active in inducing a shrinkage in tumor mass, the combined use of different biologic agents and cytotoxic drugs needs to be explored in advanced MTC. However, at present, surgery is the only curative treatment for MTC. Copyright 2001 American Cancer Society.
7. Prognostic factors in patients with differentiated thyroid carcinoma. Steinmuller T, Klupp J, Rayes N, Ulrich F, Jonas S, Graf KJ, Neuhaus P Eur J Surg 2000;166:29-33. Thyroid cancers are a heterogenous group of disorders. The treatment is based on evidence available from retrospective studies as there are no prospective trials available. It is impossible to perform a prospective randomised trial as the number of cases required will be enormous and considering the indolent nature of the disease a prolonged follow up is required. For differentiated cancers the treatment is guided by risk stratification criteria. Loboisthumectomy for the low-risk group, and total/near-total thyroidectomy for the high-risk, intermidiate risk and for cases with lymph node metastases is recommended. No role of prophylactic neck dissection. Anterolateral neck dissection or MND is recommended for clinically palpable nodal metastasis. Post – operative 131I treatment is mandatory in the high and intermidiate risk group where complete removal of the thyroid gland is achieved. Surgery is the mainstay in the treatment of medullary cancers and external radiotherapy is reserved for palliation in advanced and unresectable recurrent cases. Anaplastic cancers are treated with palliative intent. OTHER SELECT PUBLICATIONS: - Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995 Dec;118:1131-6; discussion 1136-8 - Steinmuller T, Klupp J, Rayes N, Ulrich F, Jonas S, Graf KJ, Neuhaus P. Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg 2000;166:29-33
Thyroid cancers are a heterogenous group of disorders. The treatment is based on evidence available from retrospective studies as there are no prospective trials available. It is impossible to perform a prospective randomised trial as the number of cases required will be enormous and considering the indolent nature of the disease a prolonged follow up is required. For differentiated cancers the treatment is guided by risk stratification criteria. Loboisthumectomy for the low-risk group, and total/near-total thyroidectomy for the high-risk, intermidiate risk and for cases with lymph node metastases is recommended. No role of prophylactic neck dissection. Anterolateral neck dissection or MND is recommended for clinically palpable nodal metastasis. Post – operative 131I treatment is mandatory in the high and intermidiate risk group where complete removal of the thyroid gland is achieved. Surgery is the mainstay in the treatment of medullary cancers and external radiotherapy is reserved for palliation in advanced and unresectable recurrent cases. Anaplastic cancers are treated with palliative intent. |
|