Results

A. Neuroblastoma
Neuroblastoma selectede abstracts

B. Retinoblastoma
Retinoblastoma selectede abstracts

C.Wilms' Tumour
Wilms' Tumour selectede abstracts

Risk Stratification

Risk stratification depends upon many factors
Ø Age
Ø Stage
Ø Pathology (Pre chemotherapy biopsy or specimen)

Favorable Histology
1. Neuroblastoma (NB) with low or Intermediate MKI in children < 1.5 yr.
2. Differentiating NB with low MKI in children 1.5 - 5 yrs.
3. Ganglioneuroblastoma (GNB) intermixed
4. Ganglioneuroma (GN).

Unfavorable Histology
1. All NB with high MKI.
2. NB with intermediate MKI
3. Undifferentiated & Poorly differentiated NB between 1.5 - 5 years.
4. All NB > 5 years.
5. GNB nodular.

Ø Molecular studies (Optional)
1. DNA Index
2. N myc amplification
3. Chromosome 1p deletion

Guidelines for risk adapted therapies and expected outcome

Management Algorithm at Tata Memorial Hospital

Surgery
Surgery plays a pivotal role in the management of neuroblastoma, both for diagnosis and for treatment. Patients with tumors that are localized to one side of midline, or crossing the midline without encasement of major blood vessels, are candidates for primary surgical resection. Surgery alone is curative for stage I tumors. The goals of primary surgical procedures, performed before any therapy, are to establish the diagnosis, to provide tissue for biologic studies, to stage the tumor surgically, and to attempt to excise the tumor without injury to vital structures. In delayed primary or second-look surgery, the surgeon determines response to therapy and removes residual disease when possible .The importance of gross total resection in the management of disseminated neuroblastoma remains controversial.

RADIOTHERAPY
Indications :

Low-risk-patients with symptomatic life - or organ-threatening tumor that does not respond rapidly enough to chemotherapy.

Intermediate-risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also has unfavorable biologic characteristics.

Radiation therapy to the primary site is recommended for high-risk patients even in cases of complete resection.

As part of preparatory regimen for bone marrow transplant.
Palliative radiation therapy to sites of metastatic disease.

Principles of Radiation Therapy :
Target volume :
Clinical target volume (CTV) should include the primary tumor (gross/ microscopic) with adequate margins (no study till date on adequacy of margins). If the regional nodes are involved/ suspected to be involved – the region should also be included in the radiation field.

Routine inclusion of uninvolved next echelon of nodes is not advisable.

The entire vertebral body should be included in the radiotherapy portal to prevent scoliosis.

In 4S disease with liver involvement, it is not necessary to include the entire liver in the radiotherapy port to induce tumor regression. Portals can be modified to spare critical organs.

Recommendation : CTV + 1.5-2 cm margin from the tumor to the block edge.

Total Dose :
Neuroblastoma is a moderately sensitive tumor to radiation with a low repair capacity of radiation damage. Mild variability in radiosensitivity could be attributed to variations in oncogene genomic amplification e.g. n-myc amplification.

Data suggest an age-dependent dose response in neuroblastoma. Hypothetically explained by a difference in the proportion of clonogenic tumor cells.

Recommendation :
Age £ 18 months : Gross disease : 15Gy (Wide local field) + 10Gy (Boost)
                          Microscopic Disease : 15Gy (Wide local field) + 5Gy (Boost)
Age > 19 months : Gross disease : 20Gy (Wide local field) + 10Gy (Boost)
                          Microscopic Disease : 15Gy (Wide local field) + 10Gy (Boost)

Chemotherapy

Chemotherapy plays pivotal role in the management of neuroblastoma Alkylating agents - cyclophosphamide, cisplatin, doxorubicin, and the epipodophyllotoxins are the cornerstone of multi-agent regimens.

Risk Adapted Chemotherapy Regimens

A) RADIOTHERAPY TARGET VOLUME
Radiation therapy in the management of neuroblastoma: the Duke University Medical Center experience 1967-1984.
Halperin EC, Cox EB.
Int J Radiat Oncol Biol Phys. 1986 Oct;12(10):1829-37.

We have evaluated the role of radiotherapy in providing local control of primary tumors and to palliate metastases from neuroblastoma (NB). Fifty-five children with histologically verified NB were evaluated and treated from 1967 to 1984. In univariate analysis, the actuarial survival of eight children with thoracic primaries (85%) was significantly better than the survival of 39 children with intra-abdominal primaries (35%, p = 0.0287). The survival of 28 children less than or equal to 18 months of age at diagnoses was 73%, whereas 27 children older than 18 months had a survival probability of 10% (p = 0.0001). The survival by Evans stage was: I 100% (2 patients), II 85% (7), III 60% (13), IV 4% (27) and IV-S 100% (6). According to the Pediatric Oncology Group (POG) staging system, the survival was: A 100% (3), B 66% (9), C 66% (9), D 23% (34). A multivariable analysis indicated that the Evans staging system was a more powerful indicator of prognosis than the POG system. The analysis also indicated that Evans stage and patient age were independent determinants of survival. The primary tumor site did not add significant prognostic information beyond these two factors. Children with Stage I disease were treated with surgery alone. Most children with Stages II and III disease were treated with surgery, irradiation, and Cyclophosphamide or Cyclophosphamide plus Vincristine. All seven patients with Stage II disease received post-operative irradiation to the primary tumor and were locally controlled with doses of 4.8 to 26.5 Gy. Eleven of the 13 patients with Stage III disease were irradiated post-operatively. Seven of these 11 patients were locally controlled with doses of 12 to 48.4 Gy. The four Stage III patients with in-field recurrences were older children with large radiotherapy fields and/or low doses administered. The Radiation Therapy Oncology Group pain score system was used to evaluate response of painful bony metastases to irradiation. A response was observed in 65% of the sites irradiated. A response was observed at 67% of the soft tissue seven patients. All patients responded with doses ranging from 5 to 24.4 Gy. Five of the 17 children who survived for more than 5 years following treatment had significant scoliosis or kyphosis secondary to vertebral body abnormalities in irradiated bones. All five children were irradiated at a young age with megavoltage equipment.

Long-term results of therapy for stage C neuroblastoma.
Halperin EC.
J Surg Oncol. 1996 Nov;63(3):172-8.

BACKGROUND : The appropriate therapy for Stage C neuroblastoma (NB) is uncertain. Because of the need for information applicable to the development of new randomized trials, we deemed it appropriate to investigate the patient characteristics, survival, patterns of failure, and complications of therapy in these children. METHODS : Search of the medical records of Duke University Medical Center from 1/1/60 to 3/1/95 disclosed 146 patients with NB, which included 13 Stage C patients. RESULTS : Mean age at diagnosis was 3.6 years. Twelve patients had primary abdominal tumors (92%) and one had a thoracic primary (8%). Twelve (92%) of the patients received chemotherapy including cyclophosphamide. 11 (85%). Adriamycin, 6 (46%), cisplatinum, 4 (30%), and VP 16, 4 (30%). All patients received radiotherapy (RT, mean dose administered 22.6 +/- 8 Gy). With a mean follow-up of 8 years, the 10-year overall survival was 54% and the relapse-free survival was 46%. Four patients relapsed in the primary operative tumor bed and primary RT field, two relapsed in mediastinal or left supraclavicular lymph nodes as well as distantly following treatment of upper abdominal primaries, and in one the site of relapse is unknown. Long-term complications of therapy included two children who developed secondary malignancies associated with RT, two girls who developed primary ovarian failure, five children with clinically significant kyphosis and scoliosis, and one who suffered postoperative wound dehiscence following RT. CONCLUSIONS : Although this study did not include modern techniques of staging with n-myc amplification and DNA index, the occurrence of next echelon nodal failures gives credence to the continuation of the dialogue concerning the appropriate role of “prophylactic” irradiation to mediastinal and left supraclavicular nodes in locally advanced upper abdominal NB. Documentation of significant long-term ill effects reinforces the need to critically evaluate the indications for RT.

Spinal deformity in children treated for neuroblastoma.
Mayfield JK, Riseborough EJ, Jaffe N et al.
J Bone Joint Surg Am. 1981 Feb;63(2):183-93.

Of seventy-four children who were treated at a mean age of seventeen months for neuroblastoma and survived more than five years, fifty-six (76 per cent) had spinal deformity due either to the disease or to the treatment after a mean follow-up of 12.9 years. Of these fifty-six, 50 per cent had post-radiation scoliosis (mean, 18 degrees; range, 5 to 79 degrees), and 16 per cent had post-radiation kyphosis, most frequently at the thoracolumbar junction (mean, 39 degrees; range, 13 to 61 degrees), at the time of follow-up. Two kyphotic thoracolumbar curve patterns were identified: (1) an angular kyphosis with a short radius of curvature and its apex at the twelfth thoracic and first lumbar vertebrae, and (2) a thoracic kyphosis with a long radius of curvature that extended into the lumbar spine. The post-radiation deformity–both the scoliosis and the kyphosis–progressed with growth, the scoliosis at a rate of 1 degree per year and the kyphosis at a rate of 3 degrees per year. Epidural spread of the neuroblastoma was associated with most of the cases of severe scoliosis and kyphosis. The deformity was due either to the laminectomy or to the paraplegia acting in conjunction with the radiation. Eighteen per cent of 419 children with this malignant disease survived more than five years, and of the survivors, 20 per cent had spinal deformity severe enough to warrant treatment. The factors associated with the development of spinal deformity in patient treated for neuroblastoma were: (1) orthovoltage radiation exceeding 3000 rads, (2) asymmetrical radiation of the spine, (3) thoracolumbar kyphosis, and (4) epidural spread of the tumor.

B) RADIOTHERAPY DOSE
The effect on human neuroblastoma spheroids of fractionated radiation regimes calculated to be equivalent for damage to late responding normal tissues.
Wheldon TE, Berry I, O’Donoghue JA et al.
Eur J Cancer Clin Oncol. 1987 Jun;23(6):855-60.

Multicellular tumour spheroids (MTS) are a useful in vitro model of human cancer. An experiment was designed to assess the likely therapeutic advantage of hyperfractionation–a proposed strategy in radiotherapy. A cell line (NB1-G) derived from human neuroblastoma was grown as MTS. This MTS line is radiosensitive with low capacity for repair of sublethal radiation damage. These properties make NB1-G a suitable line to test the theoretical advantage of hyperfractionation. MTS were irradiated using alternative fractionated regimens, with fraction sizes varying from 0.5 to 4 Gy. In each experiment, the total dose was chosen to make the regimens theoretically isoeffective for damage to late-responding normal tissues (calculated using the linear-quadratic mathematical model with alpha/beta = 3 Gy). The radiation responses of MTS were evaluated using the end-points of regrowth delay and “proportion cured”. Regimens using smaller doses per fraction were found to be markedly more effective in causing damage to neuroblastoma MTS, as assessed by either end-point. These experimental findings support the proposal that hyperfractionation should be a therapeutically advantageous strategy in the treatment of tumours whose radiobiological properties are similar to those of the MTS neuroblastoma line NB1-G.

Dose response analysis of pediatric neuroblastoma to megavoltage radiation.
Jacobson GM, Sause WT, O’Brien RT. Am J Clin Oncol. 1984 Dec;7(6):693-7.

Children with neuroblastoma treated in Salt Lake City from 1966 through 1982 were
analyzed in an attempt to develop guidelines for external beam radiation. Particular attention was addressed to time-dose relationships in those patients with residual disease post-resection (Stages II and III). Altogether, 76 patients were analyzed and survival rates were : Stage I–100%; Stage II–84%; Stage III–69.2%; Stage IV–14.3%; Stage IV-S–71.4%.

Survival rates were correspondingly better in younger children and in infants. Indications for postoperative radiation therapy in this population were: unresectable or gross remaining tumor; residual tumor in neural foramina; tumor spill during surgery; positive regional lymph nodes or positive surgical margins. Local control was achieved in a majority of patients undergoing surgery and radiation for limited disease. In children younger than 1 year of age, no local failures were observed at doses above 1200 rad. In children between 1-2 years of age, no local failures were observed with doses as low as 1440 rad. In children older than 3 years, local failures were observed up to 4500 rad.

Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery.
Kushner BH, Wolden S, LaQuaglia MP et al.
J Clin Oncol. 2001 Jun 1;19(11):2821-8.

PURPOSE : To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS : Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS : Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION : Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.

The Changing Role of Radiation Therapy in the Treatment of Neuroblastoma.
Marcus KC, Tarbell NJ.
Semin Radiat Oncol. 1997 Jul;7(3):195-203.

Neuroblastoma (NBL) is the fourth most common pediatric malignancy. With a median age at diagnosis of 2 years, it represents half of all malignancies that present in the first month of life and one third of those that are diagnosed in the first year of life. NBL is unique among human cancers in its ability to undergo spontaneous differentiation and permanent tumor regression. This phenomenon is particularly characteristic of disseminated disease with liver, skin, and limited bone marrow involvement and involving a limited primary and presenting in children under 1 year of age. Advances in the understanding of the biologic behavior of NBL coupled with the clinical presentation have led to a risk-based approach to treatment, minimizing the treatment to some patients and supporting the need for more aggressive treatment to others. A new international staging system has been adopted that has allowed better comparisons among treatment reports from varying centers and cooperative groups. This article reviews the risk-related approach to the treatment of NBL and the changing role of radiation therapy.

Dose response analysis of pediatric neuroblastoma to megavoltage radiation.
Jacobson GM, Sause WT, O’Brien RT.
Am J Clin Oncol. 1984 Dec;7(6):693-7.

Children with neuroblastoma treated in Salt Lake City from 1966 through 1982 were analyzed in an attempt to develop guidelines for external beam radiation. Particular attention was addressed to time-dose relationships in those patients with residual disease post-resection (Stages II and III). Altogether, 76 patients were analyzed and survival rates were: Stage I–100%; Stage II–84%; Stage III–69.2%; Stage IV–14.3%; Stage IVS–71.4%. Survival rates were correspondingly better in younger children and in infants. Indications for postoperative radiation therapy in this population were: unresectable or gross remaining tumor; residual tumor in neural foramina; tumor spill during surgery; positive regional lymph nodes or positive surgical margins. Local control was achieved in a majority of patients undergoing surgery and radiation for limited disease. In children younger than 1 year of age, no local failures were observed at doses above 1200 rad. In children between 1-2 years of age, no local failures were observed with doses as low as 1440 rad. In children older than 3 years, local failures were observed up to 4500 rad.

Neuroblastoma: the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital experience.
Rosen EM, Cassady JR, Frantz CN et al.
J Clin Oncol. 1984 Jul;2 (7):719-32.

The treatment results for 118 patients with neuroblastoma seen at the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital from 1970 to 1980 were analyzed. Patients were treated with a combination of surgery, radiation therapy, and chemotherapy depending on stage and age. Disease-free survival was excellent in all patient groups except those over one year of age with stage IV disease, a group for which currently available therapy cures only a small proportion of patients. Patients with stage III disease and older patients with stage II disease did extremely well (survival of 81% and 89%, respectively) and may have benefited from intensive treatment with all three modalities. Survival for infants (under one year) with stage IV neuroblastoma (90%) has clearly improved with intensive combination chemotherapy. With combination approaches and newer, more effective systemic regimens, a real impact on survival appears to have been made in the last decade. Better approaches will be necessary to cure more than an occasional older patient with stage IV disease.

C) RADIOTHERAPY WITH BONE MARROW TRANSPLANTATION (BMT)

Patterns of failure following total body irradiation and bone marrow transplantation with or without a radiotherapy boost for advanced neuroblastoma.
Sibley GS, Mundt AJ, Goldman S et al.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1127-35.

PURPOSE : To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy, total body irradiation (TBI), and bone marrow transplantation (BMT) for advanced/relapsed pediatric neuroblastoma, with emphasis on the impact of a radiotherapy boost to primary and metastatic sites. METHODS AND MATERIALS : Between May 1986 and June 1993, 26 patients with advanced neuroblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of patients were over the age of 2 years (73%) and were Stage IV at diagnosis (81%). Multiple metastatic sites were involved including bone (17), bone marrow (15), distant nodes (11), liver (5), lung (4) and brain (1). Twenty patients (77%) received cyclophosphamide (50 mg/kg x 4 days) and TBI as consolidation therapy. TBI was delivered to a total dose of 12 Gy given in 2 Gy twice daily (b.i.d.) fractions over the 3 days preceding bone marrow infusion. A local radiotherapy boost of 8-24 Gy was given to 13 out of 26 patients (50%) to the primary and/or metastatic sites immediately prior to or following induction chemotherapy according to physician judgement. Sites not amenable to a radiotherapy boost included the bone marrow, diffuse/bilateral lung involvement, and multiple bone metastases (> four sites). RESULTS : The actuarial overall survival of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival at 5 years of 38.5%. Six patients died of transplant-related toxicity (23%). The use of cyclophosphamide as high-dose consolidation chemotherapy was significantly better than other multidrug regimens used in terms of overall survival (p<0.0001) and progression-free survival (p=0.0004). The presence of liver involvement prior to BMT was a significant adverse prognostic factor by multivariate analysis. Of the 20 patients surviving the transplant, 10 (50%) underwent a local radiotherapy boost. The patterns of failure were as follows: 3 out of 10 “boost” patients failed overall, none in previous (old) sites of disease only, 1 in new sites only, and 2 in old and new sites; 6 out of 10 “no boost” patients failed overall, 4 in old sites only, none in new sites only, and 2 in old and new sites. There was a trend toward improved 5-year progression-free survival in patients surviving the transplant that received a boost (68% vs. 33%, p = 0.24). A failure analysis was also performed for each of the 59 initially involved sites, of which the majority (64%) were amenable to a radiotherapy boost. Overall, there is a trend toward less failure in sites amenable to a radiotherapy boost that were irradiated (1 out of 10) vs. those not irradiated (6 out of 28). Failure in the liver occurred in three out of four of the patients with liver involvement that did not receive boost radiotherapy, whereas all seven patients with distant nodal involvement were controlled without a boost. Long-term sequelae include learning difficulties (2), cataract formation (1), and hearing loss (2). Sequelae attributable to a radiotherapy boost occurred in only one patient who received whole brain radiotherapy and developed a cataract and learning difficulties. CONCLUSION : We have found an actuarial 5-year survival rate of 40.4% for patients with advanced neuroblastoma treated with BMT, which compares favorably with results of other published series. Disease recurrence following BMT was most common in previous sites of disease. The majority (64%) of these sites were amenable to a radiotherapy boost. An analysis of failure suggests that a low-dose radiotherapy boost improves control of these sites.

Treatment of advanced neuroblastoma with supralethal chemotherapy, radiation, and allogeneic or autologous marrow reconstitution.
August CS, Serota FT, Koch PA et al.
J Clin Oncol. 1984 Jun;2(6):609-16.

Ten children with recurrent metastatic (stage IV) neuroblastoma received local radiation therapy, supralethal chemotherapy, and total-body irradiation. Rescue with infusions of either allogeneic (four patients) or autologous (six patients) bone marrow followed. The drugs given to the first two patients were individualized combinations based on previous tumor responses. Both patients died with recurrent tumor three and nine months posttransplant. The eight remaining patients were treated more uniformly with local irradiation, VM-26, doxorubicin, melphalan (L-phenylalanine mustard), and 1,000-rad total-body irradiation in three fractions. Two of these patients had cardiac dysfunction and received no doxorubicin. Three children died in the immediate posttransplant period with disseminated fungal infections. A fourth relapsed and died nine months posttransplant. As of December 1, 1983, two children who received allogeneic marrow grafts have survived in complete remission for 54 and 36 months, and two children who received autologous marrow grafts have survived in complete remission for 35 and 22 months. These results suggest that relapsed metastatic neuroblastoma can be controlled by supralethal combinations of chemotherapy and irradiation coupled with bone-marrow rescue.

Low Risk

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.
RP Castleberry, JJ Shuster, G Altshuler et al.
Journal of Clinical Oncology, Vol. 10, 1299-1304

PURPOSE : Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS : Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second- look surgery. RESULTS : Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease- free survival are both 93%. Toxicity was nominal. CONCLUSIONS : Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

Intermediate Risk

Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children’s Research Hospital experience, 1962 to 1988
LC Bowman, ML Hancock, VM Santana et al.
Journal of Clinical Oncology, Vol 9, 1599-1608

To gauge the impact of intensified therapy on the survival of infants (younger than 1 year, n=129) and children (greater than or equal to 1 year of age, n=275) with neuroblastoma, we analyzed the results of eight successive clinical trials comparing various combinations of antineoplastic drugs, surgery, and radiotherapy. Changes in treatment did not affect the survival of children with involved noncontiguous lymph nodes or distant metastatic disease until the combination of cisplatin and teniposide (CDDP/VM26) was added to a basic regimen of cyclophosphamide and doxorubicin (CTX/DOX). The resulting 4-year survival was 28% +/- 5% (SE) compared with 7% +/- 2% for previous treatments (P less than .001 by the log-rank test). The 4-year survival of infants with metastatic disease was improved by administering CTX/DOX to all patients, reserving CDDP/VM26 for those whose disease was resistant to the former combination: 82% +/- 6% versus 45% +/- 8% in earlier studies; P less than .001. In the subset of infants whose tumors had disseminated to bone or bone marrow at diagnosis, this therapeutic approach increased the probability of long-term survival from 48% +/- 10% to 85% +/- 9% (P=.01). The small group of children over 1 year of age with localized unresectable tumors also fared significantly better with the switch to CTX/DOX chemotherapy (4-year survival, 93% +/- 7% v 42% +/- 13%; P=.02). Multivariate analysis indicated that young age, limited-disease stage, nonadrenal primary site, and intensified treatment were independent predictors of a more favorable outcome. We conclude that substantial advances in the treatment of neuroblastoma have occurred over the past 25 years at this institution. The current overall 4-year survival probability of 57% +/- 4% compares favorably with estimates for most other common solid tumors of childhood.

Treatment of stage III neuroblastoma with emphasis on intensive induction chemotherapy: a report from the Neuroblastoma Group of the Spanish Society of Pediatric Oncology.
Castel V, Badal MD, Bezanilla JL et al.
J. Med Pediatr Oncol. 1995 Jan; 24(1): 29-35.

From October 87 to April 92, 172 children were admitted in the N-I-87 protocol of the Spanish Society of Pediatric Oncology for the diagnosis and treatment of neuroblastoma. Forty-eight were considered Evans stage III, 33 of them being older than 1 year. All children were treated with induction chemotherapy (IC) and surgery. IC consisted of three courses of high-dose cisplatin-VM-26 alternating with three further courses of cyclophosphamide-doxorubicin (CAD). Infants less than 1 year received the same drugs at lower doses. After surgery, maintenance chemotherapy was administered to all children during 14 months. It consisted of four pairs of drugs rotated every 4 weeks. Radiotherapy was administered exclusively to patients older than 1 year with residual tumor after IC and surgery. Response was evaluated after IC and surgery. In children older than 1 year, response was obtained in 28/33 (88%). Fifteen of them (47%) achieved complete remission (CR), seven (22%) good partial response (GPR), six (19%) partial response (PR); and in three patients (9%) there was progressive disease (PD). Actuarial survival at 48 months was 0.60 +/- 0.10 and EFS was 0.61 +/- 0.12. Audiologic impairment was considered the worst toxicity. In children less than 1 year the response rate to IC and surgery was 93% (14/15); nine infants obtained complete response and four had GPR. Only one patient experienced PD in the first 6 months of therapy and died. The other 14 are alive and well at a mean follow-up time of 48 months. Chemotherapy toxicity was mild and reversible.

High Risk
N7: a novel multi-modality therapy of high-risk neuroblastoma (NB) in children diagnosed over 1 year of age.
Cheung NK, Kushner BH, LaQuaglia M et al.
Med Pediatr Oncol. 2001 Jan; 36(1): 227-30.

BACKGROUND : The N7 protocol for poor-risk neuroblastoma uses dose-intensive chemotherapy (as in N6 protocol [Kushner et al.: J Clin Oncol 12:2607-2613, 1994] but with lower dosing of vincristine) for induction, surgical resection and 2100 cGy hyperfractionated radiotherapy for local control, and for consolidation, targeted radioimmunotherapy with 131I-labeled anti-GD2 3F8 monoclonal antibody and immunotherapy with unlabeled/unmodified 3F8 (400 mg/m2). PROCEDURE : The chemotherapy consists of: cyclophosphamide 70 mg/kg/d x 2 and a 72-hr infusion of doxorubicin 75 mg/m2 plus vincristine 2 mg/m2, for courses 1, 2, 4, and 6; and cisplatin 50 mg/m2/d x 4 and etoposide 200 mg/m2/d x 3, for courses 3, 5, and 7. 131I-3F8 is dosed at 20 mCi/kg, which is myeloablative and therefore necessitates stem-cell support. RESULTS : Of the first 24 consecutive previously untreated patients more than 1 year old at diagnosis, 22 were stage 4 and two were unresectable stage 3 with MYCN amplification. Chemotherapy achieved CR/VGPR in 21 of 24 patients. Twenty patients to date have completed treatment with 131I-3F8, and 15 patients have completed all treatment. With a median follow-up of 19 months, 18 of 24 patients remain progression-free. CONCLUSIONS : Major toxicities were grade 4 myelosuppression and mucositis during chemotherapy, and self-limited pain and urticaria during antibody treatment. Late effects include hearing deficits and hypothyroidism.

Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic Acid
Katherine K. Matthay, Judith G. Villablanca, Robert C. Seeger et al.
NEJM,Volume 341:1165-1173 October 14, 1999 Number 16.

Background : Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. Methods : All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. Results : The mean (±SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34±4 percent vs. 22±4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46±6 percent vs. 29±5 percent, P=0.027). Conclusion : Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.

NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology
C Coze, O Hartmann, J Michon et al.
Journal of Clinical Oncology, Vol 15, 3433-3440.

PURPOSE : NB87 was designed to test the efficacy of a short, non cross- resistant, induction protocol for unselected patients over 1 year of age with stage 4 neuroblastoma. A secondary objective was to compare in a randomized study the toxicity of two modalities of cisplatin administration. PATIENTS AND METHODS : A total of 183 patients received two cycles of alternating sequences: cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1 and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary tumor (126 patients). Ninety-one were randomized to receive cisplatin either as bolus (BO; n=48) or continuous infusion (CI; n=43). International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with emphasis on skeletal evaluation by meta- iodobenzylguanidine (MIBG). RESULTS : Hematotoxicity was predominant, with a higher incidence of neutropenia (P=.01) for CADO and of thrombocytopenia for CVP (P<.001). Severe infections, as well as nonhematologic toxicities, occurred more often after the first sequence. Gastrointestinal complications were predominant during both courses of CVP. The toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%). Combining all metastatic sites resulted in a 39% CR rate. After surgery, the final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000 Hz was reported equally in both arms (n=6 for CI v n=5 for BO). CONCLUSION : Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter induction duration. However, the rate of MIBG normalization remains unsatisfactory and could be raised through the dose-intensive use of agents such as cyclophosphamide.

OPEC/OJEC for stage 4 Neuroblastoma in children over 1 year of age.
Tweddle DA, Pinkerton CR, Lewis IJ et al.
Med Pediatr Oncol. 2001 Jan; 36(1): 239-42.

BACKGROUND : This paper reports the toxicity of OPEC/OJEC chemotherapy in stage 4 neuroblastoma patients over 1 year of age. PROCEDURE: Ninety-five patients with stage 4 neuroblastoma received alternating courses of OPEC/OJEC – vincristine 1.5 mg/m2 (O), cisplatin 80 mg/m2 (P), etoposide 200 mg/m2 (E), cyclophosphamide 600 mg/m2 (C), and carboplatin 500 mg/m2 (J), every 21 days if there was haematological recovery. RESULTS : Seventy out of ninety-five (74%) patients completed seven or more courses and were evaluable for toxicity. Of these 70 patients, 33% had more than three episodes of fever and sepsis, 35% required more than five blood or platelet transfusions, 36% had grade 2 or more gastrointestinal toxicity and 9% had neurotoxicity. There was a median reduction in GFR of 32 ml/min/1.73 m2 (-46 to 134) and there was one toxic death. CONCLUSIONS :

OPEC/OJEC is a well-tolerated therapy for stage 4 neuroblastoma over 1 year of age. stage 4 neuroblastoma with MYCN amplification.
Kaneko M, Tsuchida Y, Mugishima H et al.
J Pediatr Hematol Oncol. 2002 Nov; 24(8): 613-21.

PURPOSE : Patients with high-risk neuroblastoma who have multiple copies of MYCN fare much worse than do those without MYCN amplification; however, it has not been clarified whether intensified chemotherapy with or without blood stem cell transplantation can alter the extremely poor prognosis of patients with amplified MYCN. METHODS AND RESULTS : Between 1985 and 1999, 301 patients older than age 12 months with stage 4 neuroblastoma were treated. From January 1985 to February 1991, 80 patients with stage 4 neuroblastoma with and without MYCN amplification uniformly received induction chemotherapy with regimen A(1) (cyclophosphamide 1,200 mg/m(2) and vincristine 1.5 mg/m(2) on day 1, tetra-hydropyranyl [THP]-Adriamycin 40 mg/m(2) on day 3, and cisplatin 90 mg/m(2) on day 5). Among 22 patients with MYCN amplification, nine (40.9%) achieved a complete remission and seven (31.8%) underwent stem cell transplantation. Of 58 patients without MYCN amplification, 43 (74.1%) achieved a complete remission and 14 (24.1%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 23.2% for stage 4 patients with MYCN amplification and 33.3% for those without MYCN amplification (P=0.029); the 5-year overall survival rates were 32.8% for stage 4 patients with MYCN amplification and 42.8% for those without MYCN amplification (P>0.05). From March 1991 to June 1998, patients with stage 4 neuroblastoma who had 10 or more copies of MYCN were treated with regimen A(3) (cyclophosphamide 1,200 mg/m(2) per day on days 1 and 2, THP-Adriamycin 40 mg/m(2) on day 3, etoposide 100 mg/m(2) per day on days 1 to 5, and cisplatin 25 mg/m(2) per day on days 1 to 5); those with fewer than 10 copies of MYCN received regimen new A (cyclophosphamide 1,200 mg/m on day 1, THP-Adriamycin 40 mg/m on day 3, etoposide 100 mg/m per day on days 1 to 5, and cisplatin 90 mg/m on day 5), which is similar in intensity to regimen A. Among 88 patients with MYCN amplification, 63 (71.6%) achieved a complete remission and 63 (71.68%) underwent stem cell transplantation. Of 133 patients without MYCN amplification, 93 (69.9%) achieved a complete remission and 71 (53.4%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 36.0% for stage 4 patients with MYCN amplification and 32.2% for those without MYCN amplification (P>0.05), the 5-year overall survival rates were 34.0% for stage 4 patients with MYCN amplification and 38.9% for those without MYCN amplification (P>0.05). The difference in relapse-free survival rates was significantly different (P=0.003) between patients with MYCN-amplified tumor treated before [regimen A(1)] versus after 1991 [regimen A(3)]. CONCLUSIONS : With the use of the more intensive induction regimen A plus blood stem cell transplantation for MYCN-amplified patients, survival curves for those with or without MYCN amplification now appear similar. Higher doses of chemotherapy may ameliorate the effect of MYCN amplification in patients with high-risk neuroblastoma.

Induction chemotherapy in metastatic neuroblastoma–does dose influence response? A critical review of published data standards, options and recommendations (SOR) project of the National Federation of French Cancer Centres (FNCLCC).
Pinkerton CR, Blanc Vincent MP, Bergeron C et al.
Eur J Cancer. 2000 Sep;36(14):1808-15.

The purpose of this study was to determine, from a review of published data, whether in stage 4 neuroblastoma in children over 1 year of age, the dose or scheduling of induction chemotherapy influenced the response rate in distant metastases. Publications relating to induction chemotherapy since the introduction of cisplatin/epipodophyllotoxin combinations were identified using Medline, Current Contents and personal reference lists. Thirteen publications were identified which described 17 regimens involving 948 children. The doses and the scheduling of the various regimens were compared with a standard regimen OPEC (vincristine, cisplatin, teniposide, cyclophosphamide). These were correlated with the reported response rates in the bone marrow. Due to a lack of standardisation in the nature of restaging investigations, timing of restaging and definitions of response it was difficult to compare all studies. The complete response rate at distant metastases ranged from less than 40% to over 90%. For individual drugs; the comparative doses given in each course ranged up to 4.2 g/m(2) for cyclophosphamide, 280 mg/m(2) for cisplatin, 600 mg/m(2) for etoposide and 4.5 mg/m(2) for vincristine. There was no evidence of any positive correlation between response rate in the marrow and either the dose of any individual drug or the schedule used. In contrast to a previous study which included a number of older studies where disease assessment was even more variable, this analysis has failed to show any justification for the routine use of very intensive induction regimens in this disease. Such an approach should only be taken in the context of randomised trials in which timing and methods of reassessment can be standardised. Until such studies demonstrate superiority either in terms of response rate or progression-free survival lower morbidity regimens should remain the standard therapy.

Autologous Bone Marrow Transplant (ABMT)
Treatment of High-Risk Neuroblastoma With Triple-Tandem High-Dose Therapy and Stem-Cell Rescue: Results of the Chicago Pilot II Study
By Morris Kletzel, Howard M. Katzenstein, Paul R. Haut et al.
Cohn Journal of Clinical Oncology, Vol 20, Issue 9 (May), 2002: 2284-2292
PURPOSE : To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS : From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS : Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% ± 11% and 79% ± 10%, respectively. CONCLUSION : The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

Reese-Ellsworth Classification of Retinoblastoma
(Criteria for Suitability for Local Treatment)

Group I : Very favorable prognosis
A. Solitary tumor, less than 4 disc diameters (dd)= in size, at or behind the equator
B. Multiple tumors, none over 4 dd in size, all at or behind the equator

Group II : Favorable prognosis
A. Solitary lesion 4-10 dd in size, at or behind the equator
B. Multiple tumors, 4-10 dd in size, behind the equator

Group III- Doubtful prognosis
A. Any lesion anterior to the equator
B. Solitary tumors larger than 10 dd behind the equator

Group IV : Unfavorable prognosis
A. Multiple tumors, some larger than 10dd
B. Any lesion extending anteriorly to the ora serrata

Group V : Very unfavorable prognosis
A. Massive tumors involving over half the retina
B. Vitreous seeding

One disc diameter = 1.6 mm.

Staging in patients with Retinoblastoma (St Judes)
I. Tumor (unifocal or multifocal) confined to retina
A. Occupying 1 quadrant or less.
B. Occupying 2 quadrants or less.
C. Occupying more than 50% of retinal surface.

II. Tumor (unifocal or multifocal) confined to globe
A. with vitreous seeding
B. Extending to optic nerve head.
C. extending to choroid and optic nerve head
D. Extending to emissaries.

III. Extraocular extension of tumor (regional)
A. extending beyond cut end of optic nerve (including sub-arachnoid extension)
B. Extending through sclera into orbital contents.
C. extending to choroid and beyond cut end of optic nerve (including sub-arachnoid extension)
D. extending through sclera into orbital contents and beyond cut end of optic nerve (including sub-archnoid extension)

IV. Distant metastases
A. extending through optic nerve to brain
B. blood-borne metastases to soft-tissues and bone marrow metastases

GENERAL PRINCIPLES OF MANAGEMENT
Although retinoblastoma is the most common primary intraocular tumor in children, the treatment of this disease is a complex topic. Therapeutic plans usually require a multidisciplinary approach by a team consisting of ocular oncologist, pediatric oncologist and radiation oncologist. Treatment should be highly individualized. Treatment strategies for retinoblastoma have gradually evolved over the past few decades. The driving force behind these new approaches is to avoid enucleation and/or external beam radiation therapy and trend towards focal “conservative” treatment. Every effort has been made to save the child’s life with preservation of eye and sight, if possible. The aims of treatment are firstly, to preserve the life of the child; secondly, to preserve vision, and thirdly, to minimize any complications or side effects of treatment.

Recent research in the treatment of retinoblastoma has concentrated on methods of combining chemotherapy with other local treatment modalities. This approach combines the principle of chemotherapeutic debulking in pediatric oncology with conservative focal therapies in ophthalmology. Termed “chemoreduction”, intravenous chemotherapy is used to debulk the initial tumor volume and allow for focal treatment with transpupillary thermal therapy, laser therapy, cryotherapy and plaque radiotherapy.
Chemotherapy may be useful in all three clinical settings in intra-ocular retinoblastoma, in cases of micrometastatic spread, and when there are overt extraocular metastases. Tumor shrinkage with chemoreduction may allow treatment with less invasive measures such as cryotherapy, laser photocoagulation, thermotherapy or plaque radiotherapy, thereby, avoiding enucleation and external beam radiotherapy.
While chemotherapeutic agents vary according to the preference of the pediatric oncologist, most of the current studies have relied on vincristine, etoposide and carboplatin. To circumvent the multidrug resistance, cyclosporine has been added to chemotherapy at some centers.

The main issues for consideration when selecting treatment options for a child with retinoblastoma are as follows :
(1) Is the disease unilateral or bilateral?
(2) Does the affected eye have potential for useful vision?
(3) Is the, tumor confined to the globe or does it extend to the optic nerve?
(4) Are there orbital / lymph-nodal / bony / central nervous system or, hematogenous metastasis present?

The usual management approach used in our institution is as shown in Figs. 1,2,3.

RADIOTHERAPY FOR RETINOBLASTOMA
Principles for Radiotherapy :

Indications :
     Intent to preserve useful vision in patients with multifocal lesions.
     Lesions close to macula/ optic nerve.
     Large tumors with vitreous seeding.
     Recurrent disease and as an adjuvant after enucleation/ evisceration.
     Palliative radiotherapy

Target volume :
Primary aim is to deliver a homogeneous tumoricidal dose to the entire retina and vitreous while sparing the surrounding normal tissues. Reasons for this target volume are :
1) RB represents a “field change” and thus all cells have a neoplastic potential.
2) Vitreous seeding can occur.
3) Multiple lesions could be present.
4) Subretinal spread of tumor can occur.
5) Lens sparing techniques should be done only in selected patients with group I & II disease.
a) Group I & II lesions (lesions close to macula/ optic nerve).
     Entire Retina upto the Ora-Serrata (CTV) + 5mm (PTV).
     Proximal 1cm of optic nerve (CTV) + 5mm (PTV) – when uninvolved.
     Can try and avoid vitreous irradiation if possible (e.g. IMRT)
b) Group III, IV, & V lesions
     Entire Retina upto the Ora-Serrata (CTV) + 5mm (PTV).
     Proximal 1cm of optic nerve (CTV) + 5mm (PTV) – when uninvolved.
c) Post operative (in locally advanced lesions)
     Entire Orbit (GTV) + 5mm (PTV).
     Any disease extension beyond the orbit to be covered adequately.

Total dose :
     Treatment should ideally be done daily (5 days a week) – even with anesthesia
     Dose per fraction should be £ 2Gy / fraction
     In children <1year of age, radiation dose should be reduced:
          Microscopic disease (post op radiotherapy) 39.6Gy/22#/ 4.5wks
          Gross disease (definitive radiotherapy) 45Gy/25#/ 5wks
a) Group I & II lesions
     45Gy / 25# / 5wks (@1.8Gy / fr.) – Daily treatment
     45Gy / 18# / 6wks (@2.5Gy / fr.) – Alternate day treatment
b) Group III, IV, & V lesions
     50.4Gy / 28# / 6wks (@1.8Gy / fr.) – Daily treatment
     50.4Gy / 20# / 7wks (@2.5Gy / fr.) – Alternate day treatment
c) Post operative
     Microscopic residual disease
          45Gy / 25# / 5wks (@1.8Gy / fr.) – Daily treatment
          45Gy / 18# / 6wks (@2.5Gy / fr.) – Alternate day treatment

     Gross residual disease
          50.4Gy / 28# / 6wks (@1.8Gy / fr.) – Daily treatment
          50.4Gy / 20# / 7wks (@2.5Gy / fr.) – Alternate day treatment

Radioactive Plaque Therapy :

Can be used for patients with solitary, unilateral lesions, 2-16mm basal diameter, located more than 3mm away from the optic disc. Ideally the tumors should be less than 10mm in thickness. Plaques can also be used for patients with minimal vitreous seeding close to the apex of the tumor. Used especially in children who have failed other methods.

Types of Plaques available :
     Cobalt 60 - Energy:1.17-1.33MV, Half life - 5.2yrs.
     Iodine 125 - Energy:27-35KeV, Half life – 60days.
     Iridium 192 - Energy:295-612KeV, Half life – 74.5days.
     Ruthenium 106 - Energy: Beta, Half life – 368days.

Dose :
     35-40Gy to apex and 100-150Gy to Sclera (base) of tumor

FOLLOW UP POLICY
(A) During treatment : Children to be kept under close supervision. Response to treatment has to be evaluated every 6 to 8 weeks with EUA and USG studies and treatment individualized as per the response.
(B) Off Treatment : Patients with retinoblastoma should be monitored indefinitely, initially for control of their primary tumor and later for development of a new tumor. Most recurrences occur within first 3 years after diagnosis. EUA should be done every 2 to 3 months for the first year, every 4 months during the second year and every 6 months to age 5 years. After age 5, new retinoblastomas are rare and patients are examined yearly without anesthesia. In addition to routine visual acuity and ophthalmologic testing patients with retinoblastoma require careful follow-up throughout their lifetime because of their increased risk of second malignant tumors.
(C) Infants at risk for developing retinoblastoma (siblings, offspring) : They should be examined in the office every month till 3 months of age and then every 3 to 6 months until 3 years old. Families of patients with heritable retinoblastoma should undergo genetic counseling.
(D) Long term issues that can arise : Impairment of vision, Cataracts, Dry Eye, Facial asymmetry, Retinal Detachment, Trilateral Retinoblastoma, Metastatic disease, orbital recurrence, second Tumors.

A) MANAGEMENT OF RETINOBLASTOMA

Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients.
Shields CL, Shelil A, Cater J, Meadows AT, Shields JA.
Arch Ophthalmol. 2003 Nov;121(11):1571-6.

OBJECTIVE : To evaluate the occurrence of new retinoblastomas in patients treated with 6 cycles of chemoreduction. DESIGN: Prospective nonrandomized single-center case series. SETTING : Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children’s Hospital of Philadelphia. PARTICIPANTS : A total of 162 eyes of 106 patients with retinoblastoma treated with 6 cycles of chemoreduction between January 1, 1995, and May 31, 2002. INTERVENTION : All patients received intravenous chemoreduction with vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURE : Development of new intraretinal retinoblastoma during or after treatment with chemoreduction. Recurrent subretinal tumor seeds or vitreous seeds were excluded from this analysis, and only primary new intraretinal tumors were included. RESULTS : Of 28 patients with unilateral retinoblastoma, new intraretinal tumor development was found during or after chemoreduction in 2 (9%) of the 23 patients with sporadic disease and 4 (80%) of the 5 patients with familial disease. The new tumor was located in the macula in none, between the macula and equator in 7 (54%), and between the equator and ora serrata in 6 (46%). Of the 78 patients with bilateral retinoblastoma, new tumor development was found during or after chemoreduction in 11 (19%) of the 57 patients with sporadic disease and 8 (38%) of the 21 patients with familial disease. The new tumor was macula in 2 (4%), between the macula and equator in 30 (55%), and between the equator and ora serrata in 23 (42%). Overall, according to Kaplan-Meier analysis, new tumor development occurred in 23% of patients by 1-year follow-up and 24% by 5-year follow-up. By multivariate analysis, the most important risk factors for the development of new tumors was younger age at presentation (median age, 2 months with new tumor vs 9 months without new tumor) and family history of retinoblastoma (12 [48%] of patients with new tumor vs 14 [17%] without new tumor). CONCLUSIONS : Children with retinoblastoma treated with chemoreduction should be followed for new intraretinal tumor development, as it peaks at a mean interval of 5 months after initiation of chemoreduction and affects 24% of patients by 5 years of follow-up. New tumors are most commonly found in those who develop disease as young infants and those with a family history of retinoblastoma.

Globe conserving treatment of the only eye in bilateral retinoblastoma.
Lee V, Hungerford JL, Bunce C et al.
Br J Ophthalmol. 2003 Nov;87(11):1374-80.

AIMS : To quantify the rates of eye preservation and patient survival, local tumour relapse and recurrence, and development of new tumours in the remaining eye of children with bilateral retinoblastoma with one eye already enucleated. Also, in the same children, to describe the types of primary and secondary treatment procedures, and to define the anatomical outcome. METHODS : This is a retrospective observational case series report. The study participants consisted of 107 patients with bilateral retinoblastoma with one eye enucleated within 1 month of baseline examination and had their remaining eye treated conservatively. The main outcome measure were: primary treatment failures, new tumours, enucleation of the only eye, death, remission, and anatomical outcomes (retinal detachment, vitreous haemorrhage, and cataract). RESULTS : The median age at diagnosis was 8.4 (range 0.2-44, SD 10.1) months with a median ophthalmic follow up of 44.3 (8.1-114, SD 10.1) months. In 22 of the 107 patients (21%) the treated eye was in Reese Ellsworth groups I or II and in the remaining 85 (79%) in groups III-V at diagnosis. The primary treatment was cryotherapy in 14% (15/107) of eyes, radioactive plaque brachytherapy in 3.7% (4/107), and chemotherapy in 10% (11/107). It was lens sparing radiotherapy in 37% (40/107), whole eye radiotherapy in 29% (31/107), combined radiotherapy and chemotherapy in 2.8% (3/107), chemothermotherapy in 0.9% (1/107), and combined focal therapy in 1.8% (2/107). The primary treatment failed to achieve local tumour control during the follow up period in 37% (40/107) of eyes. In 17 eyes failure was due to inadequate control of the presenting tumour, in 16 to development of a new tumour, and in eight eyes to a combination of both. 35 (88%) of the 40 failures were managed by secondary conservative treatment and the remaining five were treated by enucleation of the only eye. There were eight (7.4%) deaths and the 3 year survival rate was 93% (100/108). Anatomical results included vitreous haemorrhage in four cases, tractional retinal detachment also in four cases, and 24 children required cataract surgery. CONCLUSIONS : Aggressive conservative treatment achieved a good rate of globe salvage without impairing survival.

Treatment of intraocular retinoblastoma with vincristine and carboplatin.
Rodriguez-Galindo C, Wilson MW, Haik BG, Merchant TE, Billups CA, Shah N, Cain A, Langston J, Lipson M, Kun LE, Pratt CB.
J Clin Oncol. 2003 May 15;21(10):2019-25.

PURPOSE : To evaluate the efficacy of chemoreduction using vincristine and carboplatin in preventing or delaying external-beam radiotherapy (EBRT) or enucleation in patients with intraocular retinoblastoma. PATIENTS AND METHODS : Twenty-five patients (43 eyes) with newly diagnosed intraocular retinoblastoma received primary treatment with eight courses of vincristine and carboplatin. Focal treatments were delayed until documentation of disease progression. Outcome measures for each eye were length of time to disease progression, avoidance or delay of EBRT, and globe survival. Event-free survival was defined as the length of time to EBRT or enucleation. RESULTS : Disease in all eyes responded to chemotherapy and progressed in only two patients before completion of the eight courses of therapy. Disease in all but four eyes progressed and required focal treatments. Event-free survival estimates at 2 years were 59.2% +/- 12.0% for Reese-Ellsworth group I, II, and III eyes and 26.3%
+/- 9.2% for group IV and V eyes. Nineteen eyes (44.2%) required EBRT and 13 eyes (30.2%) were enucleated. The ocular salvage rate was 83.3% for Reese-Ellsworth group I to III eyes and 52.6% for group IV and V eyes. For those patients receiving EBRT, the median time from enrollment to EBRT was 9.5 months (median age at EBRT, 21 months). CONCLUSION: In combination with appropriate early intensive focal treatments, chemoreduction with vincristine and carboplatin, without etoposide, may be an alternative treatment for patients with early-stage intraocular retinoblastoma, although additional studies are needed. Patients with advanced intraocular disease require more aggressive treatments.

Thermochemotherapy in hereditary retinoblastoma.
Schueler AO, Jurklies C, Heimann H et al.
Br J Ophthalmol. 2003 Jan;87(1):90-5.

BACKGROUND : The combination of chemotherapy and transpupillary thermotherapy, thermochemotherapy (TCT) has become an established part of the treatment plan in advanced retinoblastoma. The aim of this study was to identify safe indications, the complications as well as the limitations of this new treatment for retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth classification system, nine of 35 eyes were classified as type I, 13 eyes as type II, 10 eyes as type III, and three eyes as type V. The mean age of the children was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5) thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25 (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated with tumour height. The recurrence rate was 17% for tumours with a height less than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger retinoblastomas. Multivariate analysis identified fish flesh regression after TCT (p=0.0007) as the most important risk factor for tumour recurrence besides tumour height (p=0.001) and the necessity of increased laser power during TCT sessions (p=0.018). Complications during therapy included transient corneal opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye, 3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION : TCT using an indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the recurrence rate was unacceptably high. Fish flesh regression after TCT correlates with a higher rate of local tumour recurrence. Treatment related complications occurred in less than 9% of the treated eyes.

Chemoreduction for unilateral retinoblastoma.
Shields CL, Honavar SG, Meadows AT et al.
Arch Ophthalmol. 2002 Dec;120(12):1653-8.

OBJECTIVE : To evaluate conservative management of unilateral retinoblastoma using chemoreduction and focal treatment. DESIGN : Prospective nonrandomized single-center clinical trial. SETTING : Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children’s Hospital of Philadelphia. PARTICIPANTS : Thirty eyes of 30 patients with unilateral retinoblastoma treated with chemoreduction between June 1, 1994, and August 31, 1999, that would otherwise have been managed with enucleation or external beam radiotherapy. INTERVENTION : All patients received treatment for retinoblastoma with a planned 6 cycles of chemoreduction using vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURES : The main outcome measure was the postchemoreduction need for external beam radiotherapy or enucleation. The cumulative probability of each outcome was estimated using Kaplan-Meier survival analysis. A secondary outcome measure was final visual acuity in the affected eye. The clinical features at the time of patient presentation were analyzed for their impact on the main outcomes using a series of Fisher exact tests and Cox proportional hazards regressions. RESULTS : Eighteen eyes (60%) were classified as having Reese-Ellsworth (RE) groups I through IV retinoblastoma and 12 eyes (40%), group V retinoblastoma. By using Kaplan-Meier estimates, we found a need for either external beam radiotherapy or enucleation in 68% of eyes by 5 years. In fact, 38% of those in groups I through IV required either treatment, whereas all of those in group V required the additional use of either treatment. Specifically, the need for external beam radiotherapy occurred in 27% of eyes by 5 years. Eleven percent of those in groups I through IV and 50% of group V required external beam radiotherapy by 5 years. The factors predictive of the need for external beam radiotherapy included RE group V disease, tumor thickness greater than 5 mm, and presence of vitreous seeds. The need for enucleation occurred in 47% of eyes by 5 years using Kaplan-Meier analysis. Specifically, 29% of those in groups I through IV and 67% of group V required enucleation by 5 years. The factors predictive of the need for enucleation included age at diagnosis older than 12 months, RE group V disease, tumor base diameter greater than 15 mm, and tumor thickness greater than 5 mm. At a mean follow-up of 29 months, the final visual acuity was 20/200 or better in 6 eyes (20%) and worse than 20/200 in 14 (47%); enucleation was needed in 10 (33%). Of the 26 eyes with initial macular involvement of retinoblastoma, final visual acuity was 20/200 or better in 6 (23%). No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms. CONCLUSIONS : Chemoreduction is an option for selected eyes with unilateral retinoblastoma. Those with advanced RE group V retinoblastoma showed poorest results, while those with less advanced groups I through IV disease showed best results, maintaining the globe in 71% of eyes, sometimes with satisfactory functional visual acuity.

Current treatment of retinoblastoma.
De Potter P.
Curr Opin Ophthalmol. 2002 Oct;13(5):331-6.

Chemotherapy has recently achieved a major role in the primary management of intraocular retinoblastoma. Tumor reduction by first-line chemotherapy (chemoreduction) followed by local treatments is now accepted as treatment strategy for intraocular retinoblastoma with the goal of avoiding external beam radiotherapy (EBRT) or enucleation. Although efficient in reducing tumor volume, chemotherapy cannot cure retinoblastoma. Different chemoreduction protocols are used to shrink the tumor, making it treatable with cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy. Systemic chemotherapy used with local ophthalmic therapies during or after the chemotherapy can eliminate the need for enucleation or external beam radiotherapy in Reese-Ellsworth group 1, 2, or 3 retinoblastoma. This combination is not sufficient to obtain tumor control in most eyes with large tumors and diffuse vitreous and subretinal seeds (Reese-Ellsworth group 4 and 5 tumors), and EBRT or enucleation is eventually required. The resultant visual acuity after globe-conserving therapies in those eyes with Reese-Ellsworth group 4 and 5 tumors is often poor. Preliminary results of a phase I/II study of subconjunctival carboplatin injection are encouraging. Enucleation is still recommended in situations such as eyes containing large tumors, long standing retinal detachment, neovascular glaucoma, pars plana tumor seeding, anterior chamber involvement or choroid, optic nerve or orbital tumor extension, and no expectation for useful vision. Chemoprophylaxis is necessary for patients with tumor extending to the surgical margin of the optic nerve and is likely beneficial in preventing metastases in patients with tumor extending beyond the lamina cribrosa. Intensified chemotherapy with autologous stem cell rescue appears effective for patients with metastatic retinoblastoma.

Chemothermotherapy in the management of retinoblastoma.
Lumbroso L, Doz F, Urbieta M et al.
Ophthalmology. 2002 Jun;109(6):1130-6.

OBJECTIVE : To evaluate the results of chemothermotherapy for the treatment of retinoblastoma. DESIGN : Non-comparative interventional case series. PATIENTS : Fifty-one children (65 eyes and 103 tumors) were treated with chemothermotherapy in a single institution from January 1995 to May 1998. METHODS : Chemothermotherapy consists of a combination of transpupillary thermotherapy delivered shortly after intravenous (IV) injection of carboplatin [560 mg/m(2)]. Each tumor is treated separately with a diode laser using a microscope. Laser intensity, spot size, and duration are adapted to the size of each tumor and to the clinical response. After 8 days, thermotherapy alone is repeated. This cycle is performed from one to six times, every 28 days. The treatment data and outcome are analyzed separately. MAIN OUTCOME MEASURES : Assessment of local tumor control. RESULTS : One hundred three tumors were treated in 65 eyes of 51 children. Age at diagnosis was 0 to 60 months (median, 7 months). Median tumor diameter at the time of treatment was 3.5 mm (range, 1.5-12 mm). Laser modalities were as follows: median intensity, 450 mW (range, 150-1000 mW); median spot size, 1.2 mm (range, 0.3-2.0 mm); and median number of cycles required to obtain tumor control, three. Tumor regression was obtained for 99 tumors (96.1%) after a median follow-up of 30 months (17-61 months). Seven tumors relapsed after initial control (6.8%). Salvage treatment (external beam radiation, iodine plaques, or enucleation) was necessary for a total of 11 tumors (10.7%). The only risk factor for relapse was the initial diameter of the lesion greater than 3.5 mm, whereas the other tumor characteristics or treatment variables were not significantly correlated with relapse. Ninety-seven percent of treated eyes were able to be preserved, and 92% of cases were treated without external beam radiation. CONCLUSIONS : Chemothermotherapy is an effective technique to treat small- to medium-sized retinoblastomas in children, avoiding external beam irradiation.

Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation.
Shields CL, Honavar SG, Meadows AT et al.
Am J Ophthalmol. 2002 May;133(5):657-64.

PURPOSE : To report the results of chemoreduction and focal therapy for retinoblastoma with determination of factors predictive of the need for treatment with external beam radiotherapy or enucleation. DESIGN : Interventional case series. METHODS : One-hundred three patients with retinoblastoma (158 eyes with 364 tumors) at the Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University in conjunction with the Division of Oncology at Children’s Hospital of Philadelphia from June 1994 to August 1999 were enrolled for this prospective clinical trial. The patients received treatment for retinoblastoma with six planned cycles (one cycle per month) of chemoreduction using vincristine, etoposide, and carboplatin combined with focal treatments (cryotherapy, thermotherapy, or plaque radiotherapy). The two main outcome measures after chemoreduction and focal therapy were the need for external beam radiotherapy and the need for enucleation. The clinical features at the time of patient presentation were analyzed for impact on the main outcome measures using a series of Cox proportional hazards regressions. RESULTS : Using Reese-Ellsworth (RE) staging for retinoblastoma, there were nine (6%) eyes with group I disease, 26 (16%) eyes with group II disease, 16 (10%) eyes with group III disease, 32 (20%) eyes with group IV disease, and 75 (48%) eyes with group V retinoblastoma. All eyes showed initial favorable response with tumor regression. The median follow-up was 28 months (range, 2-63 months). Failure of chemoreduction and need for treatment with external beam radiotherapy occurred in 25% of eyes at 1 year, 27% at 3 years, and no further increase at 5 years. More specifically, external beam radiotherapy was necessary at 5 years in 10% of RE groups I-IV eyes and 47% of RE group V eyes. Multivariate factors predictive of treatment with external beam radiotherapy included non-Caucasian race, male sex, and RE group V disease. Failure of chemoreduction and the need for treatment with enucleation occurred in 13% eyes at 1 year, 29% at 3 years, and 34% at 5 years. More specifically, enucleation was necessary in 15% of RE groups I-IV eyes at 5 years and in 53% of RE group V at 5 years. Multivariate factors predictive of treatment with enucleation included patient age older than 12 months, single tumor in eye, and tumor proximity to foveola within 2 mm. Overall, of the 158 eyes, 50% required external beam radiotherapy or enucleation and 50% were successfully managed without these treatments. No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms over the 5-year follow up. CONCLUSIONS : Chemoreduction offers satisfactory retinoblastoma control for RE groups I-IV eyes, with treatment failure necessitating additional external beam radiotherapy in only 10% of eyes and enucleation in 15% of eyes at 5-year follow-up. Patients with RE group V eyes require external beam radiotherapy in 47% and enucleation in 53% at 5 years.

B) ORGAN AND VISION PRESERVATION USING RADIOTHERAPY
Radiation therapy for retinoblastoma: a retrospective review of 120 patients.
Pradhan DG, Sandridge AL, Mullaney P et al.
Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):3-13.

PURPOSE : To characterize the patient population and treatment outcomes in patients with Retinoblastoma (RB) referred for External Beam Orbital Radiotherapy (EBORT) to King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh, Saudi Arabia from 1976 to 1993. METHODS AND MATERIALS : A retrospective study of 120 patients with RB affecting a total of 192 eyes. Patients were divided into three groups. Group A are 60 patients (64 eyes) treated with EBORT to the intact eye to preserve vision. Reese-Ellsworth (RE) Staging was: 1: 12%; 2: 10%; 3: 12%; 4: 23%; and 5: 43%. Twenty-eight patients (47%) also received Vincristine, Adriamycin, and Cyclophosphamide chemotherapy (C/T). Mean follow-up, per patient, was 48.5 months. Standard treatment until 1992 was 45 Gy in 12 fractions of 3.75 Gy, three times weekly over 18 days. Assuming the alpha/beta ratio for early effects and tumor control at 10, Tk = 21 days, Tpot = 5 days, then the Biological Equivalent Dose (BED) was 62 Gy10 for early effects, and 101 Gy3 for late effects. Group B are 28 patients (28 eyes) treated for curative intent with EBORT to the orbit for locally advanced disease, usually after enucleation (24 eyes). Nineteen patients (83%) also had C/T. Mean follow-up was 22.6 months. Group C are 37 patients with advanced disease treated with radiotherapy for palliation. Seventeen (46%) also received C/T. Mean follow-up was 11.7 months. RESULTS: Group A-following EBORT useful vision was retained in RE Stage 1 to 5: 7 of 7, 6 of 6, 4 of 8, 10 of 15, and 7 of 28 eyes, respectively. There was no significant difference between patients who received adjuvant chemotherapy and those who did not. Complications included cataract (27%), retinopathy (25%), vitreous hemorrhage (19%), and orbital deformities (11%). In Group B the local control rate was 71%. In Group C, 10 (27%) of the 37 patients were alive at last contact, and 27 (73%) were either terminal or dead of disease. None of Group A or B patients had positive CSF cytology, bone scan, or bone marrow examination. In Group C 19% had positive CSF cytology, and bone marrow, and 14% had a positive bone scan. CONCLUSIONS : 1) EBORT preserved useful vision in a significant proportion of patients even in eyes with advanced RE Stage RB, but longer follow-up is likely to reveal an even higher complication rate with this regime. 2) High dose per fraction probably contributed to the increased complications. 3) Chemotherapy did not demonstrate any effect on retaining vision in this study. 4) For disease that is confined to within the eye clinically and radiologically, invasive procedures for CSF cytology, bone marrow examination, and bone scan do not seem warranted. 5) The optimum technique, fractionation, and dosage for RB is still not well defined.

Globe conserving treatment of the only eye in bilateral retinoblastoma.
Lee V, Hungerford JL, Bunce C et al.
Br J Ophthalmol. 2003 Nov;87(11):1374-80.

AIMS : To quantify the rates of eye preservation and patient survival, local tumour relapse and recurrence, and development of new tumours in the remaining eye of children with bilateral retinoblastoma with one eye already enucleated. Also, in the same children, to describe the types of primary and secondary treatment procedures, and to define the anatomical outcome. METHODS : This is a retrospective observational case series report. The study participants consisted of 107 patients with bilateral retinoblastoma with one eye enucleated within 1 month of baseline examination and had their remaining eye treated conservatively. The main outcome measure were: primary treatment failures, new tumours, enucleation of the only eye, death, remission, and anatomical outcomes (retinal detachment, vitreous haemorrhage, and cataract). RESULTS : The median age at diagnosis was 8.4 (range 0.2-44, SD 10.1) months with a median ophthalmic follow up of 44.3 (8.1-114, SD 10.1) months. In 22 of the 107 patients (21%) the treated eye was in Reese Ellsworth groups I or II and in the remaining 85 (79%) in groups III-V at diagnosis. The primary treatment was cryotherapy in 14% (15/107) of eyes, radioactive plaque brachytherapy in 3.7% (4/107), and chemotherapy in 10% (11/107). It was lens sparing radiotherapy in 37% (40/107), whole eye radiotherapy in 29% (31/107), combined radiotherapy and chemotherapy in 2.8% (3/107), chemothermotherapy in 0.9% (1/107), and combined focal therapy in 1.8% (2/107). The primary treatment failed to achieve local tumour control during the follow up period in 37% (40/107) of eyes. In 17 eyes failure was due to inadequate control of the presenting tumour, in 16 to development of a new tumour, and in eight eyes to a combination of both. 35 (88%) of the 40 failures were managed by secondary conservative treatment and the remaining five were treated by enucleation of the only eye. There were eight (7.4%) deaths and the 3 year survival rate was 93% (100/108). Anatomical results included vitreous haemorrhage in four cases, tractional retinal detachment also in four cases, and 24 children required cataract surgery. CONCLUSIONS: Aggressive conservative treatment achieved a good rate of globe salvage without impairing survival.

C) RADIOTHERAPY TARGET VOLUME :

External beam irradiation for retinoblastoma: patterns of failure and dose-response analysis.
Foote RL, Garretson BR, Schomberg PJ et al.
Int J Radiat Oncol Biol Phys. 1989 Mar;16(3):823-30.

Eighteen children with retinoblastoma (25 eyes) were treated with external beam radiation at the Mayo Clinic between January 1977 and January 1987; 15 eyes were in groups I to III and 10 were in groups IV and V (Reese-Ellsworth classification). The median number of tumors per eye was 3. Radiation therapy consisted of 4- or 6-MV photons. Doses varied from 39 to 51 Gy in 1.8- to 3.0-Gy fractions. Fourteen eyes were treated through lateral fields by anterior segment-sparing techniques, and 11 eyes were treated by an anterior approach with no attempt at anterior segment sparing. All patients survived (median follow-up, 31.5 months). Cataracts developed in five eyes at a median of 23 months, four in eyes treated with anterior segment-sparing techniques. Of the 15 group I to III eyes, 6 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation and 2 were enucleated. Of the 10 group IV and V eyes, 8 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation, 1 with persistent disease is being followed closely, and 3 were enucleated. Ten (71%) of the 14 eyes treated with anterior segment-sparing techniques required additional treatment (9 of the 10 for tumors anterior to the equator). Four (36%) of the 11 eyes treated with an anterior approach required additional treatment (3 of the 4 for tumors in the posterior pole of group IV or V eyes). Ninety percent of the tumors 10 disc diameters or smaller (1 disc diameter = 1.6 mm) were controlled independently of dose and fractionation used when they were not in the low-dose area of the anterior retina of an eye treated with an anterior segment-sparing technique. We find that use of lateral, anterior segment-sparing techniques has a high risk of anterior retinal tumor development and cataract formation and should be abandoned in favor of techniques that treat the entire retina. A dose of 45 Gy in 1.8-Gy fractions appears to be adequate for local control of tumors smaller than 10 disc diameters. Larger tumors may require additional treatment.

External beam radiation therapy and retinoblastoma: long-term results in the comparison of two techniques.
Blach LE, McCormick B, Abramson DH.
Int J Radiat Oncol Biol Phys. 1996 Apr 1;35(1):45-51.

PURPOSE : This study compares the long-term actuarial local control, eye conservation rate, survival, and ocular complications in children with retinoblastoma treated with two different external beam treatment techniques. METHODS AND MATERIALS : From 1979-1991, 182 eyes in 123 children (104 bilateral) received primary external beam radiation therapy. An anterior lens-sparing electron beam technique delivering 38 to 50 Gy in 2.5 Gy fractions was used in 67 eyes from 1979-1984 and a modified lateral beam technique, delivering 42 to 46 Gy in 2 Gy fractions, was used in 113 eyes from 1984-1991. These groups were balanced with respect to known prognostic variables. RESULTS : For Group I-III eyes, the 5- and 8-year local control was significantly improved using the modified lateral beam technique (84%) compared to (38%) using the anterior lens sparing technique (p < or = 0.0001). For Group IV-V eyes, the 5- and 8-year local control rates were not statistically different, despite a trend favoring the modified lateral beam technique. Survival endpoints including eye survival (no enucleation), cause-specific survival, and overall survival comparing the two treatment techniques were not significantly different. Overall, 22% of eyes developed cataracts. There was no difference between the two treatment groups in terms of cataract development. No eyes required enucleation for ocular complications. CONCLUSION : There is a significant improvement in local control using the modified lateral beam technique compared to an anterior lens-sparing approach for Group I-III eyes. However, there was no difference in survival end points between the two treatment techniques. The incidence of ocular complications using these two external beam techniques is acceptable.

External beam radiotherapy for retinoblastoma: II. Lens sparing technique.
Toma NM, Hungerford JL, Plowman PN et al.
Br J Ophthalmol. 1995 Feb;79(2):112-7.

A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.

D) RADIOTHERAPY DOSE :

External beam radiation for retinoblastoma: results, patterns of failure, and a proposal for treatment guidelines.
Hernandez JC, Brady LW, Shields JA et al.
Int J Radiat Oncol Biol Phys. 1996 Apr 1;35(1):125-32.

PURPOSE : To analyze treatment results and patterns of failure following external beam radiation for retinoblastoma and propose treatment guidelines according to specific clinical variables. METHODS AND MATERIALS : We analyzed 27 patients (34 eyes) with retinoblastoma who received external beam radiation as initial treatment at Hahnemann University Hospital from October 1980 to December 1991 and have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I-II (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV-V. Doses ranged from 34.5-49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5-2.0 Gy fractions generally delivered through anterior and lateral wedged pair fields. RESULTS : At a mean follow up of 35.2 months (range 12-93 months), local tumor control was obtained in 44% (15 out of 34) of eyes with external beam radiation alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or photocoagulation) controlled an additional 10 eyes (29.5%), so that overall ocular survival has been 73.5%. Local tumor control with external beam radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I-II, but in only 20% (4 out of 20) of eyes in Groups III-V. A total of 67 existing tumors were identified prior to treatment in the 34 treated eyes and local control with external beam radiation alone was obtained in 87% (46 out of 53) of tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a total of 28 failure sites were identified and consisted of progression of vitreous seeds in seven instances (25% of failure sites) recurrences from previously existing tumors in 10 instances (36% of failure sites) and development of new tumors in previously uninvolved retina in 11 instances (39% of failure sites). CONCLUSIONS : 1) We find that external beam radiation to a dose of 45 Gy in fractions of 1.5 to 2.0 Gy provides adequate tumor control in retinoblastoma eyes Groups I-II (Reese-Ellsworth classification) or tumors measuring 15 mm in diameter or less. Eyes in more advanced group staging or containing tumors larger than the 15 mm seem to require higher radiation doses. We propose treatment guidelines for external beam radiation of retinoblastoma that specifically take into account the important clinical variables of tumor stage and patient age. 2) External beam radiation does not prevent the appearance of new tumors in clinically uninvolved retina. Therefore, the traditional belief that external beam radiation can treat the retina “prophylactically” should be seriously questioned. Due to this finding and their significant less morbidity, focal treatment modalities (plaque brachytherapy, photocoagulation, and/or cryotherapy), when clinically feasible, should be considered the treatment of choice for intraocular retinoblastoma. External beam radiation should be considered only when focal treatment modalities are not clinically indicated.

Use of irradiation for therapy of retinoblastoma in children more than 1 year old: the St. Jude Children’s Research Hospital experience and review of literature.
Fontanesi J, Pratt CB, Hustu HO et al.
Med Pediatr Oncol. 1995 May;24(5):321-6.

Fifteen children (> 1 year old at diagnosis) were treated for retinoblastoma (RB) with primary irradiation at St. Jude Children’s Research Hospital between January 1963 and January 1992. Staging of the 19 treated eyes was as follows: Reese-Ellsworth (R-E) Groups I and II, n=7; Group III, n=3; Group IV, n=1; Group V, n=7; information on one globe is incomplete. Total dosage ranged from 25 to 45 Gy (median=40 Gy) in fractions of 170-225 cGy delivered 5 x/week (n=13) or 225-265 cGy delivered 4 x/week (n=4 eyes) or x 5/week (n = 2 eyes). Treatment techniques included anterior field (n=11) or lens-sparing technique (n=8). One patient has died of progressive central nervous system (CNS) disease at 13 months; one patient succumbed to second malignant neoplasm within the irradiated field at 194 months; the remaining 13 patients remain alive from 27 to 301 months (median=178 months). Local control with irradiation alone has been maintained in 12 eyes. Four eyes with local recurrence were salvaged using cryotherapy or reirradiation. Enucleation was required for three eyes for progressive disease at 4, 7, and 7 months postirradiation. Cataract formation was documented in nine eyes treated with anterior fields and in one patient treated with lens-sparing technique. At last follow-up, 7 patients had visual acuity of 20/100 or better. Radiation dose of 40 Gy appears to be adequate for local control of early stage RB (R-E Groups I-III and VB whose tumors are R-E Groups I-III) in patients > 1 year old. The results of this limited series which has lengthy follow-up is compared with the results of previously published data in an effort to define the benefits and disadvantages of the different treatment techniques which have been reported in the treatment of RB in children > 1 year old.

Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation.
Fontanesi J, Pratt CB, Kun LE et al.
Med Pediatr Oncol. 1996 May;26(5):297-304.

Thirty-three infants ( < 1 year at diagnosis) were treated for retinoblastoma with primary irradiation at St. Jude Children’s Research Hospital (SJCRH) between 1963 and June 1992. Staging of the 44 treated eyes was as follows: Reese-Ellsworth (R-E) Groups I (n=20), Group II (n=9), Group III (n=6), Group IV (n=2), Group V (n=7). Irradiation was delivered using either a single anterior field (31 eyes) or lens-sparing techniques (13 eyes). Total doses ranged from 21-45 Gy (median=36 Gy) in fractions of 150-180 cGy (n=34) or > 180 cGy (n=10). One child died of metastatic disease at 42 months. Three patients have developed second malignant neoplasms; two have succumbed at 88 and 125 months post-RB diagnosis; the remaining patients are alive at 6-259 months postdiagnosis (median follow-up=127 months). Local control with irradiation alone and supplemented cryotherapy given within 2 months (n=2) was maintained in 29 eyes, with no statistical difference seen for total doses < or=36 Gy (21/8 eyes) vs. > 36 Gy (8/16). Of 15 eyes that required salvage therapy, tumor control has been maintained in 13. Enucleation was required for four patients, two with recurrent retinoblastoma and one with a phthisical eye. Cataract formation was documented in 23 eyes (87.5%) treated with lens-sparing techniques developed cataract. At last follow-up, 23 of 30 patients tested (77%) had visual acuity of 20/100 or better. This experience confirms early observations in that doses > or = 36 Gy do not appear to improve local control with irradiation alone in infants (< 365 days) with retinoblastoma.

E) OCULAR PLAQUE THERAPY/ BRACHYTHERAPY:

Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors.
Shields CL, Shields JA, Cater J et al.
Ophthalmology. 2001 Nov;108(11):2116-21.

OBJECTIVE: To evaluate the clinical factors predictive for tumor recurrence and treatment complications in a large series of children who underwent plaque radiotherapy for retinoblastoma. DESIGN : Retrospective, noncomparative case series. PARTICIPANTS : The participants included 141 children with retinoblastoma who were managed on the Oncology Service at Wills Eye Hospital with plaque radiotherapy between July 1976 and June 1999. MAIN OUTCOME MEASURES : Tumor recurrence and treatment complications. RESULTS : There were 208 tumors managed with plaque radiotherapy. The mean patient age at plaque treatment was 19 months. Prior treatment to the retinoblastoma of concern was delivered to 148 tumors (71%) and included various combinations of treatments such as intravenous chemoreduction, external beam radiotherapy, laser photocoagulation, thermotherapy, and cryotherapy. For 72 retinoblastomas (35%), more than one therapeutic method had failed to achieve tumor control before the use of plaque radiotherapy. Of the 208 retinoblastomas managed with plaque radiotherapy, Kaplan-Meier estimates of tumor control were 83% at 1 year and 79% at 5 years. Of the 60 tumors treated only with plaque radiotherapy (primary treatment), recurrence at 1 year was 12%. Of the 148 tumors treated after failure of other methods (secondary treatment), specific Kaplan-Meier estimates of tumor recurrence at 1 year was detected in 8% of tumors previously treated with chemoreduction, 25% of tumors previously treated with external beam radiotherapy, 34% tumors previously treated with both chemoreduction and external beam radiotherapy, and 8% of tumors previously treated with laser photocoagulation, thermotherapy, or cryotherapy (methods other than chemoreduction and external beam radiotherapy). Using multivariable analysis, the risks for tumor recurrence included the presence of tumor seeds in the vitreous, presence of subretinal tumor seeds, and increasing patient age. Using Kaplan-Meier estimates, radiation complications at 5 years of follow-up included nonproliferative retinopathy in 27%, proliferative retinopathy in 15%, maculopathy in 25%, papillopathy in 26%, cataract in 31%, glaucoma in 11%, and scleral necrosis in 0%. CONCLUSIONS : Plaque radiotherapy for retinoblastoma provides tumor control in 79% of cases at 5 years of follow-up. It is particularly useful for those tumors that fail treatment with chemoreduction, laser photocoagulation, thermotherapy, and cryotherapy. Tumors in young patients without vitreous or subretinal seeding show the best long-term control.

Plaque radiotherapy for residual or recurrent retinoblastoma in 91 cases.
Shields JA, Shields CL, De Potter P et al.
J Pediatr Ophthalmol Strabismus. 1994 Jul-Aug;31(4):242-5.

Plaque radiotherapy has been used successfully as primary treatment for selected solitary retinoblastomas. However, there is relatively little information on its role as a secondary treatment after other methods have failed to control the tumor. We have used solitary plaque radiotherapy to treat 91 children with residual or recurrent retinoblastoma after failure of one or more treatment modalities, which included external beam radiotherapy in 63 children, plaque radiotherapy in 9, cryotherapy in 26, and photocoagulation in 18, for a total of 116 treatments in the 91 children. Despite the fact that enucleation was considered to be the only remaining option in many of these children, tumor regression was achieved in 81 cases (89%) and recurrence developed in only 10 cases (11%) during a mean follow up lf 52 months. Treatment of the recurrence following plaque radiotherapy in these 10 cases included repeat plaque radiotherapy in 6 cases, enucleation in 3 cases, and external beam radiotherapy in 1 case. In view of the fact that enucleation was being considered as the only remaining option in many of these children, control of the tumor with plaque radiotherapy in 89% of the cases is very encouraging. Plaque radiotherapy should be considered as an important option for recurrent retinoblastoma after failure of other methods to achieve tumor control.

Wilm’s tumor is the second most common abdominal tumor and constitutes 6 % of all childhood cancers. Wilm’s tumor is the paradigms for multidisciplinary treatment of Pediatric malignant solid tumor.
Wilm’s tumor develops as a result of abnormalities in development of metanephric blastema. Wilm’s tumor has been reported to be associated with various anomalies. Genitourinary anomalies are the most common and account for incidence of 4 to 8%. The anomalies include fused kidney, renal dyspiasia, cryptorchidism, hypospadias, duplications of collecting system, WAGR Syndrome (WT, aniridia, Genitourinary abnormalities and mental retardation) wilm’s tumor is also featured in many disorders of overgrowth including Beckwith-Weildmann Syndrome, Perlmann Syndrome, isolated hemihypertrophy. Although most patients with Wilms tumor are Karytypically normal, genomic studies have led to the localisation and subsequent cloning of WT genes in two regions - 11p13 & 11p15. The former is WT1 gene and is associated with WAGR Syndrome & latter is WT2 gene which is associated with Beckwith Wiedemann Syndrome.

Evaluation
1. History & physical Examination
• Detection of an asymptomatic abdominal mass bulging in the flank.
• Non specific systoms like abdominal pain, fatigue
• Haematuria (in <10%)
• Hypertension (V. rare )
• Associated Urogenital anomalies, Aniridia, overgrowth Syndrome.

Surgical staging includes
1. Through examination of the contralateral Kidney after opening Gerota’s facia.
2. Retroperitoneal node sampling
3. Palpation of Liver.

NWTS Algorithm based on NWTS 4
SIOP Algorithm based on SIOP- 9 except for stage II - IV FH Which is based on SIOP 93 - 01.
Carbo = carboplatin; CPM = cyclophosphamide; DAM = dactinomycin ; DOX = doxorubin;
EPI = epirubicin ; Ifos = ifosfamide; VCR = vincristine; RT = radiotherapy; FH = favourable histology;
UH = unfavourable histology; wk = week; PI = pulse intensive.

Prenephrectomy Chemotherapy
To decrease the need for post op abdominal radiation therapy in event of tumor rupture during nephrectomy, International Society of Pediatric Oncology (SIOP) conducted series of trials in which all patients received Chemotherapy before nephrectomy. National Wilm’s Tumor Study Group (NWTSG) recommend immediate nephrectomy to avoid several risks.

Risks of Prenephrectomy Chemotherapy
1) Chemotherapy to a patient with benign disease as in SIOP trials Prechemotherapy confirmation of diagnosis is not mandatory. This risk is 7.6 % to 9.9%
2) Modification of tumor histology
Data suggest that chemotherapy did not modify tumor histology to such an extent that diagnostic features of anaplacia could net be identified.
3) Loss of staging information.
This concern is exemplified in SIOP. 6 trial in which Postchemotherapy stg. II Lymphnode -ve patients randomised not to receive radiotherapy had high intra-abdominal recurrence suggesting that pre-op chemotherapy produced sufficient tumor response to destroy pherinephric tumor extension and deposits in Lymph nodes.
Stage distribution of patients entered on NWTS - 3 & SIOP 6 are comparable. However 50% more European Stg. I - III FH. Patients will receive anthracycline, whereas 50% more North American patients will be treated with abdominal irradiation. Thus risk of anthracycline exposure with associated risk of cardiotoxicity should be weighed against tumor rupture leading to abdominal irradiation and risk of carcinogenesis.

Absolute Indications for Prenephrectomy Chemotherapy
1. Large tumor technically difficult to deliver at surgery.
2. Presence of major tumor thrombus in the inferior venacava.
3. Bilateral Wilm’s tumor
4. Wilm’s tumor in a solitary Kidney or horse shoe Kidney.

RADIOTHERAPY FOR WILMS’ TUMOR
Indications :
Stage II unfavorable histology.
Stage III & IV favorable & unfavorable histology.
Local recurrence.
Palliative radiotherapy for metastatic disease.

Principles of Radiation Therapy :
Radiotherapy should be planned starting within 10 day of surgery.
No change of radiotherapy dose for favorable & unfavorable histology.
Rhabdoid tumors to be treated as a separate entity.

Target volume :
Volume should encompass tumor bed + site of excised kidney with 2-3cm margin.
Entire vertebral body to be encompassed.
Stage II - Tumor bed only

Stage III & IV disease

Total Dose:
Recommended radiation therapy doses in NWTS – 5