A. Esophageal Cancer
    Esophageal Cancer selected abstracts

B. Lung Cancer
    Lung Cancer selected abstracts

The oesophagus is one of the common sites of malignancy in the gastro-intestinal tract. World-over, the incidence of esophageal cancer, particularly adenocarcinoma, is on the rise. In the US, the incidence has increased five fold. At the Tata Memorial hospital, between 800 and 1000 patients of cancer oesophagus are registered every year. Unlike in the west, the majority of these are squamous carcinoma. The standard treatment of operable oesophageal cancer in the absence of medical contraindications is surgery. Radiation, chemo-radiation for definitive treatment and combination of radiation and chemotherapy with surgery are other treatment options. However, the overall survival continues to remain far from satisfactory. The reported five year survival ranges from 5% to 30%.

Staging

Staging of cancer is important for uniform reporting and comparison of results from various centres. It also determines whether the intent of treatment is curative or palliative. It is based on clinical examination and information obtained by imaging : CT scan and/or endoscopic ultrasonography (EUS). Also, TNM staging is one of the most important and reliable prognostic variables.

TNM staging
T-stage (primary tumour)

• TX : Primary tumour cannot be assessed
• T0 : No evidence of primary tumour
• Tis : Carcinoma in situ
• T1 : Tumour invades lamina propria or submucosa
• T2 : Tumour invades muscularis propria
• T3 : Tumour invades adventitia
• T4 : Tumour invades adjacent structures

N-stage (regional lymph nodes)

• NX : Regional lymph nodes cannot be assessed
• N0 : No regional lymph node metastasis
• N1 : Regional lymph node metastasis

M-stage (distant metastases)

• MX : Distant metastasis cannot be assessed
• M0 : No distant metastasis
• M1 : Distant metastasis

Tumours of the lower thoracic oesophagus :

• M1a : Metastasis in celiac lymph nodes
• M1b : Other distant metastasis

Tumours of the midthoracic oesophagus :

• M1a : Not applicable
• M1b : Nonregional lymph nodes and/or other distant metastasis

Tumours of the upper thoracic oesophagus :

• M1a : Metastasis in cervical nodes
• M1b : Other distant metastasis

For tumours of mid thoracic oesophagus use only M1b, since these tumours with metastasis in non regional lymph nodes have an equally poor prognosis as those with metastasis in other distant sites.

Stage Grouping

The current staging system for esophageal cancer is most applicable to patients with squamous cell carcinomas of the upper- and middle-thirds of the oesophagus, as opposed to distal esophageal and gastroesophageal junction adenocarcinomas. The present system of classifying coeliac lymph node metastases as M1 seems to be unreasonable. The prognosis of patients with positive abdominal lymph nodes is not the same as with metastases to distant organs. Patients with regional and/or celiac axis lymphadenopathy should not necessarily be considered to have unresectable disease due to metastases. Complete resection of the primary tumour and appropriate lymphadenectomy should be attempted when possible.

Investigations
Diagnostic Investigations

1. Barium Swallow (optional) : This continues to be the first investigation in majority of patients presenting with dysphagia. It gives information regarding the 1. Site 2. length of lesion 3. Morphology (Proliferative/Stricturous/ulcerative or combination) 4. Extra esophageal spread (axis deviation, sinuses and fistulation)

2. Esophagoscopy : Fiberoptic esophagoscopy is essential for biopsy/cytology.

Staging Investigations
1. CT scan : Chest and upper abdomen
2. Endoscopic ultrasonography (EUS)
3. Fiberoptic bronchoscopy : for tumours located at and above the level of the carina

CT scan and EUS are complimentary for assessing the lateral extension of disease and lymph node status. EUS scores over CT scan in assessment of the depth of tumour invasion, particularly in early cancer, and status of regional lymph node. However, in stricturous lesions, EUS may not always be possible. CT scan is equally accurate in assessment of T3/T4 lesions; abdominal CT scan additionally can screen liver and coeliac lymph nodes. Bronchoscopy is an essential non invasive investigation for assessing the tracheo-bronchial tree for early or frank invasion. It is recommended prior to surgery or radiation for upper and mid esophageal disease.

PET scan can effectively detect presence of disseminated disease. However, presently it is an investigational modality of investigation. Thoracoscopy and laparoscopy for staging has been investigated and reported increased rate of detecting positive lymph nodes than non invasive staging modalities (Level IIb).

Routine Investigations for assessing fitness for treatment
1. Hemogram
2. Liver Function Test/Renal Function Test
3. Chest X-ray
4. Pulmonary Function Test
5. ECG

Treatment Options
Two factors determine the treatment:
1. General condition or the Performance status
2. Stage

1. General condition or performance status is an important factor in determining the treatment of a patient with cancer oesophagus. Dysphagia, particularly if it is long standing and complete, leads to chronic dehydration and malnutrition. Such patients will not tolerate surgery, radiation or chemotherapy. Supportive care to optimise general condition should be the priority. Subsequently, if performance status improves, definitive treatment can be contemplated depending on stage of the disease.

2. Stage : Patients with localized disease are ideally treated with surgery in the absence of medical contraindications. As per the staging, presence of abdominal or celiac lymph nodes is classified as disseminated disease. However prognosis of patients with abdominal or celiac lymph node metastasis is not the same as that with systemic distant metastasis. Hence, patients with operable local disease should be offered surgery with appropriate lymphadenectomy.

• The preferred treatment of carcinoma of the cervical oesophagus is radical radiotherapy or concomitant chemoradiotherapy

Stage 0 (TisN0M0)
Patients are rarely diagnosed in this stage. The treatment of choice is surgery. If the disease is localised (preferably T1a), Endoscopic mucosal resection (EMR) can be offered in centres with expertise provided the patient is reliable for followup. For more extensive disease, esophagectomy is the treatment of choice.

Stage I (T1N0M0)
Surgery is the treatment of choice. Radiation therapy may be offered if the patient is medically unfit or not willing for surgery.

Stage II/III (T2N0M0, T3N0M0, T1N1M0, T2N1M0)
Surgery for T2 and T3 lesions

Surgery for T4 lesions with limited infiltration of pleura or pericardium which is amenable to complete resection

Neo adjuvant chemotherapy/concomitant chemo-radiation for T3/T4 tumours which are bulky or of doubtful resectability. If there is complete or partial response to neo adjuvant therapy and tumour appears resectable patient should proceed for surgery; if the response is sub optimal and disease appears non resectable, patient should either proceed for radiation or palliative therapy (see below).

Investigational treatments
1. Chemoradiotherapy alone or chemoradiotherapy followed by surgery
2. Neo adjuvant Chemotherapy followed by surgery
3. Post operative radiation therapy

Stage IVa (ant T, any N, M1a)
Surgery (per primum or following neo adjuvant therapy): If the disease is operable in the absence of distant metastases. However, more than 50% of patients will have distant metastases. Such patients will be candidates for palliative treatment.

Principles of Surgery
Surgical Approach
1. Esophago-gastrectomy through left thoraco-abdominal approach (Garlock procedure) : for adenocarcinoma of the cardio-esophageal junction.
2. Trans thoracic esophagectomy with intrathoracic anastomosis (Ivor Lewis procedure).
3. Trans thoracic total esophagectomy with cervical anastomosis.
4. Trans hiatal esophagectomy with cervical anastomosis.
Adenocarcinoma of the cardio-esophageal junction can be resected through a left thoracoabdominal approach. Surgery involves mobilization of the oesophagus upto the inferior pulmonary vein along with dissection of lower paraesophageal lymph nodes, standard mobilization of stomach along with D2 lymphadenectomy. Gastro-oesophageal anastomoses could be either mechanical (using stapler) or hand sewn.

Adenocarcinoma of the distal portion of the oesophagus or cardio-esophageal junction extending into the lower oesophagus where the proximal extent of the tumour is such that adequate margin is not possible through the left thoraco-abdominal approach should be treated by either trans thoracic or trans hiatal esophagectomy. Phase III trial comparing transhiatal esophagectomy to transthoracic esophagectomy and lymphadenectomy for adenocarcinoma of the oesophagus did not find difference in median overall and disease free survival between the two procedures. However, there was a trend towards superior long term (5-year) survival, not reaching statistical significance, in favour of transthoracic esophagectomy (Level Ib).

Carcinoma of the lower, mid and upper esophagus (excluding cervical oesophagus) is managed either by transhiatal or trans thoracic esophagectomy and esophago-gastric anastomosis in the neck or thorax. There is no consensus as to the best or the ideal surgical approach. Transthoracic esophagectomy has the advantage of mobilization of the oesophagus under vision. Also, systematic mediastinal lymph node dissection can be performed. Trans hiatal approach, according to proponents, is less morbid with fewer pulmonary complications. There are four published Phase three trials comparing the two approaches. Three of these had few patients and thus, meaningful conclusions cannot be drawn. The fourth and the latest trial has 220 patients, all adenocarcinoma restricted to the distal oesophagus or cardio-esophageal junction. There was no difference in the median overall survival; however, there was a trend towards a survival benefit at five years with the trans thoracic approach (Level Ib). The published meta analysis of over 60 trials (both prospective and retrospective) comparing transhiatal to transthoracic esophagectomy did not find any difference in the overall survival (Level IIc). Till results of large randomized trials are available the preferred surgical approach will continue to be biased by surgeons’ choice.

Extent of lymphadenectomy
Lymph node metastasis is one of the most important prognostic factors for carcinoma of the oesophagus. Since the oesophagus has extensive lymphatic network and most patients present with advanced disease, the majority of patients undergoing surgery have lymph node metastases. Three field lymph node dissection (lower cervical, mediastinal and abdominal) is reported to improve survival without increased procedure related morbidity and mortality (Level IIa). However, most reported studies are small or have compared results with historical controls. The only one randomized trial of over 60 patients has reported higher, though not statistically significant, survival in patients undergoing three field lymph node dissections (Level Ib). Extensive lymph node dissection provides ‘accurate nodal staging’ resulting in stage migration and apparent ‘improvement in survival’. In absence of conclusive Level I evidence, the advantage of three field lymph node dissection over the conventional limited lymph node dissection remains speculative. In fact, an adequately powered randomized trial could answer the question regarding the importance of lymph node dissection in management of carcinoma oesophagus and indirectly address the issue of transhiatal versus transthoracic approach.

Definitive radiation and chemo-radiation therapy
Two published (RTOG and ECOG) randomized trials have reported better overall survival with concomitant chemo-radiation than radiation therapy alone. However, increasing the dose of radiation therapy (50.4 versus 64.8) in concomitant setting did not result in increased survival (Inter Group trial). Meta analysis of 13 trials combining radiation with chemotherapy published in the Cochrane library has reported an absolute reduction in the mortality and local recurrence rate of 7% and 12% respectively in favour of combination therapy. The combination treatment is associated with increased life threatening toxicities (Level Ia). There are no trials comparing concomitant chemo-radiation with surgery alone. However two trials comparing surgery to radiation alone have reported better survival with surgery (Level Ib). Hence based on the available evidence, if a patient is to be treated with definitive radiation, it should be combined with chemotherapy, provided performance status is optimal.

Surgery as adjuvant to radiation, chemotherapy or combination of both

Pre-operative radiotherapy
A meta analysis as well as the five published randomized trials comparing preoperative radiation therapy to surgery alone have not shown benefit of pre operative radiation over surgery alone (Level Ia).

Pre-operative concomitant chemo-radiation
There are three major trials comparing preoperative concomitant chemoradiation to surgery alone. Of these, one trial has shown statistically improved survival with chemoradiation. Meta analysis of pre operative chemoradiation and surgery to surgery alone (nine trials) has reported improved 3-year survival and reduced loco-regional recurrence (Level Ia). However, combination treatment is associated with trend towards increased treatment related morbidity and mortality. In the absence of results from a large trial and increased treatment related morbidity, neo adjuvant chemo-radiation should be considered as an “Investigational treatment’ till more results are published.

Pre-operative chemotherapy
There are five major published trials of pre-operative chemotherapy in the management of carcinoma of the oesophagus. The two large trials have reported results which are divergent. The Intergroup trial of 440 patients reported by Kelsen et al observed no improvement in survival with pre operative combination of cisplatin and fluorouracil among patients with adenocarcinoma or epidermoid carcinoma of the oesophagus. The MRC trial of 802 patients published more recently reported improved survival with two cycles of cisplatin and fluorouracil without additional serious events. The meta analysis of all trials put together concludes that preoperative chemotherapy plus surgery appears to offer a survival advantage at 3, 4, and 5 years, which reached significance only at 5 years compared to surgery alone for resectable thoracic esophageal cancer of any histologic type. The number needed to treat for one extra survivor at five years is eleven patients. The results are tempered by the increased toxicity and mortality associated with chemotherapy (Level Ia). However the fact that two major trials, each with adequate number of patients, have reported diametrically opposite results keeps the issue of neo adjuvant chemotherapy far from being answered conclusively.

Post-operative radiotherapy
Three trials have compared surgery and post operative radiation to surgery alone. The Chinese trial of 495 patients observed improved 5-year survival in patients with positive lymph nodes and stage III disease receiving post operative radiation. However, the difference in the overall survival between the two groups was statistically not different. The meta analysis of all three trials also does not show benefit of post operative radiotherapy. Therefore, in the absence of Level I evidence post operative radiotherapy is indicated only for patients with positive margin and residual disease.

Post operative chemotherapy
Phase III trials of surgery and post operative chemotherapy have not reported survival benefit over surgery alone. A Phase III study by Japanese Clinical Oncology Group (JCOG) reported better disease free survival at 5-year with post operative chemotherapy; however there was no difference in the overall survival (Level Ia).In adenocarcinoma of the cardio oesophageal junction (and stomach) post operative chemo-radiotherapy is shown to improve the median overall survival (Level Ib). Thus in patients with adenocarcinoma of the cardia having good performance status, post operative chemo-radiation should be the standard of care.

Principles of Radiation therapy
Radical radiotherapy
The inclusion criteria are :
- All lesions (except stenotic) in upper / mid / lower esophagus
- Lesion £ than 5 cm on barium swallow and esophagoscopy
- Histologically proven esophageal carcinoma
- Karnofsky Performance Status (KPS) of > 60%
- Age £ 60 years.
- Metastatic work - up negative (No palpable S/C nodes, Bronchoscopy & USG abdomen normal).

• External beam radiotherapy (EBRT) alone

Dose : 60 - 64.8Gy / 33 - 36 fractions, with reducing fields

Portal design :
Extended field: esophageal lesion including the lymph drainage areas, with 5 cm margin on either side upto 39.6Gy / 22 fractions/ 4.5 weeks

Reduced fields/ boost: Lesion with 2 - 3 cm. margins, with oblique portals, upto 60 - 64.8Gy / 33 - 36 fractions

• External beam radiotherapy and brachytherapy

When feasible, external Radiotherapy can be combined with Intraluminal radiotherapy (ILRT) as a boost.

Dose of EBRT : 50.4Gy / 28 fractions with reducing fields.

ILRT Boost : 5 - 8Gy / 2-3 fractions high dose rate (HDR), one week apart or single fraction 20Gy low dose rate (LDR).

Concomitant chemo-radiation regimen

• 50Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. (RTOG regimen)
• 60Gy in 6 to 61/2 weeks. Chemotherapy to be initiated within 24 hours after the commencement of radiation therapy. 5-FU to be delivered by continuous infusion for 96 hours starting on day 2 at the rate of 1000 mg per m2 over 24 hours. This regimen of 5-FU to be repeated once again beginning on day 28. Bolus injection of mitomycin C (10 mg per m2) to be administered on day 2 and not to be repeated. The dose of mitomycin C not to exceed 18 mg and the dose of 5-FU not to exceed 1800 mg over a 24-hour period. (ECOG regimen).

Principles of Chemotherapy

Neoadjuvant chemotherapy protocols

• Two 4-day cycles, 3 weeks apart, of cisplatin 80 mg/m(2) by infusion over 4 h plus fluorouracil 1000 mg/m(2) daily by continuous infusion for 4 days. (MRC protocol)
• Cisplatin, at a dose of 100 mg per square meter of body-surface area, given as a rapid intravenous infusion after prehydration on day 1. Immediately thereafter, fluorouracil administered at a dose of 1000 mg per square meter as a continuous infusion from day 1 through day 5 (120 hours) of each cycle. The cycle to be repeated beginning on days 29 and 58. Surgery performed two to four weeks after chemotherapy (Intergroup protocol).

Palliative treatment
If the general condition is good,
1. Relief of dysphagia by placement of esophageal stent alone, preferably self expanding metallic stent as these are easy to deploy.
2. Radiation therapy with intubation if associated with significant dysphagia
3. Intraluminal radiation therapy alone.
4. Endoscopic laser destruction of tumour or electrocoagulation.

Palliative radiotherapy
The intent of treatment is to achieve quick and good palliation in the form of relief of dysphagia and pain.
The inclusion criteria are :
- Lesions in upper / mid / lower esophagus
- Lesion £ 10 cm long on barium swallow and esophagoscopy
- Histologically proven esophageal carcinoma
- Karnofsky performance status (KPS) of £ 50%
- Recurrent / metastatic disease.

Dose : 3000cGy /10 fractions /2 weeks

Portal : Esophageal lesion with 2-3 cm margin

Evaluation and response assessment is done after 4 - 6 weeks and further external Radiotherapy or Brachytherapy boost may be delivered.

Reduced field / boost : 2000cGy/10# / 2 weeks, using oblique portals

Palliative radiation can also be delivered in the form of ILRT alone or in combination with EBRT. The dose per fraction ranges from 5 - 8Gy, in 2- 3 fractions, one week apart. There is no difference in local control or survival between high dose rate brachytherapy compared with external beam radiation. (Level II)

Investigational Treatment
1. Palliative chemotherapy with intubation if associated with significant dysphagia. Response rates ranging from 30% to 50% and one year survival ranging from 0% to 5% is reported with platinum based combination chemotherapy.
If the general condition is poor with limited life expectancy
1. Nasogastric tube placement for feeding if possible.
2. Supportive care.

Treatment of esophageal fistula
1. Esophageal intubation with stent.
2. Oesophageal and tracheal/bronchial stent placement (double stenting) when possible if the fistula is large or if the tracheal lumen is compromised.

Treatment of Recurrent disease
1. Salvage surgery for localised resectable failures.
2. Palliative treatment or supportive care alone as described before.

Conclusion
The incidence of cancer oesophagus is rising. However, majority of patients are still diagnosed in advanced stage of disease. The existing management approaches yield 5-year survival of between 5% and 30%. Hence there is an urgent need for more multimodality management protocols to improve the existing dismal survival for patients with esophageal cancer. Specifically the issue of neo adjuvant chemotherapy and concomitant chemo-radiation needs to be addressed.

Workup
1. Barium swallow (optional)
2. Upper GI scopy with biopsy / cytology
3. CT scan chest and upper abdomen
4. Fiber optic bronchoscopy – for upper and middle third growths
5. Routine hematology, biochemistry
6. Pulmonary function tests – if surgery contemplated
    a. Assess stage of disease – (i) Localized (ii) Disseminated
    b. Assess performance and nutritional status

Disseminated disease with good performance status

• Stenting
• Palliative chemotherapy

Poor performance status and / or nutritional status

• Stenting

Recurrent disease

Best supportive care

• Stenting – to relieve obstruction
• Enteral feeding through nasogastric tube or gastrostomy
• Pain relief

Introduction

Lung cancer is a major problem in both developed and developing countries in the world. It is the leading type of cancer (more than a million new cases; 12.8% of all cancers) and the leading cause of cancer mortality (921,000 deaths; 17.8% of all cancer deaths) worldwide. It is expected that lung cancer will remain a major health problem at least for the next 30-40 years, even if there is a reduction in incidence as a result of smoking cessation interventions. In India, Untreated, it has a high mortality with 95% patients dying within one year.

Lung cancer is broadly divided into two types – small cell and non-small cell. This general histologic classification reflects the clinical and biological behavior of these distinct tumor types. Small cell lung cancers (SCLC) grow rapidly, metastasize widely and are treated primarily with chemotherapy. Eighty percent of SCLC are metastatic on presentation. Non-small cell lung cancers (NSCLC) are divided into squamous cell cancers, adenocarcinomas and large cell carcinomas. Nearly half of all NSCLC in developed countries (and one fourth of cases in India) are diagnosed in localized or locally advanced stage when they are treated by resection or combined modality treatment with or without surgery.

Smoking is the single most important risk factor for all types of lung cancers. Attempts to reduce lung cancer mortality should therefore primarily be focused on smoking cessation, which has the potential to be the single most important public health intervention to reduce cancer deaths.

Staging

The AJCC has adopted the TNM staging system proposed by Mountain in 1997. The TNM staging system is based on the anatomic extent of disease.

Treatment options for patients with NSCLC should take into consideration
a) Stage of disease
b) Pulmonary reserve and
c) Performance status

Table 1 : TNM staging of NSCLC
Primary Tumor (T)
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells      in sputum or bronchial washings, but not visualized by imaging or bronchoscopy.

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor p3 < 0 cm in greatest dimension, surrounded by lung or visceral pleura, and          without bronchoscopic evidence of invasion more proximal than the lobar bronchus           (i.e. not in the main bronchus)

T2 Tumor with any of the following features of size or extent:
     > 3 cm in greatest dimension
     Involves main bronchus, >2 cm distal to the carina
     Involves the visceral pleura
     Associated with atelectasis or obstructive pneumonitis that extends to the hilar region      but does not involve the entire lung
T3 Tumor of any size that directly invades any of the following: chest wall (including           superior sulcus tumors), diaphragm, mediastinal pleura, or parietal pericardium; or           tumor in the main bronchus <2 cm distal to the carina, but without involvement of the      carina; or associated atelectasis or obstructive pneumonitis of the entire lung T4           Tumor of any size that invades any of the following: mediastinum, heart, great                vessels, trachea, esophagus, vertebral body, carina; or tumor with a malignant pleural      or pericardial effusion, or with satellite tumor nodule(s) within the ipsilateral
     primary-tumor lobe of the lung

Note : The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus is also classified as T1.

Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph nodes metastasis
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and      intrapulmonary nodes involved by direct extension of the primary tumor
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral      scalene, or supraclavicular lymph node(s)

Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present

Table 2 : TNM stage grouping

Management of NSCLC
I. Patients with localized NSCLC (T1-3, N0-1)

These include patients upto T3N1 NSCLC, i.e., all stage I, II and T3N1 stage IIIA.

Workup includes
1. Chest X-ray
2. CT scan chest and upper abdomen
3. Fiber optic bronchoscopy
4. Cyto/histological diagnosis if possible – sputum cytology, bronchoalveolar lavage/brushings cytology, post bronchoscopy sputum cytology, CT guided FNAC
5. Arterial blood gas analysis
6. Pulmonary function tests
7. Ventilation-perfusion (V/Q) scan – if pulmonary function tests reveal borderline pulmonary reserve
8. Mediastinoscopy is indicated in patients with T3 and/or N1 tumors
9. Metastatic workup – CT scan brain, upper abdomen (for liver and adrenals) and bone scan – indicated in patients with T3 and/or N1 tumors

Note : A cyto/histological diagnosis is preferable but not mandatory prior to surgery.

A complete metastatic workup is indicated in
a) Patients with T3 and/or N1 tumors
b) Borderline operative patients (increased risk because of borderline PFT or intercurrent cardiac or other medical illnesses) with early stage disease
c) Patients with symptoms or signs of distant metastases.

Patients with T1-2, N0 NSCLC with no symptoms of metastatic disease do not require a routine metastatic workup.

Surgery is the treatment of choice in patients with localized disease with no involvement of mediastinal lymph nodes.
(Level III, Grade B)

Preoperative pulmonary evaluation
Many tests are available to assess adequacy of pulmonary reserve prior to lung surgery. They are summarized in the table.

* Single most important test is the predicted postoperative FEV1 (Ppo FEV 1)

Preoperative Management
1. Smoking cessation
2. Bronchodilators
3. Intermittent Positive Pressure Breathing (IPPB)
4. Chest physiotherapy
5. Antibiotics – only if infection present

Surgical resection – general principles

• Lobectomy or pneumonectomy should be done depending on the extent of disease (provided the patient has adequate pulmonary reserve). One randomized trial (LCSG) and eight non-randomized trials have shown lower survivals with sublobar resections compared to lobectomy. (Level Ib, Grade A)
• Limited resection (segmentectomy, wedge resection) may be done only if pulmonary reserve is inadequate for lobectomy, provided otherwise medically fit for surgery. Reduced survival compared to lobectomy, but better results than radical radiotherapy alone. (Level III, Grade B)
• N1 and N2 lymph nodal resection and mapping (sampling or systematic lymph node dissection) should be done. There is universal consensus that SMLND is a better staging and prognosticator than mediastinal lymph nodal sampling. There is no consensus that SMLND improves survival in patients with NSCLC. Two randomized trials found no difference in survival between mediastinal lymph node sampling and systematic mediastinal lymph node dissection, whereas one randomized and one large nonrandomized trial found superior survival with systematic mediastinal lymph node dissection. (Level Ib, Grade A)
• Curative (radical) radiotherapy should be given if the patient is medically unfit for surgery. (Level III, Grade B)
• Parenchyma preserving lung resection (sleeve resection, bronchoplasty) is preferred over pneumonectomy if anatomically appropriate and negative margins can be obtained. (Level III, Grade B)

VATS lung resections
Preliminary data from VATS lung resections suggest similar 2-3 year survival outcomes to open surgery but long term outcomes are not yet available. However, most studies of VATS lung resections have had strict selection criteria whereas comparative open surgeries have been an unselected group. There is also no objective evidence regarding the advantages of VATS lung resections over open surgery.

Postoperative care
1. Perioperative antibiotics
2. Optimal pain control
3. Early mobilization
4. Chest physiotherapy
5. Incentive spirometry
6. IPPB

Adjuvant therapy

• There is no role of adjuvant radiotherapy in completely resected early stage NSCLC. The PORT meta analysis showed higher mortality in patients treated with post operative radiotherapy compared to patients treated with surgery alone (Level Ia, Grade A)
• Adjuvant radiotherapy may be considered in patients with residual disease after lung resection or positive margins. (Level III, Grade B)
• There is no role of non-cisplatin based chemotherapy in resected NSCLC. (Level Ia, Grade A)
• There may be a benefit with cisplatin-based adjuvant chemotherapy in completely resected NSCLC. A recent large multicenter randomized controlled trial showed a significant survival advantage with postoperative chemotherapy in completely resected NSCLC. (Level Ib, Grade A)

II. Patients with positive mediastinal lymph nodes (T1-3, N2)
Workup includes
1. Chest X-ray
2. CT scan chest and upper abdomen
3. Fiber optic bronchoscopy
4. Cyto/histological diagnosis – sputum cytology, bronchoalveolar lavage/brushings cytology, post bronchoscopy sputum cytology, CT guided FNAC
5. Mediastinoscopy and biopsy
6. Metastatic workup – CT scan brain, upper abdomen and bone scan.

A. Preoperatively diagnosed N2 disease

• Patients with clinico radiological N2 disease should undergo mediastinoscopy for histological evidence of N2 disease.
  (Level Ib, Grade A)
• Patients should undergo multimodality treatment protocols.
• Patients are primarily treated with neoadjuvant chemotherapy followed by surgery. Two randomized trials have shown significantly improved survival with neoadjuvant chemotherapy compared to patients treated with surgery alone. (Level Ib, Grade A)
• Patients progressing on neoadjuvant chemotherapy should be treated with definitive chemoradiotherapy. (Level III, Grade B)
• Patients who do not progress on NACT and who have resectable disease should be treated with surgery provided they have adequate pulmonary reserve. (Level III, Grade B)
• Patients with inadequate pulmonary reserve to tolerate lung resection should be treated with definitive chemoradiotherapy. (Level III, Grade B)
• Patients with T3 N2 disease should be treated with chemoradiotherapy and only a highly selected subset considered for surgery after neoadjuvant chemotherapy.
  (Level IV, Grade C)

B. Surgically discovered N2 disease

• Patients with N2 disease detected on thoracotomy should undergo lung resection provided the tumor can be completely resected. (Level III, Grade B)
• Systematic lymph node dissection should be done. (Level III, Grade B)
• Adjuvant therapy should be considered. (Level III, Grade B)

Adjuvant therapy

• The role of adjuvant radiotherapy in completely resected N2 NSCLC is unclear. Subset analysis in the PORT meta analysis showed no difference in survival
• Adjuvant radiotherapy may be indicated in patients with residual disease after surgery or positive margins. (Level III, Grade B)
• There is no role of non-cisplatin based chemotherapy (Level Ia, Grade A)
• There may be a benefit with cisplatin-based adjuvant chemotherapy. (Level Ib, Grade A)

III. Patients with locoregionally advanced disease (T4 and N3)

• Treatment of patients with T4 and N3 NSCLC is predominantly non surgical. (Level III, Grade B)
• Patients with good performance status should be treated with combination chemo radiotherapy. Evidence from a meta analysis and 12 randomized controlled trials show a survival benefit with cisplatin-based chemotherapy and radical radiotherapy compared to radiotherapy alone. (Level Ia, Grade A)
• Concurrent chemo radiotherapy is preferable to sequential chemo radiotherapy. (Level III, Grade B)
• There is no difference between daily and weekly chemoradiotherapy regimens. (Level Ia, Grade A)
• Cisplatin based chemotherapy regimens are better than non-cisplatin based chemotherapy. (Level Ia, Grade A)
• Patients who may not tolerate combination chemo radiotherapy should be treated with radiotherapy alone. (Level III, Grade B)
• Patients with malignant pleural effusion should be treated with pleurodesis. Palliative chemotherapy should be given in patients with good performance status. (Level III, Grade B)
• Highly selected patients with stage III B disease may benefit from surgery as part of multimodality treatment protocols.
  (Level IV, Grade C)

IV. Patients with metastatic disease

• The aim of treatment is palliation
• Patients with good performance score (ECOG 1, 2) should be treated with cisplatin - based chemotherapy.
  (Level Ia, Grade A)
• Combination chemotherapy regimens are better than single agent chemotherapy. (Level Ia, Grade A)
• Patients with poor performance score should be treated with best supportive care (BSC). (Level Ia, Grade A)
• Painful bone metastases and metastases in weight-bearing bones should be treated with palliative radiotherapy.
  (Level Ia, Grade A)
• Bisphosphonates may reduce adverse bone events in patients with bone metastases. (Level Ia, Grade A)
• Highly selected patients with solitary brain, adrenal and lung metastasis may benefit from resection of the metastasis along with lung resection. (Level IV, Grade C)

Management of malignant pleural effusion (unknown primary)
Workup includes
1. Clinical examination – look for primary in breast, lungs, abdomen, pelvis; lymph node biopsy if enlarged (lymphoma)
2. Chest X-ray
3. Pleural fluid cytology
4. Tumor markers – CEA, CA-125 (females) and CEA, PSA (males)
5. Fiber optic bronchoscopy
6. Thoracoscopy – if pleural fluid cytology is negative

• The best palliation for patients with malignant pleural effusion with complete lung expansion after chest tube drainage is pleurodesis.
• Talc has better results in pleurodesis than bleomycin and tetracycline.
• Patients with incomplete lung expansion after chest tube drainage may be treated with a pleuro peritoneal shunt or an indwelling pigtail catheter.
• Palliative chemotherapy may be offered to patients with good performance status

Radiotherapy Protocols

Radical Radiotherapy

Indications – in early NSCLC – medically unfit for surgery or patient refusing surgery.
        60-65 Gy / 33-36 fr / 6-7 weeks
        Phase I : 40 Gy / 20 fr across the mediastinum
        Phase II : 10 Gy / 6 fr / 2 cm margin (spinal cord shielding)
        Phase III : 10-15 Gy / 1 cm margin
        Supraclavicular fossa is included as primary coverage in upper lobe tumors.

Palliative Radiotherapy

Indications – unresectable disease
        KPS > 60%
        39Gy / 13 fr / 2.5 weeks
        Phase I : 30Gy / 10 fr / 2 weeks / maximum margin 2 cm
        Phase II : 9Gy / 3 fr / 3 days / spinal cord shielding
        KPS = 60%
        10Gy / 1 fr / 1 day (or) 17Gy / 2 fr / 1 week (or) 20Gy / 5 fr / 1 week
        (No difference in IAEA pilot study)
        Supra clavicular fossa is not included in the field.

Postoperative Radiotherapy

Indications – Positive margins and residual disease
        50-54Gy / 25-27 fr / 5-6 weeks
        Phase I : 40Gy / 20 fr across the mediastinum
        Phase II : 10-14Gy / 5-7 fr / 2 cm margin (spinal cord shielding)

Metastatic Disease
Parenchymal Brain Metastases
        30Gy / 10 fr / 2 weeks
        Low performance score – 20Gy / 5 fr / 1 week

Spinal Cord Compression
        30Gy / 10 fr / 2 weeks (or) 20Gy / 5 fr / 1 week
        (along with steroids and supportive care)

Painful bone metastases
        Single fr : 6-8Gy / 1 fr
        Multiple fr : 30Gy / 10 fr / 2 weeks (or) 20Gy / 5 fr / 1 week
        Rarely, hemibody irradiation may be used for multiple bone metastases

Endobronchial Radiotherapy
Indications – salvage treatment for recurrent / residual endobronchial lesion.
        7.5Gy / fr X 2 fr 1.2 weeks apart 1 cm off axis.

Superior Vena Cava Syndrome
        20Gy / 5 fr / 1 week – assess the response
        20Gy / 10 fr / 2 weeks with reduced fields
        (along with steroids and supportive care)

Small Cell Lung Cancer

Small cell lung cancer (SCLC) represents a distinct entity that is biologically and clinically different from Non Small cell Lung cancer. It is an aggressive cancer with a rapid proliferation index thereby making it very chemosensitive.

SCLC is staged according to the International Association for Study of Lung Cancer, into Limited stage disease (LD) and Extensive stage disease (ED).

Limited stage disease (LD) is defined as disease restricted to one hemithorax, with or without involvement of ipsilateral regional nodes including hilar, mediastinal and supraclavicular. It also includes involvement of contralateral mediastinal and supraclavicular nodes and an ipsilateral pleural effusion.

Disease more extensive than described above is considered Extensive stage disease (ED).

Management of LD SCLC

Patients with LD SCLC are treated for potential cure with chemoradiotherapy. The standard treatment of LD SCLC is concurrent radiation therapy with cisplatin based chemotherapy. (Level IIa, Grade B)

Role of chemotherapy
SCLC are known to be chemosensitive tumours and have shown good response rates with cisplatin based chemotherapy. Current standard chemotherapeutic protocol is to give 4-6 cycles of cisplatinum and etoposide based regimen. (Level IIa)

However, even with this protocol- though response rates were as high as 70-80% (including 50% complete responses), most patients still die of tumour progression/recurrence.

Therefore, newer chemotherapeutic regimens with dose intensification were attempted. These showed very high toxicities with no documented significant increase in survival in all phase II-III studies. (Level Ib, Grade A)

Role of Radiation therapy (RT) in LD SCLC
In patients treated with chemotherapy alone, locoregional failure in the thorax occurs in upto 80% of patients with SCLC.

RT was accepted as a part of combined modality approach as a result of 2 meta-analyses which clearly showed an improvement in local control with subsequent improvement in overall survival (Level Ia, Grade A). Thoracic RT should be administered early, i.e during the 1st or 2nd cycle of chemotherapy at curative doses to achieve increase in the overall survival. (Level Ib, Grade A)

Role of Surgery
Surgery plays a much less definitive role in SCLC as compared to NSCLC.

The available data indicate that surgery can be useful in T1, T2 tumours without nodal involvement. For small lesions, surgery can also be considered as first line treatment followed by chemotherapy.
(Level IV, Grade C)

Role of Prophylactic Cranial Irradiation (PCI)
The central nervous system is a frequent site for metastases in SCLC (about 50% of isolated metastases) which results in significant morbidity.

In a meta-analyses performed by the Collaborative Group, PCI showed an absolute increase of 5.4% in 3 year survivals with an increase of 8.8% in the disease free survival. (Level Ia, Grade A) However the role of PCI, regarding the timing, dose and fractionation, eligibility of patients and neurological toxicity remains unclear.

In conclusion, the standard accepted treatment for LD SCLC of the lung is concurrent chemoradiation (platinum based) with emphasis on an early start of thoracic radiation. Surgery has a small role to play in small peripherally located tumours.

Management of Extensive stage SCLC
Platinum based chemotherapy remains the mainstay of management of ED SCLC.
Two meta-analyses have clearly indicated the superior role of cisplatinum based chemotherapy regimens as compared to other agents.
(Level Ia, Grade A)

Carboplatin can also be used as an alternative to cisplatin, with no difference in efficacy or toxicity. The usual course of management is to give 4 cycles of cisplatin/carboplatin with etoposide. There is no evidence for the use of maintenance therapy in ED SCLC outside of a trial setting. (Level Ib, Grade A) Further, there is no evidence for the use of dose intensification or change of chemotherapeutic agent. Trials have shown no increase in survivals with the above measures.

Management of refractory/relapsed ED SCLC
Inspite of being very chemosensitive, the progression free survival in ED SCLC, after chemotherapy, is only 4 months. Most patients will relapse and the prognosis of such patients is very poor.

For patients relapsing after 3 months from completion of induction treatment the same protocol as induction can be repeated. For patients who relapse within 3 months of induction, or for refractory disease, 2nd line chemotherapy should be given. (Level IV, Grade C) Topotecan used as a single agent is at present the best option available.
(Level Ib, Grade A)

Surgery plays no role in management of ED SCLC.

In all cases of ED SCLC supportive care should include, radiation therapy for bony metastases and the management of paraneoplastic syndromes.

In conclusion, as ED SCLC is a disease with a poor prognosis to begin with and complete treatment will increase survival only by 8-10 months, good patient selection is of utmost importance. Age and performance status form important patient selection criteria. In fit patients, chemotherapy is the standard of care.

Role of screening in lung cancer
Screening for lung cancer is a volatile issue in international medical forums and amongst the general public. Current evidence does not support lung cancer screening with chest radiography or sputum cytology. Six randomized controlled trials and a meta analysis do not support frequent screening with chest radiography or sputum cytology. In fact, the ‘most definitive’ Mayo Lung Project had a non-significant higher mortality in the screened arm. The conundrum of improved survival and higher mortality has been explained by lead-time bias, length-time bias and overdiagnosis bias. Although many of these trials have been criticized (predominantly by advocates of screening) on grounds of inadequate study power and imperfect methodology, it is clear that chest radiography and sputum cytology have no role in screening protocols. Newer methods of diagnosis including low-dose spiral CT and biological markers in exhaled air have not been evaluated in prospective randomized trials.

Current evidence does not support screening with chest radiography or sputum cytology as an intervention to reduce mortality from lung cancer. (Level Ia, Grade A)

Management Algorithm For Non Small Cell Lung Cancer (NSCLC)

Management Algorithm For Non Small Cell Lung Cancer