7 - Carcinoma of the Lung

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 7 - Carcinoma of the Lung

Chapter 7

Carcinoma of the Lung

Sophie Sun

Joan H. Schiller

Carcinoma of the lung is responsible for more than 165,000 deaths each year in the United States. This represents one third of all deaths due to cancer and more than the number of deaths due to breast, colon, and prostate cancers combined. Lung cancer consists of four major histologic types: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma. Because of the unique biologic features of small cell lung cancer (SCLC), its staging and treatment differ radically from those of the other three types of lung cancer, which are collectively called non small cell lung cancer (NSCLC). Therefore, these two groups are addressed in two separate sections.

I. Etiology

Lung cancer is predominantly a disease of smokers. Eighty-five percent of lung cancer occurs in active or former smokers, and an additional 5% of cases are estimated to occur as a consequence of passive exposure to tobacco smoke. Tobacco smoke causes an increased incidence of all four histologic types of lung cancer, although adenocarcinoma (particularly the bronchoalveolar variant) is also found in nonsmokers. Other risk factors for lung cancer include exposure to asbestos or radon. Familial factors such as polymorphisms in carcinogen-metabolizing hepatic enzyme systems may also play a role in determining an individual's propensity to develop lung cancer.

II. Molecular biology

Numerous genetic changes have been associated with lung tumors. Most common among these include activation or overexpression of the myc family of oncogenes in SCLC and NSCLC and of the K-ras oncogene in NSCLC, particularly adenocarcinoma. Inactivation or deletion of the p53 and retinoblastoma tumor suppressor genes and a tumor suppressor gene on chromosome 3p (the FHIT gene) have been found in 50% to 90% of patients with SCLC. Abnormalities of p53 and 3p have been associated with 50% to 70% of cases of NSCLC. The K-ras mutation is more frequently found in smokers, those with adenocarcinoma, and those with poorly differentiated tumors. It is also associated with poor prognosis.

Recently, abnormalities in the epidermal growth factor (EGF) pathway have been identified, making this pathway an attractive target for anticancer therapy. The epidermal growth factor receptor (EGFR) is frequently expressed or overexpressed in NSCLC tumors. Binding of ligand to the EGFR causes dimerization of the receptor, which in turn activates tyrosine kinase on the intracellular domain of the receptor. Autophosphorylation of the receptor induces a cascade of intracellular events leading to cell proliferation, inhibition of apoptosis, angiogenesis, and invasion, all resulting in tumor growth and spread. Inhibition of the EGFR pathway leads to apoptosis and tumor regression in preclinical models. Hence, the EGFR, ligands, and signaling pathway have become active targets for anticancer therapy. Agents targeting

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this pathway include EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib; monoclonal antibodies to EGFR, which block ligand binding to EGFR (e.g., cetuximab); and antisense oligonucleotides, which inhibit the expression of EGFR by basepair hybridization with its messenger ribonucleic acid. Mutations and overexpression of the receptor have been described and may predict response to therapy. Of the EGFR inhibitors, gefitinib and erlotinib have been the most studied and are discussed in the subsequent text.

III. Screening

Three U.S. randomized screening studies in the 1980s failed to detect an impact on mortality of screening high-risk patients with chest radiography or sputum cytology, although earlier-stage cancers were detected in the screened groups. Since then, however, low-dose spiral computed tomography (CT) has emerged as a possible new tool for lung cancer screening. Spiral CT is CT imaging in which only the pulmonary parenchyma is scanned, thereby negating the use of IV contrast medium and the necessity for the presence of a physician. This type of scan can usually be done quickly (within one breath) and involves low doses of radiation. In a nonrandomized controlled study from the Early Lung Cancer Action Project, low-dose CT was shown to be more sensitive than chest radiography in detecting lung nodules and lung cancer at an early stage. However, despite these promising results, it is unclear whether screening with spiral CT will result in a reduction in lung cancer mortality. Concerns include issues related to lead-time bias, length-time bias, and overdiagnosis . In addition, in some geographic regions, such as the Midwest United States, the incidence of benign nodules is extremely high, making the cost of the test with subsequent follow-up testing very expensive. To help resolve the issue, the National Cancer Institute has recently completed a large randomized controlled trial (the Lung Screening Study), involving approximately 50,000 participants over several years, and results are awaited.

IV. Non small cell lung cancer

A. Histology

Although histologic differences (adenocarcinoma vs. large cell carcinoma vs. squamous cell carcinoma) among the NSCLCs affect their natural history and presentation, these differences are of relatively little importance in determining patient management, with two possible exceptions. First, bronchioalveolar carcinoma, a disease which presents in two forms (nodular and diffuse) tends to occur in younger women who have never smoked, which is a subgroup of patients that is more likely to derive benefit from EGFR inhibitors. Secondly, patients with squamous cell carcinoma are more likely to develop hemoptysis with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF) (Section IV.D.3.c).

B. Staging

The prognosis and treatment of NSCLC are dependent primarily on the stage of disease at the time of diagnosis. The current TNM definitions and staging system are shown in Table 7.1 and 7.2. Items of note: a pulmonary nodule within the same lobe of the primary is staged as T4, whereas if it is in a different lobe, it is M1; a bloody or exudative pleural effusion is T4 even if it is cytology negative. Patients with wet stage IIIB NSCLC have a prognosis similar to those

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patients with metastatic disease, and are therefore often included in advanced NSCLC trials, whereas dry stage IIIB patients are usually included in locally advanced trials.

Table 7.1. TNM definitions

Primary tumor (T)
TX Tumor proved by the presence of malignant cells in bronchopulmonary secretions but not visualized roentgenographically or bronchoscopically or any tumor that cannot be assessed, as in a retreatment staging
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 A tumor that is 3 cm in the greatest dimension, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy
T2 A tumor >3 cm in the greatest dimension or a tumor of any size that either invades the visceral pleura or has associated atelectasis or obstructive pneumonitis extending to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be within a lobar bronchus or at least 2 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung
T3 A tumor of any size with direct extension into the chest wall (including superior sulcus tumors), diaphragm, or the mediastinal pleura or pericardium without involving the heart, great vessels, trachea, esophagus, or vertebral body or a tumor in the main bronchus within 2 cm of the carina without involving the carina
T4 A tumor of any size with invasion of the mediastinum or involving the heart, great vessels, trachea, esophagus, vertebral body, or carina, or presence of malignant pleural effusion; a satellite nodule within the same lobe
Nodal involvement (N)
N0 No demonstrable metastasis to regional lymph nodes
N1 Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region or both, including direct extension
N2 Metastasis to ipsilateral mediastinal lymph nodes or subcarinal lymph nodes or both
N3 Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or contralateral scalene or supraclavicular lymph nodes
Distant metastasis (M)
MX Cannot be assessed
M0 No distant metastasis
M1 Distant metastasis, including pulmonary nodule not in the same lobe as the primary tumor

Table 7.2. 1997 Revisions to the international staging classification for lung cancer

Stage TNM Subset 5-year Survival Rate (%)
Clinical Stage Pathologic Stage
IA T1, N0, M0 61 67
IB T2, N0, M0 38 57
IIA T1, N1, M0 34 55
IIB T2, N1, M0
T3, N0, M0
24 39
IIIA T3, N1, M0
T1 3, N2, M0
9 25
IIIB T4, any N, M0
Any T, N3, M0
13 23
IV Any T, any N, M1 1
From Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710 1717.

C. Pretreatment evaluation

The diagnosis of lung cancer is usually made by bronchial biopsy or percutaneous needle biopsy. Although the disease is usually discovered on chest radiographs, a CT scan of the chest is necessary to evaluate the extent of the primary disease, mediastinal extension, or lymphadenopathy, and the presence or absence of other parenchymal nodules in patients in whom surgical resection is a consideration. CT of the upper abdomen is performed to look for asymptomatic hepatic or adrenal metastases. (The latter should be distinguished from benign adrenal adenomas.) Bone scans should be obtained for the patient with bone pain, chest pain, or an elevated calcium or alkaline phosphatase level. Head CT or magnetic resonance imaging is not routinely done in the absence of central nervous system (CNS) signs or symptoms.

Mediastinal nodal metastasis is a critical factor in determining tumor resectability. Mediastinoscopy has long been considered the gold standard for mediastinal staging and has been recommended for mediastinal lymph nodes greater than 1 cm on CT scan. Recently, however, positron emission tomography (PET), ametabolic imaging scan using [18F]fluorodeoxyglucose, has been developed as a useful complementary tool for staging. PET scans are more sensitive and specific than CT scans and could therefore potentially save patients with advanced disease, either within or outside the chest, from unnecessary invasive procedures. However, it is not yet clear as to whether PET scanning can replace mediastinoscopy, as the scan can be falsely positive in inflammatory processes and

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falsely negative in lung tumors with low metabolic activity such as bronchoalveolar carcinoma or carcinoid tumors.

Pulmonary function testing is necessary before definitive surgery. Increased postoperative morbidity is associated with a predicted postoperative 1-second forced expiratory volume of less than 800 to 1,000 mL, a preoperative maximum voluntary ventilation less than 35% of that predicted, a carbon monoxide diffusing capacity less than 60% of that predicted, and an arterial oxygen pressure (PO2) of less than 60 mm Hg or a carbon dioxide pressure (PCO2) of more than 45 mm Hg.

D. Management

  • Early stage NSCLC

    • Stage I disease. Lobectomy is the primary treatment for stage I NSCLC, with cure rates of 60% to 80%. In patients with medical contraindications to surgery but with adequate pulmonary function, high-dose radiotherapy results in cure in approximately 20% of patients. Patients with T2, N0 (stage IB) disease do not fare as well as those with T1, N0 (stage IA) cancers. Adjuvant (postoperative) chemotherapy has been of interest because a meta-analysis in 1995 showed a borderline statistically significant survival benefit with surgery and chemotherapy as compared with surgery alone (p = 0.07). Recent randomized clinical trials using adjuvant platinum-based doublet chemotherapy have demonstrated significant survival advantage in early stage patients (Table 7.3). A Cancer and Leukemia Group B trial (CALGB 9633) of patients with completely resected stage IB NSCLC randomized patients to four cycles of adjuvant carboplatin plus paclitaxel or observation. In a reported preliminary planned interim analysis, adjuvant chemotherapy was associated with a significant improvement in 4-year overall survival (71% vs. 59%). A recently published National Cancer Institute of Canada trial (NCIC JBR.10) of patients with stages IB and II (excluding T3, N0) NSCLC randomly assigned to surgery alone or followed by four cycles of cisplatin and vinorelbine reported a 15% absolute improvement in overall survival at 5 years (69% vs. 54%) in patients with stages IB to IIIA disease, favoring the chemotherapy arm.

      The evidence for adjuvant chemotherapy for patients with resected stage IA disease is less clear. A Japanese trial of stage INSCLC patients (73% stage IA; 27% stage IB) randomized patients to an oral 5-fluorouracil derivative (tegafur plus uracil, UFT) versus surgery alone. The results showed a modest but significantly improved 5-year survival in the UFT group (88% vs. 85%). However, in subgroup analysis, the improved 5-year survival was observed with stage IB patients (5-year survival 85% vs. 74%) with no difference in stage IA disease (5-year survival 89% vs. 90%). UFT is currently not available in North America. Given these data, it is reasonable to offer adjuvant platinum-based doublet chemotherapy to patients with completely resected stage IB disease and with good performance status until more definitive

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      results are reported. Additional studies are needed for stage IA disease before adjuvant therapy can be routinely recommended for this group of patients.

      Table 7.3. Randomized studies of adjuvant chemotherapy for resected non small cell lung cancer

      Trial Patient Population (Stage) No. of Patients   Chemotherapeutic Regimen Absolute Overall Survival Benefit
      CALGB 9633 (2004) IB 344 Carboplatin
      Paclitaxel
      AUC 6, on day 1
      200 mg/m2 IV on day 1 every 3 weeks x four cycles
      12% (4-year)
      NCIC JBR.10 (2005) IB, II 482 Cisplatin
      Vinorelbine
      50 mg/m2 IV on days 1, 8 every 4 weeks x 4 cycles
      25 mg/m2 IV weekly x 16
      15% (5-year)
      ANITA (2005) IB, II, IIIA 840 Cisplatin
      Vinorelbine
      100 mg/m2 IV on day 1 every 4 weekly x four cycles
      30 mg/m2/weeks IV x 16
      9% (5-year)
      8% (7-year)
      IALT (2004) I, II, IIIA 1867 Cisplatin 80 mg/m2 IV on days 1, 22, 43, 64
      100 mg/m2 IV on days 1, 29, 57
      5% (4-year)
      (options) 100 mg/m2 IV on days 1, 29, 57, 85
      120 mg/m2 IV on days 1, 29, 71
      Vindesine 3 mg/m2 IV weekly days 1 29, then every 2 weeks after days 43 until last cisplatin
      or
      Vinblastine 4 mg/m2 IV weekly days 1 29, then every 2 weeks after days 43 until last cisplatin
      or
      Vinorelbine 30 mg/m2 IV weekly day 1 to last cisplatin
      or
      Etoposide 100 mg/m2 IV on days 1 3 with each cisplatin
      CALGB, Cancer and Acute Leukemia Group B; NCIC, National Cancer Institute of Canada; ANITA, Adjuvant Navalbine International Trialist Association; IALT, International Adjuvant Lung Cancer Trial

      Patients with resected stage I NSCLC are at high risk for the development of second lung cancers (~2% 3% per year). Neither vitamin A nor its derivatives, -carotene or cis-retinoic acid, have been found to have any benefit in chemoprevention, and contrary to predictions, may even be deleterious. Other agents, such as selenium, are under investigation.

    • Stage II disease. Surgical resection is a standard component of the treatment for stage II NSCLC. The subset of T3, N0 disease has a natural history and treatment strategy different from those of stage III N2 disease and has therefore been moved to stage II. Patients with peripheral chest wall invasion should undergo resection of the involved ribs and underlying lung. Chest wall defects are then repaired with chest wall musculature or Marlex mesh and methylmethacrylate. Postoperative radiotherapy is often given. Five-year survival rates as high as 50% have been reported.

      Recent randomized trials have demonstrated a role for adjuvant chemotherapy after resection for patients with stage II NSCLC (Table 7.3). One of the first positive trials published in 2004 by the International Adjuvant Lung Cancer Trial (IALT) Collaborative Group randomly assigned patients with completely resected NSCLC (pathologic stage I to IIIA) to surgery alone or surgery plus three to four cycles of a cisplatin-containing doublet. The choice of doublet (cisplatin plus either etoposide, vinblastine, vinorelbine, or vindesine) and the use of adjuvant thoracic radiotherapy was decided at the level of each participating institution. The study demonstrated an improvement in overall survival of 5% (45% vs. 40%) at 5 years in favor of chemotherapy. The results of the Adjuvant Navelbine International Trialist Association (ANITA) trial (ANITA) trial have provided further support for adjuvant chemotherapy. In this study, patients with stage IB to IIIA NSCLC were randomized to surgery alone as compared with cisplatin plus vinorelbine for four cycles. In a preliminary report, overall survival was significantly improved at 5 years (51% vs. 43%), although the survival benefit was restricted to patients with stage II and IIIA disease. These data, in combination with the results of the NCIC trials detailed in the preceding text, have led to the recommendation to offer patients adjuvant platinum-based chemotherapy following complete resection of pathologic stage IB, II, and IIIA NSCLC.

  • Locally advanced (stage IIIA and IIIB) disease. Treatment of locally advanced NSCLC is one of the most controversial issues in the management of lung cancer. Interpretation of the results of clinical trials involving patients with locally advanced disease has been clouded by a number of issues including changing diagnostic techniques,

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    different staging systems, and heterogeneous patient populations that may have disease that ranges from nonbulky stage IIIA (clinical N1 nodes, with microscopic N2 nodes discovered only at the time of surgery or mediastinoscopy) to bulky N2 nodes (enlarged adenopathy clearly visible on chest radiographs or multiple nodal level involvement) to clearly inoperable stage IIIB disease.

    • Nonbulky stage IIIA disease. The optimal treatment for nonbulky stage IIIA is controversial. Current investigational efforts are directed at identifying the optimal combined-modality approach, involving treatments directed at local control of the disease (surgery or radiotherapy) and micrometastatic disease (chemotherapy). Possibilities include surgery followed by adjuvant chemotherapy; preoperative chemotherapy plus surgery; or chemotherapy plus radiotherapy.

      The primary treatment of stage II and early stage IIIA (clinical N0 or N1) disease is surgical resection. However, even with a complete resection, the cure rate is disappointing, prompting investigation of adjuvant chemotherapy and radiotherapy. Postoperative radiotherapy has been shown to reduce local recurrences after resection of stage II or III squamous cell carcinoma of the lung but does not prolong survival. Randomized studies with adjuvant cisplatin-based doublet chemotherapy have confirmed an overall survival benefit of 5% to 15% at 5 years and this is now routinely offered to good performance status patients with resected stage II or IIIA NSCLC.

      Although patients with N2 disease are also usually treated with combined chemoradiation therapy, there have been studies looking at the role of surgery in this disease. Two small positive randomized studies involving more than 40 patients, compared surgery with or without preoperative chemotherapy in this patient population. In a European study, preoperative chemotherapy (mitomycin, ifosfamide, and cisplatin for three courses) followed by surgery was compared with surgery without preoperative chemotherapy in patients with stage IIIA disease. All patients also received postoperative mediastinal radiotherapy after surgery. The median survival time was 26 months for 30 patients receiving preoperative chemotherapy plus surgery compared with 8 months for 30 patients treated with surgery alone.

      Investigators at the M.D. Anderson Cancer Center randomized patients to surgery or three cycles of cyclophosphamide, etoposide, and cisplatin followed by surgery and three cycles of postoperative chemotherapy. The median survival time of the 32 patients randomized to the surgery-alone group was 14 months compared with 21 months in the 28 patients randomized to the combined-modality arm.

      In a larger randomized trial, French investigators compared preoperative mitomycin, ifosfamide, and cisplatin plus surgery with surgery alone in 355 patients

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      with resectable stage I (except T1, N0), stage II, and stage IIIA (including N2 disease). The difference in median survival between two arms was not statistically significant (37 vs. 26 months; p = 0.15). However, subset analysis suggested a survival advantage of neoadjuvant chemotherapy for N0 to N1 but not N2 disease.

      Trimodality therapy has also been explored in a randomized intergroup trial, where patients with advanced stage IIIA disease receive 45 Gy of induction radiotherapy plus two cycles of cisplatin and etoposide and are subsequently randomized to surgery or boost radiotherapy plus an additional two cycles of chemotherapy. In a planned second interim analysis, there was significant improvement in progression-free survival at 5 years for the trimodality arm (22% vs. 11%; p = 0.017) and although there was a trend for better 5-year overall survival with trimodality therapy, this was not significant (27% vs. 20%; p = 0.10). There were greater treatment-related mortalities in the surgery arm compared with the chemoradiation-alone arm (8% vs. 2%), with most deaths occurring in patients undergoing pneumonectomy. The role of trimodality therapy for stage IIIA NSCLC remains controversial because of treatment-related morbidity and mortality, particularly for patients requiring right-sided pneumonectomy.

      Several studies have shown, in subset analysis, that those patients receiving neoadjuvant therapy who subsequently have their N2 nodes cleared with preoperative therapy do better than those who do not. This has prompted some investigators to give preoperative treatment and then resample the N2 nodes. If positive, the thorax is closed and patients go on to receive definitive chemoradiation. However, if the nodes have turned negative, the patient goes on to have definitive surgery. Of note, patients undergoing a right pneumonectomy following chemoradiation have a mortality rate of up to 20% in some series.

      As of this writing, there is no level 1 evidence to recommend neoadjuvant chemotherapy over adjuvant chemotherapy, although several theoretical reasons for doing so include the fact that patients are more likely to tolerate preoperative chemotherapy over postoperative chemotherapy. Results from randomized studies are awaited.

    • Pancoast tumors. Pancoast tumors are upper-lobe tumors that adjoin the brachial plexus and are frequently associated with Horner syndrome or shoulder and arm pain; the latter is due to rib destruction, involvement of the C8 or T1 nerve roots, or both. Treatment consists of a combined-modality approach with radiotherapy and surgery. Five-year survival rates range from25% to 50%. Combined preoperative chemotherapy and radiotherapy is being studied.

    • Bulky stage IIIA (N2) and stage IIIB with no pleural effusion. Bulky stage IIIA and IIIB are generally considered unresectable, with the treatment

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      consisting of combined chemoradiation or, in the case of stage IIIB with malignant pleural effusion, chemotherapy alone.

      Chemotherapy plus radiation therapy. Chemotherapy plus radiotherapy is the treatment of choice for patients with bulky or inoperable stage IIIA or IIIB disease without pleural effusion. Numerous randomized studies have demonstrated an improvement in median and long-term survival with chemotherapy plus by radiation therapy versus radiotherapy alone. Active areas of investigation include proper sequencing of thoracic radiation therapy and chemotherapy (concurrent vs. sequential), choice of chemotherapy, fractionation, and treatment fields.

      A randomized Japanese trial reported a 3-month survival advantage with concurrent chemoradiation over a sequential approach. Initial reports from a confirmatory randomized Radiation Therapy Oncology Group trial also showed a trend in favor of concurrent cisplatin and vinblastine with radiation over sequential chemoradiation, albeit with more toxicities, making concurrent chemoradiation therapy the treatment of choice for good performance status patients.

      Chemotherapy can be given in full systemic doses with radiotherapy, in weekly radiosensitizing doses, or a combination of both. One of the most commonly used chemotherapeutic regimens for stage III NSCLC is carboplatin in combination with paclitaxel (Table 7.4). Although single-agent weekly carboplatin has not resulted in a survival benefit when given with radiotherapy, weekly doses of paclitaxel 50mg/m2 and carboplatin AUC 2 with concurrent radiation have proved promising in randomized phase II studies.

      Other areas of investigation include the role of standard systemic doses of chemotherapy either before or after concurrent weekly radiosensitizing chemotherapy with radiotherapy. In a phase III trial, the CALGB did not show a survival benefit when induction chemotherapy was given before weekly low-dose chemoradiation therapy compared with weekly low-dose chemoradiation therapy alone. However, a randomized phase II Southwest Oncology Group (SWOG) trial showed promising results with standard dose chemoradiation therapy (cisplatin and etoposide) followed by docetaxel. These results need to be confirmed in phase III studies.

  • Stage IV disease. Chemotherapy improves survival in patients with metastatic NSCLC (~10% 1-year survival rate in untreated patients vs. 30% to 35% 1-year survival rate with treatment). Goals for treatment should include palliation of symptoms and a modest improvement in survival.

    The principal factors predicting response to chemotherapy and survival are performance status and extent of disease. Patients with a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 2 to 4) are less likely to respond to treatment and

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    they tolerate the therapy poorly, although recent subset retrospective analysis have suggested that performance status 2 patients may also enjoy a modest benefit in survival with treatment. Favorable prognostic factors include no weight loss, female sex, normal serum lactic dehydrogenase level, and no bone or liver metastases.

    Table 7.4. Chemotherapeutic regimens for concurrent chemoradiation for stage III non small cell lung cancer

    Induction Chemotherapy (Concurrent with Radiation)   Consolidation Chemotherapy  
    EP
    Etoposide 50 mg/m2 days 1 5, 29 33 Etoposide 50 mg/m2 IV on days 1 5 every 3 weeks x two cycles
    Cisplatin 50 mg/m2 days 1, 8, 29, 36 Cisplatin 50 mg/m2 IV on days 1, 8 every 3 weeks x two cycles
    EP followed by docetaxel
    Etoposide 50 mg/m2 days 1 5, 29 33 Docetaxel 75 100 mg/m2 IV every 3 weeks x three cycles
    Cisplatin 50 mg/m2 days 1, 8, 29, 36 - Starting 4 6 weeks after induction therapy
    Carboplatin plus paclitaxel
    Carboplatin AUC 2 weekly Carboplatin AUC 6, on days 1 every 3 weeks x two cycles
    Paclitaxel 50 mg/m2 over 1 h weekly Paclitaxel 200 mg/m2 IV on days 1 over 3 h every 3 weeks x two cycles
    EP, etoposide and platinum (cisplatin); AUC, area under the curve.

    • First-line chemotherapy. Chemotherapy for patients with metastatic NSCLC and a good performance status should be a chemotherapeutic regimen consisting of two drugs. A meta-analysis of large randomized trials indicated that there is a small but significant survival advantage with platinum-based therapy compared with best supportive care. Whereas best supportive care resulted in median survival rates of 4 to 5 months and 1-year survival rates of 5% to 10%, current third-generation regimens with paclitaxel and docetaxel, gemcitabine, vinorelbine, and irinotecan have yielded median survivals of 8 to 9 months and 1-year survivals of 35% to 40%. In addition, randomized studies have shown an improvement in symptoms and quality of life compared with patients treated with best supportive care.

    • Choice of chemotherapy. Numerous randomized studies have failed to show a major advantage of one

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      new doublet regimen over another. The common chemotherapeutic regimens for NSCLC are shown in Table 7.5.

      Although a direct comparison of cisplatin-based therapies and carboplatin-based therapies is limited, metaanalysis has suggested that cisplatin may have a small benefit in terms of survival over carboplatin, albeit with a different toxicity profile. Whereas this small difference may be of limited clinical consequence for patients with metastatic disease, it may be more important in the adjuvant setting, where cure is the goal.

      Table 7.5. Common chemotherapeutic regimens for metastatic non small cell lung cancer

      Cisplatin plus vinorelbine
      Cisplatin 100 mg/m2 IV on day 1
      Vinorelbine 25 mg/m2 weekly
      Repeat cycle every 4 weeks
      Carboplatin/paclitaxel plus bevacizumaba
      Carboplatin AUC of 6 on day 1
      Paclitaxel 225 mg/m2 IV on day 1 over 3 h
      Repeat cycle every 3 weeks
      Bevacizumaba 15 mg/kg IV every 3 weeks until progression
      Cisplatin/carboplatin plus gemcitabine
      Cisplatin 100 mg/m2 IV on day 1
      Gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15
      Repeat each cycle every 4 weeks
      or
      Cisplatin 80 mg/m2 IV on day 1
      Gemcitabine 1,250 mg/m2 IV on days 1 and 8
      Repeat each cycle every 3 weeks
      or
      Carboplatin AUC of 5 on day 1
      Gemcitabine 1,000 mg/m2 IV on days 1 and 8
      Repeat each cycle every 3 weeks
      Cisplatin/carboplatin plus docetaxel
      Cisplatin 75 mg/m2 IV on day 1
      Docetaxel 75 mg/m2 IV on day 1
      Repeat each cycle every 3 weeks
      or
      Carboplatin AUC of 6 on day 1
      Docetaxel 75 mg/m2 IV on day 1
      Repeat each cycle every 3 weeks
      AUC, area under the curve.
      aPatients with brain metastases, squamous cell histology, on anticoagulants, or a recent history of thromboembolic events should NOT receive bevacizumab off of a clinical study

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    • Inhibitors of angiogenesis. Inhibition of angiogenesis is based on the observations that neovascularization occurs in tumor tissues and rarely in other physiologic processes except wound healing. Theoretical advantages for targeting angiogenesis include the fact that endothelial cells are diploid, nonmutated cells and therefore less likely to be able to develop resistance to drugs. Vascular endothelial growth factor (VEGF) is a potent stimulator for formation of new blood vessels. Through binding to its receptor (vascular endothelial growth factor receptor [VEGFR]) on endothelial cells, VEGF initiates biologic pathways leading to different events including endothelial cell proliferation and migration, remodeling of extracellular matrix, and tumor vascularization. Although many antiangiogenesis agents are under investigation, such as VEGFR tyrosine kinase inhibitors, the drug that has been shown to have survival benefit in NSCLC is the anti-VEGF monoclonal antibody bevacizumab (Avastin).

      Bevacizumab has been evaluated in a randomized ECOG trial in combination with standard cytotoxic chemotherapy for advanced NSCLC. In this recently reported trial, 878 chemona e patients with advanced NSCLC were randomized to receive carboplatin and paclitaxel with or without bevacizumab (15 mg/kg) every 3 weeks for six cycles. Bevacizumab was continued for up to 1 year in patients with nonprogressing disease. Patients with squamous cell histology, brain metastases, history of bleeding or hemorrhagic disorders, and individuals on anticoagulation were excluded on the basis of phase II data showing increased hemorrhagic events as a complication with bevacizumab therapy. The study demonstrated an improvement in median survival (12.5 vs. 10.2 months; p = 0.007), overall response rates (27.2% vs. 10.0%) and progression-free survival (6.4 vs. 4.5 months), favoring the bevacizumab arm.

    • Duration of therapy. Four randomized studies failed to show a survival difference with prolonged (more than six) cycles of chemotherapy compared with a fewer (four to six) number of cycles. Therefore, continuing chemotherapy until progression cannot be routinely recommended.

    • Doublets versus triplets . Most randomized trials have failed to demonstrate a survival advantage of three drugs over two, and have been at the expense of enhanced toxicity. Therefore, three-drug regimens cannot be routinely recommended outside of a clinical trial.

    • Non platin-based regimens. Given the toxicities associated with cisplatin, there is considerable interest in combining two nonplatin drugs. Most recent randomized trials have failed to show a significant difference in survival with platin regimens compared with non platin-based regimens, although the toxicity profile is different.

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    • Isolated brain metastases. In patients with controlled disease outside of the brain who have an isolated cerebral metastasis in a resectable area, resection followed by whole-brain radiotherapy is superior to whole brain radiotherapy alone.

  • Second-line chemotherapy. Docetaxel, pemetrexed, and erlotinib are currently approved by the U.S. Food and Drug Administration (FDA) for second-line monotherapy for patients with metastatic NSCLC.

    • Docetaxel. There have been two randomized trials evaluating second-line docetaxel versus best supportive care in patients who have failed first-line therapy. Docetaxel at a dose of 75 mg/m2 every 3 weeks prolongs survival significantly in comparison with best supportive care and, in comparison with either vinorelbine or ifosfamide, improves time to progression and 1-year survival. Moreover, it also improves quality of life. It was noted that previous paclitaxel exposure did not affect patients' response to docetaxel, suggesting no cross-resistance between the two taxane agents.

    • Pemetrexed. Pemetrexed, a multi-targeted antifolate, has similar antitumor activity as docetaxel in the second-line setting, with less toxicity. In a randomized trial, patients were treated with pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 every 3 weeks and the overall response rates were similar (9.1% vs. 8.8% for pemetrexed and docetaxel, respectively) with no differences in median survival (8.3 vs. 7.9 months for pemetrexed and docetaxel, respectively). Docetaxel was associated with higher rates of neutropenia, neutropenic fever, and hospitalization due to neutropenic events or other drug-related adverse events as compared with pemetrexed.

    • EGFR tyrosine kinase inhibitors.

      • Gefitinib. Monotherapy with gefitinib has been investigated in two phase II multicenter trials: one conducted in the United States and the other primarily in Japan and Europe. Both studies included advanced NSCLC patients who failed at least one chemotherapeutic regimen. In the European/ Japanese study, 210 patients who had primarily one prior chemotherapy were randomly assigned to receive 250 or 500 mg of gefitinib orally daily. The overall response rate was 18.7%, with no difference between the two doses. In the U.S. study involving patients with two prior chemotherapeutic regimens, including docetaxel, the response rate was 11%. On the basis of these favorable results, gefitinib was subsequently approved in the United States in 2003 as third-line treatment of patients with NSCLC who have progressed either during or after therapy with platinum and docetaxel. However, the data of a large randomized trial of gefitinib 250 mg daily versus best supportive care have recently been published with negative results. In this trial of 1,692 patients with locally advanced or metastatic NSCLC who had received one or two prior chemotherapeutic regimens,

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        no survival benefit was seen with gefitinib treatment in the overall population (medial survival of 5.6 vs. 5.1 months for gefitinib and best supportive care, respectively). However, subgroup analysis showed significant benefit for patients of Asian origin and in nonsmokers (median survival 8.9 vs. 6.1 months; p = 0.012). Until 2005, the FDA has limited the use of gefitinib in patients with NSCLC who have previously taken gefitinib and who are or have benefited from its use.

      • Erlotinib. Erlotinib is a similar orally available tyrosine kinase inhibitor of EGFR. Single-agent treatment with erlotinib in the second- and third-line setting for metastatic NSCLC has been evaluated in a recently published randomized trial, BR21, from Canada. This study randomized 731 patients with stage IIIB or IV NSCLC who had failed one or two prior treatment regimens in a 2:1 ratio to receive erlotinib versus placebo. The overall response rate for erlotinib was 9% versus <1% for placebo (p < 0.001). Stable disease was observed in 35% of patients on the erlotinib arm as compared with 27% of patients on placebo. In contrast to the results with gefitinib, there was a significant improvement in progression-free survival (2.2 vs. 1.8 months; p < 0.001) and overall survival (6.7 vs. 4.7 months; p < 0.001), in favor of erlotinib. The reason for the different outcomes with erlotinib as compared to those with gefitinib is unclear. Possible explanations include differences in drug disease, patient demographics and/or intrinsic differences in drug activity.

        Clinical parameters that appear to predict response to these drugs include never-smoking history, East Asian ethnicity, adenocarcinoma, and female gender. However, in BR21, all patient subtypes derived a survival benefit, although the hazard ratio of 0.4 for never-smokers was significantly different statistically than the hazard ratio of 0.9 for smokers. (p 0.001). Mutations of the EGFR appear to predict dramatic response, while mutations and overexpression by fluorescent in situ hybridization (FISH) and immunohistochemistry also appear to predict for survival.

        Both gefitinib and erlotinib have been studied in the first-line setting in combination with cytotoxic chemotherapy. Randomized trials have demonstrated no benefit of adding either erlotinib or gefitinib to standard platinum-based doublet chemotherapy. Interestingly, in one of the studies, in a prospectively designed subset analysis, a subgroup of never-smokers treated with combined chemotherapy and erlotinib did significantly better as compared with treatment with chemotherapy alone.

V. Small cell carcinoma

SCLC differs from NSCLC in a number of important ways. First, it has a more rapid clinical course and natural history, with the rapid development

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of metastases, symptoms, and death. Untreated, the median survival time for patients with local disease is typically 12 to 15 weeks and for those with advanced disease, it is 6 to 9 weeks. Second, it exhibits features of neuroendocrine differentiation in many patients (which may be distinguishable histopathologically) and is associated with paraneoplastic syndromes. Third, unlike NSCLC, SCLC is exquisitely sensitive to both chemotherapy and radiotherapy, although resistant disease often develops. Because of the rapid development of distant disease and its extreme sensitivity to the cytotoxic effects of chemotherapy, this mode of therapy forms the backbone of treatment for this disease, irrespective of stage.

A. Staging

Although SCLC has a propensity to metastasize quickly and micrometastatic disease is presumed to be present in all patients at the time of diagnosis, this disease is usually classified into either a local or an extensive stage. Local disease is typically defined as disease that can be encompassed within one radiation port, usually considered limited to the hemithorax and to regional nodes, including mediastinal and ipsilateral supraclavicular nodes. Extensive-stage disease is usually defined as disease that has spread outside these areas.

B. Pretreatment evaluation

Common sites of metastases for SCLC include the brain, liver, bone marrow, bone, and CNS. For this reason, a complete staging workup has traditionally consisted of a complete blood cell count; liver function tests; CT of the brain, chest, and abdomen; a bone scan; and bone marrow aspiration and biopsy. However, this complete staging workup need not be undertaken unless the patient is a candidate for combined-modality treatment with chest radiation and chemotherapy, the patient is being evaluated for a clinical study, or the information is helpful for prognostic reasons. If the patient is not a candidate for combined-modality treatment or a clinical study, stopping the staging at the first evidence of extensive-stage disease is usually appropriate. Given that isolated bone marrow metastases are rare, bone marrow biopsies and aspirates are not usually done.

C. Prognostic factors

As in NSCLC, the major pretreatment prognostic factors are stage, performance status, and bulky disease. Hepatic metastases also confer a poorer prognosis. If the patient's initial poor performance status is due to the underlying malignancy, these symptoms often disappear quickly with treatment, resulting in a net improvement in quality of life. However, major organ dysfunction from nonmalignant causes often results in an inability of the patient to tolerate chemotherapy.

D. Therapy

A number of combination chemotherapeutic regimens are available for SCLC (Table 7.6). No clear survival advantage has been consistently demonstrated for any one regimen over another. With these chemotherapeutic regimens, overall response rates of 75% to 90% and complete response rates of 50% for localized disease can be anticipated. For extensive-stage disease, overall response rates of approximately 75% and complete response rates of 25% are common. Despite these high response rates, however, the median survival time remains approximately 14 months for limited-stage disease and 7 to 9 months for extensive-stage disease. Less

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than 5% of patients with extensive-stage disease survive for more than 2 years.

Table 7.6. Chemotherapeutic regimens for small cell lung cancer

Cisplatin-based regimens
Etoposide 120 mg/m2 IV on days 1 3 or
120 mg/m2 PO b.i.d. on days 1 3
Cisplatin 60 mg/m2 IV on day 1
or
Cisplatin 25 mg/m2 IV on days 1 3
Etoposide 100 mg/m2 IV on days 1 3
Repeat cycle every 3 weeks
Carboplatin-based regimens
Carboplatin 300 mg/m2 IV on day 1
Etoposide 100 mg/m2 IV on days 1 3
or
Carboplatin 100 mg/m2 IV on days 1 3
Etoposide 120 mg/m2 IV on days 1 3
Repeat cycle every 4 weeks
Irinotecan plus cisplatin
Irinotecan 60 mg/m2 IV on days 1, 8, and 15
Cisplatin 60 mg/m2 IV on day 1
Repeat cycle every 4 weeks

At present, either cisplatin or carboplatin, together with etoposide, is the standard of care in North America for the treatment of SCLC. In a randomized phase III study from Japan published in 2002, four cycles of irinotecan/cisplatin were compared with four cycles of etoposide/cisplatin. The enrollment was stopped early because of an interim analysis showing a clear survival benefit in the investigational arm, with a median survival of 12.8 months for the irinotecan/cisplatin group versus 9.4 months for the etoposide/ cisplatin group. The 1- and 2-year survival for the two groups were 58% and 19.5% versus 38% and 5%. A randomized trial from the United States has been conducted to confirm these results and the results have recently been reported. This study randomly assigned previously untreated patients with extensive-stage SCLC to etoposide/cisplatin or irinotecan/cisplatin and there was no difference in response rates, time to progression or median survival between the two treatment arms. Potential explanations as to why these results differed from the Japanese study include biologic differences in drug metabolism and activity between different study populations and/or dosing or scheduling of chemotherapy between the two studies.

  • Dose intensity. A dose intensity meta-analysis of chemotherapy in SCLC, which evaluated doses not requiring bone marrow transplantation support, showed no

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    consistent correlation between dose intensity and outcome. There have been several phase I and II clinical trials evaluating the role of marrow-ablative doses of chemotherapy with subsequent progenitor cell replacement (e.g., autologous bone marrow transplantation) with disappointing survival results. In a randomized phase III study, when compared with conventional-dose chemotherapy, high-dose regimen with stem cell support prolonged relapse-free, but not overall survival.

  • Duration of therapy. Most randomized studies do not show a survival benefit for prolonged administration of chemotherapy. Several studies have demonstrated no survival benefit of prolonged first-line treatment over treatment on relapse. The optimal duration of treatment for SCLC is 4 to 6 months.

  • Second-line therapy. No curative regimens for patients with recurrent disease have been identified. The only drug approved for second-line therapy of SCLC is topotecan, which has a 20% to 40% response rate in patients with sensitive SCLC (those patients in whom disease relapsed 2 to 3 or more months after the first-line therapy), with a median survival of 22 to 27 weeks. For patients with refractory disease (progressed through or within 3 months of completion of first-line therapy), the response rate in phase II studies is only between 3% and 11%. Median survival is approximately 20 weeks. Other agents including oral etoposide and the combination of cyclophosphamide, doxorubicin, and vincristine have been used with low response rates.

E. Chemotherapy plus chest irradiation

Numerous studies have been done with chemotherapy and thoracic radiotherapy for patients with limited-stage SCLC. Conflicting results have been attributed to differences in chemotherapeutic regimens and different schedules integrating chemotherapy and thoracic radiation (concurrent, sequential, and sandwich approach). Two meta-analyses concluded that thoracic irradiation does result in a small but significant improvement in survival and major control of the disease in the chest, although no conclusions could be made regarding the optimal sequencing of chemotherapy and thoracic radiation. In one randomized study, twice-daily hyperfractionated radiation was compared with a once-daily schedule; both were given concurrently with four cycles of cisplatin and etoposide. Survival was significantly higher with the twice-daily regimen (median survival of 23 vs. 19 months, 5-year survival of 26% vs. 16%), albeit at the expense of more grade 3 esophagitis. In another randomized trial, early administration of thoracic irradiation in the combined-modality therapy of limited-stage SCLC was superior to late or consolidative thoracic irradiation. These data suggest that patients with good performance status and with limited disease should receive concurrent chemoradiation, preferably with twice-daily hyperfractionation.

F. Prophylactic cranial irradiation

Most randomized trials failed to show that prophylactic brain irradiation enhanced survival but did demonstrate a decrease in the risk of brain metastases without a decrease in mental function. However,

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in a meta-analysis of seven randomized trials, prophylactic cranial irradiation was shown to significantly increase 3-year survival with a net gain of 5.4%. It also increased disease-free survival and decreased the risk of developing brain metastasis.

VI. Palliation

A. Radiotherapy

Palliative radiotherapy is often helpful in controlling the pain due to bone metastases or neurologic function in patients with brainmetastases. Chest radiotherapy may help control hemoptysis, superior vena cava syndrome, airway obstruction, laryngeal nerve compression, and other local complications.

B. Pleural effusions

Common sclerosing agents include doxycycline, talc, and bleomycin. The disadvantage of bleomycin is its cost; talc, although effective, had the disadvantage of requiring a thoracoscopy and general anesthesia for insufflation. Comparative randomized trials are under way.

C. Brachytherapy

For patients with bronchial obstruction who have received maximum external-beam radiotherapy, the use of high-dose endobronchial irradiation may be of temporary benefit.

D. Cachexia

Megestrol acetate 160 to 800 mg daily may improve the appetite of some patients.

E. Chemotherapy

In randomized trials involving both NSCLC and SCLC patients, chemotherapy has been shown to reduce the incidence of cancer-related symptoms such as pain, cough, hemoptysis, and shortness of breath.

F. Colony-stimulating factors

Filgrastim (granulocyte colony-stimulating factor) decreases the incidence of neutropenic fevers, the median duration of neutropenia, days of hospitalization, and days of antibiotic treatment in patients. However, the clinical benefit of maintaining a dose-intense approach in the treatment of patients with lung cancer has not been established. In addition, caution must be exercised when using colony-stimulating factors in patients receiving combined-modality treatment with both chemotherapy and thoracic irradiation. A randomized study by the SWOG found that patients receiving sargramostim (granulocyte macrophage colony-stimulating factor) and chemotherapy with concurrent thoracic irradiation had a significant increase in thrombocytopenia over patients receiving concurrent chemotherapy and radiation therapy without growth factor.

G. Fatigue

Stimulants such methylphenidate (Ritalin) may be helpful in improving fatigue.

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Handbook of Cancer Chemotherapy
Handbook of Cancer Chemotherapy
ISBN: 0781765315
EAN: 2147483647
Year: 2007
Pages: 37

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