Chemotherapy of Lung Cancer

Saiama N. Waqar

Jankiraman Subramanian

Daniel Morgensztern

Kumar Rajagopalan

Ramaswamy Govindan

Lung cancer is the most common and most lethal malignancy worldwide with approximately 1.6 million new cases, and 1.37 million deaths predicted for the year 2008.¹ Similar findings are seen in the United States, where lung cancer is the most commonly diagnosed and most lethal malignancy for both sexes combined, with estimated new cases and deaths for the year 2010 of 222,520 and 157,300, respectively.² The incidence of lung cancer has been decreasing in men since the period 1982 to 1991 but continues to increase in women, although it appears to be reaching a plateau, with the annual percent change (APC) decreasing from 3.4 in the period 1982 to 1991 to 0.4 in the period 1991 to 2006. Death rates, however, have been decreasing in both sexes, with negative APC in men during the period 1990 to 1994 and in women during the period 2003 to 2006. Lung cancer is typically divided by histology as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (adenocarcinoma, squamous cell, and large-cell carcinoma).

SMALL CELL LUNG CANCER

SCLC constitutes approximately 13% of all newly diagnosed lung cancer cases.³ Overall, there has been a steady decrease in the proportion of SCLC among the primary lung cancers, with an accompanied increase of disease in women, which reached approximately 50% of all cases in 2002. SCLC is nearly always attributed to smoking and is characterized by rapid doubling time and early development of metastatic disease.⁴ Owing to the rapid dissemination, the initial staging system developed by the Veterans Administration Lung Study Group (VALSG) consisted of two main subgroups named limited-stage disease (LD-SCLC) and extensive-stage disease (ED-SCLC), with the former designed to include patients with disease limited to one ipsilateral hemithorax, which can safely be encompassed within a tolerable radiation field, and the latter used for patients with disease beyond this boundary.⁵ Despite the simplicity and applicability of this two-tiered staging system, subsequent studies revealed a significant heterogeneity among patients with LD-SCLC, with difference in outcomes according to the tumor, node, metastasis (TNM) classification. The survival for patients with SCLC classified according to the 7th edition of TNM staging showed a significant difference in outcomes among all the LD-SCLC subgroups, with 5-year survival rates ranging from 38% in stage IA to 9% in stage IIIB.⁶ Therefore, to improve the patient stratification, the International Association for the Study of Lung Cancer (IASLC) recommended the staging of SCLC with the same TNM system used for NSCLC. Nevertheless, the VALSG remains the main factor in therapeutic decision making, with initial optimal therapy for LD-SCLC and ED-SCLC consisting of chemoradiotherapy and chemotherapy, respectively, whereas surgery is reserved for a selective patient population (Table 31.1).

TREATMENT OF LD-SCLC

Chemoradiotherapy

The standard therapy for patients with limited-stage SCLC is the combination of chemotherapy and radiation. The addition of thoracic radiotherapy has been shown to improve local control rates compared to combination chemotherapy alone, and the use of chemoradiotherapy was further supported by the results of two meta-analyses conducted in 1992. Pignon and colleagues⁷ found a 5.4% 3-year survival improvement in patients treated with chemoradiotherapy compared to chemotherapy alone in a study involving 13 randomized trials, whereas Warde and Payne⁸ showed a 5.4% survival benefit at 2 years favoring chemoradiotherapy.

The optimal timing of thoracic radiotherapy has been debated for a while, although the administration of radiotherapy with the first two cycles of chemotherapy appears to be better. In a multivariate analysis, involving 1,524 patients enrolled into seven trials, Fried and colleagues⁹ compared early chemoradiotherapy defined as radiation starting within 9 weeks from the first chemotherapy or prior to the third cycle with late chemoradiotherapy. Early concurrent therapy was associated with a significant improvement in 2-year survival (5% improvement, P = .03). Similar modest benefit was observed in a subsequent meta-analysis, providing further support to early chemoradiotherapy as the standard of care in patients with LD-SCLC.¹⁰^,¹¹^,¹²

Although the optimal radiotherapy schedule has not been defined, there is evidence to support a dose-response effect. The National Cancer Institute of Canada study showed increased median local progression-free survival (PFS) from 38 to 49 weeks and decreased incidence of local failure after 2 years from 80% to 69% when the dose of radiation therapy (RT) administered after six cycles of chemotherapy in responding patients increased from 25 Gy in 10 fractions over 2 weeks to 37.5 Gy in 15 fractions over 3 weeks.¹³ Despite improved control, however, there were no improvements in overall survival (OS) between the two arms. In a retrospective analysis of patients treated at the Massachusetts General Hospital (MGH) between 1974 and 1986, Choi and Carey¹⁴ showed local control at 30 months of 16%, 51%, and 61% for patients treated with 35, 40, and 45 Gy, respectively.

Table 31-1 Standard Therapy for SCLC

Setting	Treatment 1	Treatment 2
Limited-Disease
EP	Cisplatin 60 mg/m² on day 1	Etoposide 120 mg/m² on days 1-3
EC	Carboplatin AUC 5	Etoposide 100 mg/m² on days 1-3
Extensive-Disease (First-Line)
EP	Cisplatin 75 mg/m² on day 1	Etoposide 100 mg/m² on days 1-3
EP	Cisplatin 80 mg/m²	Etoposide 80 mg/m² on days 1-3
EC	Carboplatin AUC 5-6	Etoposide 100 mg/m² on days 1-3
IP	Cisplatin 60 mg/m² on day 1	Irinotecan 60 mg/m² on days 1, 8, 15
IC	Carboplatin AUC 5	Irinotecan 50 mg/m² days 1, 8, 15
CAV	Cyclophosphamide	Doxorubicin 45 mg/m² day 1
	1,000 mg/m²	Vincristine 1.4 mg/m² day 1
Second-Line
IV topotecan	Topotecan 1.5 mg/m² days 1-5
Oral topotecan	Topotecan 2.3 mg/m² days 1-5
Radiation Therapy
Once daily	60-70 Gy
Twice daily	45 Gy
PCI	20-30 Gy
AUC, area under the curve; PCI, prophylactic cranial irradiation.

In a second retrospective review from patients treated at MGH from 1987 to 2000, radiation doses of 50 to 72 Gy were associated with a 30-month local control of 78%.¹⁵ The Cancer and Leukemia Group B (CALGB) 8837 demonstrated the feasibility of administering once-daily RT to the target dose of 70 Gy, starting with the fourth cycle of chemotherapy.¹⁶ In this study, the maximum-tolerated dose (MTD) for twice-daily RT was 45 Gy on 30 fractions of 1.5 Gy over 3 weeks. The use of accelerated radiotherapy was evaluated in a large Intergroup trial by Turrisi and colleagues.¹⁷ In this study, 417 patients were randomized to radiotherapy at a total of 45 Gy administered either as 25 fractions of 1.8 Gy daily for 5 weeks or as 30 fractions of 1.5 Gy twice daily for 3 weeks. RT started with the first of the four cycles of chemotherapy with cisplatin and etoposide (EP). Twice-daily RT was associated with decreased local failure (36% vs. 52%, P = .06) and improved 5-year survival (26% vs. 16%, P = .04). The only significant difference in toxicity between the two arms was a higher incidence of esophagitis including all grades (56% vs. 37%) and grade 3 (27% vs. 11%). Despite the improved survival rates in patients receiving twice daily, this approach is not being used widely for several reasons including the inconvenient schedule, increased toxicities, and the use of subtherapeutic radiation dose in the control arm. To address this issue, two ongoing trials are evaluating the optimal radiotherapy schedule in LD-SCLC.¹⁸ The CALGB 30610/Radiation Therapy Oncology Group (RTOG) 0538 is a three-arm study comparing twice-daily 45 Gy radiotherapy, 70 Gy once-daily radiotherapy, and 61.2 Gy given as 34 fractions of 1.8 Gy of once-daily for 16 days followed by the same dose twice daily for 9 days, with all arms starting on the first day of chemotherapy with EP. The Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) trial was designed to compare 45 Gy twice-daily RT to 66 Gy of daily radiotherapy, with radiation in both arms starting on day 22 of chemotherapy with EP. Therefore, until the final results of these two randomized phase III clinical trials define the best radiotherapy regimen, both 45 Gy twice daily and 60 to 70 Gy once daily remain the standard options.

The standard chemotherapy regimen used in combination with radiotherapy for patients with LD-SCLC is EP (etoposide and cisplatin). The most commonly used doses are the ones used in the Intergroup trial with cisplatin 60 mg per m² day 1 and etoposide 120 mg per m² on days 1 to 3.¹⁷ Alternative doses include cisplatin 75 to 80 mg per m² on day 1 and etoposide 100 mg per m² on days 1 to 3. Carboplatin is often substituted for cisplatin in elderly patients or those with renal impairment.

Surgery

Early studies evaluating the role of surgery in patients with SCLC showed dismal survival rates, with Mountain¹⁹ reporting one survivor beyond the first year among 368 who underwent resection, and Fox and Scadding²⁰ observing only one survivor
at 5-years among the 71 patients undergoing surgery. However, more recent studies showed a possible role for surgery in selected patients stratified by the TNM system and treated with adjuvant or neoadjuvant chemotherapy.²¹ In the subset analysis of the IASLC study, 349 (2.8%) of the 12,620 eligible cases underwent complete surgical resection.²² The 5-year survival for stages IA, IB, IIA, IIB, IIA, and IIB were 53%, 44%, 43%, 35%, 8%, and 21%, respectively. In a surveillance epidemiology and end results (SEER) study, the 5-year survival for 205 patients undergoing surgery without adjuvant radiation was 50.3%.²³ At this time, surgical resection followed by adjuvant therapy is considered a reasonable approach for patients with clinical stage I (although such a presentation is rather unusual) after invasive mediastinal staging and comprehensive imaging studies to rule out extrathoracic metastases.²⁴^,²⁵

TREATMENT OF ED-SCLC

The standard therapy for ED-SCLC is combination chemotherapy. The transition from alkylating-based regimens to EP occurred after the early reports showing the feasibility and response rates obtained with the latter combination in both untreated and previously treated patients. This was further supported by the results of randomized clinical trials comparing this regimen to a triplet involving cyclophosphamide, an anthracycline, and vincristine.²⁶^,²⁷ The Southeastern Oncology Group conducted a phase III study where 437 patients were randomized to receive EP, cyclophosphamide, doxorubicin, and vincristine (CAV) or an alternation of the two regimens (CAV/EP).²⁸ Although there were no significant differences in response rate and median survival among the three arms, EP was associated with higher incidence of anemia and thrombocytopenia, whereas CAV was associated with increased risk of neutropenia and infection. In a study with the same three arms (EP, CAV, and CAV/EP), Fukuoka and colleagues²⁹ showed increased response rates for EP compared to CAV (78% vs. 59%) with no significant differences in median survival (8.3 vs. 8.7 months). The CAV-containing arms were associated with increased incidence of grade 3 or 4 leukopenia and peripheral neuropathy. In a more recent trial, Sundstrom and colleagues³⁰ randomized 222 patients with ED-SCLC to EP or the combination of cyclophosphamide, epirubicin and vincristine (CEV). EP was associated with a trend in median survival benefit (8.4 vs. 6.5 months), but not in 2-year survival or quality of life (QoL). With at least similar efficacy and decreased toxicity compared to CAV or CEV, EP has been the most commonly used chemotherapy regimen for the last 25 years. Subsequent studies including the addition of a third agent to EP such as paclitaxel or ifosfamide, prolonged chemotherapy, and dose intensification resulted in increased toxicity and no clear evidence of survival improvement.³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰

The first important challenge to EP as the standard of care came from the Japan Clinical Oncology Group (JCOG) 9511, which randomized patients with ED-SCLC to receive four cycles of either cisplatin (80 mg per m² on day 1) plus etoposide (100 mg per m² on days 1 to 3) (EP) every 3 weeks or cisplatin (60 mg per m² on day 1) plus irinotecan (60 mg per m² on days 1, 8, and 15) (IP) every 4 weeks.⁴¹ Although the planned accrual was 230 patients, the study was terminated early due to an interim analysis showing a statistically significant benefit for the IP arm after the first 154 patients, with improved response rates from 67.5% to 84.4%, PFS from 4.8 to 6.9 months, median survival from 9.4 to 12.8 months (P = .002), 1-year survival from 37.7% to 58.4%, and 2-year survival from 5.2% to 19.5%. IP was associated with a significant increase in the incidence of diarrhea and decreased neutropenia compared to EP.

To confirm these findings in a non-Japanese population, two randomized clinical trials were performed. Hanna and colleagues⁴² randomized 331 patients, in a 2:1 IP to EP ratio, to receive cisplatin (60 mg per m² on day 1) plus etoposide (120 mg per m² on days 1 to 3) every 3 weeks or cisplatin (30 mg per m² on days 1 and 8) plus irinotecan (65 mg per m² on days 1 and 8) every 3 weeks. Compared to EP, IP was associated with no significant improvement in response rates (48% vs. 43.65%), time to disease progression (4.1 vs. 4.6 months), median survival (9.3 vs. 10.2 months, P = .74), 1-year survival (34.9% vs. 35.1%), or 2-year survival (8% vs. 7.9%). EP was associated with a significant increase in grade 3 or 4 neutropenia, anemia, thrombocytopenia, and alopecia, whereas IP was associated with increased diarrhea, vomiting, and dehydration. The Southwest Oncology Group (SWOG) trial 0124 used a virtually identical eligibility criteria and identical treatment regimens to the JCOG, randomizing 651 patients to EP or IP.⁴³ Confirming the previous trial and unlike the JCOG study, IP was not associated with a significant improvement in response rate (60% vs. 57%), median PFS (5.7 vs. 6.1 months), median survival (9.9 vs. 9.1 months), and 1-year survival (41% vs. 34%). Similar to previous studies, IP was associated with increased rates of grade 3 or 4 diarrhea and EP with higher risk of myelosuppression.

Carboplatin is commonly used instead of cisplatin in patients with ED-SCCL, based on a better toxicity profile and likely similar efficacy as shown in the Hellenic Cooperative Oncology Group, where the median survival for the 31 patients with ED-SCLC treated with carboplatin (300 mg per m²) plus etoposide (100 mg per m²) and the 30 patients treated with cisplatin (50 mg per m² on days 1 and 2) plus etoposide (100 mg per m² on days 1 to 3) were not statistically different 11.8 and 12.5 months, respectively.⁴⁴ An additional option is the combination of carboplatin and irinotecan. A randomized phase II trial compared carboplatin (AUC 5) plus irinotecan (50 mg per m² on days 1, 8, and 15) or etoposide (140 mg per m² on days 1 to 3).⁴⁵ The irinotecan arm was associated with increased response rates (67% vs. 59%, P = .24) and median PFS (9 vs. 6 months, P = .03). However, in the subsequent phase III trial involving 216 patients, the irinotecan group was not associated with improved response rates (54% vs. 51%) PFS (6 months in each group) or median survival (10 vs. 9 months).⁴⁶

TREATMENT OF RELAPSED SCLC

Despite the common initial response to treatment, essentially all patients with ED-SCLC and approximately 80% of those with LD-SCLC will develop progressive disease. The strongest predictor for outcomes in patients with relapsed disease is the
duration of remission, measured as the time from the last treatment to the diagnosis of relapse. Patients with progression-free intervals of at least 3 months and <3 months are named sensitive and refractory, respectively.⁴⁷

Topotecan, at a dose of 1.5 mg per m² daily for 5 days every 3 weeks, showed significant efficacy in a phase II study, with overall response rate of 21.7% in 92 pretreated patients.⁴⁸ The benefit, however, was mainly restricted to patients with sensitive disease, with a response rate of 37.8% in the 45 patients with sensitive disease and 6.4% in the 47 patients with refractory disease. The role of topotecan was further defined when it was compared to CAV in 211 patient who relapsed at least 60 days following completion of the first-line chemotherapy.⁴⁹ Topotecan and CAV were associated with similar response rates (24.3% vs. 18.3%), time to progression (13.3 vs. 12.3 weeks), and survival (25 vs. 24.7 weeks). However, topotecan emerged as the favorite regimen due to a significant improvement in disease-related symptoms compared to CAV, including dyspnea, anorexia, and fatigue. An alternative to intravenous (IV) topotecan is its oral form. In a multicenter trial, Eckardt and colleagues⁵⁰ randomized 309 patients with ED-SCLC and treatment-free interval of at least 90 days to receive either standard dose of IV topotecan (1.5 mg per m² daily for 5 days) or oral topotecan (2.3 mg per m² daily for 5 days) every 21 days. Oral topotecan, when compared to the IV form, was associated with similar response rate (18.3% vs. 21.9%), median time to progression (11.9 vs. 14.6 weeks), and median survival (33 vs. 35 weeks), and toxicity profile. The use of oral topotecan was further supported by the results of a randomized clinical trial comparing this drug to best supportive care (BSC) in 141 patients who were not considered candidates for IV therapy.⁵¹ Oral topotecan at 2.3 mg per m² daily for 5 days every 3 weeks was associated with a significant prolongation of OS (25.9 vs. 13.9 weeks, P = .01) in all patients, with the benefit preserved in patients with treatment-free interval of 60 days or less (23.3 vs. 13.2 weeks). At this time, topotecan remains the only drug that showed benefit in comparison to BSC and is approved for the use in relapsed SCLC. Nevertheless, because the outcomes remain suboptimal, several new agents are being tested in patients with SCLC.

Irinotecan, vinorelbine, gemcitabine, and paclitaxel showed modest response rates in phase II trials.⁵²^,⁵³^,⁵⁴^,⁵⁵ Two studies showed that it is possible to escalate pemetrexed from the conventional dose of 500 to 900 mg per m² every 3 weeks, although neither showed meaningful benefit from this agent.⁵⁶^,⁵⁷ Although picoplatin showed modest efficacy in a phase II study, it did not improve survival in comparison to BSC in a large phase III trial.⁵⁸^,⁵⁹ Similarly, there was no benefit observed in patients treated with gefitinib or imatinib.⁶⁰^,⁶¹^,⁶²^,⁶³

The most promising new agent at this time is the anthracycline derivative amrubicin. In the Japanese Thoracic Oncology Research Group trial 0301, 44 patients with sensitive disease, defined as progression 60 or more days after treatment discontinuation, and 16 with refractory disease were treated with amrubicin 40 mg per m² daily for 3 days every 3 weeks.⁶⁴ Overall response rate and 1-year survival for patients with refractory disease (50% and 40.3%, respectively) were similar to sensitive disease (52% and 45.5%, respectively). The most frequent grade 3 or 4 toxicities were neutropenia, occurring in 83.3% of patients, anemia (33.3%), and thrombocytopenia (20%). In a phase II trial comparing amrubicin to topotecan in 60 patients with pretreated SCLC, the North Japan Lung Cancer Group Trial 0402 showed a statistically significant increase in responses for amrubicin in both sensitive (53% vs. 21%) and refractory disease (17% vs. 0%).⁶⁵ Patients treated with amrubicin also had improved PFS (3.9 vs. 3 months in sensitive disease and 2.6 vs. 1.5 months in refractory disease) and similar OS (9.9 vs. 11.7 months in sensitive disease and 5.3 vs. 5.4 months in relapsed disease). Further analyses showed that the majority of long survivors in the topotecan arm received subsequent therapy with amrubicin. Amrubicin was associated with increased toxicity, which may be at least partially explained by the lower dose of topotecan used in the study (1 mg per m² daily for 5 days every 21 days).

The efficacy of amrubicin in patients with refractory disease, defined in the study as progression within 90 days from first-line, generated increased interest in this drug. Nevertheless, because experience with irinotecan indicated that results from trials conducted in Japan are not always applicable to Western patients, confirmatory studies were subsequently performed. In the first study, Ettinger and colleagues⁶⁶ treated 70 refractory patients with the standard dose of amrubicin. Overall response, median PFS, and OS were 21.3%, 3.2 months, and 6 months, respectively, indicating promising activity in this population with significant benefit when compared to historical controls. Similar to the Japanese trials, the most common toxicity was myelosuppression, particularly grade 3 or 4 neutropenia, which occurred in 66.7% of patients. In the first non-Japanese trial directly comparing the two therapies, 76 sensitive patients were randomized in a 2:1 ratio to amrubicin or topotecan, with both drugs given at conventional doses. In this study, amrubicin was associated with a significant improvement in response rates (44% vs. 15%). Increases in PFS (4.5 vs. 3.3 months) and OS (9.2 vs. 7.6 months), although numerically superior, were not statistically significant. The safety profile was similar in both groups, with a slightly increased risk of grade 3 or 4 neutropenia and thrombocytopenia in patients treated with topotecan. The role of amrubicin in previously treated patients will be further defined by the results of an ongoing phase III trial comparing amrubicin to topotecan in both sensitive and refractory population.

Prophylactic Cranial Irradiation

SCLC is associated with extraordinarily high rates of brain metastasis. Approximately one in five patients have brain metastasis at presentation and nearly half will develop brain metastasis over time.⁶⁷^,⁶⁸ Therefore, prophylactic cranial irradiation (PCI) is of great interest in order to decrease the morbidity and mortality from brain metastases. Because the initial studies on PCI were inconclusive, the Prophylactic Cranial Irradiation Overview Collaborative Group analyzed individual data on 987 patients with SCLC in complete remission who were enrolled into one of the seven randomized trials comparing PCI to no PCI.⁶⁹ This study showed a significant decrease
in the incidence of brain metastases at 3 years (33.3% vs. 58.6%, P < .001) and improved 3-year survival (15.3% to 20.7%). Because the study involved only patients achieving complete response (CR) or near CR, the role of PCI in patients with ED-SCLC, where this magnitude of response is unlikely to occur, remained less defined.

The European Organization for Research and Treatment of Cancer (EORTC) randomized 286 patients with ED-SCLC and response to first-line chemotherapy to either PCI or no PCI.⁷⁰ PCI was used as 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, or 30 Gy in 10 to 12 fractions, starting 4 to 6 weeks after chemotherapy. PCI was associated with a significant decrease in the cumulative risk of brain metastases at 1 year (14.6% vs. 40.4%), increased PFS (14.7 vs. 12 weeks), median OS (6.7 vs. 5.4 months), and 1-year survival (27.1% vs. 13.3%). Main toxicities from PCI were fatigue, anorexia, leg weakness, nausea, and vomiting did not have a clinically significant effect on the global health status. Therefore, PCI is a standard therapy for patients with SCLC responding to first-line therapy, regardless of initial stage.

OVERVIEW OF ADJUVANT THERAPY IN NON-SMALL CELL LUNG CANCER

Approximately a third of all patients diagnosed with NSCLC present with early stage disease, where surgery is potentially curative. Despite curative surgery, a significant proportion of these patients eventually relapse, possibly due to micrometastatic disease. Adjuvant chemotherapy could potentially improve their outcomes. The 1995 meta-analysis by the NSCLC collaborative Group reviewed 14 trials including 4,357 patients addressing postoperative therapy. Five trials using alkylators actually showed inferior survival with adjuvant chemotherapy, whereas eight trials (1,394 patients) using a cisplatin-based regimen showed a 5% improvement in OS (hazard ratio (HR), 0.87; 95% CI, 0.74 to 1.02; P = .08).⁷¹ Although this meta-analysis did not change practice patterns, it led to additional studies, and today adjuvant chemotherapy for resected NSCLC stages II and IIIA, is the standard of care. Table 31.2 lists the major adjuvant chemotherapy trials in NSCLC.

Table 31-2 Major Adjuvant Chemotherapy Studies

IALT	1,867 patients	Stages I-IIIA	Cisplatin 80 mg/m² every 3 wk for 4 courses (or) 100 mg/m² every 4 wk for 3-4 courses (or) 120 mg/m² every 4 wk for 3 courses
			Plus one of the agents below:
			Etoposide 100 mg/m² × 3 d each cycle (or) Vinorelbine 30 mg/m² weekly (or) Vinblastine 4 mg/m² weekly (or) Vindesine 3 mg/m²
JBR.10	482 patients (242 received chemotherapy; 240 observation)	Stages I and II	Cisplatin 50 mg/m² days 1 and 8 every 4 wk × 4 courses. Plus
			Vinorelbine 25 mg/m² weekly × 16 wk
ANITA	840 patients (433 observation; 407 adjuvant)	Stages IB-IIIA	Cisplatin 100 mg/m² days 1, 29, 57, and 85 Plus Vinorelbine 30 mg/m² days 1, 8, 15, and 22 every 4 wk × 16 doses
CALGB 9633	344 patients	Stage IB	Carboplatin AUC 6 day 1 Plus Paclitaxel 200 mg/m² Every 3 wk × 4 courses

Adjuvant Chemotherapy Trials

In the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with completely resected stage I, II, or III NSCLC were randomly assigned to observation or four cycles of chemotherapy (cisplatin with vindesine or vinorelbine, or etoposide).⁷² Regimen choice and postoperative RT policy were at the discretion of each center. Over 50% of the patients received cisplatin and etoposide. After a median follow-up of 56 months, OS was significantly better among patients assigned to chemotherapy compared to those on observation (HR, 0.86; 95% CI, 0.76 to 0.98; P < .03), translating into a 4% absolute survival benefit at 5 years. A recent update of this trial with long-term follow-up data reported a higher incidence of noncancer deaths in the chemotherapy arm after 5 years, and the differences in the overall and disease-free survival between the treatment and observation arms were no longer significant.⁷³

The JBR.10 trial was conducted by the National Cancer Institute of Canada (National Cancer Institute of Canada Clinical Trials Group [NCIC CTG]): 482 patients with completely
resected stage IB, IIA, and IIB NSCLC were randomized to four cycles of vinorelbine and cisplatin (VC) chemotherapy or observation. Postoperative RT was not allowed in this trial. Both OS (HR, 0.69; 95% CI, 0.52 to 0.91; P = .0009, P = .04 after interim analysis) and recurrence-free survival (HR, 0.60; 95% CI, 0.45 to 0.79; P < .001) were better in chemotherapy group compared to observation. This study also showed that elderly patients (>65 years) had similar improvements in OS (HR, 0.61; 95% CI, 0.38 to 0.98) although they received less chemotherapy overall, and there were no differences in toxicities or hospitalizations. Subgroup analysis showed no statistically significant OS benefit (P = .79) for patients with stage IB disease receiving adjuvant chemotherapy. In contrast to IALT, a recent update showed survival benefit even after 9-year follow-up for adjuvant chemotherapy.⁷⁴

A large-scale international trial, Adjuvant Navelbine International Trialist Association (ANITA) trial from 101 centers including 840 patients, with a median follow-up of 76 months, showed an absolute survival benefit of 8.6% at 5 years (8.4% at 7 years), with adjuvant cisplatin and vinorelbine compared to observation alone in patients with resected stage IB to IIIA NSCLC.⁷⁵ In patients with stage IB disease, there was no benefit to receiving adjuvant chemotherapy. Treatment with adjuvant chemotherapy was associated with significant OS benefit in patients with stages II and IIIA disease. This trial confirmed the benefits of adjuvant therapy for patients with stages II and IIIA NSCLC following surgical resection. Unplanned analysis of the subgroup receiving postoperative radiation (28% of the total group: 33% observation and 22% treatment group), confirmed benefit for N2 disease, whereas N1 disease did worse with adjuvant radiation.

Unlike the studies mentioned earlier, the trial conducted by the CALGB (CALGB 9633) examined the role of a carboplatincontaining regimen following resection in patients with stage IB (T2 N0 M0 by the staging system then in vogue) NSCLC.⁷⁶ Interim analysis showed an improvement in OS with adjuvant chemotherapy (71% vs. 59%; HR, 0.62; 95% CI, 0.41 to 0.95; P = .028). However, with a longer follow-up, adjuvant carboplatin and paclitaxel (CP) failed to confirm the initially observed survival advantage.⁷⁷ Unplanned subset analysis showed a benefit from adjuvant chemotherapy in patients with tumors >4 cm in size. Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis of the five major adjuvant trials (BLT, ALPI, IALT, JBR.10, ANITA) showed a 5-year absolute survival benefit of 5.4% from chemotherapy at a median follow-up of 5.2 years for patients with stages II and IIIA NSCLC.⁷⁸ This analysis also established cisplatin-based regimen as the standard (choice of second agent among the vinca alkaloids was not that important) and also showed that chemotherapy was detrimental to patients with PS-2 or greater.

Other Chemotherapy Regimens

Meta-analysis of six randomized trials in Japan showed higher 5- and 7-year survival rates with Uracil-tegafur regimens administered postoperatively in patients with NSCLC compared with observation alone.⁷⁹ Overall pooled HR was 0.74 (95% CI, 0.61 to 0.88; P = .001). No studies have been conducted outside Japan with this regimen and UFT is currently not available in the United States.

The Eastern Cooperative Oncology Group (ECOG) led intergroup phase III study is currently enrolling patients with stage IB (≥4 cm)—IIIA NSCLC to address the important question of whether addition of bevacizumab to chemotherapy would improve the OS compared to chemotherapy alone. Other approaches including cancer vaccines are being pursued in this setting (www.clinicalTrials.gov).

Postoperative Radiation Treatment

Postoperative radiation treatment (PORT) meta-analysis showed an adverse effect on outcomes for patients with N0-N1 disease treated with postoperative RT.⁸⁰ There was no clear evidence of an adverse effect on survival for patients with N2 disease. SEER database showed a survival benefit with PORT in patients with resected stage III NSCLC.⁸¹ Definitive data should become available with the phase III Lung adjuvant radiation trial (Lung-ART), which randomizes patients with N2 disease to PORT versus no PORT after resection and stratifies according to postoperative chemotherapy.⁸¹

Conclusions

Based on current data, adjuvant cisplatin-based chemotherapy is the standard of care in patients with resected stages II and IIIA NSCLC. Based on retrospective, unplanned subset analysis of CALGB 9633 trial, adjuvant chemotherapy can be considered for patients with large (>4 cm) node negative tumors, after surgery.

Postoperative RT could potentially be considered as a choice in patients with resected stage IIIA disease. Results from the Lung ART study should further clarify the role of PORT in patients with resected NSCLC.

Neoadjuvant Chemotherapy

A recent meta-analysis of 13 randomized clinical trials comparing preoperative chemotherapy to surgery alone reported improved OS with preoperative chemotherapy (HR, 0.84; 95% CI, 0.77 to 0.92).⁸² An intergroup study comparing preoperative chemotherapy with CP followed by surgery to surgery alone had to be closed early when the benefits for adjuvant chemotherapy became evident.⁸³ At the time of study closure, 354 patients had been enrolled and the median OS was better for patients receiving preoperative chemotherapy compared to patients on the surgery-only arm, although the difference was not statistically significant; median OS 62 versus 41 months (P = .11). Thus, neoadjuvant chemotherapy could potentially benefit patients with operable disease, however, surgery followed by adjuvant chemotherapy has been more extensively studied and has now become the standard in the management of patients with resectable disease.

Locally Advanced NSCLC

Role of Surgery in Locally Advanced NSCLC

Several phase II studies have shown the induction with chemoradiation to improve the rates of CR and survival compared to historical outcomes with preoperative radiation alone for patients with superior sulcus tumors.⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷ The current approach
for patients with superior sulcus tumors in the absence of mediastinal nodal involvement or vertebral body destruction, is to treat with two cycles of cisplatin and etoposide along with concurrent thoracic radiation followed by surgical resection.

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