Despite aggressive surgical management, 5-year survival rates of non–small-cell lung cancer (NSCLC) patients range from 73% for those with pathologic stage IA to 25% for those with stage IIIA. Clinical or preoperative staging often underestimates the extent of the disease (particularly if positron-emission tomography and mediastinoscopy are not used), and the estimated survival rates for a given clinical stage are much lower than those for the corresponding surgical/pathologic stage.
ABSTRACT: ABSTRACTDespite aggressive surgical management, 5-year survival rates of patients with nonâsmall-cell lung cancer (NSCLC) range from 73% for those with pathologic stage IA to 25% for stage IIIA. Given the low survival rate associated with treatment by surgery alone, numerous trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or in combination. A meta-analysis published in 1995 showed that cisplatin-based regimens produce the best adjuvant chemotherapy results in NSCLC patients, and this finding has been validated by three large randomized trials. Neoadjuvant chemotherapy offers theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. However, most large randomized trials of neoadjuvant chemotherapy have failed to show statistically significant results. This article reviews the pros and cons of each strategy, current guidelines, and treatment methods that are being explored.
Despite aggressive surgical management, 5-year survival rates of non–small-cell lung cancer (NSCLC) patients range from 73% for those with pathologic stage IA to 25% for those with stage IIIA. Clinical or preoperative staging often underestimates the extent of the disease (particularly if positron-emission tomography and mediastinoscopy are not used), and the estimated survival rates for a given clinical stage are much lower than those for the corresponding surgical/pathologic stage. Given the low survival rate associated with treatment by surgery alone, a number of trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or combined.
In an individual data-based (IPD) meta-analysis published in 1995, the use of a cisplatin-based regimen emerged as the best adjuvant (postoperative) chemotherapeutic option, which was subsequently validated by three large randomized trials.[2-5] The meta-analysis was updated 12 years later, confirming a 4% absolute improvement of the 5year survival rate in more than 8,000 patients (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.81–0.93).
Neoadjuvant chemotherapy offers several theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. To date, most of the large randomized trials of preoperative chemotherapy have shown statistically nonsignificant results, with the most recent meta-analysis on 1,507 patients reporting a hazard ratio of 0.88 (95% CI = 0.76–1.01; P = .07).
We will review the pros and cons of each strategy, review current guidelines, and summarize treatment methods that are currently being explored.
Adjuvant Chemotherapy Milestones
The first trials evaluating postoperative adjuvant chemotherapy for NSCLC suggested that alkylating agents and older chemotherapy treatments were detrimental for survival. Randomized trials of postoperative cisplatin-based chemotherapy subsequently failed to show any relevant individual benefit. A meta-analysis based on individual patient data from these studies was published in 1995. Eight trials used total doses of cisplatin between 50 and 240 mg/m² in diverse combinations with doxorubicin, cyclophosphamide, or vindesine. The analysis found that such chemotherapy was associated with a 13% reduction in the risk of death, with an overall hazard ratio of 0.87 (P = .08). The absolute benefit of chemotherapy was 5% at 5 years (95% CI = 1% detriment to 10% benefit), but the results were not statistically significant. Nevertheless, these findings led to adjuvant cisplatin-based chemotherapy trials in completely resected NSCLC.
Adjuvant Lung Project Italy
The Adjuvant Lung Project Italy (ALPI) randomly allocated 1,209 completely resected stage I, II, or IIIA NSCLC patients to observation or three cycles of MVP (mitomycin/vindesine/cisplatin). Radiotherapy was administered at the discretion of the individual participating center. As the recruitment rate declined at the end of the recruiting period, the trial enrolled 93% of the intended sample size (1,300 patients). Of these patients, 13 did not match study criteria, and data corresponding to 108 others were considered nonreliable; these patients were therefore excluded. Of all patients included, 39% had stage I disease, 33% had stage II disease, and 28% had stage IIIA disease. After a median follow-up of 64.5 months, there was no significant difference in overall survival between the two groups (HR = 0.96; 95% CI = 0.81–1.13; P = .589).
Big Lung Trial
The Big Lung Trial (BLT) was a randomized trial from the United Kingdom investigating cisplatin-based chemotherapy in patients with completely resected stage I–III NSCLC. This trial was not sufficiently powered to detect clinically significant differences in survival. The 381 patients were randomly assigned to two groups: surgery alone or two to three cycles of cisplatin-based chemotherapy (with vindesine, mitomycin/ifosfamide, mitomycin/vinblastine, or vinorelbine). Approximately 27% of patients had stage I disease, 38% had stage II, and 34% had stage III. Resection was macroscopically complete in roughly 95% of cases, but microscopically incomplete in 15%. The median follow-up was only 2.9 years and provided no evidence that chemotherapy has a positive effect on overall survival (HR = 1.02; 95% CI = 0.77–1.35; P = .90).
International Adjuvant Lung Cancer Trial
In 2003, the International Adjuvant Lung Cancer Trial (IALT) collaborative group reported the first positive large adjuvant chemotherapy trial. The 1,867 completely resected stage I, II, or III NSCLC patients were randomly assigned to groups receiving or not receiving three or four cycles of cisplatin-based chemotherapy (combined with either vinblastine, vindesine, vinorelbine, or etoposide). Postoperative radiotherapy was carried out at the discretion of each center. The trial was discontinued due to a low rate of enrolment (3,300 patients initially planned).
Treatment and control groups were matched for stage of disease. Of all patients studied, 10% had stage IA disease, 27% stage IB, 24% stage II, and 39% stage III. After a median follow-up of 56 months, the overall survival rate was significantly higher for patients receiving chemotherapy than for those who underwent observation only (HR = 0.86; 95% CI = 0.76–0.98; P < .03). The effect was no longer significant after a median follow-up of 90 months (HR = 0.91; 95% CI = 0.81–1.02; P = .1). The IALT investigators reported a higher rate of non–cancer-related deaths after 5 years of follow-up.
Two trials examined the combination of cisplatin at 100 mg/m² every 4 weeks with weekly vinorelbine, for a total of 16 weeks: JBR.10 and ANITA. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) studied completely resected stage IB and II (excluding T3, N0) NSCLC patients in the JBR.10 trial. Patients did not receive postoperative thoracic radiotherapy. The study included 482 patients (45% had T2, N0; 40% T2, N1; and 15% T1, N1 disease). Overall survival was significantly higher in the chemotherapy group than in controls (94 vs 73 months; HR = 0.69; 95% CI = 0.52–0.91; P = .04). An update of this trial, with a longer follow-up, will be presented at the American Society of Clinical Oncology annual meeting in 2009.
The Adjuvant Navelbine International Trialist Association (ANITA) trial included 840 patients with stage IB–IIIA NSCLC. Postoperative radiotherapy was recommended for patients with node-positive disease but was administered at the discretion of the participating center. Of all patients included, 36% had stage IB disease, 24% stage II, and 39% stage IIIA. Median follow-up was 76 months in the chemotherapy group and 77 months in the observation group. The median overall survival was higher in the chemotherapy group (HR = 0.80; 95% CI = 0.66–0.96; P = .017). Subgroup analysis showed that only patients with stage II and IIIA disease benefitted.
A smaller randomized trial was conducted in Italy, with 140 completely resected stage IB (pT2, N0) NSCLC patients. Patients receiving six cycles of adjuvant cisplatin/etoposide were compared to patients managed through observation alone. No patients received postoperative radiotherapy. The initial report described 66 patients. However, a later study was carried out on a larger cohort based on a 10-year follow-up. The median survival was 84.8 months for the group receiving adjuvant cisplatin/etoposide and 41.6 months for the controls (P = .02).
Japan Clinical Oncology Group Trial 9304
The Japan Clinical Oncology Group trial 9304 compared therapy with three courses of cisplatin and vindesine to observation in completely resected NSCLC patients with ipsilateral mediastinal lymph node involvement. No patients received postoperative radiotherapy. The recruitment rate was low, and only 119 patients were included. Median survival was 36 months in both groups and 5-year survival was 28% for chemotherapy patients vs 36% for controls (P = .89).
Other trials, mainly including patients with stage I disease, have been conducted with carboplatin- or UFT (tegafur/uracil)-based chemotherapy and will not be reported here.
Induction Chemotherapy Milestones
A number of phase II trials have evaluated the benefit of induction chemotherapy in stage I–IIIB NSCLC. The radiologic response rates in these trials have ranged from 39% to 79%. Surgical resection was feasible following induction chemotherapy and a complete pathologic response was observed in some patients. The first randomized phase II trial comparing induction chemotherapy to surgery alone was stopped prematurely (after 26 patients were enrolled) due to disease progression in four patients, which led to cancellation of surgical resection in two patients.
However, two subsequent randomized phase III trials had a significant impact on medical practice due to their impressive results.[16-17] Both trials randomized 60 stage IIIA patients and were interrupted for positive interim results. The first, by Roth et al, compared surgery alone to three cycles of cyclophosphamide/etoposide/cisplatin followed by surgery, without adjuvant radiotherapy. The response rate was 35%. After 37 months of follow-up, the median survival was 64 months for the group receiving induction chemotherapy and 11 months for controls (P = .008); after 82 months, median survival was 21 and 14 months in the two groups, respectively (P = .056).
The study by Rosell and colleagues concerned cN2 patients treated by either surgery or three cycles of MIP (mitomycin/ifosfamide/cisplatin) followed by surgery and radiotherapy. Objective response rates were reported in 60% of the cases. Updated median survival was 22 months for the induction therapy group and 10 months for controls (P = .005). Some have suggested that the unusually low survival in the control arm (0% at 5 years) might be the result of a study bias.
Only two published randomized phase III study have reported the number of patients that were initially planned. The French study included patients with disease stages between IB and IIIA (cN2, pN2 was optional). In the experimental arm, patients received two induction cycles with MIP, and in responders only (64% of the cohort), an additional two adjuvant cycles with MIP. Adjuvant radiotherapy was planned for pT3 and pN2 patients, or for patients with incomplete resection. About 37% of the patients had stage I NSCLC, 16% stage II, and 47% stage IIIA. The statistical hypothesis of a 15% benefit in terms of 2-year survival was not confirmed in the experimental arm (HR = 0.78; 95% CI = 0.60–1.02). Median survival was 37 months in the chemotherapy arm and 26 months in the surgery arm (P = .15). An unplanned post hoc analysis suggested a potential benefit in the pN0/pN1 subgroup.
MRC LU22/NVALT 2/EORTC 0812 Trial
In the Medical Research Council (MRC) LU22/Dutch Society of Pulmonologists (NVALT) 2/European Organisation for Research and Treatment of Cancer (EORTC) 08012 trial, 519 patients were randomly selected for either treatment with surgery alone or chemotherapy with three cycles of vinorelbine/cisplatin (45%), gemcitabine (Gemzar)/cisplatin (25%), mitomycin/vinblastine/cisplatin (12%) or docetaxel (Taxotere)/carboplatin (12%). Most of the patients had stage I disease (61%), and only 7% had stage III. The response rate was 49% (95% CI = 43%–55%), but no overall survival benefit was seen (HR = 1.02; 95% CI = 0.80–1.31, P = .86).
Among other studies that are either unpublished or that ended prematurely due to the positive results of adjuvant studies, the S9900 trial evaluated the benefit of three cycles of paclitaxel/carboplatin in 354 patients (600 planned) with stage IB–IIIA disease (without N2). About 67% of the patients had stage IB–IIA disease, and 33% were stage IIB or IIIA. The response rate was 38 %. After 31 months of follow-up, the hazard ratio for death was 0.84 (95% CI = 0.63–1.18; P = .32), favoring the chemotherapy arm. After 53 months of follow-up, the hazard ratio was 0.81 95% CI = 0.60–1.10; P = .19).
Ch.E.S.T. and Other Studies
The same population was eligible in the Chemotherapy for Early Stages Trial (Ch.E.S.T.), comparing surgery alone or three cycles of gemcitabine/cisplatin in 270 of 700 planned patients. Stage IB/IIA disease was observed in 55% and 46% of the patients, respectively. The response rate was 35% (95% CI = 27%–44%), with 6% having progressive disease after chemotherapy. The overall 3-year survival rate was 60% after surgery alone (95% CI = 51%–68%) compared to 67% in the experimental arm (95% CI = 58%–75%) with a P value of .053. (HR = 0.63; 95% CI = 0.42–0.93; P = .005).
Other trials that were stopped early and/or unpublished will not be discussed here due to the small size of the population or the lack of updated available data [22,23].
Pros and Cons
• Adjuvant Trials-To evaluate the benefit of adjuvant chemotherapy, the Lung Adjuvant Cisplatin Evaluation (LACE) analysis pooled individual data from 4,584 patients included in five recent randomized adjuvant cisplatin-based chemotherapy trials. The ALPI, IALT, ANITA, BLT, and JBR.10 trials were selected because they were conducted after the IGR-MRC 1995 meta-analysis and their cohorts each included more than 300 patients.[3-5,8,9] Patients were divided into approximately equal groups as a function of disease stage (IA: 8%, IB: 30%, II: 35%, III: 27%). With a median follow-up of 5.1 years (3.1–5.9), the 5-year survival rate was significantly higher in the chemotherapy group (HR for death = 0.89; 95% CI = 0.82–0.96; P = .004), corresponding to an absolute benefit of 5.3% for chemotherapy. The benefit was different for patients with different stages of disease (test for trend, P = .046). The hazard ratio was 1.41 (95% CI = 0.96–2.09) for stage IA, 0.93 (0.78–1.10) for stage IB, 0.83 (0.73–0.95) for stage II, and 0.83 (0.73–0.95) for stage III.
The IGR-MRC individual patient meta-analysis (1995) was updated in 2007. The authors compared chemotherapy combined with surgery to treatment by surgery alone.[2,6] Data from 30 of the 37 identified trials were available, allowing the analysis of 8,147 patients (as opposed to 2,312 patients in the 1995 analysis). Cisplatin was used in 22 trials (with vinca alkaloid or etoposide in 10 trials, UFT in 8 trials, and other drugs in 4 trials). Median follow-up for all trials was 5.3 years. Of all patients included in the analysis, 65% had stage I disease, 16% had stage II, 17% had stage IIIA, and 1% had stage IIIB (with less than 1% unknown). Overall, adjuvant chemotherapy significantly increased the overall survival rate, with an absolute benefit at 5 years of 4% (60% with surgery alone vs 64% in patients receiving adjuvant therapy; HR= 0.87; CI 95% = 0.81–0.93; P < .0000001). However, antimetabolite agents without cisplatin were used in eight trials, mainly in Asian populations and in stage I adenocarcinomas, reducing the relevance of this analysis for our purposes. Cisplatin-based chemotherapy (without UFT) was only used for 54% of the patients.
• Neoadjuvant Trials-No IPD meta-analyses of neoadjuvant therapy trials have previously been carried out, and available studies based on abstracted or pooled data are less useful. The first study, published in 2005 and based on six randomized trials (590 patients), found a benefit of cisplatin-based induction chemotherapy (HR = 0.66; 95% CI = 0.48–0.93). When the effect of induction chemotherapy was analyzed in the subgroup of patients with clinical stage III disease, the hazard ratio was 0.65 (95% CI = 0.41–1.04). Despite a strong trend in favor of preoperative chemotherapy in stage III disease, this value did not reach statistical significance (possibly due to the number of patients included).
A second meta-analysis by Burdett et al included 7 of the 12 eligible randomized trials (5 trials were excluded, as the data that could be extracted from the published studies were insufficient). Two trials used carboplatin-based chemotherapy, while all others were cisplatin-based chemotherapy combinations. A total of 988 patients were included. The authors found that preoperative chemotherapy improved survival, with a hazard ratio of 0.82 (95% CI = 0.69–0.97, P = .02). This is equivalent to an absolute benefit of 6% at 5 years. This meta-analysis was recently updated, incorporating the MRC LU22/NVALT 2/EORTC 08012 trial. With a total of 1,507 patients, a hazard ratio of 0.88 (95% CI = 0.76–1.01, P = .07) was obtained, equivalent to an absolute improvement in survival of 5% at 5 years.
Improved Patient Compliance
One of the major advantages favoring induction chemotherapy is an improved compliance, since adjuvant chemotherapy is dependent on the absence of surgical complications. Table 3 summarizes the compliance to chemotherapy in the main randomized phase III studies of induction and adjuvant chemotherapy. Although methods for reporting compliance may differ, neoadjuvant chemotherapy appears to result in improved compliance.
This has been demonstrated in perioperative chemotherapy trials. In the Depierre trial, 90% of patients received two cycles of neoadjuvant therapy, and only 84% received two cycles of adjuvant therapy. In the Intergroupe Francophone de Cancrologie Thoracique (IFCT) 0002 study, four cycles of preoperative chemotherapy were compared to two cycles of preoperative chemotherapy and two postoperative cycles; 90.4% of the patients received the four neoadjuvant cycles in the “all preoperative” group, compared to 75.2% in the “perioperative” group.
Compliance to adjuvant chemotherapy might be improved by the use of less toxic agents, such as the cytotoxic drug pemetrexed (Alimta) or targeted agents such as the EGFR inhibitor erlotinib (Tarceva). This is currently being evaluated in clinical trials.
Type of Chemotherapy
Many neoadjuvant chemotherapy regimens have been evaluated in phase II trials. Comparisons of phase II trials are difficult to interpret, due to the heterogeneity of study populations (stage of disease, smoking status, histologic features, etc) and the type of treatment modalities (ie, surgery and radiotherapy) following induction chemotherapy. Optimizing chemotherapy with one or two new agents or with a triplet has not proved superior to date. In one trial, the docetaxel/cisplatin/gemcitabine combination was associated with a response rate of 48%, whereas in another randomized phase II trial, response rates of 61% and 65% were reported for gemcitabine/cisplatin/vinorelbine and gemcitabine/cisplatin combinations, respectively.[28,29]
Whatever the cisplatin-based regimen used, the optimal number of cycles is unkown. A striking result comes from the French intergroup IFCT 0002 study, in which two or four cycles of preoperative chemotherapy were given (with an additional two postoperative cycles in the perioperative arm). Clinical responses to treatment did not differ between the two- and four-cycle regimens (50.6% and 50.9%, respectively), using either gemcitabine/cisplatin or paclitaxel/carboplatin.
In the LACE analysis, the effect of adjuvant chemotherapy did not differ significantly (test for interaction, P = .10) for the drugs used, even if the vinorelbine/cisplatin combination (HR = 0.80; 95% CI = 0.70–0.91) appeared superior to etoposide/vinca-alkaloid/cisplatin (0.93; 0.80–1.07), and other combinations (0.98; 0.84–1.14).
To improve the efficacy of cytotoxic agents, new selected targeted drugs such as antiangiogenic agents are currently being evaluated for perioperative therapy. The use of the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin), with a half-life of about 21 days, is being evaluated in the Eastern Cooperative Oncology Group (ECOG) 1505 adjuvant trial. However, it may not be suitable for use as preoperative treatment due to the risk of impaired tissue repair. This is currently being tested in the BEvacizumab And Chemotherapy for Operable NSCLC (BEACON) study. Pazopanib (an oral antiangiogenic agent) has been evaluated preoperatively in early-stage NSCLC; no increase in postoperative complications was observed. Finally, a randomized phase II/III trial comparing the use of adjuvant pazopanib and placebo is underway in stage I NSCLC patients (IFCT 0703–NCT00775307).
Meta-analyses have revealed similar HR values for death associated with neoadjuvant or adjuvant therapy: 0.87 (0.81–0.93) for the adjuvant IPD IGR-MRC meta-analysis, 0.89 (0.82–0.96) for the adjuvant IPD LACE meta-analysis, and 0.88 (0.76–1.01) for the more recent non-IPD meta-analysis of neoadjuvant chemotherapy.[6,7,24] More data are available for the efficacy and tolerance profiles of adjuvant chemotherapy than for neoadjuvant chemotherapy. Thus, physicians tend to be more confident about the therapeutic value of adjuvant treatment than that of neoadjuvant treatment, but respective indications need to be clarified. As an example, cisplatin-based adjuvant therapy may not be beneficial in selected stage I NSCLC patients. The World Health Organization classification will be modified in 2009, and will influence the interpretation of all data accumulated thus far, particularly for stage I disease.
Response rates for neoadjuvant therapy did not affect the rate of complete resection (Table 2), and this strategy did not appear to lower the rate of pneumonectomies (although sparing normal lung is a potential advantage of preoperative chemotherapy). The value of postoperative radiotherapy also remains unknown and needs to be clarified. This is currently being addressed in the ongoing Lung Adjuvant Radiotherapy Trial (LungART) for patients with N2 disease.
Rather than asking whether neoadjuvant or adjuvant chemotherapy should be used, the key issue may be to determine which patients should be treated with adjuvant and/or neoadjuvant therapy. Developing molecular-based therapeutic strategies will be one of the major challenges over the next few years. A number of trials-including the TAilored post-Surgical Therapy in Early-stage NSCLC (TASTE) trial (IFCT 0801)-examining the use of personalized regimens for adjuvant chemotherapy are therefore underway (Figure 1).
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