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Ann Thorac Surg 2006;81:1926-1936
© 2006 The Society of Thoracic Surgeons
a Memorial Sloan-Kettering Cancer Center, New York, New York
b University Health Network, Princess Margaret Hospital and the University of Toronto, Toronto, Ontario, Canada
c Cancer Care Ontario Program in Evidence-Based Care, McMaster University, Hamilton, Ontario, Canada
d Juravinski Cancer Centre at Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
Accepted for publication April 25, 2005.
* Address correspondence to Dr Darling, c/o Ms Mackay, Cancer Care Ontario Program in Evidence-Based Care, McMaster University Courthouse T27 Building, 1280 Main St W, Hamilton, ON, L8S 4L8 Canada (Email: mackayj{at}mcmaster.ca).
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsOutcomesCommentFootnotesAcknowledgmentsReferences |
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Adjuvant or postoperative chemotherapy previously did not appear to be effective, but renewed interest in this approach has led to a number of recent clinical trials. Given the volume of research on this issue in recent years and the development of new chemotherapy agents, an updated review of the data on postoperative adjuvant chemotherapy is warranted.
This systematic review was conducted to evaluate the impact of postoperative chemotherapy on the survival of patients with completely resected NSCLC. The review will form the basis for a practice guideline currently under development by the Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care and will be a companion to its practice guideline on the role of postoperative adjuvant radiation therapy [5]. This group consists of experts in the fields of oncology and research, including medical and radiation oncologists, thoracic surgeons, nurses, a medical sociologist, and research coordinators. Practice guidelines developed through the Program follow the methods of the Practice Guidelines Development Cycle [6] and are available on the Internet at http://www.cancercare.on.ca.
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Material and Methods |
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Literature Search
The following databases were searched for evidence: MEDLINE (1966 to February 2005), EMBASE (1980 to 2005, week 13), CANCERLIT (1975 to October 2002), and the Cochrane Library (2005, issue 1). Search terms included the following subject headings: carcinoma, non-small-cell lung, lung non small cell cancer, lung carcinogenesis, lung adenocarcinoma, lung alveolus cell carcinoma, lung squamous cell carcinoma, antineoplastic agent(s), drug therapy, chemotherapy adjuvant, cancer chemotherapy, surgery, cancer surgery, pleurectomy, and lung surgery; text words: non small cell lung, chemotherapy, drug therapy, adjuvant, surgery, surgical, resect, and postop; and publication types and study designs (practice guidelines, systematic reviews, meta-analyses, randomized controlled trials, phase III clinical trials, and major clinical studies). Abstract reports from the American Society of Clinical Oncology, the European Cancer Conference, and the European Society for Medical Oncology (2000 to 2004) and reference lists from relevant articles and review articles were hand searched.
Eligibility Criteria
Fully published reports or published abstracts of meta-analyses or randomized controlled trials comparing postoperative chemotherapy with the same treatment without chemotherapy in patients with completely resected NSCLC were included in this review. Data from slide presentations associated with abstract reports were included if the presentations were publicly available on meeting websites. Trials involving alkylating chemotherapy agents alone or in combination with non-platinum agents were excluded, because those agents have been shown to be detrimental to patient survival in an adjuvant setting [7]. In addition, trials that involved immunochemotherapy, trials that did not report overall or disease-free survival, or trials that were published in a language other than English or French were not considered.
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Results |
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The recently published Big Lung Trial, which compared surgery with or without chemotherapy in 381 patients, did not meet the inclusion criteria for this review because of a non-uniform approach to treatment, including neoadjuvant chemotherapy in 3% of patients and incomplete or no resections in 5% to 16% of cases [44].
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Outcomes |
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The NSCLCCG also found that the combination of postoperative radiotherapy and chemotherapy was not associated with a significant survival benefit compared with postoperative radiotherapy alone across seven trials (hazard ratio, 0.98; p = 0.76) or a subset of six cisplatin-based trials (hazard ratio, 0.94; 95% confidence interval, 0.79 to 1.11; p = 0.46). In the seven trials, the planned dose of radiotherapy varied between 40 Gy in 10 fractions and 65 Gy in 33 fractions, and in the cisplatin-based trials the planned dose of cisplatin varied between 40 mg/m2 and 100 mg/m2 per cycle.
In a meta-analysis of six Japanese trials (2,003 patients), Hamada and colleagues [10, 11] compared an adjuvant oral combination of uracil and tegafur (UFT) with surgery alone in patients with completely resected, primarily early-stage NSCLC (99% with pT1 or pT2). The treatment effect across the six studies was not heterogeneous (p = 0.76), and an absolute survival advantage of 4.6% at 5 years in favor of UFT was detected (hazard ratio, 0.77; p = 0.011).
Results of the five subsequent meta-analyses based only on published data [8, 9, 12–14] were consistent with those obtained in the two individual patient data meta-analyses [7, 10, 11].
Randomized Controlled Trials
The trials included in this review are summarized in Tables 2
(survival outcomes) and 3 (resection description). A quality assessment of the trials revealed that none reported blinding of treatment administration and few described the method of randomization used in detail, although 10 reported that randomization was centralized [17, 19, 21, 23, 24, 35, 36, 39, 41, 43]. All randomized or eligible patients were included in the survival analyses in 14 trials [16, 17, 19, 20, 22–26, 33, 35, 36, 39, 41, 43]. Four trials received support from pharmaceutical companies [24, 28–30, 41, 43].
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Postoperative Platinum-Based Chemotherapy With Radiotherapy
The Eastern Cooperative Oncology Group randomized patients with stage II or IIIA NSCLC to postoperative adjuvant radiotherapy or the same radiotherapy administered concurrently with four cycles of cisplatin-etoposide [21]. Between 82% (combined-treatment group) and 86% (radiotherapy-alone group) of patients completed the planned radiotherapy. After a median follow-up of 44 months, survival was comparable for both treatment groups. The result of that trial is consistent with the NSCLCCG meta-analysis [7], which also found no survival benefit of adjuvant chemotherapy when added to radiation. No treatment-related differences on survival were observed for the different subgroups, including disease stage. Among the 232 patients who received chemotherapy, 69% were given at least part of the four planned cycles. Grade 3 or greater toxicities were more frequent with combined chemoradiotherapy, with hematologic toxicity ranging from 14% (anemia) to 79% (leukopenia) of patients compared with 1% or less in the radiotherapy group. Grade 3 or 4 esophagitis was also more frequent with combined treatment (17% vs 1%), but pneumonitis (2% to 4%) and treatment-related deaths (1% to 2%) were comparable across treatments.
In the large multicenter Adjuvant Lung Project Italy (ALPI), 1,196 eligible patients (of the planned 1,300) with stage I-IIIA NSCLC were randomized to three cycles of adjuvant mitomycin-vindesine-cisplatin chemotherapy or no adjuvant chemotherapy [23]. Radiotherapy that was administered according to each center's policy was planned for 238 chemotherapy patients and 232 control patients. Full data on radiation treatment were available from 179 chemotherapy patients and 152 control patients, with 92% receiving some of the planned radiotherapy and between 65% (chemotherapy group) and 82% (control group) completing planned radiotherapy. After a median follow-up of 64.5 months, there was no statistically significant difference in overall or progression-free survival. Survival by treatment group was not differentially affected by disease stage. Grade 3 or 4 neutropenia was the most common chemotherapy-related toxicity (28%), and grade 2 to 3 esophagitis (15% to 16%), acute pneumonitis (6% to 9%), and treatment-related deaths (1%) were similar in both treatment groups.
The International Adjuvant Lung cancer Trial (IALT) is the largest trial to date of adjuvant chemotherapy [24]. To facilitate accrual of the target sample of 3,300 patients, the participating clinical centers were permitted to select from among the following entry criteria and treatment approaches, but they had to remain constant throughout the trial: qualifying disease stage, cisplatin dose, chemotherapy agent combined with cisplatin (etoposide, vinorelbine, vinblastine, or vindesine), and use of radiotherapy after completion of chemotherapy. Of the 572 patients assigned to receive radiotherapy, only 70.4% in the chemotherapy group and 84.2% in the control group received the treatment, with a median total dose of 50 Gy. Within the chemotherapy group, 74% of patients received at least 240 mg/m2 of cisplatin compared with the planned 300 to 400 mg/m2. After a median follow-up of 56 months, overall (44.5% vs 40.4%) and disease-free (39.4% vs 34.3%) survival at 5 years was longer in the chemotherapy treatment arm, with a 14% relative reduction in risk of death (hazard ratio, 0.86; p < 0.03). No heterogeneity-of-treatment effect across clinical site was detected (p = 0.11). The survival advantage observed with chemotherapy was not differentially associated with the planned use of radiation, choice of second drug, dose of cisplatin, or covariates such as disease stage. Grade 4 toxicity was common among patients allocated to chemotherapy (22.6%), with neutropenia the most frequent event (18%), and 7 patients (< 1%) who died of chemotherapy-related adverse effects.
Postoperative Platinum-Based Chemotherapy Alone
The results of two North American cooperative group trials using postoperative chemotherapy alone were presented in the abstract form in 2004 [25, 28]. The two trials were not included in the most recent meta-analyses of postoperative chemotherapy [13, 14].
In the Cancer and Leukemia Group B trial (CALGB 9633), patients with stage IB NSCLC received four cycles of adjuvant paclitaxel-carboplatin or observation alone [25, 26]. Of the 124 chemotherapy patients with available data, 85% received all four cycles of chemotherapy. After a median follow-up of 34 months, a significant survival advantage (hazard ratio, 0.62; p = 0.028) was detected for adjuvant chemotherapy, with an absolute benefit of 12% at 4 years (71% vs 59%). Failure-free survival was also improved in the chemotherapy group (hazard ratio, 0.69; p = 0.035). The risk of death due to lung cancer was reduced with adjuvant chemotherapy even when the effect of prognostic factors, including patient age and gender; tumor size, histology, and differentiation; and presence of symptoms were taken into account (hazard ratio, 0.62; 95% confidence interval, 0.40 to 0.97; p = 0.034). Although grade 3 or 4 neutropenia occurred in 36% of chemotherapy patients, there were no chemotherapy-related deaths.
In the multicenter National Cancer Institute of Canada Clinical Trials Group intergroup study, 482 patients with completely resected stages IB and II (excluding T3N0) tumors were randomized to four cycles of adjuvant vinorelbine-cisplatin or observation alone [28–30]. The weekly dose of vinorelbine was reduced from 30 mg/m2 to 25 mg/m2 early in the trial because of hematologic toxicity associated with the higher dose. Of the 215 chemotherapy patients receiving the lower dose of vinorelbine, 50% completed all four cycles of treatment [30]. All patients had a good performance status (0 to 1), and 53% of cases involved adenocarcinoma histology. Overall survival strongly favored the adjuvant chemotherapy treatment arm, with an absolute survival benefit of 15% at 5 years (69% vs 54%) and a 30% relative reduction in risk of death (p = 0.012). Similarly, the use of adjuvant chemotherapy resulted in an absolute recurrence-free survival benefit of 13% at 5 years (61% vs 48%; hazard ratio, 0.61; p = 0.0004). Grade 3 or 4 neutropenia was common (73%) in the chemotherapy treatment arm, but febrile neutropenia occurred in only 7% of patients. There were two (< 1%) chemotherapy-related deaths (1 due to febrile neutropenia, and 1 due to pulmonary fibrosis).
Oral Agents Alone or Combined With Other Chemotherapy Agents
In Japan, the oral antimetabolite UFT has been used in nine trials [34–36, 38–43], including two reported in abstract form [38, 40]. The dose of UFT in most trials was 400 mg/day [35, 36, 38–40, 42, 43] administered for 1 year [35, 36, 38, 43] or 2 years [39, 40, 42]. Of the six trials that reported patient performance status, four primarily included status 0 to 1 (91% to 100% of patients) [34, 39, 41, 42] and two included status 0 to 2 [36, 43]. In addition, three trials of adjuvant tegafur (also known as ftorafur) were identified but are not discussed in detail because they provided limited data [31–33, 37]. The results of the 12 trials are summarized in Tables 2 and 3.
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Seven trials compared surgery plus oral UFT with surgery alone [35, 38–43] with mixed results. Five-year survivals for patients receiving surgery alone varied considerably across the trials, suggesting underlying differences in the patient populations, the surgical procedures performed, or the supportive treatment received. In the largest fully published trial of adjuvant UFT to date, Kato and colleagues [41] administered UFT (in the combination of 250 mg/m2 tegafur and 224 mg uracil per 100 mg of tegafur) postoperatively for 2 years to patients who had pathologic stage I adenocarcinoma. Treatment compliance ranged from 80% at 6 months to 61% at 24 months, with 3% of patients receiving no chemotherapy. After a median follow-up of 72 to 73 months, a survival benefit was detected in favor of UFT administration (5 year, 88% vs 85%; hazard ratio, 0.71; p = 0.04). A multivariate analysis detected a significant interaction between the treatment group and tumor stage (p = 0.04), with a survival benefit favoring UFT administration in T2 disease (n = 263; 5-year, 85% vs 74%; hazard ratio, 0.48; 95% confidence interval, 0.29 to 0.81; p = 0.005 log rank), but not T1 disease (n = 716; 5-year, 89% vs 90%; hazard ratio, 0.97; 95% confidence interval, 0.64 to 1.46; p = 0.87 log rank). In addition, the survival benefit associated with UFT was greatest for larger tumors (> 3cm vs 
2 cm in diameter; p = 0.05). In contrast, after a median follow-up of 6.2 years, Nakagawa and colleagues [43] did not detect a statistically significant survival benefit for UFT in patients with pathologic stage I adenocarcinoma or squamous cell carcinoma, although in subgroup analyses, longer survival was associated with UFT administration in T1 adenocarcinomas (5-year survival, 89.5% vs 80.2%; p = 0.011). No significant survival benefit was observed with UFT in T2 disease (p = 0.807) or T1 squamous cell carcinomas (p = 0.728). Compliance with UFT administration was lower in that trial, ranging from 80% at 6 months to 51% at 12 months.
Grade 3 or 4 toxicity was limited ( 2 %) in the UFT trials, and no toxic deaths were reported.
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Comment |
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Since the 1995 meta-analysis was published, five large randomized controlled trials of adjuvant platinum-based chemotherapy have been completed [21, 23–26, 28–30]. The three fully published trials also permitted postoperative radiotherapy [21, 23, 24]. Those trials mainly used older chemotherapy agents in the adjuvant treatment regimens, although some patients in the IALT were treated with vinorelbine-cisplatin [24], and chemotherapy delivery within one cycle of the planned treatment ranged from 69% [21, 23] to 74% [24]. Only the IALT, which combined cisplatin with one of etoposide, vinblastine, vinorelbine, or vindesine, and administered radiation on a center-by-center basis, demonstrated an absolute survival benefit in favor of chemotherapy (4.1% at 5 years; p < 0.03) [24]. Neither the use of radiation nor the choice of the second chemotherapy agent influenced survival. In both of the other fully published trials, no statistically significant survival advantage was detected for adjuvant cisplatin-etoposide combined with concurrent radiotherapy [21] or adjuvant cisplatin-vindesine-mitomycin with or without radiotherapy [23].
Results from the two North American cooperative group trials presented in abstract form in 2004 and not yet fully published strongly support the administration of adjuvant platinum-based (either cisplatin or carboplatin) chemotherapy [25, 26, 28–30] in combination with a newer chemotherapy agent (vinorelbine or paclitaxel). Those trials included only early-stage resected NSCLC (stage IB or II), and radiotherapy was not permitted. Overall survival (12% at 4 years and 15% at 5 years) was significantly longer with postoperative chemotherapy in both trials, as was progression-free survival. Furthermore, treatment was relatively well tolerated.
A recent trial presented at ASCO 2005 by the Adjuvant Navelbine International Trialists Association (ANITA) also demonstrated a significant survival benefit for adjuvant cisplatin-vinorelbine (HR 0.79, 95% CI, 0.66–0.95, p = 0.013, 8.6% absolute survival benefit at 5 years) [47, 48]. This trial randomized patients with stages IB, II, as well as IIIA NSCLC to receive adjuvant vinorelbine and cisplatin or observation alone, and used radiotherapy according to center choice. This trial was presented after the search was completed for this review, and is not included in the results.
A number of factors may explain the variation in the survival benefit associated with adjuvant chemotherapy: no benefit in two trials [21, 23], 4.1% benefit at 5 years in the IALT [24], 12% benefit at 4 years in the Cancer and Leukemia Group B trial [25, 26], and 15% benefit at 5 years in the National Cancer Institute of Canada Clinical Trials Group trial [28–30]. The trials with the longest survival included only patients with stage IB or stage II NSCLC and did not involve radiotherapy [25, 26, 28–30]. In contrast, in the IALT, 39% of patients had stage III disease, and 24% (including 21% of chemotherapy patients) received radiotherapy [24]. Similarly, in the trials that did not detect a significant treatment effect, between 28% and 58% of patients had stage III disease [21, 23], and radiotherapy was planned for between 43% [23] and 100% [21] of chemotherapy patients. The trials largely used different chemotherapy regimens, with newer agents included in the treatment schedules of the Cancer and Leukemia Group B trial and the National Cancer Institute of Canada Clinical Trials Group trial [25, 26, 28–30].
Three meta-analyses of Japanese UFT trials [10, 11, 13, 14] and the largest trial to date of this combination [41] have also suggested a survival advantage for adjuvant UFT chemotherapy compared with surgery alone, with a 5-year absolute benefit (3% to 4.6%) similar to that obtained with platinum-based chemotherapy. Adjuvant UFT is associated with limited grade 3 or 4 toxicity (2% or less). However, to date, UFT is not currently available in North America and has only been tested in lung cancer patients in Japan.
The evidence suggests that postoperative radiotherapy in combination with chemotherapy is not beneficial, at least for stage I and II NSCLC. No clear survival benefit has been detected for postoperative chemoradiotherapy compared with radiotherapy alone [7, 19–21, 23]. Treatment-related deaths associated with the combination treatment were reported for 2% to 9% of patients [19–21], whereas in the trials of adjuvant chemotherapy, chemotherapy-related deaths occurred in less than 1% of patients. In addition, a large individual patient data meta-analysis [49, 50] and one large randomized controlled trial [51] both detected a significant survival detriment for postoperative radiotherapy compared with surgery alone. The Lung Cancer Disease Site Group practice guideline on postoperative radiotherapy recommended against the use of that treatment for patients with completely resected stage II NSCLC [5]. The evidence for stage III disease is not clear, and the guideline made no definitive recommendation for or against the use of postoperative radiotherapy in patients with completely resected stage IIIA disease.
Surgeons have been reluctant to refer resected early-stage lung cancer patients for adjuvant chemotherapy because of concerns that the toxicity associated with chemotherapy may outweigh the small, although clinically significant survival benefit reported in the NSCLCCG meta-analysis [7]. However, the recent North American cooperative group trials have both demonstrated a significant improvement in survival in patients with early-stage resected NSCLC that cannot be discounted [[25, 26, 28–30]. Furthermore, with modern day supportive therapies, current chemotherapy is fairly well tolerated with acceptable toxicities. Some clinicians favor the administration of neoadjuvant (ie, preoperative) chemotherapy over adjuvant treatment, citing the poor compliance rates and decreased dose delivery of chemotherapy in the postoperative setting. Although these points are valid, to date there has been no randomized clinical trial to show a convincing survival benefit for neoadjuvant therapy. In addition, with the weight of the evidence firmly behind adjuvant chemotherapy, we expect that compliance and dose delivery will improve as patients and their oncologists are more accepting of non-dose limiting toxicities.
In conclusion, postoperative adjuvant platinum-based chemotherapy improves survival compared with surgery alone in patients with completely resected (R0) NSCLC. Evidence is insufficient to determine if specific subgroups of patients may differentially benefit from the use of this therapy; however most trials have mainly involved patients with a good performance status (0 to 1) and the greatest survival benefits have been obtained in trials of patients with stage IB or II disease. Although platinum-based chemotherapy is associated with a number of potentially severe toxicities, including neutropenia, nausea and vomiting, and fatigue, for patients fit enough to receive this treatment, the survival benefits strongly outweigh the adverse effects. Postoperative adjuvant chemotherapy involving alkylating agents has been found to be detrimental to survival and should not be used as a treatment for completely resected NSCLC. Similarly, the evidence to date does not support the use of postoperative radiotherapy in combination with chemotherapy as a treatment for patients with completely resected NSCLC.
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Appendix |
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