Based on available data, cisplatin plus vinorelbine is the best and most studied drug regimen for adjuvant treatment of NSCLC. Randomized trials to establish alternative or superior chemotherapy will require large sample sizes and years of follow-up. Meanwhile, the list of promising drugs for the treatment of metastatic NSCLC continues to grow.
In 1994, vinorelbine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic NSCLC, both as a single agent and in combination with cisplatin. Since the positive adjuvant trials were launched in 1995, there have been three additional drugs approved by the FDA in combination with cisplatin for first-line therapy of metastatic NSCLC (paclitaxel, gemcitabine, and docetaxel). There are also drugs in common use based on phase III efficacy (most notably carboplatin), which have not been FDA approved. Many phase III comparisons of two-drug, cytotoxic combinations in patients with metastatic NSCLC have shown relative equivalence in efficacy among cisplatinbased, carboplatin-based, and nonplatinum combinations.9,15–18
Recent meta-analyses suggest that cisplatin combinations are superior to carboplatin combinations in terms of response rate and survival.19,20
These data suggest that cisplatin should be included as part of a planned adjuvant regimen.
There are three drugs that have been shown to improve survival as single-agents in second-line therapy for metastatic NSCLC: docetaxel, erlotinib, and pemetrexed. To date, only one targeted therapy, the anti–vascular endothelial growth factor agent bevacizumab, has improved survival for selected patients with metastatic NSCLC when given in combination with chemotherapy compared with chemotherapy alone.21
The efficacy of bevacizumab in the adjuvant setting will be examined in the upcoming intergroup randomized adjuvant trial, Eastern Cooperative Oncology Group (ECOG) 1505.22
In addition to bevacizumab, numerous other molecularly targeted drugs with demonstrated activity in metastatic NSCLC are on the horizon.
Given the pace with which new drugs are being developed, it is difficult or impossible to test them all in the adjuvant setting. ECOG has gone so far as to intuitively adopt regimens for adjuvant therapy based on data in metastatic patients. The treatment regimens for the ECOG 1505 intergroup adjuvant trial are docetaxel/cisplatin, gemcitabine/cisplatin, and vinorelbine/cisplatin, all given alone or in combination with bevacizumab.22
These regimens were adopted based on efficacy data in the metastatic setting and to allow for a variety of regimens to enhance accrual to the trial. A carboplatin-based regimen was not included given meta-analyses of trials in metastatic NSCLC, suggesting inferiority compared with cisplatin and the lack of positive clinical trial data using anything but cisplatin combinations in the adjuvant setting.23
At this time, carboplatin should not be routinely recommended as part of an adjuvant regimen.
The adoption of regimens for use in the adjuvant setting in the absence of data is innovative and unfounded. There are examples in other disease types in which chemotherapy regimens of superior efficacy in the metastatic setting proved to be no better or even harmful in the adjuvant setting. For example, novel combinations of fluorouracil and irinotecan, which have been shown to be superior to fluorouracil alone for the treatment of metastatic colon cancer,24
repeatedly failed in the adjuvant setting due to increased toxicity and lack of clinical benefit.25–27
Similarly, there are data that suggest that docetaxel is superior to paclitaxel for metastatic breast cancer28
; however, paclitaxel and docetaxel have equivalent efficacy, with higher toxicity for docetaxel when given after doxorubicin and cyclophosphamide in the adjuvant treatment of breast cancer.29
Conversely, novel combinations of docetaxel and cyclophosphamide are less toxic and more effective than doxorubicin and cyclophosphamide in the adjuvant setting.30
The design of our trial rested on the assumption that drug delivery is an important determinant of the effectiveness of adjuvant chemotherapy for NSCLC and that drug delivery is a reasonable endpoint for a phase II tolerability study. The results of a randomized trial comparing docetaxel/cisplatin with vinorelbine/cisplatin in patients with metastatic NSCLC suggested that the combination docetaxel/cisplatin was superior in terms of drug delivery, response rate, and survival.9
The median number of treatment cycles delivered was five over 15 weeks for docetaxel/cisplatin and four over 16 weeks for vinorelbine/cisplatin, with a lower relative dose intensity for vinorelbine/cisplatin (0.94 versus 0.78). Similar proportions of patients were taken off study for disease progression (30% in both arms). These data are corroborated by randomized phase II data showing similar trends in drug delivery, response rate, and survival between these two regimens.10
However, patients with NSCLC who have recently undergone surgery are clearly a different population than patients with metastatic NSCLC and may exhibit a different tolerance and side effect profile.
This is the first clinical trial to test the tolerability of docetaxel/cisplatin in the adjuvant setting. Our trial was designed to demonstrate that docetaxel/cisplatin delivered to patients with completely resected NSCLC allowed a higher total dose of cisplatin than with the chemotherapy regimens used in IALT (including cisplatin combined with etoposide, vinorelbine, vindesine, and vinblastine). As a result of early closure due to poor drug delivery, the sample size of this trial is small (n = 27). Nevertheless, conclusions can be drawn regarding dose-limiting toxicities, which have immediate implications for patients treated with this regimen.
Our data suggest that the combination of cisplatin at 80 mg/m2
IV with weekly docetaxel (35 mg/m2
) IV or docetaxel (75 mg/m2
) IV every 3 weeks is no better tolerated than chemotherapy regimens used in IALT. The most common reason to stop postoperative cisplatin and docetaxel was intolerable fatigue, which most often occurred after the first cycle. Neutropenia was seldom an issue in early discontinuation of therapy on either schedule. The every 3 weeks docetaxel plus cisplatin regimen is more amenable to the routine use of filgrastim, or pegylated filgrastim, to prevent neutropenia compared with weekly chemotherapy regimens. In this study, only four of 11 patients on the every 3 weeks cohort (36%) required treatment with pegylated filgrastim. Eleven of 27 patients treated in either cohort (41%) required treatment with darbepoetin. Despite using state-of-the-art acute and delayed emesis prophylaxis, seven patients (26%) experienced grade 3–4 nausea, and it was dose limiting in six patients. This is not unexpected, as the addition of aprepitant to standard antiemetics had little effect on the prevention of nausea in randomized trials.31,32
In this study, fatigue was the dose-limiting toxicity in eight of 11 patients who dropped out early, and 30% of all patients treated experienced grade 3–4 fatigue. The published adjuvant trials report rates of grade 3–4 fatigue as high as 28% using high-dose cisplatin with vinorelbine.3
In patients with metastatic NSCLC treated with cisplatin plus docetaxel or vinorelbine, grade 3–4 fatigue was reported in only 12% to 14% of patients.9,10
Clearly, patients immediately postoperatively are more susceptible to fatigue from cisplatin-based chemotherapy than patients with metastatic NSCLC.
Of note, grade 3–4 fatigue occurred less frequently in the BR10 trial (compared with ANITA) in which cisplatin was administered as a split dose with 50 mg/m2 IV given on days 1 and 8 of each monthly cycle, with weekly vinorelbine. Despite lower rates of fatigue and nausea with this approach, similar proportions of patients completed one, two, three, and four cycles of chemotherapy in ANITA and BR10. Our trial did not explore whether split-dose cisplatin might mitigate fatigue or improve drug delivery in combination with docetaxel.
Based on our phase II data and the phase III adjuvant data using cisplatin plus vinorelbine, it is anticipated that approximately one half of patients will be unable to receive all four planned chemotherapy cycles in the intergroup adjuvant study (ECOG 1505). Treatment with split-dose cisplatin is not an option in ECOG 1505. Drug delivery will likely be even lower in the experimental arm of the study as the coadministration of bevacizumab will lead to increased toxicity, particularly neutropenia, hypertension, venous and arterial thrombotic events, and toxic deaths.
In conclusion, docetaxel plus cisplatin was difficult to deliver in the postoperative setting in this phase II trial. The most common dose-limiting toxicities are more likely attributable to cisplatin rather than the docetaxel, given that the same problems were encountered whether the docetaxel was delivered at a single high or lower weekly dose. These results predict difficulty in delivering cisplatin and docetaxel in both the control and experimental treatment arms of ECOG 1505. The results of ongoing randomized trials comparing preoperative versus postoperative delivery of docetaxel/cisplatin will be of significant interest. Priority should be given to developing noncisplatin adjuvant regimens for evaluation in a phase III trial.
The therapeutic benefit of adjuvant chemotherapy should be enhanced through identification of more efficacious regimens and alternatives to cisplatin-based therapy. As demonstrated in this study, many patients prove intolerant to cisplatin and cannot complete prescribed therapy. Others are not candidates for cisplatin due to comorbid medical illness. In the future, the development of better prognostic molecular tests will allow low-risk patients to be spared adjuvant therapy, 23
and better predictive molecular tests may allow molecularly tailored adjuvant therapies. Recent research has identified subpopulations of patients who are inherently resistant to cisplatin-based chemotherapy. For example, overexpression of the DNA repair protein ERCC1 (excision repair cross-complementation group 1) in the resected tumor predicted a lack of benefit from adjuvant cisplatin, theoretically due to de novo resistance of the cancer to cisplatin-induced DNA damage.33
Selection of noncisplatin regimens for these patients may improve outcome, and a phase II tolerability study of vinorelbine plus docetaxel in ERCC1-positive patients is planned for possible evaluation in a phase III trial.