Efficacy and Tolerability of a Non-Platinum Based Doublet for Advanced Non-Small Cell Lung Cancer
Preliminary results from a phase II trial indicate that the combination of vinorelbine (Navelbine) plus gemcitabine (Gemzar) demonstrated comparable efficacy to carboplatin (Paraplatin) plus paclitaxel (Taxol) chemotherapy in terms of response and median survival for the treatment of advanced non-small cell lung cancer (NSCLC).1 Furthermore, the vinorelbine plus gemcitabine combination produced a more favorable hematologic toxicity profile compared to the carboplatin plus paclitaxel doublet. Presenting the results for the very first time, Rogerio C. Lilenbaum, MD, of the Mount Sinai Comprehensive Cancer Center in Miami Beach, Florida advised that the vinorelbine plus gemcitabine doublet is an appropriate alternative to well-established platinum-based chemotherapy.
Platinum-Based Doublets are Currently the NSCLC Standard
According to Dr. Lilenbaum, the standard of care for patients with advanced NSCLC and good performance status is a platinum-based doublet. A number of platinum-based doublets have shown similar survival outcomes in phase II or III trials for NSCLC including cisplatin plus vinorelbine,2,3 cisplatin plus paclitaxel,4,5 cisplatin plus docetaxel,5,6 cisplatin plus gemcitabine,3,5 and carboplatin plus paclitaxel.3,5,7 "Two trials in particular have helped oncologists reach this conclusion," stated Dr. Lilenbaum.
The first trial, conducted by Schiller et al for the Eastern Cooperative Oncology Group (ECOG),5 evaluated whether any of three chemotherapy regimens was superior to cisplatin plus paclitaxel in patients with advanced NSCLC. A total of 1207 patients with advanced NSCLC were randomly assigned to a reference regimen of cisplatin plus paclitaxel or to one of three platinum-based doublets: cisplatin plus gemcitabine, cisplatin plus docetaxel, or carboplatin plus paclitaxel.
The response rate for 1155 eligible patients was 19%, with a median survival time of 7.9 months (95% Confidence Interval (CI), 7.3-8.5 months); a one-year survival rate of 33% (95% CI, 30%-36%), and a two-year survival rate of 11% (95% CI, 8%-12%) [Table 1]. The response rate and survival did not differ significantly between patients receiving cisplatin plus paclitaxel and the other three platinum-based doublets. Treatment with cisplatin plus gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin plus paclitaxel. Dr. Lilenbaum noted that this difference was not clinically meaningful. However, cisplatin plus gemcitabine was more likely to cause grade 3, 4, or 5 renal toxicity than cisplatin plus paclitaxel (9% vs 3%, respectively). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. Therefore, investigators concluded that none of the four platinum-based doublets provided a significant advantage over the other in the treatment of advanced NSCLC.
"The results of the second study," continued Dr. Lilenbaum, "I had the privilege to present at ASCO 2002." "In this phase III randomized trial of 584 patients with advanced NSCLC, we compared single-agent paclitaxel to carboplatin plus paclitaxel.8 Not only did we look at efficacy, but also quality of life and cost-effectiveness." The median patient age was 63.5 years with 158 patients >70 years of age.
"There was a difference in failure-free survival and median survival time in favor of the carboplatin plus paclitaxel. [Table 2] However, the one-year survival rates were approximately the same, with no statistically significant difference. There was no difference in quality of life, implying that there was no detrimental effect of the platinum-based doublet in comparison to single-agent paclitaxel, despite what we found to be a numerically higher toxicity rate. So I think it is reasonable to conclude that patients with advanced NSCLC and good performance status should be treated with a platinum-based doublet," advised Dr. Lilenbaum.
Viable Alternative to Platinum-Based Doublets: Vinorelbine plus Gemcitabine
Speaking to the issue of patients in daily clinical practice, Dr. Lilenbaum commented that not every patient may be a candidate for a platinum-based doublet. "The basic premise of non-platinum-based doublets is to deliver comparable survival with less toxicity, leading to perhaps a better therapeutic index. The non-platinum-based doublets represent an alternative to patients who are not felt to be optimal candidates for platinum-based doublets."
Dr. Lilenbaum further divided non-platinum-based regimens into two categories, non-platinum taxane-based regimens and non-platinum non-taxane based regimens. Selecting a recent trial as representative of the non-platinum taxane-based regimens, Dr. Lilenbaum discussed the study conducted by Giuseppe Giaccone.9 The study compared three treatment arms with cisplatin plus paclitaxel as the control arm, and cisplatin plus gemcitabine and gemcitabine plus paclitaxel as the experimental treatment arms.
Response rates ranged from 27% to 36% with median survival times ranging from 6.9 to 8.8 months. One-year survival rates ranged from 26.5% to 35.5% with progression-free survival slightly higher in the cisplatin plus gemcitabine treatment arm. There were no statistically significant differences between the three treatment arms. Moreover, there were no significantly beneficial improvements in toxicity (grade 3-4 neutropenia) or neurotoxicity and neuropathy.
"Based on this study, I think it's reasonable to state that the non-platinum taxane-based doublets offer comparable efficacy to platinum-based doublets. Toxicity, however, remains substantial, especially in patients with less than optimal performance status. So the premise of equivalent or comparable survival with better toxicity profiles has not been conclusively demonstrated for the taxane-based regimens. This leads us to non-platinum non-taxane based doublets and our discussion of the vinorelbine plus gemcitabine doublet."
"One trial that evaluated the vinorelbine plus gemcitabine doublet that I would like to discuss is the trial conducted by Greco and colleagues10 at the Minnie Pearl Cancer Research Network. The trial compared the toxicity, response rate, and progression-free survival of four chemotherapy regimens in patients with advanced NSCLC. The regimens included two triplets (paclitaxel plus carboplatin plus gemcitabine; paclitaxel plus carboplatin plus vinorelbine) and two doublets (paclitaxel plus gemcitabine; vinorelbine plus gemcitabine). The overall response rates (range, 32%-45%), median survival times (range, 8.7-10.7 months) and one-year survival rates (range, 38%-44%) were comparable between all treatment arms."
"The interesting point of this trial is really the toxicity analysis. [Table 3]. As would be expected, there was more leukopenia in the triplets. There was more thrombocytopenia in the carboplatin plus paclitaxel plus gemcitabine treatment arm. There was no significant alopecia with vinorelbine plus gemcitabine compared to the other regimens. There was more arthralgia and myalgia in the paclitaxel-based regimens. The incidence of severe toxicity in the vinorelbine plus gemcitabine treatment arm was quite, quite low."
"The second trial that evaluated vinorelbine plus gemcitabine and represented, I think, a true test of non-platinum non-taxane based doublets versus their platinum-based counterparts was the Italo-Canadian study conducted by Cesare Gridelli which he presented at ASCO 2002.11 The trial compared vinorelbine plus gemcitabine to cisplatin plus vinorelbine or gemcitabine chemotherapy. There was no significant difference in response rates between the treatment arms. Although the six-month probability of progression-free survival was greater in the platinum-based doublets, there was no significant difference in overall survival. However, the primary endpoint of the study was quality of life. The vinorelbine plus gemcitabine treatment arm was associated with less gastrointestinal, hematologic and auditory toxicity and were thus, less likely to exhibiting worsening of quality of life with no significant difference in terms of survival."
Further Evaluation of Vinorelbine plus Gemcitabine
Looking to further investigate the more favorable toxicity profile of the vinorelbine plus gemcitabine doublet, Dr. Lilenbaum conducted a study of 164 patients (median age 64 years) with previously untreated advanced NSCLC. Patients were randomized to receive vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 on Days 1 and 8, or carboplatin area-under-curve (AUC) 6 plus paclitaxel 200 mg/m2 by 3-hour infusion on Day 1 of each cycle. Cycles were repeated every 21 days up to a maximum of 6 cycles. The study assessed toxicity, efficacy and quality of life. The percentage of patients with stable and progressive disease was comparable between the two treatment arms.
Response rates, time to progression, and median survival were comparable between the two treatment arms with no statistically significant differences. [Table 4]
Commenting on the toxicity profiles, Dr. Lilenbaum reported significantly more neutropenia in the carboplatin plus paclitaxel treatment arm compared to the vinorelbine plus gemcitabine treatment arm. He noted that the difference observed in thrombocytopenia was not statistically different. As seen in other trials, there was no significant alopecia in the vinorelbine plus gemcitabine treatment arm, as well as less peripheral neuropathy. Quality of life parameters were similar between the two treatment arms.
The standard of care for patients with advanced NSCLC and good performance status is a platinum-based doublet. Preliminary results suggest that the non-platinum, non-taxane-based doublet of vinorelbine plus gemcitabine offers an attractive alternative therapeutic option to platinum-based doublets in the treatment of advanced NSCLC. Vinorelbine plus gemcitabine offers comparable efficacy and an improved toxicity profile compared to carboplatin plus paclitaxel.
Excerpts from the Question & Answer Period following the "Breakfast with the Professors"
Responding to a comment about using single-agent chemotherapy first and switching to platinum-based doublets and how the patient's acceptance might be different than if the patient had received the platinum-based doublet first and how everything may be relative to the patient at that point in time...
Dr. Lilenbaum: I think there is a difference between some of the platinum-based and the non-platinum-based regimens, especially the non-taxane doublets such as vinorelbine plus gemcitabine. And, yes, everything is relative. If they receive a platinum-based doublet up front and they move on to vinorelbine plus gemcitabine, for example, or even one of those two agents alone, I think they're likely to have less toxicity.
I think what matters here is the balance between efficacy and quality of life. And please understand that quality of life is a much greater assessment, I guess, or domain than just toxicity...quality of life is not just a reflection of toxicity. Quality of life is probably the result of toxicity versus improvement in lung cancer symptoms. So while there may be more toxicity in some of the platinum-based doublets, I do believe that some of their symptoms may be palliated faster. So, there is at the end, no difference in quality of life.
Some of the toxicities that we saw, for example, in the CALGB trial were basically numerical toxicities. There was no significant difference in the major clinical end points. Yes, there was a little more anemia, a little more neutropenia, perhaps a little more thrombocytopenia. There was no difference whatsoever in febrile neutropenia. There was no difference in toxic death. There was no difference in quality of life in general.
Again, if you can prove that there is a clinical benefit, which I believe is meaningful in favor of a combination in first-line, without a detriment in quality of life, I still think that this is how we should treat our patients. Once in a while, or perhaps more than once in a while, we'll see patients...that we just don't feel comfortable with these regimens. But again, that's not a research question. That's your judgment and my judgment and everybody else's judgment.
Asked for final comments...
Dr. Lilenbaum: Patients with advanced non-small-cell lung cancer are not all the same. And this may sound silly, but this goes beyond our own judgment on whether someone can handle a platinum-based doublet versus a non-platinum regimen or even a single agent. The biology is different.
And the impact that we have on this disease is actually, quite honestly, a lot less than we wish it was. So I think what the CALGB study did for me, at least, was very formative. Because when you look at the overall survival, the curves split at the very beginning in favor of the combination regimens. And then they come together.
Of course, at ASCO I said maybe some of these patients are being rescued by second-line chemotherapy. And I think to some extent this may be true. But what I think is even more true is that the patients who are really sick from this disease, are the ones who benefit from an aggressive platinum-based doublet. Once those patients, unfortunately, expire, and you get to ten months, twelve months, you're left with the patients that have less aggressive disease and a different biology. And in those patients, it doesn't really matter if you give a single agent or a combination regimen, or even a triplet.
But, I think the challenge for us is to try to identify those patients. So, we don't have good clinical correlates, other than just perhaps our judgment, but I think it's important to think about these data when we look at our patients in our practice.
1. Lilenbaum RC. Vinorelbine and gemcitabine versus paclitaxel and carboplatin in previously untreated patients with advanced non-small cell lung cancer: results of a phase II trial. Presented at the "Breakfast with the Professors" Symposium held in conjunction with the Chemotherapy Foundation Symposium XX, November 14, 2002, New York, New York.
2. Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994;12: 360-367.
3. Kelly K, Crowley J, Bunn PA, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001;19:3210-3218.
4. Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000;18:623-631.
5. Schiller JH, Harrington D, Belani CP, et al for The Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98.
6. Belani CP. Docetaxel (Taxotere) in combination with platinum-based regimens in non-small cell lung cancer: results and future developments. Semin Oncol. 1999;26(3 suppl 10):15-18.
7. Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol. 1995;13:1860-1870.
8. Lilenbaum RC, Herndon J, List M, et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Prog Proc Am Soc Clin Oncol. 2002; 21. Abstract 2.
9. Giaccone G. Early results of a randomized phase III trial of platinum-containing doublets versus a nonplatinum doublet in the treatment of advanced non-small cell lung cancer: European Organization for Research and Treatment of Cancer 08975. Semin Oncol. 2002;29:47-49.
10. Greco FA, Gray JR, Thompson DS, et al. Prospective randomized study of four novel chemotherapy regimens in patients with advanced nonsmall cell lung carcinoma: a Minnie Pearl Cancer Research Network Trial. Cancer. 2002;95:1279-1285.
11. Gridelli C, Shepherd F, Perrone F, et al. Gemvin III: a phase III study of gemcitabine plus vinorelbine (GV) compared to cisplatin plus vinorelbine or gemcitabine chemotherapy (PCT) for stage IIIb or IV non-small cell lung cancer (NSCLC): an Italo-Canadian study. Prog Proc Am Soc Clin Oncol. 2002; 21. Abstract 1165.