|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Phase III Trial Comparing a Defined Duration of Therapy Versus Continuous Therapy Followed by Second-Line Therapy in Advanced-Stage IIIB/IV Non–Small-Cell Lung CancerByFrom the Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Department of Medicine and Center on Outcomes Research and Education, Northwestern University, Chicago, IL. Address reprint requests to Mark A. Socinski, MD, Director, Multidisciplinary, Thoracic Oncology Program, CB #7305, University of North Carolina, Chapel Hill, NC 27599; email: socinski{at}med.unc.edu
PURPOSE: To compare four cycles of therapy versus continuous therapy to determine the optimal duration of chemotherapy in advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB/IV NSCLC patients were randomized to arm A (four cycles of carboplatin at an area under the curve of 6 and paclitaxel 200 mg/m2 every 21 days) or arm B (continuous treatment with carboplatin/paclitaxel until progression). At progression, all patients on both arms were to receive second-line weekly paclitaxel at 80 mg/m2/wk. The primary end points were survival and quality of life (QOL). RESULTS: Two hundred thirty patients were randomized. Fifty-seven percent of arm A patients completed four courses of therapy. In the 116 arm B patients, the median number of cycles delivered was four (range, zero to 19 cycles). Forty-two percent received five or more cycles; 18% received eight or more cycles. Overall response rates were 22% and 24% for arms A and B, respectively (P = .80). Median survival time and 1-year survival rates were 6.6 months and 28% for arm A and 8.5 months and 34% for arm B, respectively (log-rank P = .63). Rates of hematologic and nonhematologic toxicity were similar between the two arms, except for neuropathy. The rate of grade 2 to 4 neuropathy increased from 19.9% (95% confidence interval [CI], 13.6% to 26.2%) at cycle 4 to 43% (95% CI, 28.6% to 57.4%) at cycle 8. There were no differences in QOL. Only 45% of patients received second-line therapy (42% in arm A v 47% in arm B, P = .42). CONCLUSION: This study shows no overall benefit in survival, response rates, or QOL to continuing treatment with carboplatin/paclitaxel beyond four cycles in advanced NSCLC.
NON–SMALL-CELL lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States.1 In the year 2001, approximately 169,500 new diagnoses will be made, and 157,400 deaths from NSCLC will occur.1 Approximately 30% to 40% of all new cases will present with stage IV or stage IIIB (malignant pleural effusion) disease.2 Unfortunately, these patients are not curable and treatment is given to prolong survival and palliate symptoms and maintain or improve quality of life (QOL).3,4 Although platinum-based regimens clearly improve median and 1-year survival rates,3 only 30% to 40% of patients survive 1 year, and less than 15% survive 2 years.4 Given the noncurative nature of chemotherapy in advanced metastatic NSCLC, the duration of chemotherapy administration must be balanced against the toxicity it engenders. The optimal duration of therapy that maximizes the survival and palliative effects that patients receive is unclear. In 1997, the American Society of Clinical Oncology issued guidelines5 regarding the treatment of advanced NSCLC. In that guideline, it was stated that there was insufficient data available to make a firm recommendation on the optimal duration of therapy. Only one trial was referenced that addressed the question of chemotherapy duration in advanced NSCLC.6 In that trial, continuing chemotherapy with a non–cisplatin-based regimen beyond two to three cycles in patients with stable disease did not demonstrate a survival advantage. Despite the lack of data, the American Society of Clinical Oncology guidelines recommended two to eight cycles of treatment with platinum-based combination chemotherapy. It seems that if palliation or objective response occurs, it does so in the first three to four cycles of therapy.7 Smith et al8 recently reported a trial in which patients with advanced NSCLC were randomized to three versus six cycles of mitomycin, vinblastine, and cisplatin. They failed to show a survival advantage for the longer duration of therapy. In addition, there was a suggestion that fatigue and certain toxicities (ie, nausea and vomiting) were more frequent in those patients receiving six cycles of therapy. This study suggests that prolonging the duration of therapy may not result in additional clinical benefit, while causing more cumulative toxicity. Recently, the fact that two phase III trials9,10 have suggested that second-line therapy can improve survival and QOL also raises another issue relative to the optimal treatment strategy in advanced NSCLC. The use of second-line therapy and its potential to impact survival makes it a confounding variable if survival is the primary end point in the design of a first-line trial. It also allows for the fact that patients with advanced NSCLC may be better served by brief durations of first-line therapy followed by second-line therapy at the time of progression. The combination of carboplatin and paclitaxel represents a standard-of-care regimen based on several phase III trials11-13 and is commonly used as first-line therapy in the United States.14 The better tolerability of carboplatin-based compared with cisplatin-based regimens makes this doublet an attractive candidate to address a duration of therapy question in this disease setting. To address this issue, we designed a prospective, randomized phase III trial in which patients with advanced NSCLC were randomized to either four cycles of carboplatin/paclitaxel or continuous therapy with carboplatin/paclitaxel until objective progression of disease. Given the potential impact of second-line therapy on survival,9,10 we designated a second-line therapy for patients on both arms of the study. At the time this trial was initiated, there was no standard regimen in the second-line setting. Because low-dose weekly paclitaxel has activity in patients failing every-3-week paclitaxel infusion schedules in other disease settings15,16 and has a favorable toxicity profile, low-dose weekly paclitaxel was chosen as the second-line regimen in this trial. The primary end points of this trial were survival and QOL.
Patient Selection Patients were required to have histologic or cytologic proof of stage IIIB/IV NSCLC. In the case of stage IIIB, patients selected were not candidates for combined-modality therapy (malignant pleural effusion or advanced supraclavicular adenopathy). Patients could have measurable or assessable disease and could not have received prior chemotherapy for NSCLC. Prior radiotherapy was allowed; however, patients had to be at least 1 week from completion of radiotherapy. Patients with treated brain metastases were allowed. For first-line treatment, patients were required to have a Karnofsky performance status (PS) of  70% and adequate end-organ function defined as an absolute neutrophil count 1,500/mm3, platelets 100,000/mm3, creatinine  2.0 x the institutional upper normal limits (IUNL), bilirubin 1.5 x IUNL, AST 2.5 x IUNL, and no clinically significant baseline peripheral neuropathy. For second-line weekly paclitaxel treatment, the same eligibility criteria were required with the exception of Karnofsky PS (patients with a PS of 60% were allowed). All patients were required to participate in the QOL component of the study and were required to give written informed consent. This trial was reviewed by the Protocol Review Committee of the Lineberger Comprehensive Cancer Center (LCCC) and the institutional review board of the University of North Carolina School of Medicine (as well as all participating centers) and labeled LCCC 9719 (Fig 1).
Treatment Plan and Response Assessment Patients were randomized to either arm A or arm B. Patients randomized to arm A received four cycles of carboplatin and paclitaxel, whereas patients on arm B received carboplatin and paclitaxel until disease progression. On both arms, carboplatin was given at an area under the curve of six (using the Calvert Equation17) and paclitaxel at 200 mg/m2 over 3 hours every 21 days. Standard premedications for paclitaxel were administered and included dexamethasone 20 mg intravenous (IV), diphenhydramine 50 mg, and ranitidine 50 mg IV or cimetidine 300 mg IV, given 30 minutes before paclitaxel. On arm A, disease assessment evaluating response to treatment was performed after cycles 2 and 4. After completion of the four cycles of therapy on arm A, patients were to be seen and evaluated every 6 weeks. Appropriate testing to evaluate for disease progression was performed at the discretion of the treating physician because the treating physician determined what evaluations would be used to assess each individual patient’s disease status. When disease progression was documented and the patient met the eligibility criteria, second-line weekly paclitaxel was administered (see below). On arm B, patients were to receive therapy until disease progression. However, other criteria for stopping therapy on arm B included voluntary withdrawal, excessive toxicity, and when deemed in the best interest of the patient by the treating physician. Disease assessments were performed every two cycles. If therapy was stopped, patients were assessed for disease progression every 6 weeks in a similar fashion to the patients on arm A. When disease progression was documented and the patient met the eligibility criteria, second-line weekly paclitaxel was administered. For second-line therapy, patients received paclitaxel at 80 mg/m2/wk until further disease progression. Standard medications noted above were given weekly for paclitaxel; however, a reduction in the dose of dexamethasone was allowed if patients exhibited no signs of hypersensitivity. Patients were assessed for disease progression every 8 weeks. After the initial 8 weeks of weekly paclitaxel, patients were allowed 1- to 2-week treatment breaks at the discretion of the treating physician. Standard criteria for response to chemotherapy were used. Patient response to treatment was categorized as either complete, partial, stable, or progressive according to these criteria.
QOL
Randomization
Statistical Design Three analyses were conducted with the FACT-L to evaluate the impact of duration of therapy on QOL. For all analyses, the time by treatment interaction was examined to determine whether QOL change over time was differentially affected by treatment arm. First, an intent-to-treat general linear model-pattern mixture model20 was used to allow for the inclusion of all available data and to account for nonrandom missing data (ie, data missing as a result of death from disease or treatment toxicity). Second, a similar analytic model was used to compare arm A with the subset of arm B who completed more than four cycles of treatment. In the third analysis, a repeated measures analysis of variance was conducted using only data from those who completed the baseline and 25-week interviews. Although it is unusual to analyze clinical trial QOL data using only subjects with complete data, no difference in QOL would be expected for data collected at baseline and at 5 and 11 weeks because both treatment arms received exactly the same treatment for four cycles (12 weeks).
Patient Demographics Between January 1998 and January 2000, 230 patients were entered onto this trial. Table 1 shows the demographics of all patients entered as well as the distribution of these factors between arm A and arm B patients. The median age was 63 years (range, 32 to 82 years). The majority of the patients were male (63%), had stage IV disease (87%), and nonsquamous histology (78%). Performance status was equally divided between Karnofsky PS 90% to 100% (52%) and 70% to 80% (48%). Minorities comprised 26% of the population entered onto the study. There were no statistically significant differences in these factors between arm A and arm B.
Treatment Administration Summary Table 2 lists the number of treatment cycles delivered to both arms. As is noted, the median number of treatment cycles on both arms was four (range, arm A, one to six cycles; arm B, one to 19 cycles). On arm A, three patients were inadvertently given more than four cycles (one patient received five cycles, and two patients received six cycles). On arm B, 42% of patients received greater than four cycles, and 18% received eight or more cycles. The reasons for treatment discontinuation on both arms are also listed in Table 2. On arm A, the majority of patients completed four cycles. As expected, more patients on arm B discontinued treatment because of progression (17% on arm A v 37% on arm B, P = .0005), toxicity (4% on arm A v 16% on arm B, P = .001), and physician/patient choice (12% on arm A v 36% on arm B, P = .0001).
Toxicity The toxicity profile of carboplatin in combination with paclitaxel has been well documented.11-13 Since patients on both arm A and arm B received identical treatment through the initial four cycles, the rates of toxicity would be expected to be similar. Indeed, the overall rates of hematologic toxicity on this study were similar on both arms, and there was no evidence of cumulative hematologic toxicity on arm B. The percentage of patients experiencing grade 3 or 4 toxicity was as follows for arm A versus arm B: neutropenia, 39% versus 42%; thrombocytopenia, 8% versus 11%; anemia, 7% versus 10%; and febrile neutropenia, 1% versus 1%, respectively. The overall rates of nonhematologic toxicity were also similar on both arms, with the exception of peripheral neuropathy. The percentage of patients experiencing grade 2, 3, or 4 nonhematologic toxicity was as follows for arm A versus arm B: myalgia/arthralgia, 13% versus 14%; nausea/vomiting, 14% versus 16%; malaise/fatigue, 10% versus 14%; anorexia, 5% versus 9%; and hypersensitivity reactions, 8% versus 9%, respectively. Grade 2 to 4 neuropathy was seen in 14% and 27% of arm A and arm B patients, respectively (P = .02). The neuropathy was cumulative in nature. Figure 2 shows the rate of neuropathy by cycle of therapy accounting for patient dropout using Kaplan-Meier methods. After four cycles of carboplatin/paclitaxel, 19.9% (95% confidence interval [CI], 14% to 26%) of patients had experienced grade 2 to 4 neuropathy. At cycle 8, 43% (95% CI, 29% to 54%) of patients still receiving therapy had experienced grade 2 to 4 neuropathy. This method appropriately accounts for patient dropout and provides an unbiased estimate for the neuropathy probability.
Second-Line Therapy The percentage of patients receiving some form of second-line chemotherapy after first-line carboplatin/paclitaxel is listed in Table 3. As is shown, only 45% of all patients (103 of 230 patients) received second-line chemotherapy after progression after first-line therapy. Of the 103 patients receiving second-line chemotherapy, 48 were from arm A and 55 from arm B (P = .42). The majority of patients (62 of 103 patients) received second-line weekly paclitaxel per protocol design; however, 35% (41 of 103 patients) did not. The most common reason for not receiving second-line weekly paclitaxel was residual grade 2 or 3 peripheral neuropathy from first-line carboplatin/paclitaxel. The most common alternative chemotherapy administered was single-agent gemcitabine. The overall response rate to second-line weekly paclitaxel was 8% (all partial responses). Also, 39% of patients had stable disease. The details of weekly paclitaxel in the second-line setting will be reported separately.
QOL Baseline FACT-L data was available for 218 of the 230 subjects enrolled onto the trial. Subsequently, telephone interviews were used to obtain QOL information from all subjects still enrolled onto the trial. That is, QOL information was not collected when a subject withdrew from the study (2.2% at 5 weeks to 4.9% at 25 weeks), had such severe disease or treatment toxicity that he or she felt unable to answer the questions (3.6% at 11 weeks and 12.9% at 25 weeks), or died (6.2% at 5 weeks, 12.4% at 11 weeks, and 24.9% at 25 weeks); for the purpose of these analyses, these data are therefore considered to be missing not-at-random. Of the remaining subjects, QOL data was available on 93.2% at 5 weeks, 85.8% at 11 weeks, and 70.5% at 25 weeks; the reasons for noncompletion were classified as patient refusal and included other illness, delays in notification of subject enrollment, mild treatment toxicity, and inability to reach subject by phone. As expected, there were no statistical differences between baseline and week 11 QOL scores comparing arm A with arm B. Use of a pattern mixture model has been advocated by Fairclough et al19 to analyze QOL data in clinical trials when at least some of the data is missing not-at-random (ie, is missing because of reasons related to the disease or treatment being studied). Accordingly, we classified data into one of the following four patterns: complete, missing as a result of death, missing as a result of disease severity/treatment toxicity, and missing as a result of patient refusal to complete the interview(s). A general linear model-pattern mixture model was then used to evaluate the effect of time, treatment, and the interaction of treatment with time. Results indicated no main effect of treatment (ß = -1.35, SE = 2.62, P = .64) and a significant deterioration in QOL over time (ß = -4.12, SE = 0.63, P = .007) but no difference between treatment arms in the QOL change over time (ß = 1.27, SE = 1.14, P = .35). A similar pattern mixture model was conducted for the subset analysis comparing all subjects on arm A to the 42% of subjects on arm B who received more than four cycles of therapy. The results mirrored those of the intent-to-treat analysis above, with a significant main effect of time (ß = -5.20, SE = 0.80, P = .007) and no effect of treatment (ß = -3.92, SE = 4.1, P = .41) and no interaction between treatment and time (ß = 2.63, SE = 1.62, P = .20). One hundred twenty-nine subjects remained in the trial at 25 weeks and of those, 65.1% (37 patients on arm A and 47 on arm B) were available for QOL evaluation at that time. As noted above, the 25-week assessment was the only one at which differences might be noted between defined and continuous treatment. The results of the repeated measures analysis of variance (baseline to 25 weeks) replicate those of the pattern mixture model, with a significant QOL deterioration over time (P = .002), no main effect of treatment (P = .08), and no interaction between time and treatment (P = .94).
Response and Survival
Of the 230 assessable patients, 38 remain alive. Their median time of follow-up is 19.8 months (range, 9.5 to 36.1 months). The overall median survival for all patients on this trial was 7.6 months (95% CI, 6.2 to 9.0 months) with 1- and 2-year survival percentages of 31% (95% CI, 25% to 36%) and 13% (95% CI, 8% to 18%), respectively. Figure 3 shows the survival curves for the two arms of the study. No statistically significant differences were seen between the two arms (log-rank P = .63). Figure 4 shows the survival curves for those patients on arm A who completed four cycles and those patients on arm B who received four or more cycles of therapy. Also included are the patients from both arm A and B who received less than four cycles of treatment. No statistically significant differences within the two subgroups (< four and
Using a main effects Cox model, males (P = .027) and patients with Karnofsky PS 70% to 80% (P < .0001) were found to have poorer survival, whereas treatment arm (P = .28), age (P = .73), stage of disease (P = .77), and histology (P = .40) failed to achieve statistical significance. A time-varying covariate was identified for sex, with males having poorer survival for early times and better survival later. We identified 15 months as a reasonable breakpoint in the shifting hazard ratio. Males have a 1.5-fold risk of failing compared with females up through 15 months (P = .008) and a 0.23-fold risk beyond 15 months (P = .006). Finally, a statistically significant PS-treatment interaction was identified, with poor performance patients (PS 70% to 80%) who were treated on arm A faring worse. This interaction is illustrated in Fig 5, which shows the Kaplan-Meier plots for each combination of treatment and PS group. Using patients on arm B with a PS 90% to 100% as the baseline group in a Cox model, the hazards ratios of arm A patients with a PS 90% to 100% (hazard ratio = 0.9; P = .44) and arm B patients with PS 70% to 80% (hazard ratio = 1.4; P = .12) were not statistically different. However, arm A patients with PS 70% to 80% had a substantially greater hazard ratio (hazard ratio = 2.0; P = .019).
Platinum-based chemotherapy improves survival in advanced, metastatic NSCLC,3,4 and leads to symptom palliation in a substantial proportion of patients.4,7 These benefits must be weighed against the toxicity, costs, and inconvenience of chemotherapy in a population of patients whose median survival time is approximately 8 months.11-13 Traditionally, most trials have used at least six courses of treatment,12,13,21-23 and some have advocated that treatment be continued for up to 10 courses11 or be continued until disease progression.19,24 The results of our trial show no overall benefit to extending chemotherapy with carboplatin/paclitaxel beyond four cycles in terms of survival, response rate, or QOL. Additionally, there is real concern that cumulative toxicities specific to the regimen used in this setting may be prohibitive in this patient population and may negatively impact on an individual patient’s QOL. The results of our trial are consistent with results recently published by Smith et al8 in a study carried out in the United Kingdom. In that study, 308 patients were randomized to either three or six cycles of mitomycin (8 mg/m2 on day 1), vinblastine (6 mg/m2 on day 1), and cisplatin (50 mg/m2 on day 1) (MVP). In the patients randomized to receive six cycles, the median number of cycles delivered was four, and only 31% of patients received all six cycles. This is similar to our study where on the continuous arm, the median number of cycles delivered was four, and 31% of patients received six or more cycles of therapy. In terms of clinical benefit, there was no difference in median survival, 1-year survival, response rate, or duration of symptom relief in the comparison of three versus six cycles of MVP. In addition, patients receiving six cycles had more fatigue and nausea/vomiting, which are cumulative toxicities of cisplatin-based regimens. This was seen even with the attenuated cisplatin dose (50 mg/m2) used in the study. The rates of cumulative toxicity secondary to cisplatin may be worse when using doses of 75 to 100 mg/m2, which are typically used in trials conducted in the United States.11-12 One consideration relating to the Smith et al8 study is that it used a second-generation cisplatin-based triplet regimen uncommonly used in the first-line setting at this time. The substitution of carboplatin for cisplatin and inclusion of one of the new agents (paclitaxel) could theoretically improve the therapeutic index of a regimen, which may then yield improved survival with prolonged therapy. Our trial suggests that the impact of carboplatin-based third-generation regimens is similar to the regimen studied by Smith et al.8 Because recent trials12,13 have suggested equivalent survival results when using any of the new regimens (cisplatin/vinorelbine, cisplatin, or carboplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel) it is unlikely that any clinical benefit to prolonged therapy would be seen with these alternative regimens. Beyond our trial and that of Smith et al,8 we are unaware of other published, prospective, randomized trials addressing this issue in advanced NSCLC. Larsen et al25 reported a retrospective analysis on the optimal duration of chemotherapy deriving data from phase II trials. They noted that 80% of patients who achieved a response did so within the first 12 weeks of therapy, whereas 98% of patients did so within 24 weeks. On this basis, they questioned the value of extending chemotherapy beyond 12 weeks in the absence of a response. We attempted to get some information about whether patients capable of receiving more therapy beyond four cycles could potentially benefit from it by comparing those patients who completed four cycles of therapy on arm A with those patients who received four or more cycles on arm B (Fig 4). There did not seem to be any survival benefit in this subset analysis; however, this was not an objective of our trial. In recent studies in the United States using carboplatin/paclitaxel in similar doses and schedules,11-13 the median number of cycles delivered has consistently been four. Disease progression and disease- or treatment-related complications likely account for the relatively rapid dropout of patients who are eligible for prolonged chemotherapy. A trial designed to randomize patients who had received four cycles of treatment and could potentially receive more to either continued treatment or observation would be rational. Whether patients would accept this type of randomization is unclear. One previous attempt to complete a trial of this design failed as patient preferences strongly favored continued treatment.26 Recently, DePierre et al27 reported results of a trial in which responding patients who had received four cycles of mitomycin, ifosfamide, and cisplatin (MIP) were randomized to either observation or continued treatment with vinorelbine. Of the 585 patients with stage IIIB/IV NSCLC entered onto that study, 217 (37%) responded during the induction MIP; however, only 179 (31%) were randomized. No survival advantage was seen for this maintenance strategy. The toxicity of vinorelbine was mainly myelosuppression. There were seven toxic deaths in 90 patients randomized to maintenance vinorelbine. The observation in this trial that prolonged therapy offers no survival advantage but increases toxicity is consistent with the results of Smith et al8 as well as our study. The majority of patients randomized to receive a defined duration (arm A) completed therapy. In the patients randomized to receive continuous therapy (arm B), a median of four cycles of carboplatin/paclitaxel was delivered. The majority of patients (37%) on arm B discontinued therapy because of disease progression, followed closely by patient or physician choice (36%). We did not query patients or physicians involved in this trial as to why they made the choice to stop therapy. Undoubtedly, this was a decision made within the context of the confidential patient-physician relationship. Possible reasons include lack of a perceived benefit by either the patient or physician to continuing therapy, chronic low-grade toxicity impacting day-to-day QOL, costs (both monetary and otherwise), inconvenience, or a combination of any or all of these issues. The results of the three QOL analyses converge to confirm that QOL does decrease significantly over time in these patients who have advanced stage IIIB/IV disease. There was, however, no evidence that duration of treatment affected that decrease; this might be expected if, for example, there is an equal trade-off of control of disease symptoms and treatment toxicity. It should be noted that it is only possible to generalize these results to the population of advanced NSCLC patients who are able to participate in a QOL assessment 6 months after the start of chemotherapy treatment. Because a large number of subjects died or dropped out of the study for disease- and treatment-related reasons before the 6-month interview, long-term data derives from a selected fraction of patients. Thus, the results indicate that even in the best-case scenario in this setting, treatment duration does not differentially affect QOL deterioration over time. As expected, patients with a poor PS did not fare as well as patients with a good PS. In a Cox regression model, an unexpected PS-treatment interaction was identified. Patients with a poor PS receiving treatment on arm A (four cycles) fared worse than those patients on arm B (continuous treatment). Forty percent of patients on arm A with a Karnofsky PS of 70% to 80% received four cycles of therapy, whereas 57% of arm B patients received four or more cycles of therapy. This is somewhat counter-intuitive because we would have expected the poorer PS patients to tolerate treatment less well. Given the exploratory nature of this model, one cannot make definitive conclusions about the impact of duration of therapy differing based on PS. However, based on our analysis, a potential interaction must not be dismissed. In summary, this trial has failed to show an overall clinical benefit to continuing therapy with carboplatin/paclitaxel in advanced NSCLC beyond four cycles. This finding is consistent with the previously reported experience comparing three versus six cycles of MVP showing no clinical benefit derived from extending therapy beyond three cycles8 and the trial comparing maintenance vinorelbine after four cycles of MIP.27 These three trials challenge the current standard both in practice as well as in the clinical trial setting of recommending six or more cycles of treatment in this disease setting. The use of a brief duration of first-line treatment yields equivalent survival, would reduce the risk of any cumulative toxicities that may negatively impact on a patient’s individual QOL, and would likely improve resource utilization. The possible benefit of prolonged treatment in poor PS patients, however, is worthy of further study. Future trials integrating new therapies or strategies (sequential administration of single-agent or combination chemotherapy regimens or timing of second-line chemotherapy) should be designed taking into account this paradigm.
Supported by an investigator-initiated grant from Bristol-Myers Squibb Oncology, Princeton, NJ.
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer Statistics, 2001. CA Cancer J Clin 51: 15-36, 2001 2. Ihde DC, Minna JD: Non-small cell lung cancer: Part I. Biology diagnosis, and staging. Curr Probl Cancer 15: 61-104, 1991[Medline]
3.
Pignon JP, Stewart LA, Souhami RL, et al: Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311: 899-909, 1995 4. Bunn PA Jr, Kelly K: New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: A review of the literature and future directions. Clin Cancer Res 4: 1087-1100, 1998[Abstract] 5. American Society of Clinical Oncology: Clinical practice guidelines for the treatment of unresectable non-small cell lung cancer. J Clin Oncol 15: 2996-3018, 1997[Abstract] 6. Buccheri GF, Ferrigno D, Curcia A, et al: Continuation of chemotherapy versus supportive care alone in patients with inoperable non-small cell lung and stable disease after two or three cycles of MACC. Cancer 63: 428-432, 1989[CrossRef][Medline] 7. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small cell lung cancer. Br J Cancer 71: 366-370, 1995[Medline]
8.
Smith IE, O’Brien MER, Talbot DC, et al: Duration of chemotherapy in advanced non–small-cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19: 1336-1343, 2001
9.
Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18: 2095-2103, 2000
10.
Fossella FA, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 18: 2354-2362, 2000 11. Belani CP, Natale RB, Lee JS, et al: Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17: 455a, 1998 (abstr 1751) 12. Kelly K, Crowley J, Bunn PA, et al: A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in untreated advanced non–small-cell lung cancer (NSCLC): A Southwest Oncology Group (SWOG) trial. Proc Am Soc Clin Oncol 18: 461a, 1999 (abstr 1777) 13. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapy regimens in advanced non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18: 1a, 2000 (abstr 2) 14. Choy H, Shyr Y, Cmelak AJ, et al: Patterns of practice survey for non-small cell lung cancer in the U.S. Cancer 88: 1336-1346, 2000[CrossRef][Medline]
15.
Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187-192, 1997 16. Alvarez AM, Mickiewicz E, Brosio C, et al: Reinduction of response with Taxol (T) in advanced breast cancer (ABC). Proc Am Soc Clin Oncol 18: 165a, 1999 (abstr 636) 17. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748-1756, 1989[Abstract] 18. Cella DF, Bonomi AE, Lloyd SR, et al: Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 12: 199-220, 1995[CrossRef][Medline]
19.
Bonomi P, Kim C, 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 18: 623-631, 2000 20. Fairclough D, Peterson H, Cella D, et al: Comparison of several model-based methods of analyzing incomplete QOL: Data in cancer clinical trials. Stat Med 17: 781-796, 1998[CrossRef][Medline] 21. Giaccone G, Splinter TA, Debruyne C, et al: Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non–small-cell lung cancer: The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 16: 2133-2141, 1998[Abstract]
22.
Cardenal F, Lopez-Cabrerizo MP, Anton A, et al: Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 17: 12-18, 1999
23.
Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non–small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17: 3522-3530, 1999 24. Le Chevalier T, Brisgand D, Douillard J-Y, 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 12: 360-367, 1994[Abstract]
25.
Larsen H, Sorensen JB, Nielsen AL, et al: Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small cell lung cancer (NSCLC). Ann Oncol 6: 993-997, 1995 26. Hickish TF, Smith IE, Middleton G, et al: Patient preference for extended palliative chemotherapy for non-small cell lung cancer. Lancet 345: 857-858, 1995 (letter)[CrossRef][Medline] 27. DePierre A, Quiox E, Mercier J, et al: Maintenance chemotherapy in advanced non–small-cell lung cancer (NSCLC): A randomized study of vinorelbine (V) versus observation (OB) in patients (Pts) responding to induction therapy (French Cooperative Oncology Group). Proc Am Soc Clin Oncol 20: 309a, 2001 (abstr 1231) Submitted July 16, 2001; accepted November 7, 2001.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
