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Phase III Randomized Trial of 12 Versus 3 Months of Maintenance Paclitaxel in Patients With Advanced Ovarian Cancer After Complete Response to Platinum and Paclitaxel-Based Chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group Trial

From the Cleveland Clinic Foundation, Cleveland; Ohio State University Health Center, Columbus, OH; Southwest Oncology Group Statistical Center, Seattle, WA; City of Hope National Medical Center, Duarte; University of California Irvine Medical Center, Orange, CA; University of Alabama Medical Center at Birmingham, Birmingham, AL; and University of Arizona Cancer Center, Tucson, AZ.

Address reprint requests to Maurie Markman, MD, The Cleveland Clinic Foundation (R35), 9500 Euclid Ave, Cleveland, OH 44195; email: markmam{at}ccf.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine whether continuing paclitaxel for an extended time period in women with advanced ovarian cancer who had achieved a clinically defined complete response to a platinum/paclitaxel-based chemotherapy could prolong subsequent progression-free survival (PFS) and affect ultimate survival.

Patients and Methods: Patients were randomly assigned to either three or 12 cycles of single-agent paclitaxel administered every 28 days and were then followed up for progression-free and overall survival.

Results: As of September 6, 2001, 277 patients (262 assessable) had entered the trial, with a total of 54 PFS events having developed among 222 patients with follow-up data. With the exception of peripheral neuropathy, there were no major differences in toxicity between the regimens. The median PFS was 21 and 28 months in the three-cycle and 12-cycle paclitaxel arms, respectively. One-sided P values from an unadjusted log-rank test and an adjusted Cox model analysis (for stratification factors) were .0035 and .0023, respectively, both in favor of the 12-cycle arm. The Cox model-adjusted three-cycle versus the 12-cycle progression hazard ratio was estimated to be 2.31 (99% confidence interval, 1.08 to 4.94). With a protocol-specified early termination boundary of P = .005, these findings led the Southwest Oncology Group Data Safety Monitoring Committee to discontinue the trial. As of the date of study closure, there was no difference in overall survival between the treatment arms.

Conclusion: Twelve cycles of single-agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial platinum/paclitaxel-based chemotherapy significantly prolongs the duration of PFS.

	INTRODUCTION

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STANDARD INITIAL therapy for ovarian cancer is generally considered to include five to six courses of a platinum/taxane regimen,^1,2 with limited randomized trial data failing to reveal any advantage for additional treatments or a consolidation strategy either in ovarian cancer^3–5 or other malignancies.^6,7

However, nonrandomized experience in ovarian cancer has suggested the possible clinical utility for a more protracted treatment program when paclitaxel, a cycle-specific antineoplastic agent, is used.^8–10 In one evaluation, a subset of patients with heavily pretreated disease survived for more than 3 years after the initiation, and continuation until disease progression, of single-agent paclitaxel.⁹

It might be hypothesized that more prolonged treatment with this drug in patients who had previously demonstrated major inherent chemosensitivity to a front-line treatment program, which included paclitaxel, could favorably affect both time to subsequent disease progression and overall survival. To test this hypothesis, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) initiated a trial of single-agent paclitaxel in women with advanced ovarian cancer who had achieved a clinically defined complete response to front-line platinum/paclitaxel chemotherapy.

	PATIENTS AND METHODS

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Eligibility
Criteria included the following: (1) histologically confirmed stages III/IV epithelial ovarian cancer, fallopian-tube cancer, or primary carcinoma of the peritoneum; (2) treatment with five to six cycles of a platinum/paclitaxel regimen; and (3) attainment of a clinically defined complete response (ie, no cancer-related symptoms; normal physical examination, computed tomography scan of the abdomen/pelvis and chest x-ray; CA-125 level ≤ 35 U/mL).

Patients who had received prior treatment on a SWOG or GOG front-line chemotherapy regimen where either progression-free or overall survival were study end points or had ≥ grade 2 persistent neuropathy from prior therapy were ineligible.

Treatment Plan
Arm 1 treatment consisted of paclitaxel 175 mg/m² over 3 hours every 28 days for three cycles; arm 2 treatment consisted of paclitaxel 175 mg/m² over 3 hours every 28 days for 12 cycles.

Treatment Modifications
The dose was reduced to 135 mg/m² for grade 4 neutropenia, grade 3/4 thrombocytopenia, or grade 2 neuropathy. If grade 4 neutropenia recurred, subsequent cycles were delivered with prophylactic granulocyte colony-stimulating factor. Dose re-escalation was not permitted.

Recovery from all toxicities to ≤ grade 1 was required before a subsequent cycle was delivered. The maximum permitted treatment delay for toxicity was 2 weeks. Persistent episodes of grade 4 neutropenia that occurred despite mandated dose reductions and prophylactic use of granulocyte-colony–stimulating factor or ≥ grade 3 neuropathy resulted in treatment discontinuation.

Evaluation
All patients were followed monthly for 1 year. A history, physical examination, toxicity evaluation, complete blood cell count, differential count, and serum CA-125 reading were obtained at each visit. After 1 year, patients were followed at regularly scheduled intervals until their deaths.

Statistical Considerations
The primary objective of this study was to investigate whether a regimen of 12 cycles’ continuation of paclitaxel after a clinically defined complete response to induction platinum/paclitaxel chemotherapy results in superior progression-free survival (PFS) and overall survival compared with a three-cycle continuation of paclitaxel. PFS was used for the purpose of sample-size estimation. Based on prior published experience,^1,11,12 the median PFS after a clinical complete response to induction therapy for the control arm was estimated to be approximately 16 months for those with stage IV or suboptimal (> 1 cm residual) stage III disease and 24 months for stage III patients with optimal (< 1 cm residual) disease. Assuming equal numbers of patients in the two strata, a total of 450 eligible patients were to be entered into this trial over approximately 5 years. With uniform accrual, 2 additional years’ follow-up, exponential survival distribution, and a one-sided log-rank test at .05 significance level, the power to detect a hazard ratio of 1.33 in PFS is approximately 0.85. With 225 patients per arm, the power to detect an absolute 15% difference in the incidence rate of any toxicity is at least 0.93 using a one-sided .05 test.

Interim analysis was to be conduced when 225 eligible patients had been entered and again when 50% and 75% of the anticipated events had been observed. The interim analysis was conducted to guard against extreme findings—either excessive toxicity or a substantial improvement in efficacy. Evidence suggesting early termination of the study would be if the null hypothesis of no difference in PFS, or the alternative hypothesis that the progression hazard ratio of the control arm over the prolonged paclitaxel arm is 1.33 or greater, were rejected at the .005 level. The actual decision to terminate the study early would be made by the SWOG Data and Safety Monitoring Committee and would take into consideration other factors, such as overall survival, toxicities, and complications.

Stratification factors used for randomization in this trial included (1) prior treatment with paclitaxel for greater than ≥ 24 hours versus less than 24 hours; (2) initial presentation with optimal stage III versus suboptimal stage III versus stage IV ovarian cancer (for purposes of this study, suboptimal disease was defined as residual disease after exploratory laparotomy with at least one lesion ≥ 1 cm in its greatest dimension); and (3) age ≤ 65 versus more than 65 years.

Criteria for Evaluation and End Point Definitions
Overall survival was measured from the date of registration until death, and PFS was measured from the date of registration to the date of first recurrence or death (if before recurrence). Disease recurrence was defined as appearance of a new lesion or effusion, reappearance of any lesion that had disappeared, or development of tumor-related symptoms.

	RESULTS

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Patient Characteristics
As of September 6, 2001, a total of 277 patients (15 ineligible) had entered into this trial (Table 1), with the treatment arms being well balanced in terms of clinical features.

Toxicity
Table 2 outlines the observed toxicity. The only major difference between the study arms was the incidence of treatment-related neuropathy. There were no significant differences in the side-effect profiles of any other evaluated clinical parameter (eg, emesis, renal or hepatic toxicity). Also, as the trial did not prospectively evaluate the duration of neuropathy, no information is available regarding how long symptoms persisted after discontinuation of treatment in the three-cycle versus the 12-cycle treatment arms.

An unadjusted log-rank test and a Cox model analysis adjusting for randomization stratification factors revealed the one-sided P values from the unadjusted test and the adjusted Cox model analysis were .0035 and .0023, respectively, in favor of the 12-cycle arm (Fig 1). The Cox-model–adjusted three-cycle versus the 12-cycle progression hazard ratio was estimated to be 2.31, with a 99% confidence interval of 1.08 to 4.94. These highly favorable results led the independent SWOG Data Safety and Monitoring Committee to recommend study closure in October 2001.

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival of 222 assessable patients treated with either three monthly cycles or 12 monthly cycles of single-agent paclitaxel as consolidation therapy of stages III/IV advanced ovarian cancer after the attainment of a clinically defined complete response.

A natural question that arises based on these data is whether the rate of subsequent disease progression increased shortly after treatment was discontinued. An exploratory analysis was performed to assess whether the current data provide any support for this hypothesis. A treatment-stop indicator was added to the Cox model, which also included treatment and stratification factors, as before. Unlike the baseline stratification factors, the values of which do not change over time within a patient, the value of the treatment-stop indicator is time dependent. Specifically, this indicator starts out as 0 for each patient but changes to 1 at 28 days after treatment stopped. The change point of 28 days posttreatment was chosen because that is when the next cycle of paclitaxel would have been given had treatment continued. For those patients whose disease progressed during treatment (three patients on the three-cycle arm and seven patients on the 12-cycle arm), the value of this indicator remains as 0 throughout.

The results showed the treatment-stop indicator to be highly significant (one-sided P = .0004), suggesting a higher hazard for disease progression after treatment stopped. The estimated hazard ratio posttreatment versus during treatment was 5.80, with a 95% confidence interval of 2.09 to 16.10. Treatment with 12-cycle versus 3-cycle paclitaxel became nonsignificant (hazard ratio = 1.07, one-sided P = .43). This is partially due to the fact that the treatment-stop indicator is inherently confounded with treatment assignment, which differed in duration. The analysis was then repeated in the 12-cycle arm only, and the treatment-stop indicator was equally significant (one-sided P = .0005) with an estimated post versus during treatment progression hazard ratio of 9.17, and a 95% confidence interval of 2.47 to 34.0. In both cases, the wide confidence intervals reflect the relatively limited number of events in the data set.

For a crude description of the observed progression risk, the actual event rates by three-month intervals during the first 2 years are presented in Table 3. Because of the low numbers of patients at risk, event rates after 2 years are not presented.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The decision to use a short-course (three cycles) paclitaxel control arm, rather than a no-further-treatment control, was made for both practical and theoretical considerations. Despite the absence of definitive randomized controlled trial data demonstrating any value for consolidation or maintenance therapy in women with ovarian cancer who achieved a clinically defined complete response, there was concern that when women were presented with the justification for the conduct of this trial, few would accept randomization to a no-treatment control. This assessment resulted from the fact that patients considered for entry onto this trial would need to be told the following: (1) approximately 75% of patients in this clinical setting ultimately experience recurrence of their cancer^1,2,12; (2) if disease recurs, there is no evidence for the curative potential of any second-line regimen; (3) the drug they would receive in the trial (paclitaxel) was a component of the regimen to which they had already attained a clinical complete response and tolerated (otherwise, they would not be a candidate for the trial); (4) there is currently evidence that paclitaxel can be given safely for extended periods⁹; and (5) a reasonable rationale could be presented to support the potential clinical utility of extending the duration of paclitaxel administration (eg, exposure of tumor during active cell cycling¹³; antiangiogenetic effect associated with continued intermittent drug exposure¹⁴).

Finally, because paclitaxel was commercially available when this trial was initiated, a patient presented with this information could simply elect to ask her oncologist to administer additional cycles of the agent. However, as the study was ultimately designed, it could be rationally (and ethically) argued that even patients randomized to a three-cycle control arm would be receiving some additional treatment beyond that known to be associated with an extremely high recurrence rate.

Despite the absence of a pure evidenced-based control arm in this randomized trial, the investigators recognized that the truly important question being addressed in the study was whether an extended paclitaxel treatment regimen (eg, 12 monthly cycles) would produce a favorable clinical effect. We reasoned that if 12 courses of monthly paclitaxel were not shown to be superior to three courses, it would be most appropriate to conclude that we had failed to demonstrate the benefit of any extension of the duration of paclitaxel treatment in this clinical setting.

A second question to be addressed is whether it was appropriate to consider PFS to be the primary end point in this trial, rather than overall survival. Although the ultimate goal of any antineoplastic treatment should be its impact on survival, the investigators believed that prolongation of PFS, resulting from a treatment program that does not cause a major impairment in overall quality of life, is a highly clinically relevant goal, particularly in a disease such as ovarian cancer, where multiple second-line treatment programs may affect ultimate survival independent of what has occurred during initial treatment.¹⁵

While this study, initiated in 1997, did not include a formal quality-of-life assessment, it would be difficult to argue this extended paclitaxel program is associated with an unacceptable side-effect profile. For example, the incidence of significant neurotoxicity (grade 2/3) observed was comparable to that noted when a platinum agent (cisplatin or carboplatin) plus paclitaxel are used as initial chemotherapy for this malignancy.^1,12,16,17 This degree of neurotoxicity is generally believed to be acceptable in routine clinical practice.

Lowering the dose of paclitaxel in any future study and in standard clinical practice should make the issue of peripheral neuropathy less of a concern. Moreover, because it is far more likely that the observed improvement in PFS resulted from the extended treatment schedule, rather than the specific dose of paclitaxel used in the trial, it is likely that reducing the dose of paclitaxel should enhance the therapeutic ratio associated with this management strategy (ie, no change in efficacy, but reduced toxicity). However, it must be noted that the current study provides no data on either the efficacy or toxicity associated with initiating maintenance paclitaxel at a lower dose level (eg, 135 mg/m²).

Third, it might be asked if the SWOG Data and Safety Monitoring Committee might have closed this study prematurely, particularly considering the likely negative impact on our ultimate ability to evaluate the effect of this treatment program on overall survival. This is due to the fact that patients currently on the three-cycle arm, when informed of the results of the study, may elect to be treated with a total of 12 cycles. Furthermore, patients who were randomized to the three-cycle arm, have recently completed therapy and have not as yet experienced disease progression may also request additional courses of paclitaxel.

Despite this concern, it would be inappropriate for the investigators to comment on the decision of this federally mandated review panel, whose sole purpose is to independently evaluate the results of ongoing studies and determine whether a trial should be discontinued based on excessive toxicity or extremely favorable or unfavorable results.¹⁸ We must accept this decision, regardless of its potential impact on the ultimate study results or other ongoing or future clinical trials.

Fourth, it is important to question the potential implications of the provocative results of the exploratory analysis examining the rate of disease progression after discontinuation of consolidation chemotherapy. Acknowledging the limitations associated with the small sample size and the observational nature of the analysis, this evaluation revealed a highly statistically significant acceleration in the risk of disease progression shortly after the completion of treatment. Although it might be argued that this result is obvious and may be explained simply by the fact patients will ultimately progress with the passage of time independent of the continuation (or discontinuation) of therapy, the strikingly similar findings observed in both the three-cycle and 12-cycle study arm and the contrast in progression rates between the two arms during the first year are consistent with the role of the maintenance program in at least delaying disease progression.

To address the concern that patients discontinuing therapy before the planned completion of their treatment program (eg, toxicity, refusal) may have actually done so because of unrecognized symptoms of disease progression, we examined the ultimate date of documented recurrence for all such patients. Although several patients removed from study early did experience clinical progression, these events occurred many months after discontinuation of treatment (data not shown). This evaluation leads us to doubt the conclusion that the results of this exploratory analysis were substantially influenced by patients experiencing unrecognized disease progression while on active therapy.

It is therefore interesting to speculate that continuation of single-agent paclitaxel for more prolonged time periods (eg, 2 years, 3 years) may exert an even greater impact on time to disease progression and possibly ultimate survival. A mechanism for the activity of paclitaxel, when delivered in this clinical setting, remains to be elucidated and might include the persistent chemosensitivity of slowly dividing tumor cells to the cycle-specific agent¹³ or an antiangiogenic effect associated with intermittent drug exposure.¹⁴

The clinical utility of such a prolonged maintenance strategy using single-agent paclitaxel is worthy of investigation in a randomized controlled phase III trial. However, it should be noted that in addition to the issue of the impact of such a management approach on quality of life (eg, neurotoxicity, continued alopecia), there is the concern for the development of additional adverse effects that have been observed when other cytotoxic agents are delivered over extended time periods (eg, secondary acute leukemia).¹⁹

Finally, it must be asked whether the standard of care for all patients treated for advanced ovarian cancer has been changed as a result of this trial. For several reasons it would be inappropriate to provide a definitive affirmative answer to this question. First, as of this date, there is no evidence that the 12 additional monthly cycles of single-agent paclitaxel favorably influences overall survival. In addition to the concern noted above regarding the effect of early closure on the study’s final results, a variety of second-line treatment regimens may impact overall survival in this malignancy independent of the initial chemotherapy strategy.¹⁵

Second, because entry into this trial required patients to be in a clinically defined complete response and without significant preexisting peripheral neuropathy, it would be inappropriate to generalize regarding the potential efficacy and toxicity of this management approach in those who did not meet these precise clinical characteristics (eg, responsive but documented persistent disease or the presence of treatment-related grade 2 neuropathy). In other patient populations, the continuation of paclitaxel, as used in this trial, may be ineffective or result in excessive toxicity.

However, despite these concerns and recognized study limitations, it is most reasonable to conclude that oncologists should discuss with appropriate patients the results of this trial and the possible implications for their subsequent management. When presented with the evidence of a favorable impact on PFS, some patients may elect to continue paclitaxel, with its associated treatment-related toxicity, whereas others may decide to stop therapy when the initial front-line platinum-paclitaxel regimen is complete.

Finally, the highly provocative results of this study should stimulate further investigation of the role of a variety of consolidation/maintenance antineoplastic strategies (including both cytotoxic and cytostatic agents) in advanced ovarian cancer. This trial, although not establishing a new standard of care in the management of ovarian cancer, has demonstrated the potential for a maintenance strategy to have a considerable impact on progression of the disease process. Thus it would perhaps be most appropriate to consider the trial to serve as a critically important proof of principle that should be built on in future studies. In ovarian cancer, a malignancy increasingly characterized by prolonged survival, it is appropriate to argue that substantial lengthening of the time to subsequent disease progression is a worthy goal of antineoplastic therapy if it can be convincingly shown that such treatment is not associated with toxicity of such severity that it negates the benefits of the therapeutic program.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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5. Lambert HE, Rustin GJS, Gregory WM, et al: A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. Ann Oncol 8:327–333, 1997[Abstract/Free Full Text]

6. Einhorn LH, Williams SD, Loehrer PJ, et al: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: A Southeastern Cancer Study Group protocol. J Clin Oncol 7:387–391, 1989[Abstract]

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Submitted July 2, 2002; accepted January 24, 2003.

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