Randomized Trial First to Demonstrate a Survival Benefit in Patients with Recurrent Cervical Cancer
Randomized Trial First to Demonstrate a Survival Benefit in Patients with Recurrent Cervical Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D., Anderson Cancer Center, Houston, Texas, is Associate Editor for OB/GYN Clinical Alert
Dr. Coleman is on the speaker’s bureau for GlaxoSmithKline, Bristol Myers Squibb, and Ortho Biotech.
Synopsis: Despite increased toxicity, CT did not significantly reduce patient QOL when compared with cisplatin alone. Patient-reported QOL measures may be an important prognostic tool in advanced cervix cancer
Source: Long HJ, et al. Randomized Phase III Trial of Cisplatin with or without Topotecan in Carcinoma of the Uterine Cervix. J Clin Oncol. 2005 Jun 6; [Epub ahead of print].
Cisplatin has long been considered the standard first-line chemotherapy of choice for cervical cancer patients demonstrating disease recurrence. A series of randomized trials has established that 1) higher doses of this agent are not associated with longer survival but are associated with higher toxicity and 2) cisplatin-based combinations (to date) can increase response and progression-free survival, but without increasing overall survival, and at the expense of significant toxicity. As such, single-agent cisplatin has remained the benchmark for efficacy trials. Under these conditions, Long and colleagues conducted a randomized clinical trial to evaluate 2 promising cisplatin- based combinations (topotecan/cisplatin and methotrexate, vinblastine, doxorubicin, cisplatin [MVAC]) against standard single-agent cisplatin in recurrent cervix cancer patients with measurable disease. Overall survival was the primary end point. Three hundred fifty-seven patients were enrolled and randomized. Treatment-related mortalities in 4 of 63 patients randomized to MVAC prompted closure of this arm to further accrual. The remaining 294 patients were randomized to either cisplatin or cisplatin/topotecan. Nearly 60% of enrolled patients had previously received cisplatin-based chemoradiation as therapy for their primary disease. Toxicity, particularly hematologic, was significantly higher for the cisplatin/topotecan arm. Significant treatment-related infection was also higher in the combination arm. However, both progression-free and overall survivals were significantly longer for the combination. The hazard for progression and death was reduced 26% and 23%, respectively, relative to single agent cisplatin. The absolute differences in median progression-free and overall survival were 1.7 mos and 2.9 mos, respectively. In addition, objective response to therapy doubled (13% to 27%), a statistical improvement. Two patient characteristic factors were identified as important in the interpretation of these results: 1) previous exposure to platinum as chemoradiation, and 2) disease-free survival until recurrence. Both were found to be significant prognosticators of response to subsequent treatment; patients not previously exposed to platinum as a radio-sensitizer and those presenting with a long progression-free interval were most likely to benefit from cisplatin/topotecan. Long and colleagues concluded that the combination was more efficacious than single agent cisplatin. This trial is the first to demonstrate an overall survival advantage for any combination over cisplatin.
Commentary
Effective therapy for recurrent cervix cancer remains a significant challenge—one in which very little progress has been made over the last 20 years despite an expansion of new chemotherapeutics. Patients recurring after primary surgical treatment may have a curative radiotherapy option if the disease is localized. However, most, including those who have received radiotherapy as primary treatment or as an adjuvant to surgery, have disease that encompasses a mixture of regional and distant sites not amenable to curative radical resection. The natural history of this recurrence is one of progression, and most patients discovered with disease recurrence succumb to their disease in short order. Since effective systemic strategies have not been identified, it is not surprising that our experience with randomized chemotherapy trials is one in which overall survival is not affected by new treatment combinations, despite an improvement in response and progression-free survival. In light of this background, the current study by Long et al is noteworthy and deserves our attention.
A key benefit of phase III investigation is that the effects known and unknown, which could positively or negatively affect one’s primary objectives, are balanced by the randomization process. In the study of recurrent cervical cancer therapy, this is not a trivial point. We and others have demonstrated that the location of recurrence alone can affect the likelihood of response 2-fold.1,2 Patients with "in-the-radiated-field" recurrences are much less likely to achieve tumoricidal doses of chemotherapy and fair much worse than those with distant site recurrences. In addition, many exploratory trials of new chemotherapeutic include patients who have advanced, but previously untreated disease and of varying performance status. Nonetheless, trials such as these provide new candidates for the phase III investigation where the standard of care is tested.
Since the discovery of cisplatin and the demonstration of its activity in cervix cancer, the agent has been a staple of therapy. Within the GOG, successive clinical trials have addressed quantity of drug, schedule and various platinum combinations (see Table). Prior to the current study, the overwhelming consensus has been that "more is not better." However, the results of the current trial call this mantra into question and have renewed interest in exploring novel combinations against the likely new standard. Indeed, the recently opened follow-up clinical trial is studying paclitaxel, vinorelbine and gemcitabine platinum doublets against cisplatin/topotecan. However, accompanying more therapy is more toxicity; for those with short life expectancies this is a major consideration and has largely been responsible for keeping the single agent as standard despite gains in intermediate end points such as response and progression-free survival. To better understand the nature and degree to which toxicity affects enrolled patients in balance with their response to therapy, sophisticated quality of life (QoL) measures have were developed and administered in this trial. In an accompanying article regarding the QoL in this study, Monk and colleagues demonstrated that despite the increased toxicity, QoL did not decrease either on therapy or following treatment conclusion.3 Taken as a whole, the combination appears a good candidate to replace the current standard.
In the bigger picture, the gains made, though significant, are still too small and should not be satisfactory to either patients or clinicians. Better strategies are needed such as disruptors of angiogenesis and/or cell signaling. Our search needs to continue if real progress is to be made in this disease.
| Table | |||
| Randomized GOG Trials in Recurrent Cervix Cancer | |||
| Study GOG-043 GOG-110 GOG-149 GOG-169 GOG-179, Current Study |
Response + + - + + |
PFS - + - + + |
OS - - - - + |
| KEY PFS: Progression-free survival; OS: Overall survival GOG-043: Cisplatin 50 mg/m2 vs Cisplatin 20 mg/m2/day ´ 5 vs Cisplatin 100 mg/m2 GOG-110: Cisplatin vs Cisplatin/Mitolactol vs Cisplatin/Ifosfamide GOG-149: Cisplatin/Ifosfamide vs Cisplatin/Ifosfamide/Bleomycin GOG-169: Cisplatin vs Cisplatin/Paclitaxel |
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References
- Brader KR, et al. Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design. J Clin Oncol. 1998;16:1879-1884.
- Zanetta G, et al. Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma: a multivariate analysis. Gynecol Oncol. 1995;58:58-63.
- Monk BJ, et al. Quality of Life Outcomes From a Randomized Phase III Trial of Cisplatin With or Without Topotecan in Advanced Carcinoma of the Cervix: A Gynecologic Oncology Group Study. J Clin Oncol. 2005. Jun 6;[Epub ahead of print].
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