Expert Commentary

Philip J. DiSaia, MD, The Dorothy Marsh Chair in Reproductive Biology, Professor, Department of Obstetrics and Gynecology, Director, Division of Gynecologic Oncology, University of California, Irvine, California; Chairman, Gynecologic Oncology Group

According to the results of studies presented at the 35th Annual Meeting of the Society of Gynecologic Oncologists (SGO), the combination of topotecan and cisplatin is superior to single-agent cisplatin with respect to response, progression-free survival and overall survival for patients with advanced cervical cancer.¹ Moreover, a companion study showed the addition of topotecan to cisplatin did not result in any statistically significant differences in quality of life when compared to patients receiving single-agent cisplatin.² These results suggest a promising new treatment option that may revolutionize the standard of care in advanced or recurrent cervical cancer. The combination of topotecan and cisplatin is the first combination regimen to demonstrate a survival advantage over single-agent cisplatin in the treatment of advanced cervical cancer. In my opinion, because of the improvement in all key outcome parameters and the maintenance of quality of life, I believe that the combination of topotecan and cisplatin therapy may now represent the optimal approach to the treatment of patients with advanced or recurrent cervical cancer when chemotherapy is warranted.

Although advances in the primary treatment of cervical cancer have improved response rates and prolonged survival, approximately 33% of new cervical cancer cases results in mortality.³ The determination of effective and tolerable chemotherapy for advanced and recurrent disease is therefore of paramount importance.

Cisplatin is the single most active chemotherapeutic agent to treat cervical cancer.^4-6 In the Gynecologic Oncology Group (GOG) studies, cisplatin was associated with response rates of 20 to 30% for recurrent cervical cancer with a median survival of approximately 7 months.^4,5,7 While various cisplatin-based combinations have been associated with improvements in response rates, none have achieved an improvement in overall survival compared to single-agent cisplatin. For example, GOG Protocol 110 demonstrated that the combination of cisplatin and ifosfamide was associated with a higher response rate (31% vs 17%) and longer progression-free survival compared with single-agent cisplatin.⁸ However, the observed improvements were at the cost of greater toxicity with no improvement in overall survival. GOG Protocol 169 showed nearly a doubled response rate with the addition of paclitaxel to cisplatin (19.4% to 36.2%; P = .002).⁹ Similarly however, survival was unchanged and there was unacceptable toxicity.

This Oncology Express Report^TM will review the results of these studies in greater detail and discuss the clinical implications on the treatment of advanced or recurrent cervical cancer.

Topotecan/Cisplatin Combination Therapy Yields First-ever Improvement in Survival

The combination of topotecan plus cisplatin proved superior in multiple outcome parameters over single-agent cisplatin in the treatment of advanced or recurrent cancer of the cervix according to Harry J. Long III, MD, Professor of Oncology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.¹

Between 1999 and 2002, a total of 356 patients with stage IVB recurrent or persistent carcinoma of the cervix were treated at seven institutions. Patients were randomized to one of three treatment arms: single-agent cisplatin 50 mg/m² every 3 weeks (n = 146), topotecan 0.75 mg/m² on Days 1-3 plus cisplatin 50 mg/m² on Day 1 every 3 weeks (n = 147), and methotrexate plus vinblastine plus doxorubicin plus cisplatin (MVAC) every 4 weeks (n = 63). However, the MVAC treatment arm was closed to patient entry due to excessive toxicity. Survival was the primary endpoint, with overall response rate and progression-free survival as secondary endpoints. Quality of life data was collected prior to cycles 1, 2, 5, and at 9 months (reported in companion study-discussion to follow).

The treatment arms were balanced for Performance Status, age, grade, histology and disease status. Patient and disease characteristics included stage IV disease in 12% of patients in each treatment arm, persistent disease in 8-12%, and recurrent disease in 76-80%. Nearly 80% of patients had received radiotherapy and almost 60% received prior cisplatin-based chemotherapy.

The combination of topotecan and cisplatin doubled the response rate over single-agent cisplatin. Responses were achieved in 39 of 147 patients (27%) on the combination, compared to 19 of 146 patients (13%) treated with single-agent cisplatin (P = .004) (Table 1). Fourteen patients achieved complete responses with the combination of topotecan and cisplatin (10%) while only 4 patients (3%) achieved a complete response with single-agent cisplatin. Stable disease was observed in 45% and 50% of patients treated with the combination of topotecan and cisplatin and single-agent cisplatin, respectively, and progressive disease in 28% versus 37% of patients, respectively.

Importantly, there was a significant improvement in median progression-free survival, 4.6 months versus 2.9 months, and median overall survival, 9.4 months versus 6.5 months for the combination of topotecan and cisplatin versus single-agent cisplatin, respectively. "These outcomes yielded hazard ratios of 0.76 for progression-free survival (P = .014) and 0.76 for overall survival (P = .017), for a 24% reduction in the risk of mortality," explained Dr. Long.

Due to the clearly superior outcomes of treatment with the combination of topotecan and cisplatin over single-agent cisplatin, Dr. Long proffered, "Topotecan and cisplatin should be considered the new standard for treatment of advanced or recurrent cancer of the cervix."

"This is the first randomized clinical trial of combination chemotherapy compared to single-agent cisplatin that has demonstrated a significant survival advantage for the combination," noted Dr. Long. But while a 24% improvement in progression-free survival is significant, "we still have a long way to go before we lay claim to curing this disease in its advanced stage."

According to Peter G. Rose Sr., MD, MetroHealth Medical Center, Cleveland, Ohio, who served as discussant for this trial at the Main Plenary Session, "An impact on survival has not been seen until this trial, showing improvements in all the characteristics of response. The benefit is statistically significant for the group overall and also when adjusted for a number of covariates for risk. Moreover, there were no adverse effects on quality of life."

The most favorable results were observed in the 40% of patients who had not received prior cisplatin as a radiosensitizer. However, multivariate analysis did not identify cisplatin as an independent predictor of treatment failure. The difference between the platinum-treated and non-platinum-treated patients is most likely due to biologic factors (eg, platinum resistance) and is not drug-related, Dr. Long maintained, adding, "This is not unlike ovarian cancer, where we consider that patients who relapse in the first six months have an unfavorable biology."

In his commentary, Dr. Rose supported the use of combination topotecan and cisplatin therapy regardless of prior platinum treatment stating, "Whether with prior platinum or not, there was a statistical benefit with the combination of topotecan and cisplatin."

A factor that did affect treatment efficacy was the time-to-relapse after primary treatment. Patients who relapsed early (<6 months) had worse outcomes, while the hazard ratios improved progressively by each 6-month interval between initial diagnosis and recurrence.

"The time from diagnosis to treatment of recurrent disease does significantly impact both progression-free and overall survival and should be considered an independent risk factor in future clinical trials," suggested Dr. Long, noting that 3-year survival was 70% for patients who had no relapses within 3 years of diagnosis. "The further they are from treatment before relapse, the better the response. Those patients who relapse within the first couple of months after primary treatment are probably not candidates for any chemotherapy."

Major (grade 3 and 4) toxicities were similar for the combination of topotecan and cisplatin and single-agent cisplatin, with the exception of neutropenia (70% vs 1%, respectively). Other observed toxicities for combination topotecan and cisplatin versus single-agent cisplatin, respectively, included: anemia, 37% vs 23%; febrile neutropenia/infection, 16% vs 8%; nausea, 13% vs 8%; emesis, 14% vs 8%; and metabolic abnormalities, 12% vs 10%.

"We have a slightly more toxic regimen that is well tolerated and produces a doubling in response and an improvement in survival. The only caveat is it's an early first step," commented Dr. Long. "We have been doing research for over twenty years with no improvement over single-agent cisplatin, and now we have a regimen that shows a 24% reduction in death from cervical cancer. It offers hope."

Quality of Life Outcomes

In a companion study, Bradley J. Monk, MD, Assistant Professor, Division of Oncology, University of California, Irvine, School of Medicine, Irvine, California presented the quality of life outcomes from the same trial.² Patients receiving the combination of topotecan and cisplatin had quality of life scores similar to patients receiving single-agent cisplatin.

Quality of life measures were evaluated by means of the Functional Assessment of Cancer Therapy-Cervix (FACT-G + FACT-Cx) questionnaire, a treatment-specific Neurotoxicity Subscale (NTX), the Brief Pain Inventory (BPI), and the visual analog UNISCALE (UNI). Patients were surveyed prior to randomization, before the second and fifth doses of chemotherapy, and 9 months after randomization. Ninety-seven percent of the questionnaires were completed prior to randomization, and 83%, 66%, and 55% were completed subsequently, respectively. There were no statistical differences in quality of life at baseline according to all methods of assessment.

During therapy, the FACT-G + FACT-Cx, NTX, BPI, and UNI scores remained stable, with no statistically significant differences between the two treatment regimens. The baseline FACT-G, BPI, and Performance Status were associated with overall survival.

"These measures remained stable over the course of therapy, and yielded similar results whether the patient received single-agent cisplatin or topotecan plus cisplatin. Therefore, the addition of topotecan results in a greater than two-month increase in survival, with comparable effects on quality of life," advised Dr. Monk.

Improved quality of life scores and Performance Status also suggests improved survival, which further emphasizes the importance of using regimens that maintain quality of life. Dr. Monk added, "Patients who are feeling better, both from a physical and emotional standpoint, live longer."

Conclusion

The results of new studies demonstrate that the addition of topotecan to cisplatin improves response rates, progression-free survival, and overall survival while maintaining quality of life in the treatment of advanced cervical cancer. The combination of topotecan and cisplatin is the first regimen to demonstrate an improvement in survival compared to single-agent cisplatin in this setting. The combination of topotecan and cisplatin provides the basis for a new standard of care in the treatment of advanced or recurrent cervical cancer.

References

1. Long HJ, Bundy BN, Grendys ED, et al. Randomized phase III trial of cisplatin (P) vs cisplatin plus topotecan (T) vs MVAC in stage IVB, recurrent or persistent carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Presented at the 35th Annual Meeting of the Society of Gynecologic Oncologists (SGO), February 7-11, 2004, San Diego, California. Abstract 9.
2. Monk BJ, Huang H, Wenzel L, Cella D, Long HJ. Quality of life outcomes from a phase III trial of cisplatin vs cisplatin plus topotecan in stage IVB, recurrent or persistent carcinoma of the cervix: results of GOG protocol 179. Presented at the 35th Annual Meeting of the Society of Gynecologic Oncologists (SGO), February 7-11, 2004, San Diego, California. Abstract 177.
3. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5-26.
4. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340:1154-1161.
5. Thigpen T, Shingleton H, Homesley H, Lagasse L, Blessing J. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Cancer. 1981;48:899-903.
6. Bonomi P, Blessing JA, Stehman FB, DiSaia PJ, Walton L, Major FJ. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1985;3:1079-1085.
7. Thigpen JT, Blessing JA, DiSaia PJ, Fowler WC Jr, Hatch KD. A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1989;32:198-202.
8. Omura GA, Blessing JA, Vaccarello L, et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997;15:165-171.
9. Benda J, Blessing J, Boggess J, et al. A randomized phase III study of cisplatin versus cisplatin plus paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of the cervix. Presented at the 32nd Annual Meeting of the Society of Gynecologic Oncologists (SGO), March 3-7, 2001, Nashville, Tennessee. Abstract 304.

Disclosure

Philip J. DiSaia, MD: No significant relationships to disclose.

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