With metastatic or recurrent disease, surgical intervention or radiotherapy is often not an option. In such cases, therefore, platinum-based combination chemotherapy is selected instead. Several randomized trials reported combination therapy with cisplatin and paclitaxel (TP) to be the most effective regimen in the treatment of recurrent or metastatic cervical cancer.1,2 However, selecting the most suitable regimen in the treatment of recurrent cervical cancer can present problems, particularly when treating patients who have received prior platinum-based therapy or in whom disease has occurred in irradiated fields.
Some randomized trials for recurrent and advanced cervical cancer reported a response rate of 22% to 29.1% to a platinum-containing doublet combination.1–5 Tewari and Monk reported the impact of prior platinum exposure on response rates in advanced or recurrent cervical cancer. With no prior cisplatin (CDDP), the response rate was 20% in CDDP monotherapy, 39% in CDDP and topotecan combination chemotherapy, and 37% in TP combination chemotherapy; with prior CDDP, it was 5% to 8% in CDDP monotherapy, 15% in CDDP and topotecan combination chemotherapy, and 32% in TP combination chemotherapy.6 These results indicate that a history of platinum exposure is a key indicator in predicting the effectiveness of second-line chemotherapy, and that combination chemotherapy is likely to be more effective than CDDP monotherapy with prior exposure to platinum.
In the treatment of ovarian cancer, on the other hand, the treatment-free interval (TFI) is usually used to select the appropriate regimen.7 The response to rechallenge with platinum improves with increase in the TFI. Moreover, the TFI is equal to the platinum-free interval (PFI) in most cases of recurrent ovarian cancer.
Meanwhile, it was reported that time-to-recurrence after primary chemotherapy is predictive of survival after recurrence in the ancillary data analysis of a Gynecologic Oncology Group trial of the treatment of advanced and recurrent endometrial cancer.8 That study also suggested that TFI is an important indicator when single agents are used as second-line chemotherapy for endometrial cancer. These findings raise the possibility that TFI or PFI could be used in selecting the second-line chemotherapy regimen in cervical cancer.
The primary aim of the present study was to determine whether PFI is a predictive indicator in the treatment of cervical cancer in patients who have undergone prior platinum-based chemotherapy. The role of PFI in selecting second-line regimens in other gynecologic malignancies is also discussed.
MATERIALS AND METHODS
In this retrospective study, we examined the clinical records of patients with recurrent or metastatic cervical cancer treated at the Cancer Institute Hospital in Tokyo, Japan. From among these patients, we selected those who had received platinum-containing combination regimens as second-line chemotherapy. All patients had received prior platinum-containing chemotherapy or concurrent chemoradiotherapy with CDDP alone or TP. All patients had measurable disease, and tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors as follows: complete response (CR) was defined as the complete disappearance of all measurable lesions for at least 4 weeks; partial response (PR) was defined as a more than 30% reduction in measurable lesions for at least 4 weeks; progression disease was defined as a more than 20% increase in measurable disease or the appearance of any new lesions; stable disease was defined as any situation that did not qualify as response or progression. Radiologic findings were analyzed after every 2 cycles, where possible. Adverse events were evaluated and classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 4.0).
The regimens included paclitaxel and carboplatin (TC), docetaxel and carboplatin (DC), irinotecan and cisplatin (CPT-11/CDDP), and irinotecan and nedaplatin (CPT-11/NDP). Nedaplatin is a CDDP analog considered to reduce the incidence of renal or gastrointestinal toxicities.9 At our institution, when a taxane-containing regimen is used as first-line chemotherapy, an irinotecan-containing regimen is generally selected for second-line chemotherapy, and vice versa.
A treatment diagram is shown in Figure 1. The PFI was defined as the time between the end of prior platinum-based chemotherapy and the start of secondary platinum-based combination chemotherapy. Progression-free survival (PFS) was defined as the duration from the end of second-line chemotherapy to the time of disease progression. Overall survival (OS) was defined as the duration from the start of chemotherapy to the time of death or last admission to hospital. Response rates, PFS, and OS in second-line chemotherapy were examined in relation to various clinicopathological factors, including PFI. Survival was calculated using the Kaplan-Meier method. Differences between factors were analyzed using the log-rank statistic. Values of P < 0.05 were considered statistically significant. Univariate and multivariate analyses were performed using the Cox regression model. Statistical analyses were performed using “R” software.10
Between January 2005 and December 2011, a total of 93 patients with recurrent or metastatic cervical cancer received platinum-based regimens as second-line chemotherapy. Patient characteristics are presented in Table 1.
Median age was 46 years (range, 27–72 years). Thirty-three of the patients had undergone surgery and adjuvant chemotherapy or surgery alone as initial treatment plus chemotherapy for recurrent disease. Fifty of the patients had received prior radiotherapy, 4 had undergone radiotherapy and chemotherapy, and 46 concurrent chemoradiotherapy. Forty-eight patients received CPT-11/CDDP or CPT-11/NDP, and 45 received TC or DC. All patients had measurable disease. In 71 of the patients, the maximum recurrent tumor size was within 30 mm; whereas in the remaining 22, it was more than 30 mm. Recurrent or metastatic site was pelvic in 18 patients, distant in 57, or both in 18. The disease site was pelvic in 9 (18.0%) and 9 (20.9%), distant in 31 (62.0%) and 26 (60.4%), and both in 10 (20.0%) and 8 (18.6%) in patients with prior radiotherapy and no prior radiotherapy, respectively.
Response and Survival
The response rates to second-line chemotherapy in relation to the clinicopathological parameters investigated are shown in Table 2. The overall response rate was 25.8%; 7 patients achieved CR; and 17 patients achieved PR. The disease control rate was 54.5%; 30 patients had stable disease. The response rate was 33.8% when the tumor was less than 3 cm in diameter, but 0% when the tumor was larger.
Median PFS was 5.1 months, and median OS was 13.5 months. The results of the multivariate analysis of PFS and OS are shown in Table 3. Age (>50 years), size (>3 cm), prior radiotherapy, and PFI (>24 months) were identified as prognostic factors. Figures 2 and 3 show response rate, PFS, and OS in relation to PFI. It seems that a PFI of more than 24 months was the discriminating point between platinum-sensitive and platinum-resistant cervical cancer.
Grade 3 to 4 hematologic toxicities were the most frequently observed. No treatment-related deaths occurred. Treatment was discontinued in 16 patients due to unacceptable toxicity.
The main aim of the present study was to determine whether PFI was a predictive indicator of response to second-line platinum-based chemotherapy in recurrent cervical cancer. The results indicate that only a long PFI of more than 24 months is a prognostic indicator in rechallenge with a platinum-based regimen. This differs from ovarian cancer, in which platinum-sensitive cases are defined as those which show a PFI of more than only 6 months. Tanioka et al11 reported that PFI had both predictive and prognostic value in second-line platinum therapy in advanced and recurrent cervical cancer. However, they also reported that a PFI of less than 12 months was more discriminating. The reason why the interval is so long in cervical cancer compared to ovarian cancer is unclear. However, the fact that most of the study population had squamous cell carcinoma or had previously received radiotherapy may at least partially be responsible. Chemoresistance in irradiated fields has been reported in a number of studies.12–14 With a PFI of less than 24 months, the response rates to second-line chemotherapy for recurrent cervical cancer are limited, ranging from 12.5% to 22.2%, suggesting that non–platinum chemotherapy is preferable, when considered from the viewpoints of effectiveness and morbidity.
In ovarian cancer, chemotherapy with a single agent is recommended if the case is platinum-resistant (a PFI of <6 months). The current study has demonstrated that rechallenge with a platinum-containing combination regimen is ineffective in patients with a short PFI. However, it remains unclear as to whether the use of single agents should be recommended in such cases. Moore et al15 examined predictive indicators in chemotherapy for advanced or recurrent cervical cancer using data from previous Gynecologic Oncology Group studies. They found several adverse parameters, including a poor performance status, the presence of pelvic disease, a time-to-recurrence of less than 1 year, a history of previous irradiation, and CDDP monotherapy, and concluded that non–platinum chemotherapy or participation in clinical trials should be recommended if there were more than 4 such negative factors.
Recently, a 4-arm, phase III trial including a platinum-based combination regimen with or without the molecularly targeted agent bevacizumab and a non–platinum-based combination regimen with or without bevacizumab was performed in patients with advanced or recurrent cervical cancer.16 The results showed that concurrent and sustained administration of bevacizumab substantially prolonged OS. Bevacizumab is also known to prolong PFS in ovarian cancer, not only when used with multiple agents in platinum-sensitive cases,17 but also in conjunction with a single agent in platinum-resistant cases.18 The concomitant use of a molecularly targeted agent may change the theory of PFI in recurrent cervical cancer. Further study is needed, however, to clarify this point.
In summary, the current study investigated the role of PFI in predicting response to second-line chemotherapy in recurrent cervical cancer. The results showed that the discriminating PFI was much longer than that in ovarian cancer. Although little information is available regarding treatment in patients with a short PFI, it would seem that PFI offers a useful tool in selecting agents in second-line chemotherapy in a wide range of gynecologic malignancies. Clearly, however, 1 limitation of this study was that it was carried out retrospectively. Further analysis based on prospective study may be needed to confirm the most discriminating PFI for response to second-line chemotherapy in cervical cancer.
1. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent
, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol
. 2004; 22: 3113–3119.
2. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent
, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol
. 2009; 27: 4649–4655.
3. 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.
4. Bloss JD, Blessing JA, Behrens BC, et al. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol
. 2002; 20: 1832–1837.
5. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol
. 2005; 23: 4626–4633.
6. Tewari KS, Monk BJ. The rationale for the use of non-platinum chemotherapy
doublets for metastatic and recurrent
cervical carcinoma. Clin Adv Hematol Oncol
. 2010; 8: 108–115.
7. Markman M., Rothman R., Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J. Clin Oncol
. 1991; 9: 389–393.
8. Moore KN, Tian C, McMeekin DS, et al. Does the progression-free interval after primary chemotherapy
predict survival after salvage chemotherapy
in advanced and recurrent
endometrial cancer?: a Gynecologic Oncology Group ancillary data analysis. Cancer
. 2010; 116: 5407–5414.
9. Kato T, Nishimura H, Yakushiji M, et al. Phase II study of 254-S (cis-diammine glycolato platinum) for gynecological cancer. Gan To Kagaku Ryoho
. 1992; 19: 695–701.
10. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.r-project.org/
11. Tanioka M, Katsumata N, Yonemori K, et al. Second platinum therapy in patients with uterine cervical cancer
previously treated with platinum chemotherapy
. Cancer Chemother Pharmacol
. 2011; 68: 337–342.
12. Benjapibal M, Thirapakawong C, Leelaphatanadit C, et al. A pilot phase II study of capecitabine plus cisplatin in the treatment of recurrent
carcinoma of the uterine cervix. Oncology
. 2007; 72: 33–38.
13. Kosmas C, Mylonakis N, Tsakonas G, et al. Evaluation of the paclitaxel-ifosfamide-cisplatin (TIP) combination in relapsed and/or metastatic cervical cancer
. Br J Cancer
. 2009; 101: 1059–1065.
14. Pactasides D, Fountzilas G, Papaxoinis G, et al. Carboplatin and paclitaxel in metastatic or recurrent cervical cancer
. Int J Gynecol Cancer
. 2009; 19: 777–781.
15. Moore HD, Tian C, Monk BJ, et al. Prognostic factors for response to cisplatin-based chemotherapy
in advanced cervical carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol
. 2010; 116: 44–49.
16. Tewari KS, Sill M, Long HJ 3rd, et al. Incorporation of bevacizumab in the treatment of recurrent
and metastatic cervical cancer
: a phase III randomized trial of Gynecologic Oncology Group. J Clin Oncol
. 2013; 31(suppl; abstr).
17. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy
with or without bevacizumab in patients with platinum-sensitive recurrent
epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol
. 2012; 30: 2039–2045.
18. Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy
(CT) for platinum (PT)-resistant recurrent
ovarian cancer (OC). J Clin Oncol
. 2012; 30(suppl; abstr.):LBA5002.