According to the International Federation of Gynecology and Obstetrics data1 from 1993 to 1995, the 5-year survival rates of patients with stages IB, IIB, IIIB, and IVB cervical cancer were 80.9%, 73.3%, 50.5%, and 22.0%, respectively, indicating that the prognosis of patients with advanced cervical cancer has not improved since 1950. Although surgery and radiotherapy have played a major role in the treatment of cervical cancer, new strategies combined with chemotherapy, such as concurrent chemoradiotherapy or neoadjuvant chemotherapy (NAC), have recently been adopted in an attempt to improve the prognosis in patients with bulky or locally advanced disease.
A meta-analysis of randomized studies comparing the survival benefits of radiotherapy alone and of radiotherapy with concomitant chemotherapy based on cisplatin in cases of locally advanced cervical carcinoma showed that chemoradiotherapy offers an absolute survival benefit of 12% at 5 years.2 This result led to the clinical alert from the National Cancer Institute (NCI) in 1999, and concurrent chemoradiotherapy is currently considered as the standard treatment of locally advanced cervical cancer.
On the other hand, the role of NAC in the treatment of locally advanced cervical cancer still remains controversial. A meta-analysis of studies investigating the usefulness of NAC showed the absence of any survival benefit in patients receiving NAC followed by radiotherapy as compared with that in patients treated by radiotherapy alone.3 In contrast to NAC followed by radiotherapy, NAC followed by surgery yielded an absolute increase of the 5-year survival rate4 by 14%. In most of these NAC trials, cisplatin was administered as the key drug and high response rates were obtained in cases of locally advanced cervical cancer. However, this agent exerts severe renal toxicity, which is extremely unfavorable, especially in patients with cervical cancer who often show ureteral stenosis and renal dysfunction.
The most evaluated drugs in cervical cancer are the platinums, with response rates of 15.0% to 28.2% when used as single agents, and the taxanes have demonstrated response rates of 8.7% to 34.0% when used as single agents.5-13 Recently, combination chemotherapy with docetaxel + carboplatin was shown to be effective in patients with cervical cancer, with lower nephrointestinal, neurointestinal, and gastrointestinal toxicities than cisplatin-based combination chemotherapy. Rein et al14 conducted a phase I study of weekly docetaxel + carboplatin and showed a high efficacy in a dose-dense setting, yielding an overall response rate of 65% for locally advanced primary and recurrent cervical cancers. Nagao et al15 showed in a pilot study that triweekly combination chemotherapy with carboplatin (area under the curve [AUC], 6) + docetaxel (60 mg/m2) yielded an overall response rate of 76% in cases of advanced or recurrent cervical cancer. To our knowledge, there is no phase I study of docetaxel and carboplatin in patients with cervical cancer.
Based on these pilot studies, we conducted a phase II study to evaluate the therapeutic activity and toxicity of triweekly combination chemotherapy with docetaxel (AUC, 6) + carboplatin (60 mg/m2) in patients with locally advanced or recurrent cervical cancer.
MATERIALS AND METHODS
Patients were accrued from January 2004 to December 2005 at member institutions of Japan Sankai Gynecological Cancer Study Group. The protocol was approved by the institutional review board at each institution, and all the patients provided written informed consent before entry into the study. All the patients had a pathologically confirmed cervical carcinoma with International Federation of Gynecology and Obstetrics stages IB2 to IV or recurrent disease. The patients were required to have a bidimensional tumor measurable by physical examination, radiography, computed tomography, or magnetic resonance imaging. The inclusion criteria were women aged between 20 and 74 years with an Eastern Cooperative Oncology Group performance status of 0 to 1 and adequate hematological, hepatic, and renal functions as determined by a neutrophil count equal to or higher than 2000/μL, hemoglobin level equal to or higher than 9.0 g/dL, platelet count equal to or higher than 100,000/μL, serum total bilirubin level equal to or less than 1.5 mg/dL, serum aspartate and alanine aminotransferase levels equal or less than 100 IU/L, serum alkaline phosphatase level equal to or less than 750 IU/L, and serum creatinine level equal to or less than 1.5 mg/dL. The exclusion criteria were the presence of severe systemic or uncontrolled underlying disease (infection, central nervous system disease, metabolic disease, etc), interstitial pneumonitis, peripheral neuropathy or edema of grade 2 or more, previous or concomitant malignancies, malignant or benign effusions requiring drainage, and history of previous chemotherapy including paclitaxel or docetaxel. If the measurable disease was within previous radiation therapy, at least 6 months was needed to have elapsed since the completion of the radiation therapy.
The patients were administered docetaxel at the dose of 60 mg/m2 by intravenous infusion for 1 hour, followed immediately by carboplatin at a dose based on an AUC of 6 by intravenous infusion for 2 hours. The treatments were repeated every 21 days for a total of 1 to 6 cycles, depending on the goal of the therapy. Antiemetic therapy was administered as needed according to the judgment of the attending physician. The toxicity of the chemotherapy was evaluated according to the NCI Common Toxicity Criteria version 3.0. Chemotherapy was discontinued in case of disease progression or excessive toxicity. Granulocyte colony-stimulating factor (G-CSF) was administered subcutaneously in patients with a white blood cell count of less than 1000/μL, neutrophil count of less than 500/μL, or febrile neutropenia. Prophylactic antibiotic cycles were recommended for complicated grade 4 febrile neutropenia. Treatment was delayed when the neutrophil count was under 1500/μL or the platelet count was less than 100,000/μL. In cases of febrile neutropenia, the dose of docetaxel was reduced by 10 mg/m2. If the platelet count was less than 75,000/μL, the dose of carboplatin was reduced by AUC of 0.5, and if the platelet count was less than 50,000/μL, the dose of carboplatin was reduced by AUC of 1.0 in the subsequent cycle. In patients with grade 3 or 4 nonhematological toxicity, except for vomiting or allergy, the dose of docetaxel was reduced by 10 mg/m2 and the dose of carboplatin was reduced by AUC of 1.0 in the subsequent cycle.
The response was evaluated based on the Response Evaluation Criteria in Solid Tumors. Complete response (CR) was defined as complete disappearance of all target lesions for at least 4 weeks. Partial response (PR) was defined as an at least 30% reduction in the sum of the longest diameters of the target lesions, sustained for at least 4 weeks. Progressive disease was defined as a greater than 20% increase in the sum of the longest diameters of the target lesions within 2 months of study entry, or the appearance of any new lesions within 8 weeks of study entry. Stable disease was represented by any condition not meeting any of the 3 criteria. Measurements of the tumor size of all the patients were performed by radiologists at their institutions by magnetic resonance imaging. For patients receiving chemotherapy in the NAC setting, surgery was allowed to be performed without having confirmation 4 weeks after complete disappearance of the tumor or tumor shrinkage by 30%. Responses were compared using Fisher exact test. A P < 0.05 was considered to denote significance.
A total of 71 patients were enrolled into this trial, and 66 patients were considered eligible for evaluation of the response and toxicity. The main characteristics of the patients are shown in Table 1. Of the 66 patients, 62 had locally advanced cervical cancer with no history of previous treatment, whereas 4 patients had recurrent cervical cancer. In these 4 patients, 1 patient had received radiotherapy alone as the definitive treatment of the primary disease, 1 patient had received chemoradiotherapy, and 2 patients had been treated by surgery and radiotherapy. The mean age of the patients was 50.4 years. A total of 149 cycles of chemotherapy were administered, with a median of 2.3 cycles (range, 1-6) per patient.
The overall response rates (CR + PR) were 69.3% (43/62, 95% confidence interval, 57.8-80.8) in patients administered with the treatment in the NAC setting and 25.0% (1/4, 95% confidence interval, −17.4 to 67.4) in patients with recurrent disease (Table 2). When the responses were stratified according to the pathological type of the cancer, clinical responses were documented in 69.7% (23/33, 95% confidence interval, 54.0-85.4) of patients with squamous cell carcinoma and 68.9% (20/29, 95% confidence interval, 52.1-85.7) with nonsquamous cell carcinoma, with no significant difference between the 2 types, in the NAC setting. When the response to the treatment was further stratified according to the subtype of the nonsquamous cell carcinoma in the NAC setting, the overall clinical response rates were 71.4% (5/7), 40.0% (2/5), and 50.0% (1/2) for endometrioid adenocarcinoma, mucinous adenocarcinoma, and adenosquamous cell carcinoma, respectively. The response rate tended to be higher in patients with endometrioid adenocarcinoma as compared with that in the patients with the other 2 histological subtypes; however, no significant differences were found, possibly because of the small number of patients.
The nonhematological toxicities were mainly grade 1 or 2 in severity, as shown in Table 3. The most common adverse effects were grade 1 or 2 nausea/vomiting. Grade 4 neurotoxicity was observed in one patient after the first course. Hematological toxicity was mostly in the form of neutropenia and thrombocytopenia. The most frequent grades 3 and 4 toxicities were neutropenia, anemia, and thrombocytopenia. Grade 3 or 4 neutropenia was observed in 42 (63.6%) of the total patients, 33 patients (50.0%) after the first course, 36 patients (81.9%) after the second course, and 13 patients (61.9%) after the third course. Febrile neutropenia was observed in one patient after the second course and one patient after the third course. Forty-one of the total patients (62.1%) required G-CSF to leukocyte recovery. Grade 3 or 4 anemia was observed in 16 (24.2%) of the total patients, 13 patients (19.7%) after the first course, 9 patients (20.5%) after the second course, and 5 patients (23.8%) after the third course. Grade 3 or 4 thrombocytopenia was observed in 9 (13.6%) of the total patients, 3 patients (4.5%) after the first course, 6 patients (13.6%) after the second course, and 2 patients (9.5%) after the third course. Treatment was delayed or reduced owing to toxicity after the second course in 2 patients and in 3 patients after the third course; however, no treatment-related deaths were encountered.
Although a number of studies of NAC using a variety of chemotherapeutic agents have been evaluated in patients with locally advanced cervical cancer and high response rates ranging from 78% to 100% have been demonstrated,16-23 the role of NAC in the treatment of cervical carcinoma still remains controversial. A meta-analysis24 comparing NAC followed by surgery with radiotherapy alone indicated that NAC yielded an absolute increase by 14% of the 5-year survival rate; however, a recent randomized study comparing NAC (bleomycin + vincristine + mitomycin + cisplatin) followed by surgery with surgery alone for locally advanced bulky cervical carcinoma indicated no increase in the operability and inferior overall survival in the NAC arm. More recently, Eddy et al25 reported the results of a randomized phase III trial conducted by the Gynecologic Oncology Group between 1996 and 1999 and concluded that NAC (vincristine + cisplatin) offered no additional objective benefit in patients undergoing radical hysterectomy and pelvic/para-aortic lymphadenectomy for suboptimal stage IB cervical cancer. However, the clinical response rates of 61% and 52% reported by Katsumata et al24 and Eddy et al,25 respectively, seemed to be too low to conclude that NAC followed by surgery does not improve the prognosis of the patients, because several investigators have reported that good response to NAC increased the surgery rates and prolonged the survival.17,26
Based on the results of the pilot studies conducted by Rein etal14 and Nagao et al,15 we conducted the present phase II study of combined docetaxel + carboplatin in patients with cervical carcinoma. Although only 4 patients with recurrent disease were enrolled, 62 patients treated in the NAC setting followed by radical surgery were eligible for inclusion in the evaluation of the efficacy of this combined chemotherapy. In these patients treated in the NAC setting, the overall response rate was 69.3%, slightly higher than the response rate reported for cisplatin/vincristine-based chemotherapy. The most impressive finding in this trial was the response rate of 68.9% to this combination regimen of patients with nonsquamous cell carcinomas, which was almost equal to the rate of 69.7% in patients with squamous cell carcinoma. Nagao et al15 also reported that all the 5 patients with adenocarcinoma responded to this combination regimen administered in the NAC setting. According to previous reports,27-29 the response rate of patients with cervical adenocarcinoma to NAC using a variety of chemotherapeutic agents varies between 50% and 67%, indicating that adenocarcinoma tends to be less sensitive to chemotherapy than squamous cell carcinoma of the cervix. In this context, the present study indicated that the response rate to the combined regimen of docetaxel + carboplatin was similar in cases of cervical adenocarcinoma and cervical squamous cell carcinoma. Recently, the incidence of cervical adenocarcinoma has been increasing, especially in young women,30-32 and an inferior prognosis of patients with adenocarcinoma as compared with that of those with squamous cell carcinoma was reported.31,33,34 A prospective randomized trial with a large number of patients is needed to determine if a good response is associated with longer survival in patients with cervical adenocarcinoma treated with this regimen in the NAC setting.
This combined chemotherapy regimen of carboplatin + docetaxel was generally well tolerated, as demonstrated by the mild to moderate toxicity. Neutropenia was the most frequent hematologic toxicity. The neutropenia was rapidly reversible, and G-CSF was effective for elevating the neutrophil count. The frequency of grades 3 and 4 neutropenia was similar to that noted with other combination regimens. Grade 3 febrile neutropenia occurred in 2 patients. Two patients with febrile neutropenia needed to be hospitalized for the administration of broad-spectrum antibiotics and G-CSF, but neither case developed any infection or sepsis. The frequency of grades 3 and 4 anemia was high (24.2%). Presumably, the massive bleeding from the cervical tumor before the treatment was the reason for this high frequency of anemia. Three patients required platelet transfusion because of grade 4 thrombocytopenia. Only mild nonhematologic toxicities were observed. The incidence of toxicity during this study was similar to that reported for taxane-based combined regimens.17,35-37
In conclusion, the present results suggest that the docetaxel + carboplatin regimen is a safe, effective, well-tolerated treatment regimen for cervical cancer. In particular, the high response rate observed in patients with cervical adenocarcinoma warrants further phase II trials of NAC for cervical adenocarcinoma.
The authors extend their gratitude to the investigators at the participating institutions. These institutions are as follows: Fukuyama Medical Center, Iwate University, Okayama Red Cross Hospital, and Tokushima University. We also thank Ms Hiroko Shirafuji for her administrative assistance in this trial.
1. Benedet JL, Odicino F, Maisonneuve P, et al. Carcinoma of the cervix uteri. Int J Gynaecol Obstet
. 2003;83(suppl 1):41-78.
2. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet
3. Tierney JF, Stewart LA, Parmar MK. Can the published data tell us about the effectiveness of neoadjuvant chemotherapy
for locally advanced cancer of the uterine cervix? Eur J Cancer
4. Neoadjuvant Chemotherapy
for Locally Advanced Cervical Cancer
Meta-analysis Collaboration. Neoadjuvant chemotherapy
for locally advanced cervical cancer
: a systematic review and meta-analysis of individual patient data from 21 randomised trials. Eur J Cancer
5. Bonomi P, Blessing JA, Stehman FB, et al. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol
6. Thigpen JT, Blessing JA, Homesley H, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol
7. Arseneau J, Blessing JA, Stehman FB, et al. A phase II study of carboplatin
in advanced squamous cell carcinoma of the cervix (a Gynecologic Oncology Group Study). Invest New Drugs
8. Weiss GR, Green S, Hannigan EV, et al. A phase II trial of carboplatin
for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol
9. McGuire WP, Blessing JA, Moore D, et al. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol
10. Kudelka AP, Winn R, Edwards CL, et al. An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anticancer Drugs
11. Curtin JP, Blessing JA, Webster KD, et al. Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol
12. Vallejo CT, Machiavelli MR, Pérez JE, et al. Docetaxel
as neoadjuvant chemotherapy
in patients with advanced cervical carcinoma. Am J Clin Oncol
13. Garcia AA, Blessing JA, Vaccarello L, et al. Phase II clinical trial of docetaxel
in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Am J Clin Oncol
14. Rein DT, Kurbacher CM, Breidenbach M, et al. Weekly carboplatin
for locally advanced primary and recurrent cervical cancer
: a phase I study. Gynecol Oncol
15. Nagao S, Fujiwara K, Oda T, et al. Combination chemotherapy of docetaxel
in advanced or recurrent cervix cancer. A pilot study. Gynecol Oncol
16. Serur E, Mathews RP, Gates J, et al. Neoadjuvant chemotherapy
in stage IB2 squamous cell carcinoma of the cervix. Gynecol Oncol
17. Sardi JE, Giaroli A, Sananes C, et al. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy
in stage Ib squamous carcinoma of the cervix: the final results. Gynecol Oncol
18. Sardi J, Sananes C, Giaroli A, et al. Is subradical surgical treatment for carcinoma of the cervix uteri stage IB logical? Gynecol Oncol
19. Sardi J, Sananes C, Giaroli A, et al. Neoadjuvant chemotherapy
in locally advanced carcinoma of the cervix uteri. Gynecol Oncol
20. Dottino PR, Plaxe SC, Beddoe AM, et al. Induction chemotherapy followed by radical surgery in cervical cancer
. Gynecol Oncol
21. Benedetti-Panici P, Greggi S, Scambia G, et al. Long-term survival following neoadjuvant chemotherapy
and radical surgery in locally advanced cervical cancer
. Eur J Cancer
22. Sugiyama T, Nishida T, Kumagai S, et al. Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy
in locally advanced cervical cancer
. Br J Cancer
23. Park DC, Kim JH, Lew YO, et al. Phase II trial of neoadjuvant paclitaxel and cisplatin in uterine cervical cancer
. Gynecol Oncol
24. Katsumata N, Yoshikawa H, Hirakawa T, et al. Phase III randomized trial of neoadjuvant chemotherapy
followed by radical hysterectomy versus radical hysterectomy for bulky stage I/II cervical cancer
(JGOG0102) [abstract]. Proc Annu Meet Am Soc Clin Oncol
25. Eddy GL, Bundy BN, Creasman WT, et al. Treatment of ("bulky") stage IB cervical cancer
with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Gynecol Oncol
26. Napolitano U, Imperato F, Mossa B, et al. The role of neoadjuvant chemotherapy
for squamous cell cervical cancer
(Ib-IIIb): a long-term randomized trial. Eur J Gynaecol Oncol
27. Iwasaka T, Fukuda K, Hara K, et al. Neoadjuvant chemotherapy
with mitomycin C, etoposide, and cisplatin for adenocarcinoma of the cervix. Gynecol Oncol
28. Lissoni A, Gabriele A, Gorga G, et al. Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma. Ann Oncol
29. Saito T, Takehara M, Lee R, et al. Neoadjuvant chemotherapy
with cisplatin, aclacinomycin A, and mitomycin C for cervical adenocarcinoma-a preliminary study. Int J Gynecol Cancer
30. Sasieni P, Adams J. Changing rates of adenocarcinoma and adenosquamous carcinoma of the cervix in England. Lancet
31. Bray F, Carstensen B, Møller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev
32. Vizcaino AP, Moreno V, Bosch FX, et al. International trends in the incidence of cervical cancer
: I. Adenocarcinoma and adenosquamous cell carcinomas. Int J Cancer
33. Hopkins MP, Morley GW. A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol
34. Eifel PJ, Burke TW, Morris M, et al. Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol
35. Perez EA, Suman VJ, Fitch TR, et al. A phase II trial of docetaxel
as first-line chemotherapy for metastatic breast cancer: NCCTG study N9932. Oncology
36. Strauss HG, Henze A, Teichmann A, et al. Phase II trial of docetaxel
in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Gynecol Oncol
37. Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of docetaxel
in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest