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Randomized Clinical Trial of Weekly vs. Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Locally Advanced Cervical Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, pp. e577–e581, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2011.05.002
CLINICAL INVESTIGATION
Cervix
RANDOMIZED CLINICAL TRIAL OF WEEKLY VS. TRIWEEKLY CISPLATIN-BASED CHEMOTHERAPY CONCURRENT WITH RADIOTHERAPY IN THE TREATMENT OF LOCALLY ADVANCED CERVICAL CANCER SANG-YOUNG RYU, M.D., PH.D.,* WON-MOO LEE, M.D.,* KIDONG KIM, M.D.,* SANG-IL PARK, M.D.,y BEOB-JONG KIM, M.D.,* MOON-HONG KIM, M.D.,* SEOK-CHEOL CHOI, M.D.,* CHUL-KOO CHO, M.D.,z BYUNG-HO NAM, PH.D.,x AND EUI-DON LEE, M.D.y Departments of *Obstetrics and Gynecology and zRadiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; yDepartment of Gynecologic Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea; and xCancer Biostatistics Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea Purpose: To compare compliance, toxicity, and outcome of weekly and triweekly cisplatin administration concurrent with radiotherapy in locally advanced cervical cancer. Methods and Materials: In this open-label, randomized trial, 104 patients with histologically proven Stage IIB– IVA cervical cancer were randomly assigned by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m2, six cycles) and triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) chemotherapy arms during concurrent radiotherapy. The difference of compliance and the toxicity profiles between the two arms were investigated, and the overall survival rate was analyzed after 5 years. Results: All patients tolerated both treatments very well, with a high completion rate of scheduled chemotherapy cycles. There was no statistically significant difference in compliance between the two arms (86.3% in the weekly arm, 92.5% in the triweekly arm, p > 0.05). Grade 3–4 neutropenia was more frequent in the weekly arm (39.2%) than in the triweekly arm (22.6%) (p = 0.03). The overall 5-year survival rate was significantly higher in the triweekly arm (88.7%) than in the weekly arm (66.5%) (hazard ratio 0.375; 95% confidence interval 0.154–0.914; p = 0.03). Conclusions: Triweekly cisplatin 75-mg/m2 chemotherapy concurrent with radiotherapy is more effective and feasible than the conventional weekly cisplatin 40-mg/m2 regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. Ó 2011 Elsevier Inc. Locally advanced cervical cancer, Tri-weekly cisplatin-based chemoradiation therapy.
INTRODUCTION
‘‘Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiotherapy in women who require radiotherapy for treatment of cervical cancer’’ (2–6). Although recently reported meta-analyses also demonstrated improved local control rates and survival with cisplatin-based chemotherapy concurrent with radiation, the optimal cisplatin dose and dosing schedule are still undetermined (7–9). Among the previous five randomized clinical trials, two trials performed by the Gynecologic Oncology Group (GOG) used weekly cisplatin 40 mg/m2, whereas the other three trials used triweekly cisplatin at
Cervical carcinoma is one of the most common gynecologic cancers worldwide (1). The prognosis of cervical cancer is favorable, with an approximately 80–90% 5-year survival rate in early-stage disease. However, advanced disease carries a poor prognosis. Current standard treatment for locally advanced cervical cancer, which is not eligible for surgical treatment, is cisplatin-based concurrent chemoradiation. On the basis of the results of five randomized clinical trials, which consistently showed improved survival in patients treated with cisplatin-based chemoradiation, the U.S. National Cancer Institute (NCI) announced in 1992 that
This trial was funded by Grant No. RT-10-01: 50457-2010 from the Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences. Conflicts of interest: none. Acknowledgment—The authors thank the general practitioners, hospital staff, and the women who took part in this study. Received Sept 9, 2010, and in revised form April 20, 2011. Accepted for publication May 10, 2011.
Reprint requests to : Sang-Young Ryu, M.D., Ph.D., Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul 139-706, Republic of Korea. Tel: (+82) 2-970-1227; Fax: (+82) 2-970-1227; E-mail: ryu@kcch. re.kr Presented in abstract form at the 13th Biennial Meeting of the International Gynecologic Cancer Society, October 23–26, 2010, Prague, Czechoslovakia. e577
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a dose range of 50 mg/m2 to 75 mg/m2 combined with 5fluorouracil (5-FU) (2–6). Despite the diversity in cisplatin dose and dosing schedules, weekly cisplatin at a dose of 40 mg/m2 concurrent with radiation is widely accepted as the standard regimen of chemoradiation because of its convenience, equal effectiveness, and favorable toxicity in comparison with other 5-FU combined regimens. However, as a result of the GOG 165 study, which was closed prematurely because an interim analysis found that patients in the 5-FU treatment group were not likely to achieve a better outcome, the role of 5-FU (previously popularly included in clinical trials) as a radiosensitizer became subject to debate (10). Furthermore, a clinical trial performed by the NCI in Canada comparing pelvic radiotherapy alone with weekly cisplatin 40 mg/m2 concurrent with radiotherapy failed to show improvement of progression-free and 5-year survival (11). Although the authors suggested several possible reasons for their study failing to demonstrate a survival benefit with concurrent weekly cisplatin 40-mg/m2 chemotherapy, other investigators have tried to find another optimal dose and dosing schedule for cisplatin administration. In light of the results of the previous clinical trial that indicated 5-FU may not be an active radiosensitizer, weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 remain the most popular cisplatin doses and dosing schedules. However, despite the possible advantages of triweekly cisplatin 75 mg/m2, which offers an increased peak concentration of cisplatin and cisplatin administration during brachytherapy, no clinical trials to date have directly compared weekly and triweekly cisplatin-based chemotherapy concurrent with radiotherapy. In this study, we tried to compare the compliance to and toxicity of weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 administration concurrent with radiotherapy. After 5 years of observation, we report the long-term outcome of the both arms.
METHODS AND MATERIALS Eligibility From January 2002 to December 2004, 104 patients with histologically proven Stage IIB–IVA cervical cancer were randomized by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m2, six cycles) and triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) chemotherapy arms concurrent with radiotherapy. Patients had GOG performance status 0–2 and adequate hematologic function (absolute neurtophil count >1,500/mL, platelets >100,000/mL), renal function (creatinine < upper limit of normal or calculated creatinine clearance >60 mL/min), and hepatic function (bilirubin <1.5 normal, alkalinephosphate, AST (aspartate aminotransferase) <3 normal). Patients with Stage IVB disease with distant metastasis and rare tumor histology, such as melanoma and metastatic cancers, were excluded. Patients who had previous histories of chemotherapy or radiotherapy, history of other cancers, hypersensitivity to platinum agents, and serious medical disease or pregnant state were also excluded.
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Staging workup was done as recommended by the International Federation of Gynecology and Obstetrics staging system. Before randomization, the extent of the disease was investigated by chest X-ray, intravenous pyelography, and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI). Cystoscopy and colonoscopy were performed if there was suspicion of involvement of the bladder and rectum. All patients underwent positron emission tomography (PET) or PET combined with CT (PET/ CT) to exclude distant metastasis before treatment. Tumor size was determined by the largest diameter of tumor on pretreatment CT or MRI scan. Distant metastasis was confirmed by fine needle aspiration biopsy or cytology as far as possible. However, it was also diagnosed clinically in cases of enlarged lymph nodes >1 cm in short-axis diameter on CT scan and an increased size of >30% on the follow-up CT scan, which was performed 3 months later. Patients gave written informed consent, and all the data for this trial were located at the data management center in the Korea Cancer Center Hospital under the approval of its institutional review board.
Treatment Chemotherapy. For the weekly schedule, cisplatin at a dose of 40 mg/m2 diluted in 250 mL of 0.9% sodium chloride was administered i.v. over 1 to 2 h. It was repeated every week for six cycles concurrent with radiotherapy. For the triweekly schedule, cisplatin at a dose of 75 mg/m2 diluted in 250 mL of 0.9% sodium chloride was administered i.v. over 1 to 2 h. It was repeated every 3 weeks for three cycles concurrent with radiotherapy. As pre- and posthydration, at least 1,000 mL of 0.9% sodium chloride was injected i.v. before and after cisplatin administration. Radiotherapy. All patients were treated with a combination of external-beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT). External-beam radiotherapy was delivered to the whole pelvis through anterior and posterior parallel-opposed portals or a four-field box technique using 4–10-MV X-rays or g-rays. When central shields were inserted during EBRT, they were usually 4 cm in width at the isocenter of the field. The planned total dose to the pelvic sidewall was 50 Gy, given at a daily dose of 1.8–2.0 Gy. When patients had bulky parametrial tumors or gross lymph node metastases, an additional 5–10 Gy was applied to boost the external dose to the lesion to a total of 55–60 Gy. With regard to ICBT, low-dose-rate treatment with a 137Cs source was used. In low-dose-rate treatment, the prescribed dose to point A was 30– 40 Gy in 1 to 2 fractions according to the tumor volume, and it was recommended that the total point A dose combining EBRT with ICBT be more than 75–80 Gy. The first ICBT was generally performed after 30–45 Gy of whole-pelvic EBRT, and additional EBRT was delivered with a central shield. To avoid the negative impact of treatment prolongation, it was recommended that the overall treatment time be no longer than 50 days.
Compliance to treatment The percentage of completed cycles of chemotherapy and delayed radiation period longer than 1 week was compared between the two arms. Hematologic, gastrointestinal, renal, and neurotoxicities were evaluated after each cycle of chemotherapy according to the NCI Common Terminology Criteria for Adverse Events, version 3.0.
Triweekly cisplatin-based CRT in cervical cancer d S.-Y. RYU et al.
Table 1. Clinical characteristics of patients with locally advanced cervical cancer Weekly cisplatin
Characteristic Patients Age (y) Initial hemoglobin (mg/dL) Tumor size (cm) Performance status 0 1 2 Stage Stage IIB Stage III Stage VIA Histology SCC Non-SCC Pretreatment imaging Positive pelvic LN Positive para-aortic LN Interval from last chemotherapy to ICBT (d)
Triweekly cisplatin
Table 2. Compliance to treatment in patients with locally advanced cervical cancer p
51 53 54.40 1.31 51.94 1.28 0.205 11.39 0.16 11.44 0.17 0.810 4.60 0.16 22 (43.1) 23 (45.1) 6 (11.8) 28 (54.9) 19 (37.3) 4 (7.8) 46 (90.2) 5 (9.8)
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4.82 0.25 0.477 0.924 23 (43.4) 25 (47.2) 5 (9.4) 0.624 34 (64.2) 19 (30.2) 3 (5.7) 0.949 47 (88.7) 6 (11.3)
29 (56.9) 27 (50.9) 0.488 7 (13.7) 5 (9.4) 0.551 17.94 1.62 10.81 1.44 0.483
Abbreviations: SCC = squamous cell carcinoma; LN = lymph node; ICBT = intracavitary brachytherapy. Values are mean SE or number (percentage).
Follow-up Patients were followed up by physical examination, tumor marker (squamous cell carcinoma), and Papanicolaou smear every 3 months for 2 years, and every 6 months for the next 3 years. Chest X-ray, abdominopelvic CTor MRI, PET, or PET/CTwas performed annually. Recurrence of disease was defined as the presence of tumor histologically or radiologically. Any suspicious lesion on CT scan was followed up with CT scans every 3 months until the recurrence was confirmed clinically. In case of recurrence, PET or PET/CT was performed to find other sites of recurrences, and all sites of recurrences were documented.
Statistical considerations This trial was an open-label, randomized trial with 1:1 allocation ratio. The random assignment was generated by computer with a random permutation method with block size 2, 4, and 6. All the investigators were masked to the assignment of treatment group, and sequentially numbered envelopes were used for random allocation. The categoric clinical characteristics between the two treatments were compared using c2 and Fisher exact tests. For continuous variables mean and median values were compared between groups using the t test and the Wilcoxon rank-sum test. Survival curves and rates were estimated using the Kaplan-Meier method, and hazard ratio (HR) estimates and confidence intervals (CI) were generated using the Cox proportional hazard model. Data were analyzed using SPSS software for Windows (version 13.0; SPSS, Chicago, IL).
RESULTS Patient characteristics were well balanced between the two groups in terms of age, histology, stage distribution, and initial hemoglobin level (Table 1).
Treatment Chemotherapy Completed cycle Uncompleted cycle 1 2 3 4 5 Radiotherapy Completed as scheduled Delayed 1–2 wk >2 wk
Weekly cisplatin
Triweekly cisplatin
51 (100) 44 (86.3) 7 (13.7) 0 0 1 (2.0) 5 (9.8) 1 (2.0) 51 (100) 49 (96.1)
53 (100) 49 (92.5) 4 (7.5) 1 (1.9) 3 (5.7) — — — 53 (100) 52 (98.1)
2 (3.9) 2 0
1 (1.9) 1 0
p 0.482
0.971
Values are number (percentage).
The two cisplatin-based chemoradiation regimens were tolerated very well, with 86.3% and 92.5% completion rates of scheduled chemotherapy cycles for the weekly and triweekly arms, respectively. There was no statistically significant difference of compliance between the two arms (p > 0.05). There were only 3 patients with radiation delay due to toxicity (2 cases in the weekly arm and 1 case in the triweekly arm) (Table 2). The Grade 3–4 neutropenia was higher in the weekly arm than in the triweekly arm (39.2% and 22.6%, respectively, p = 0.03). However, there were no statistical differences in gastrointestinal, renal, and neurosensory toxicities between the two arms (Table 3). After 5 years of observation, there were a total of 28 recurrences: 15 cases (29.4%) in the weekly arm and 13 cases (24.5%) in the triweekly arm. Most of the recurrences occurred in distant sites (13 patients [25.5%] in the weekly arm and 9 patients [17.0%] in the triweekly arm), including the para-aortic lymph node, scalene lymph nodes, and lung parenchyma (Table 4). The cause-specific and overall 5-year survival were identical and were significantly higher in the triweekly arm compared with the weekly arm (66.5% in the weekly arm, 88.7% in the triweekly arm) (HR 0.375, 95% CI 0.154–0.914, p = 0.03; Fig. 1). DISCUSSION This study showed that triweekly cisplatin 75 mg/m2 concurrent with radiotherapy is feasible and increases the 5-year survival rate significantly compared with weekly cisplatin 40 mg/m2 in patients with locally advanced cervical cancer. The study was originally designed to compare compliance between two cisplatin-based regimens of weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 in a single-institute trial. This explains why the total number of enrolled patients was small compared with other large-scaled randomized clinical trials that investigated survival outcomes. However,
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Table 3. Toxicity in patients with locally advanced cervical cancer treated with cisplatin-based chemoradiation Weekly cisplatin
Triweekly cisplatin
Toxicity
Grade 1–2
Grade 3–4
Grade 1–2
Grade 3–4
p
Neutropenia Thrombocytopenia Nausea Vomiting Creatinine Neuropathy–sensory Alopecia
20 (39.2) 13 (25.5) 43 (84.3) 12 (23.5) 8 (15.7) 5 (9.8) 13 (25.5)
20 (39.2) 4 (7.8) 2 (3.9) 0 0 0 0
23 (43.4) 3 (5.7) 46 (86.8) 11 (20.8) 15 (28.3) 2 (3.8) 17 (32.1)
12 (22.6) 3 (5.7) 2 (3.8) 0 1 (1.8) 0 0
0.033* 0.957 >0.999
Values are number (percentage). * Statistically significant.
despite the small number of patients, there was a statistically significant difference of overall survival after 5 years’ observation favoring the triweekly cisplatin-based chemoradiation (HR 0.375, 95% CI 0.154–0.914, p = 0.03). Several clinical trials have investigated alternative cisplatin dose and dosing schedules other than weekly cisplatin-based chemoradiation (12, 13). However, most of the studies were small pilot studies and failed to show any survival benefit in comparison with the weekly 40-mg/m2 regimen. This study is the first to report that triweekly cisplatin 75-mg/m2 chemotherapy concurrent with radiotherapy is feasible and has better survival outcome compared with weekly cisplatin 40-mg/m2 chemotherapy, which is currently considered the standard regimen in locally advanced cervical cancer. A possible explanation of this study is that the higher peak concentration of cisplatin may be more critical to enhancing the synergy of chemoradiation than the weekly cisplatin exposure. Although the dose–response slope of cisplatin is not steep, the response of tumor to cisplatin has been shown to increase as the peak concentration of cisplatin increases up to 100 mg/m2 (14, 15). The high peak concentration of cisplatin may be more effective not only in enhancing the
synergy of chemoradiation but also in eliminating micrometastases, with resulting decrease of local failure and distant metastasis and improvement of survival eventually. Another explanation for this result is the possible role of cisplatin administration during brachytherapy in enhancing the chemoradiation effect. In the triweekly cisplatin regimen, the third cycle of cisplatin is usually administrated during or close to the brachytherapy. Considering the fact that almost 25% of total radiation dose is delivered during brachytherapy, the administration of cisplatin during or close to brachytherapy may be a reasonable way to increase the synergy of chemoradiation. However, because the third cycle of chemotherapy was delivered, on average, 10 days before brachytherapy in this study, we have no way of deducing what proportion of the cisplatin acted as a radiosensitizer during brachytherapy. In this study there was no difference of compliance between the triweekly and weekly cisplatin arms. Although the Grade 3 and 4 hematologic toxicities were more frequent in the weekly cisplatin arm, there was little treatment delay in either arm. Because the recovery time is shorter in the weekly cisplatin regimen than in the
Table 4. Pattern of recurrences in patients with locally advanced cervical cancer treated with cisplatin-based chemoradiation Variable Patients Recurrence Central Distant PALN Lung SCLN Peritoneal seeding Bone Brain
Weekly cisplatin
Triweekly cisplatin
51 (100) 15 (29.4) 2 (3.9) 13 (25.5) 7 (13.7) 1 (2.0) 3 (5.9) 1 (2.0)
53 (100) 13 (24.5) 4 (7.5) 9 (17.0) 4 (7.5) 1 (1.9) 3 (5.7) 0
1 (2.0) 0
0 1 (1.9)
p
0.510
Abbreviations: PALN = para-aortic lymph node; SCLN = scalene lymph node. Values are number (percentage).
Fig. Kaplan-Meier estimates of survival difference between weekly and triweekly cisplatin-based chemoradiation in patients with locally advanced cervical cancer.
Triweekly cisplatin-based CRT in cervical cancer d S.-Y. RYU et al.
triweekly cisplatin regimen, the high incidence of neutropenia in the weekly cisplatin regimen was to be expected and has already been reported (14, 16). However, the adverse effects were well tolerated and manageable in both arms (16, 17). From the point of view of the present study, weekly cisplatin 40 mg/m2 concurrent with radiotherapy can be a rather weak dose and dosing schedule to induce the synergy of chemoradiation consistently. The NCI Canada study that did not show survival gain with weekly cisplatin 40 mg/m2 concurrent with radiotherapy can be reexplained by the lack of synergy of chemoradiation with relatively weaker peak concentrations of cisplatin (11). Furthermore, a study that tried to increase compliance by reducing the cisplatin peak concentration was also never going to be able to enhance survival, also supporting our hypothesis (16). However, because this study was originally designed to compare the compliance of the two regimens but not the survival outcome, the superiority of triweekly cisplatin-based chemoradiation should be confirmed in a large-scale clinical trial.
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In this study, despite the survival difference, the recurrence rate (Table 4) and progression-free survival (data not shown) were almost identical in both arms. Although there is no statistically definitive evidence, we postulate that the discrepancy between progression-free survival and overall survival can be explained by the different pattern of recurrence between the two arms. In this study the number of distant metastases was higher in the weekly cisplatin arm than in the triweekly arm. The high number of distant recurrences, which cannot be cured by surgery or radiation, may be detrimental to overall survival in the weekly cisplatin arm and also support our hypothesis that the higher peak concentration of cisplatin can be more effective to eliminate micrometastasis. However, our study does not provide enough evidence for this issue; a prospective, randomized, Phase III clinical trial is in need. In conclusion, this study showed that triweekly cisplatin 75 mg/m2 concurrent with radiation is feasible and more effective than the conventional weekly cisplatin 40 mg/m2– based regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.
REFERENCES 1. Garcia AA, Blessing JA, Darcy KM, et al. Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: A Gynecologic Oncology Group study. Gynecol Oncol 2007;104:572–579. 2. 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. 3. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137– 1143. 4. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. 5. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. 6. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–1348. 7. 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 metaanalysis. Lancet 2001;358:781–786. 8. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;26:5802–5812.
9. Kirwan JM, Symonds P, Green JA, et al. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217– 226. 10. Lanciano R, Calkins A, Bundy BN, et al. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: A gynecologic oncology group study. J Clin Oncol 2005;23:8289–8295. 11. Pearcey R, Brundage M, Drouin P, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966–972. 12. Mitsuhashi A, Uno T, Tanaka N, et al. Phase I study of daily cisplatin and concurrent radiotherapy in patients with cervical carcinoma. Gynecol Oncol 2005;96:194–197. 13. Watanabe Y, Nakai H, Shimaoka M, et al. Feasibility of concurrent cisplatin use during primary and adjuvant chemoradiation therapy: A phase I study in Japanese patients with cancer of the uterine cervix. Int J Clin Oncol 2006;11:309–313. 14. 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 1985;3:1079–1085. 15. Thigpen T, Shingleton H, Homesley H, et al. cis-Dichlorodiammineplatinum(II) in the treatment of gynecologic malignancies: Phase II trials by the Gynecologic Oncology Group. Cancer Treat Rep 1979;63:1549–1555. 16. Ikushima H, Osaki K, Furutani S, et al. Chemoradiation therapy for cervical cancer: Toxicity of concurrent weekly cisplatin. Radiat Med 2006;24:115–121. 17. Chumworathayi B, Suprasert P, Charoenkwan K, et al. Weekly versus three-weekly cisplatin as an adjunct to radiation therapy in high-risk stage I-IIA cervical cancer after surgery: A randomized comparison of treatment compliance. J Med Assoc Thai 2005;88:1483–1492.
doi:10.1016/j.ijrobp.2011.05.002
CLINICAL INVESTIGATION
Cervix
RANDOMIZED CLINICAL TRIAL OF WEEKLY VS. TRIWEEKLY CISPLATIN-BASED CHEMOTHERAPY CONCURRENT WITH RADIOTHERAPY IN THE TREATMENT OF LOCALLY ADVANCED CERVICAL CANCER SANG-YOUNG RYU, M.D., PH.D.,* WON-MOO LEE, M.D.,* KIDONG KIM, M.D.,* SANG-IL PARK, M.D.,y BEOB-JONG KIM, M.D.,* MOON-HONG KIM, M.D.,* SEOK-CHEOL CHOI, M.D.,* CHUL-KOO CHO, M.D.,z BYUNG-HO NAM, PH.D.,x AND EUI-DON LEE, M.D.y Departments of *Obstetrics and Gynecology and zRadiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; yDepartment of Gynecologic Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea; and xCancer Biostatistics Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea Purpose: To compare compliance, toxicity, and outcome of weekly and triweekly cisplatin administration concurrent with radiotherapy in locally advanced cervical cancer. Methods and Materials: In this open-label, randomized trial, 104 patients with histologically proven Stage IIB– IVA cervical cancer were randomly assigned by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m2, six cycles) and triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) chemotherapy arms during concurrent radiotherapy. The difference of compliance and the toxicity profiles between the two arms were investigated, and the overall survival rate was analyzed after 5 years. Results: All patients tolerated both treatments very well, with a high completion rate of scheduled chemotherapy cycles. There was no statistically significant difference in compliance between the two arms (86.3% in the weekly arm, 92.5% in the triweekly arm, p > 0.05). Grade 3–4 neutropenia was more frequent in the weekly arm (39.2%) than in the triweekly arm (22.6%) (p = 0.03). The overall 5-year survival rate was significantly higher in the triweekly arm (88.7%) than in the weekly arm (66.5%) (hazard ratio 0.375; 95% confidence interval 0.154–0.914; p = 0.03). Conclusions: Triweekly cisplatin 75-mg/m2 chemotherapy concurrent with radiotherapy is more effective and feasible than the conventional weekly cisplatin 40-mg/m2 regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. Ó 2011 Elsevier Inc. Locally advanced cervical cancer, Tri-weekly cisplatin-based chemoradiation therapy.
INTRODUCTION
‘‘Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiotherapy in women who require radiotherapy for treatment of cervical cancer’’ (2–6). Although recently reported meta-analyses also demonstrated improved local control rates and survival with cisplatin-based chemotherapy concurrent with radiation, the optimal cisplatin dose and dosing schedule are still undetermined (7–9). Among the previous five randomized clinical trials, two trials performed by the Gynecologic Oncology Group (GOG) used weekly cisplatin 40 mg/m2, whereas the other three trials used triweekly cisplatin at
Cervical carcinoma is one of the most common gynecologic cancers worldwide (1). The prognosis of cervical cancer is favorable, with an approximately 80–90% 5-year survival rate in early-stage disease. However, advanced disease carries a poor prognosis. Current standard treatment for locally advanced cervical cancer, which is not eligible for surgical treatment, is cisplatin-based concurrent chemoradiation. On the basis of the results of five randomized clinical trials, which consistently showed improved survival in patients treated with cisplatin-based chemoradiation, the U.S. National Cancer Institute (NCI) announced in 1992 that
This trial was funded by Grant No. RT-10-01: 50457-2010 from the Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences. Conflicts of interest: none. Acknowledgment—The authors thank the general practitioners, hospital staff, and the women who took part in this study. Received Sept 9, 2010, and in revised form April 20, 2011. Accepted for publication May 10, 2011.
Reprint requests to : Sang-Young Ryu, M.D., Ph.D., Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul 139-706, Republic of Korea. Tel: (+82) 2-970-1227; Fax: (+82) 2-970-1227; E-mail: ryu@kcch. re.kr Presented in abstract form at the 13th Biennial Meeting of the International Gynecologic Cancer Society, October 23–26, 2010, Prague, Czechoslovakia. e577
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a dose range of 50 mg/m2 to 75 mg/m2 combined with 5fluorouracil (5-FU) (2–6). Despite the diversity in cisplatin dose and dosing schedules, weekly cisplatin at a dose of 40 mg/m2 concurrent with radiation is widely accepted as the standard regimen of chemoradiation because of its convenience, equal effectiveness, and favorable toxicity in comparison with other 5-FU combined regimens. However, as a result of the GOG 165 study, which was closed prematurely because an interim analysis found that patients in the 5-FU treatment group were not likely to achieve a better outcome, the role of 5-FU (previously popularly included in clinical trials) as a radiosensitizer became subject to debate (10). Furthermore, a clinical trial performed by the NCI in Canada comparing pelvic radiotherapy alone with weekly cisplatin 40 mg/m2 concurrent with radiotherapy failed to show improvement of progression-free and 5-year survival (11). Although the authors suggested several possible reasons for their study failing to demonstrate a survival benefit with concurrent weekly cisplatin 40-mg/m2 chemotherapy, other investigators have tried to find another optimal dose and dosing schedule for cisplatin administration. In light of the results of the previous clinical trial that indicated 5-FU may not be an active radiosensitizer, weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 remain the most popular cisplatin doses and dosing schedules. However, despite the possible advantages of triweekly cisplatin 75 mg/m2, which offers an increased peak concentration of cisplatin and cisplatin administration during brachytherapy, no clinical trials to date have directly compared weekly and triweekly cisplatin-based chemotherapy concurrent with radiotherapy. In this study, we tried to compare the compliance to and toxicity of weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 administration concurrent with radiotherapy. After 5 years of observation, we report the long-term outcome of the both arms.
METHODS AND MATERIALS Eligibility From January 2002 to December 2004, 104 patients with histologically proven Stage IIB–IVA cervical cancer were randomized by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m2, six cycles) and triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) chemotherapy arms concurrent with radiotherapy. Patients had GOG performance status 0–2 and adequate hematologic function (absolute neurtophil count >1,500/mL, platelets >100,000/mL), renal function (creatinine < upper limit of normal or calculated creatinine clearance >60 mL/min), and hepatic function (bilirubin <1.5 normal, alkalinephosphate, AST (aspartate aminotransferase) <3 normal). Patients with Stage IVB disease with distant metastasis and rare tumor histology, such as melanoma and metastatic cancers, were excluded. Patients who had previous histories of chemotherapy or radiotherapy, history of other cancers, hypersensitivity to platinum agents, and serious medical disease or pregnant state were also excluded.
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Staging workup was done as recommended by the International Federation of Gynecology and Obstetrics staging system. Before randomization, the extent of the disease was investigated by chest X-ray, intravenous pyelography, and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI). Cystoscopy and colonoscopy were performed if there was suspicion of involvement of the bladder and rectum. All patients underwent positron emission tomography (PET) or PET combined with CT (PET/ CT) to exclude distant metastasis before treatment. Tumor size was determined by the largest diameter of tumor on pretreatment CT or MRI scan. Distant metastasis was confirmed by fine needle aspiration biopsy or cytology as far as possible. However, it was also diagnosed clinically in cases of enlarged lymph nodes >1 cm in short-axis diameter on CT scan and an increased size of >30% on the follow-up CT scan, which was performed 3 months later. Patients gave written informed consent, and all the data for this trial were located at the data management center in the Korea Cancer Center Hospital under the approval of its institutional review board.
Treatment Chemotherapy. For the weekly schedule, cisplatin at a dose of 40 mg/m2 diluted in 250 mL of 0.9% sodium chloride was administered i.v. over 1 to 2 h. It was repeated every week for six cycles concurrent with radiotherapy. For the triweekly schedule, cisplatin at a dose of 75 mg/m2 diluted in 250 mL of 0.9% sodium chloride was administered i.v. over 1 to 2 h. It was repeated every 3 weeks for three cycles concurrent with radiotherapy. As pre- and posthydration, at least 1,000 mL of 0.9% sodium chloride was injected i.v. before and after cisplatin administration. Radiotherapy. All patients were treated with a combination of external-beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT). External-beam radiotherapy was delivered to the whole pelvis through anterior and posterior parallel-opposed portals or a four-field box technique using 4–10-MV X-rays or g-rays. When central shields were inserted during EBRT, they were usually 4 cm in width at the isocenter of the field. The planned total dose to the pelvic sidewall was 50 Gy, given at a daily dose of 1.8–2.0 Gy. When patients had bulky parametrial tumors or gross lymph node metastases, an additional 5–10 Gy was applied to boost the external dose to the lesion to a total of 55–60 Gy. With regard to ICBT, low-dose-rate treatment with a 137Cs source was used. In low-dose-rate treatment, the prescribed dose to point A was 30– 40 Gy in 1 to 2 fractions according to the tumor volume, and it was recommended that the total point A dose combining EBRT with ICBT be more than 75–80 Gy. The first ICBT was generally performed after 30–45 Gy of whole-pelvic EBRT, and additional EBRT was delivered with a central shield. To avoid the negative impact of treatment prolongation, it was recommended that the overall treatment time be no longer than 50 days.
Compliance to treatment The percentage of completed cycles of chemotherapy and delayed radiation period longer than 1 week was compared between the two arms. Hematologic, gastrointestinal, renal, and neurotoxicities were evaluated after each cycle of chemotherapy according to the NCI Common Terminology Criteria for Adverse Events, version 3.0.
Triweekly cisplatin-based CRT in cervical cancer d S.-Y. RYU et al.
Table 1. Clinical characteristics of patients with locally advanced cervical cancer Weekly cisplatin
Characteristic Patients Age (y) Initial hemoglobin (mg/dL) Tumor size (cm) Performance status 0 1 2 Stage Stage IIB Stage III Stage VIA Histology SCC Non-SCC Pretreatment imaging Positive pelvic LN Positive para-aortic LN Interval from last chemotherapy to ICBT (d)
Triweekly cisplatin
Table 2. Compliance to treatment in patients with locally advanced cervical cancer p
51 53 54.40 1.31 51.94 1.28 0.205 11.39 0.16 11.44 0.17 0.810 4.60 0.16 22 (43.1) 23 (45.1) 6 (11.8) 28 (54.9) 19 (37.3) 4 (7.8) 46 (90.2) 5 (9.8)
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4.82 0.25 0.477 0.924 23 (43.4) 25 (47.2) 5 (9.4) 0.624 34 (64.2) 19 (30.2) 3 (5.7) 0.949 47 (88.7) 6 (11.3)
29 (56.9) 27 (50.9) 0.488 7 (13.7) 5 (9.4) 0.551 17.94 1.62 10.81 1.44 0.483
Abbreviations: SCC = squamous cell carcinoma; LN = lymph node; ICBT = intracavitary brachytherapy. Values are mean SE or number (percentage).
Follow-up Patients were followed up by physical examination, tumor marker (squamous cell carcinoma), and Papanicolaou smear every 3 months for 2 years, and every 6 months for the next 3 years. Chest X-ray, abdominopelvic CTor MRI, PET, or PET/CTwas performed annually. Recurrence of disease was defined as the presence of tumor histologically or radiologically. Any suspicious lesion on CT scan was followed up with CT scans every 3 months until the recurrence was confirmed clinically. In case of recurrence, PET or PET/CT was performed to find other sites of recurrences, and all sites of recurrences were documented.
Statistical considerations This trial was an open-label, randomized trial with 1:1 allocation ratio. The random assignment was generated by computer with a random permutation method with block size 2, 4, and 6. All the investigators were masked to the assignment of treatment group, and sequentially numbered envelopes were used for random allocation. The categoric clinical characteristics between the two treatments were compared using c2 and Fisher exact tests. For continuous variables mean and median values were compared between groups using the t test and the Wilcoxon rank-sum test. Survival curves and rates were estimated using the Kaplan-Meier method, and hazard ratio (HR) estimates and confidence intervals (CI) were generated using the Cox proportional hazard model. Data were analyzed using SPSS software for Windows (version 13.0; SPSS, Chicago, IL).
RESULTS Patient characteristics were well balanced between the two groups in terms of age, histology, stage distribution, and initial hemoglobin level (Table 1).
Treatment Chemotherapy Completed cycle Uncompleted cycle 1 2 3 4 5 Radiotherapy Completed as scheduled Delayed 1–2 wk >2 wk
Weekly cisplatin
Triweekly cisplatin
51 (100) 44 (86.3) 7 (13.7) 0 0 1 (2.0) 5 (9.8) 1 (2.0) 51 (100) 49 (96.1)
53 (100) 49 (92.5) 4 (7.5) 1 (1.9) 3 (5.7) — — — 53 (100) 52 (98.1)
2 (3.9) 2 0
1 (1.9) 1 0
p 0.482
0.971
Values are number (percentage).
The two cisplatin-based chemoradiation regimens were tolerated very well, with 86.3% and 92.5% completion rates of scheduled chemotherapy cycles for the weekly and triweekly arms, respectively. There was no statistically significant difference of compliance between the two arms (p > 0.05). There were only 3 patients with radiation delay due to toxicity (2 cases in the weekly arm and 1 case in the triweekly arm) (Table 2). The Grade 3–4 neutropenia was higher in the weekly arm than in the triweekly arm (39.2% and 22.6%, respectively, p = 0.03). However, there were no statistical differences in gastrointestinal, renal, and neurosensory toxicities between the two arms (Table 3). After 5 years of observation, there were a total of 28 recurrences: 15 cases (29.4%) in the weekly arm and 13 cases (24.5%) in the triweekly arm. Most of the recurrences occurred in distant sites (13 patients [25.5%] in the weekly arm and 9 patients [17.0%] in the triweekly arm), including the para-aortic lymph node, scalene lymph nodes, and lung parenchyma (Table 4). The cause-specific and overall 5-year survival were identical and were significantly higher in the triweekly arm compared with the weekly arm (66.5% in the weekly arm, 88.7% in the triweekly arm) (HR 0.375, 95% CI 0.154–0.914, p = 0.03; Fig. 1). DISCUSSION This study showed that triweekly cisplatin 75 mg/m2 concurrent with radiotherapy is feasible and increases the 5-year survival rate significantly compared with weekly cisplatin 40 mg/m2 in patients with locally advanced cervical cancer. The study was originally designed to compare compliance between two cisplatin-based regimens of weekly cisplatin 40 mg/m2 and triweekly cisplatin 75 mg/m2 in a single-institute trial. This explains why the total number of enrolled patients was small compared with other large-scaled randomized clinical trials that investigated survival outcomes. However,
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Table 3. Toxicity in patients with locally advanced cervical cancer treated with cisplatin-based chemoradiation Weekly cisplatin
Triweekly cisplatin
Toxicity
Grade 1–2
Grade 3–4
Grade 1–2
Grade 3–4
p
Neutropenia Thrombocytopenia Nausea Vomiting Creatinine Neuropathy–sensory Alopecia
20 (39.2) 13 (25.5) 43 (84.3) 12 (23.5) 8 (15.7) 5 (9.8) 13 (25.5)
20 (39.2) 4 (7.8) 2 (3.9) 0 0 0 0
23 (43.4) 3 (5.7) 46 (86.8) 11 (20.8) 15 (28.3) 2 (3.8) 17 (32.1)
12 (22.6) 3 (5.7) 2 (3.8) 0 1 (1.8) 0 0
0.033* 0.957 >0.999
Values are number (percentage). * Statistically significant.
despite the small number of patients, there was a statistically significant difference of overall survival after 5 years’ observation favoring the triweekly cisplatin-based chemoradiation (HR 0.375, 95% CI 0.154–0.914, p = 0.03). Several clinical trials have investigated alternative cisplatin dose and dosing schedules other than weekly cisplatin-based chemoradiation (12, 13). However, most of the studies were small pilot studies and failed to show any survival benefit in comparison with the weekly 40-mg/m2 regimen. This study is the first to report that triweekly cisplatin 75-mg/m2 chemotherapy concurrent with radiotherapy is feasible and has better survival outcome compared with weekly cisplatin 40-mg/m2 chemotherapy, which is currently considered the standard regimen in locally advanced cervical cancer. A possible explanation of this study is that the higher peak concentration of cisplatin may be more critical to enhancing the synergy of chemoradiation than the weekly cisplatin exposure. Although the dose–response slope of cisplatin is not steep, the response of tumor to cisplatin has been shown to increase as the peak concentration of cisplatin increases up to 100 mg/m2 (14, 15). The high peak concentration of cisplatin may be more effective not only in enhancing the
synergy of chemoradiation but also in eliminating micrometastases, with resulting decrease of local failure and distant metastasis and improvement of survival eventually. Another explanation for this result is the possible role of cisplatin administration during brachytherapy in enhancing the chemoradiation effect. In the triweekly cisplatin regimen, the third cycle of cisplatin is usually administrated during or close to the brachytherapy. Considering the fact that almost 25% of total radiation dose is delivered during brachytherapy, the administration of cisplatin during or close to brachytherapy may be a reasonable way to increase the synergy of chemoradiation. However, because the third cycle of chemotherapy was delivered, on average, 10 days before brachytherapy in this study, we have no way of deducing what proportion of the cisplatin acted as a radiosensitizer during brachytherapy. In this study there was no difference of compliance between the triweekly and weekly cisplatin arms. Although the Grade 3 and 4 hematologic toxicities were more frequent in the weekly cisplatin arm, there was little treatment delay in either arm. Because the recovery time is shorter in the weekly cisplatin regimen than in the
Table 4. Pattern of recurrences in patients with locally advanced cervical cancer treated with cisplatin-based chemoradiation Variable Patients Recurrence Central Distant PALN Lung SCLN Peritoneal seeding Bone Brain
Weekly cisplatin
Triweekly cisplatin
51 (100) 15 (29.4) 2 (3.9) 13 (25.5) 7 (13.7) 1 (2.0) 3 (5.9) 1 (2.0)
53 (100) 13 (24.5) 4 (7.5) 9 (17.0) 4 (7.5) 1 (1.9) 3 (5.7) 0
1 (2.0) 0
0 1 (1.9)
p
0.510
Abbreviations: PALN = para-aortic lymph node; SCLN = scalene lymph node. Values are number (percentage).
Fig. Kaplan-Meier estimates of survival difference between weekly and triweekly cisplatin-based chemoradiation in patients with locally advanced cervical cancer.
Triweekly cisplatin-based CRT in cervical cancer d S.-Y. RYU et al.
triweekly cisplatin regimen, the high incidence of neutropenia in the weekly cisplatin regimen was to be expected and has already been reported (14, 16). However, the adverse effects were well tolerated and manageable in both arms (16, 17). From the point of view of the present study, weekly cisplatin 40 mg/m2 concurrent with radiotherapy can be a rather weak dose and dosing schedule to induce the synergy of chemoradiation consistently. The NCI Canada study that did not show survival gain with weekly cisplatin 40 mg/m2 concurrent with radiotherapy can be reexplained by the lack of synergy of chemoradiation with relatively weaker peak concentrations of cisplatin (11). Furthermore, a study that tried to increase compliance by reducing the cisplatin peak concentration was also never going to be able to enhance survival, also supporting our hypothesis (16). However, because this study was originally designed to compare the compliance of the two regimens but not the survival outcome, the superiority of triweekly cisplatin-based chemoradiation should be confirmed in a large-scale clinical trial.
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In this study, despite the survival difference, the recurrence rate (Table 4) and progression-free survival (data not shown) were almost identical in both arms. Although there is no statistically definitive evidence, we postulate that the discrepancy between progression-free survival and overall survival can be explained by the different pattern of recurrence between the two arms. In this study the number of distant metastases was higher in the weekly cisplatin arm than in the triweekly arm. The high number of distant recurrences, which cannot be cured by surgery or radiation, may be detrimental to overall survival in the weekly cisplatin arm and also support our hypothesis that the higher peak concentration of cisplatin can be more effective to eliminate micrometastasis. However, our study does not provide enough evidence for this issue; a prospective, randomized, Phase III clinical trial is in need. In conclusion, this study showed that triweekly cisplatin 75 mg/m2 concurrent with radiation is feasible and more effective than the conventional weekly cisplatin 40 mg/m2– based regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.
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