Abstract
Aim: To determine the effectiveness of postoperative concurrent daily low-dose cisplatin-based chemoradiation (CCRT) in patients with high-risk cervical cancer. Patients and Methods: Patients with stage IB, IIA, or IIB cervical cancer who were initially treated with radical hysterectomy and pelvic lymphadenectomy, and were proven to have pelvic lymph node metastasis (pN1) or microscopic involvement of the parametrium (pT2b), participated in this study. Thirty-one patients received adjuvant CCRT with daily low-dose (6-8.5 mg/m2) cisplatin (daily CCRT group). A non-randomised control group of 44 patients received adjuvant radiotherapy alone (RT group). Results: Overall survival (OS) at 4 years was 61% in the RT group and 91% in the daily CCRT group (p=0.004). Hazard ratio for poorer recurrence-free survival (RFS) in the RT group vs. the CCRT group was 7.9 (p=0.006). In the daily CCRT group, daily cisplatin chemotherapy was successfully completed in 27 out of 31 patients, although toxicity of grade ≥3 was found in 29% for neutropenia and 17% for gastrointestinal tract toxicity. Conclusion: Postoperative adjuvant CCRT with daily low-dose cisplatin improved RFS and OS of pT2b or pN1 patients, with acceptable compliance.
Radical hysterectomy with pelvic lymphadenectomy is preferred to radiation therapy as a primary therapy for patients with stage IB-IIA carcinoma of the uterine cervix. Postoperative adjuvant radiation therapy (RT) has been indicated for patients at high risk for recurrences, such as those with lymph node metastasis, invasion of the parametrium, or a positive surgical margin. Postoperative RT reduces local recurrence in patients with positive pelvic lymph nodes, but does not improve long-term survival (1-3). A new adjuvant therapy is therefore required.
In patients undergoing primary RT, the efficacy of concurrent cisplatin-based chemotherapy has been well established for the initial treatment of cervical cancer. The addition of concurrent chemotherapy (CCRT) improves prognosis of the cervical cancer when primary RT is indicated (4-7). It is, however, undetermined whether concurrent chemotherapy is beneficial in the postoperative adjuvant setting compared with radiation therapy alone. Only one relevant randomized controlled study has been published in which CCRT was compared with RT alone as a postoperative adjuvant therapy for stage IB-IIA high-risk patients (8). In that study, overall survival improved significantly for the CCRT group when compared with the RT group. Superiority of CCRT over RT alone as an adjuvant therapy was, however, not conclusive because more than half the dose of chemotherapy was given after the completion of RT. Moreover, it was not the number of concurrent cisplatin injections but the number of injections after the completion of radiation that was positively correlated with progression-free survival. Thus, the observed improvement in prognosis could be attributed to postradiation chemotherapy rather than concurrent chemotherapy. More research designed specifically to evaluate CCRT alone is necessary to conclude on the efficacy of CCRT over RT in the adjuvant setting.
The aim of this study was to investigate the efficacy of cisplatin as a radiation sensitiser in the adjuvant setting, specifically by use of daily-based administration of cisplatin.
Patients and Methods
Patients. From January 1989 to December 2007, 249 out of 302 consecutive patients with FIGO IB-IIB carcinoma of the uterine cervix were treated with radical hysterectomy and pelvic lymphadenectomy at the Chiba University Hospital (Chiba, Japan). The remaining 53 women were treated with primary RT or primary CCRT without selecting surgery, mostly depending on patient preference. Eligibility criteria for postoperative adjuvant therapy were: pelvic lymph node metastasis, parametrial invasion, a positive surgical margin, and deep stromal invasion. Seventy-five out of 212 patients who met these criteria were eventually included in this study. Forty-four out of the 75 patients were diagnosed before January 2000 and assigned to radiotherapy alone (RT group); irradiation was conducted at the National Institute of Radiological Sciences (Chiba, Japan). Thirty-one patients diagnosed after January 2000 were assigned to adjuvant concurrent chemoradiation (daily CCRT group), which was conducted at the Chiba University Hospital. The distribution of FIGO stage (IB: n=27, IIA: n=3, and IIB: n=45) was not statistically different between the daily CCRT group and the RT group. Of the 75 patients, 47 women had squamous cell carcinoma and 28 had adenocarcinoma or adenocarcinoma.
Radiotherapy. There was some difference in the RT protocols applied in the RT group and the daily CCRT group, since RT for the two groups was performed in different institutions.
The RT group underwent center splitter with brachytherapy, which was not done in the daily CCRT group. No attempt was made to irradiate para-aortic lymph nodes in the RT group.
The RT protocol for the daily CCRT group has been described elsewhere (9, 10). Briefly, RT consisted of 2 Gy per day on days 1 to 5 of each week, for a total 25 fractions (50 Gy). Eight patients with pN1 underwent extended field radiotherapy (EFRT), as described previously (9). EFRT therapy consisted of 1.8 to 2.0 Gy per day on days 1 to 5 of each week, for a total 25 fractions (45 Gy). In the RT group, 30 Gy of whole pelvic external beam radiotherapy (EBRT) was delivered, followed by 10 to 20 Gy of central shielding EBRT, up to a total EBRT of 40-50 Gy. An additional boost of 12 Gy of high-dose-rate intracavitary brachytherapy was performed for the vaginal stump at a 5-mm depth from the vaginal surface(11).
Chemotherapy. In the daily CCRT group (n=31), concurrent cisplatin was administered on a daily basis (6-8.5 mg/m2/day, five times a week) (12). In cases where serum creatinine was >1.5 mg/dl, cisplatin was cancelled until renal function recovered. Cisplatin was also withheld in any case of grade 3 toxicity (except nausea/vomiting) until toxicity regressed to less than grade 3. For grade 3 neutropenia, G-CSF was administered. The daily dose of cisplatin was reconstituted in 100 ml of normal saline. All patients received 5 mg of granisetron as an antiemetic, 1 h before cisplatin. Post-cisplatin hydration was performed with 1 l of normal saline intravenously given over 2 h.
Statistical analysis. Statistical analysis was performed using SPSS ver. 15 (SPSS Inc., Chicago, IL, USA). The χ2 test (Monte-Carlo method) and Fisher's exact test were used to compare clinicopathologic variables between the two groups. Recurrence-free survival (RFS) and overall survival (OS) were calculated by Kaplan Meier analysis and assessed by log-rank test. For RFS, Cox regression analyses were also performed. Probability values <0.05 were regarded as significant.
Results
Characteristics of patients are listed in Table I. Clinicopathologic parameters, including age, follow-up period, histology, clinical stage, presence of pelvic lymph node metastasis or parametrial invasion, and the size of the primary tumour did not differ significantly between the RT group and daily CCRT group. Planned chemotherapy was successfully performed without interruption in 77% (24/31) of the daily CCRT group. Cisplatin was withheld transiently (n=3) or permanently (n=4) in the remaining patients because of acute toxicity and continued planned irradiation. Mean dose of cisplatin was 182 mg/m2 (range; 124-224) in the daily CCRT group. All patients in both groups completed their RT regimens.
Site of recurrence. Within a median follow-up period of 48 months (range, 8-128 months), 4/31 (13%) patients in the daily CCRT group and 21/44 (48%) in the RT group developed recurrence (Table II). Pelvic recurrences were less frequent in the daily CCRT group (2/31) than in the RT group (8/44), but this difference failed to reach significance (p=0.18). In contrast, recurrence outside the pelvis was significantly reduced in the daily CCRT group (3/31, 10%) compared with that in RT group (14/44, 32%) (p<0.05). Detailed subgroup analysis showed that the difference between the two groups came from the difference in rates of distant organ metastasis (daily CCRT group: 1/31, 3%; RT group: 9/44, 20%) (p=0.04). In contrast, the difference in extrapelvic (para-aortic) lymph node metastasis was not significant (daily CCRT group: 2/31, 6%; RT group: 5/44, 11%) (p=0.69).
Eight CCRT patients who had pN1 tumors underwent EFRT. None of them developed para-aortic node recurrence, whereas 2 of 23 CCRT patients (12 with pN1 and 11 with pN0 disease) who did not undergo EFRT developed para-aortic node recurrence. The difference was, however, not statistically significant.
Survival analysis. Kaplan-Meier survival curves were compiled for RFS (Figure 1a) and OS (Figure 1b) for the daily CCRT and RT groups. The daily CCRT group had a statistically significant improvement in RFS and OS when compared with the RT group (p=0.004). Estimated 4-year RFS for CCRT patients was 85% vs. 53% for patients who underwent RT alone. Estimated 4-year OS was 91% for CCRT patients vs. 61% for RT patients. Figure 2 shows a comparison of the Kaplan-Meier RFS curves by cell type: CCRT patients showed improvement in RFS when compared with RT patients in both adenocarcinoma and squamous cell carcinoma subgroups. The difference between daily CCRT and RT groups was statistically significant for squamous cell carcinoma but not for adenocarcinoma.
Cox model analysis. To evaluate the prognostic impact of adjuvant therapies, the influence of clinicopathological and therapeutic parameters on survival outcome (RFS) was examined with Cox regression analysis (Table III). Among the six parameters, univariate analysis revealed that RT (vs. CCRT) as adjuvant therapy and FIGO stage II were significantly associated with risk of recurrence. Cox model analysis revealed that when compared with CCRT, RT had a hazard ratio of 7.9 (p=0.006) for poor RFS. In multivariate Cox regression analysis, adjuvant treatment (RT) and FIGO stage II were again extracted as independent predictors of poor prognosis.
Toxicity. Hematological toxicity was common as an acute toxicity in the daily CCRT group. As shown in Table IV, grade 3-4 leukopenia was recorded in 17/31 cases of CCRT group, but was not seen in any of the RT group. Grade 3-4 neutropenia was observed only in the daily CCRT group (n=9); 7 of these patients needed G-CSF injections. Grade 3-4 thrombocytopenia was not observed in any group. Although non-haematological toxicity was again common in the daily CCRT group compared with the RT group, severe (grade 4) toxicity was not recorded. Treatment-related death did not occur. Regarding late radiation toxicity, ileus requiring surgical intervention was identified in 3 cases in the daily CCRT group and 2 cases in the RT group.
Discussion
In the present study, it was demonstrated that postoperative CCRT with daily low-dose cisplatin is safe, and that it significantly improves the prognosis of patients with pT2b or pN1 cervical cancer compared with RT as adjuvant therapy.
The published literature contains only one randomized controlled study in which efficacy was compared between CCRT and RT as a postoperative adjuvant therapy for stage IB-IIA cervical cancer (8). Patients who were initially treated with radical hysterectomy and pelvic lymphadenectomy, and had positive pelvic lymph nodes, positive margins or microscopic involvement of the parametrium, were assigned randomly to the CCRT or RT group. RT consisted of 49.3 Gy in 29 fractions to a standard pelvic field, and chemotherapy consisted of bolus cisplatin (70 mg/m2) and a 96-hour infusion of fluorouracil (1000 mg/m2/day) every 3 weeks for 4 courses; accordingly, only the initial one or two chemotherapy cycles were concurrent with radiation and the following cycles were conducted after the completion of irradiation (8). The CCRT group showed favourable progression-free and OS when compared with RT alone and the authors concluded that addition of concurrent chemotherapy to radiation significantly improves prognosis (8). Other controlled studies have similarly described the efficacy of additional cycles of chemotherapy after RT (13, 14). In the present study, cisplatin was used on a daily basis concurrently with radiation fractions, and chemotherapy was administered only during radiation therapy and not after the completion of radiation.
It has been postulated that CCRT acts systemically as well as locally as a radiation sensitizer. In cervical cancer, it has been established that CCRT decreases in-field recurrence, whereas systemic benefits of the chemotherapy component of CCRT remain controversial (15). For example, Peters et al. (8) reported that, among 243 patients with stage IA2-IIA cervical cancer, the local recurrence rate in the adjuvant CCRT arm (8.7%) was lower than that in the radiation-only arm (21.6%) and that the distant recurrence rate was slightly lower in the CCRT arm (10.2%) than in the radiation-only arm (15.5%). However, this difference was not statistically significant. In contrast, Shibata et al. (14) reported that, among 87 patients with stage IB-IIB cervical cancer, the local recurrence rate in the adjuvant CCRT arm (3/37, 8%) was lower than that in the radiation-only arm (10/52, 19%) and the distant recurrence rate was significantly lower in the CCRT arm (2/37, 5%) than in the radiation-only arm (13/52, 25%). The benefit of adjuvant CCRT on distant recurrence was statistically significant in the present study. One possible explanation is the differences in patient background: The present study included more advanced cases (60% were stage IIB) than study of the Peters et al. (8), and therefore the distant recurrence rate was as high as 32% for the RT-only group, which could have facilitated the detection of the difference between both groups. In fact, the distant recurrence rate in the CCRT group of the present study was comparable to that reported by Peters et al. (8), while that of the RT group was more than double. The significant reduction found in metastasis to distant viscera suggests that CCRT reduced hematogenous spread.
In the present study, low-dose cisplatin based chemotherapy was employed instead of weekly or tri-weekly administration protocols that have been widely used. As previously reported, daily low-dose administration may be advantageous over weekly administration (12). For example, a weekly cisplatin dose of 40 mg/m2 caused grade 3 or 4 hematological side effects in 60% of patients and eventually only 30% of patients received planned chemotherapy with mean doses of 168 mg/m2 (12). Watanabe et al. (16) also reported similar toxicity and restricted compliance for weekly cisplatin with mean doses of 163 mg/m2. Completion rates (>87%) and mean cisplatin doses (182 mg/m2) of the present study seem to be improved compared to these weekly administrations. The fractionated administration of low-dose cisplatin may be also beneficial for highly compromised patients or ambulatory patients, due to slowing onset of acute toxicity.
In conclusion, the present study confirmed that adjuvant CCRT is beneficial to control locoregional lesion and distant organ metastasis in high-risk patients with pT2b or pN1 disease. Low-dose daily cisplatin regimen had relatively little toxicity and was an effective form of chemotherapy for CCRT.
- Received December 3, 2009.
- Revision received March 31, 2010.
- Accepted March 31, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved