Results of a phase II trial of concurrent chemoradiation in the treatment of locally advanced carcinoma of uterine cervix: an e

ARTICLE

Auteur(s) :, Elantholi P Saibishkumar, Firuza D Patel, Suresh C Sharma

Department of radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

Materials and methods

Patients

Teletherapy

Chemotherapy

Brachytherapy

High dose rate (HDR) brachytherapy was delivered by microselectron (Iridium-192) remote controlled brachy unit. Dose rate was approximately > 0.5Gy/minute. Fifty perecent correction was applied to make it equivalent to classical LDR. Two weekly sessions of 9 Gy each were given with a gap of one week after EBRT. Treatment profile is given in table 2( Table 2 ). All intracavitary applications were done in operation theatre under general/spinal anesthesia. Orthogonal X-rays were taken in simulator after the procedure for pelvic dosimetry.
Table 2 Treatment profile: CRT(n = 57), RT(n = 895)

Follow up

Statistical analysis

Results

OS at 5 years was 45.6 % with a mean of 51 months. DFS at 5 year was 43.9 % with a mean of 46 months. Overall pelvic control rate was 57.9 % with mean of 54 months. We analyzed the relation of various prognostic factors like stage, age, EBRT duration, Overall treatment time (OTT), response to EBRT, and use of ICRT with outcomes like OS, DFS and pelvic control (table 3( Table 3 )). Use of ICRT instead of supp RT was the only factor, which positively affected pelvic control and DFS in univariate analysis. But for OS, this factor was not significant. None of these factors were significant in multivariate analysis for any outcomes.

A non-randomized comparison of CRT was done with the same subset of patients (stage IIB-IIIB, bulky disease) treated with RT alone (895 pts) during the same period (demographic and treatment profiles are illustrated in tables 1 and 2). Follow up period of these patients ranged from 3months to 93 months with a mean of 37 months. Ninety patients were lost to follow up. Five year OS, DFS, pelvic control rates were 47.4 %, 45.5 % and 61.3% respectively which were not significantly different from those treated with CRT (45.6 %, 43.9 % and 57.9 % respectively). Comparison of OS and DFS are illustrated in figures. 1 and 2. ICRT was possible in 52/55 patients (91.2 %) in CRT compared to 716/895 patients (80 %) in RT alone arm (p = 0.05).

Overall 18 patients (31.6 %) had severe acute toxicities (grade 3 ≥ according to RTOG criteria) in CRT protocol. Details are as follows: grade 3 skin reactions in perineum and gluteal region in 2 patients (3.5 %), grade 3 lower gastrointestinal (GI) toxicity in 5 patients (8.8 %), grade 3 hematological toxicity in 3 patients (5.3 %), grade 4 hematological toxicity in 1 patient (1.8 %) and grade 3 upper GI toxicity in 7 patients (12.3 %). Compared to RT alone arm (11.6 %), acute toxicities were significantly higher in CRT arm (p < 0.001). This difference was more apparent when acute hematological/upper GI toxicities were compared; 19.3 % in CRT versus 0.3 % in RT alone (p < 0.001). Overall 28 % patients in CRT protocol had breaks in EBRT schedule compared to 10 % in radiation alone group, but the median OTT were not significantly different (51 days and 53 days respectively).

Late toxicities (RTOG criteria) were evaluated in detail. Overall late toxicities were 22.8 % in rectum, 7 % in bladder, 8.8 % in small intestine and 21 % in skin. Grade 3-4 proctitis was documented only in 1 patient. In skin, bladder and small intestine no grade 3-4 toxicities were seen. Vaginal adhesions were seen in 31.6 % of patients and stenosis in 40.4% of patients. No deaths were encountered due to treatment toxicity. The incidence of overall rectal toxicities were significantly higher in CRT arm (22.8 %) compared to radiation alone (12.5 %) p = 0.01. But the incidence of severe late toxicities (≥ grade 3) were similar in both arms. Comparisons of both arms in terms of late toxicities are given in table 4( Table 4 ).
Table 3 Prognostic factors versus outcome (5yrs) in CRT arm

Discussion

The recruitment was very less compared to the number of patients we treat routinely with RT mainly due to financial reasons and presentation with abnormal or borderline renal function. Also, as the definitive evidence favoring CRT was not available till late 1999, we were not able to advise patients strongly for CRT. The compliance of our patients to chemotherapy were also low evidenced by the fact that only around 80 % received 4 or more cycles of chemotherapy even though 90 % could complete the planned radiation schedule.

We tried to compare the results of CRT with RT alone, even though there is gross disparity in the number of patients in each group, to assess the benefits/risks of CRT (paper on results of RT alone got accepted for publication in International Journal of Gynecological Cancer [7]). Our results with CRT (5 yrs OS of 50 % in stage IIB and 43.6 % in IIIB and 5 yrs DFS of 50 % in stage IIB and 43.6 % in IIIB) were not significantly different compared to our own patients treated with RT alone (5 yrs OS of 61 % in stage IIB and 44.2 % in IIIB and 5 yrs DFS of 59.6 % in stage IIB and 42.1 % in IIIB) and the results from literature. Coia et al. (patterns of care study from USA) has documented 5yrs DFS of 56 % in stage II and 33 % in stage III [8]. In the patterns of care study from Canada by Fyles et al., the 5 yrs DFS were 61 % and 41 % in stage II and III respectively [9]. The best results of RT alone in cancer cervix are obtained by Horiot et al. with 5 yrs OS of 76 % in stage IIB and 50 % in stage IIIB [10]. Recent study by Ferrigno et al. [11] also have obtained impressive resuts with RT alone in cancer cervix (5 yrs OS 78 % in stage II and 46% in stage III).Our results with RT alone and CRT are acceptable considering the fact that all our patients had bulky disease. However our results are inferior to the results of CRT arms of recent major randomized trials with cisplatin based regimens [2-4, 12]. Whitney et al. [2] conducted a randomized study on 368 patients with carcinoma cervix belonging to stage IIB-IVA. One hundred and seventy seven patients received 5FU and cisplatin, and 191 patients received hydroxyurea along with RT (considered as standard arm for comparison). All patients underwent surgical sampling for paraaortic nodes and positive cases were excluded from this study. Survival at 8.7 years was 55 % in cisplatin + 5FU arm as compared to 43 % in hydroxyurea arm (p = 0.01). Rose et al. [3] carried out a 3 arm randomized trial of RT in combination with 3 different chemotherapy regimes i.e. cisplatin alone, cisplatin + 5FU + hydroxyurea, or hydroxyurea alone. All patients underwent surgical sampling for paraaortic evaluation and positive cases were excluded from this study. This analysis included 526 patients. Both the groups that received cisplatin had a higher rate of progression free survival than the group receiving hydroxyurea alone (p < 0.001). Overall survival rate was significantly higher in the groups that received cisplatin (3 yrs OS 66.5 % for cisplatin alone group and 67.8 % for cisplatin, 5FU, hydroxyurea group) than the hydroxyurea arm alone (3 yrs OS 48. 6%) with relative risks of death being 0.61 and 0.58 respectively. Treatment with cisplatin alone was less toxic than treatment with 3 drug regimen. They recommended cisplatin as a standard for a concomitant protocol in locally advanced cervical cancer. Both the trials by Whitney et al. and Rose et al. did not have a proper RT alone arm as control group as they have taken RT with hydroxyurea as control arm. Morris et al. [4] compared the effect of pelvic and prophylactic para aortic field RT with pelvic RT + concurrent chemotherapy (cisplatin and 5FU) in 388 women of advanced cervical cancer. Paraaortic lymph nodes were evaluated by bipedal lymphangiography (75% cases) or retroperitoneal exploration (25 % cases) and positive cases were excluded. One hundred and ninety three patients were assigned to each group. OS and DFS at 5 years were 73% and 67% in the combined group and 58 % and 40 % in RT alone arm (p < 0.004).This trial also have taken extended field radiation as a control group rather than standard pelvic field. Pearcey et al. [12] is the only one who conducted a prospective randomized trial comparing radiotherapy + weekly cisplatin with standard pelvic RT alone in 259 patients (stages IB2-IVA). Surgical staging was not considered mandatory and CECT scan was used to assess pelvic and paraaortic nodes and positive paraaortic node cases were excluded from this study. No significant difference was seen in DFS (60 % for CRT versus 56 % for RT) and OS (66 % for CRT versus 58 % for RT) at 5 years. This trial could not find any benefit of CRT over RT alone. Wong et al. [13] also found CRT as a superior modality than RT alone in terms of 5 yrs DFS (83 % versus 72 %, p = 0.03) and OS (80 % versus 68 %, p = 0.04) in his randomized trial but he has used epirubicin as chemotherapeutic agent both in concurrent and adjuvant fashion. In this trial also CT scans were used to rule out paraaortic nodes and nearly 4/5th of patients belonged to stages up to IIB.

The difference in results is mainly due to the stringent inclusion criteria followed in these trials. In trials by Whitney et al., Morris et al. and Rose et al. [2-4], 60 % or more of patients belonged to stage I-II and in trial by Pearcey et al. [12] nearly 50 % belonged to stages up to IIB whereas our patients were predominantly stage IIIB (68.5 %) and all had bulky disease. Moreover in trials by Whitney et al. and Rose et al. [2, 4], they excluded patients if the paraaortic lymph nodes on exploratory laprotomy were found positive for malignancy. In Morris et al. study [3], only 25 % patients underwent lymph node sampling but rest of the patients underwent Lymphangiograms. In studies by Pearcey et al. and Wong et al. [12, 13] also CT scans were done routinely to assess para aortic nodes. In our study USG abdomen was mainly used (~ 80 %, 45/57) to evaluate para aortic nodal status, which is an inferior modality (sensitivity 19%) to lymphangiography (sensitivity 79 %) and CT scans (sensitivity 34 %) [14]. Many of our patients must have had para aortic nodes that are not picked up by USG abdomen which added to our inferior results. Metaanalysis by Green et al. suggests that the benefit of CRT is more apparent in early stages and when the disease is confined to pelvis. Benefit of CRT in the presence of paraaortic nodes is not very clear [15]. Recent randomized trial by Saad et al. comparing extended field radiation with or without concurrent cisplatin in cancer cervix patients with paraaortic nodal metastasis revealed that 3 yrs disease-specific survival was 81.8 % in CRT arm versus 30 % in RT arm. But this was a small study with only 21 patients and a short follow up of 26 months [16].

Randomized trial by Pearcey et al. [12] could not find the benefit of concurrent CRT may be because the patient selection was less stringent compared to other randomized studies. In our set up also it is difficult to carry out extensive work up like laparotomy/lymphangiograms and CT scans due to financial constraints. Another reason for not finding any benefit with CRT may be the lesser doses of cisplatin we have given. Our cumulative dose of cisplatin ranged from 140-175 mg/m² that too only received by around 80 % of patients. In all the trials, which showed a benefit of CRT, the cumulative dose of cisplatin if used alone ranged from 225-240 mg/m²[2-4]. Pearcey et al. [12] has used cisplatin alone in doses of 200 mg/m² (cumulative) and they couldn’t find the benefit of CRT. Small sample size in our study and limitations of a non randomized comparison must also have contributed for the lack of benefit of CRT in our study.

We could do ICRT in nearly 90 % of patients and this was the only factor, which had an impact in pelvic control and DFS in univariate analysis. The supp RT results were inferior to ICRT gp that agree well with literature [17]. One important observation is that more number of patients were suitable for ICRT in CRT arm compared to RT alone arm.

Even though the acute toxicities were high in CRT protocol compared to radiation alone group, they were mild and manageable. Majority of them had vomiting and leucopenia, which were infrequent in radiation alone arm. Compared to the randomized CRT trials using cisplatin [2-6] we had lesser hematological complications (16-20 % versus 7 %), which is due to the lesser doses of cisplatin we have used. Breaks during EBRT were more frequent in CRT group, but were not long enough to make an impact in OTT (51 days in CRT arm versus 53 days in RT arm) .

Incidence of late toxicities was comparable with literature [10, 18]. Even though mild in severity, incidence of subcutaneous fibrosis in our patients was found to be higher compared to other studies [11] due to the use of AP/PA technique as well as low energy machines. Incidence of overall rectal toxicity was higher in CRT group compared to RT alone but grade 3-4 toxicities were similar. Few phase II trials have shown an increase in late rectal toxicities by CRT [19, 20] but not documented in phase III trials so far [2, 3, 12].

In India, majority of patients present in late stages with bulky disease compromised renal function and poor nutritional status. Most of them belong to poor socioeconomic class who cannot afford costly investigations and chemotherapy. Hence even now chemoradiation is not routinely used in Indian scenario. There is a trend to use chemoradiation after the results of randomized trials [2-6] proving superiority of chemoradiation over radiation alone. An ongoing prospective trial from India randomized 101 cases of carcinoma cervix (FIGO stages II to IV) to either RT alone (n = 49) or CRT (n = 52). Whole pelvic RT (identical in both arms, 50 Gy/25 fractions/5 weeks) was followed 1 week later by brachytherapy of 3 fractions of 6Gy HDR to point ‘A’ spaced a week apart. Chemotherapy consisted of weekly cisplatin at 35 mg/m². Radiotherapy compliance was seen in 96 % cases and scheduled 5 cycles of chemotherapy could be delivered to 82 % cases. Interim analysis showed that acute upper gastrointestinal toxicity (≥ grade II RTOG toxicity) were significantly higher in the CRT arm compared to RT alone arm (24 % versus 8 %, χ² p = 0.00) as were grade II hematological complications (24 % versus 11%, χ², p = 0.01). Pelvic control rate was similar for the RT and CRT groups at 71 % and 69 % at 3 years respectively; distant disease free survival 64 % and 58 % at 3 years, and overall survival identical at 65 % at 3 years respectively (all p values non-significant)[21]. Another prospective randomized study by Singh et al. from India conducted in cervical cancer (stage IIB-IIIB) comparing CRT using cisplatin (50 patients) versus RT alone (46 patients) found that OS at 3 yrs were 74.4 % and 56.1 % for CRT and RT alone respectively. There was an increase in early side-effects in the CRT group leading treatment delays in 16.3 % patients but no significant increase in the late treatment toxicities [22]. In our study also 28 % of patients had breaks in EBRT schedule even though breaks were too small to make any impact in OTT. Careful selection of patients who will tolerate higher doses of chemotherapy well and utmost care to deal the toxicities without producing undue prolongation of treatment time are required to obtain the benefit of CRT. RT still remains a valid option in developing countries like India.

Conclusion

Acknowledgements

References

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