Expedience of conventional radiotherapy in locally advanced cervix cancer: A retrospective analysis

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1 Original Article Expedience of conventional radiotherapy in locally advanced cervix cancer: A retrospective analysis Prakash Bhagat, Sanjoy Roy, Debarshi Lahiri, Tapas Maji, D. K. Ray, Jaydip Biswas, P. Chaudhuri Department of Radiation Oncology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India Address for the Correspondence: Dr. Sanjoy Roy, C/56, Survey Park, Kolkata , West Bengal, India. E mail: sanjoyroy56@gmail.com Access this article online Website: DOI: / Quick response code: Abstract Objective: Analysis was done to assess the implications of total radiation treatment duration towards locally advanced cervical cancer. Methods: A comparative study was conducted in CNCI, Kolkata. A total of 38 patients were studied with interdigited brachyttherapy during the course of conventional teleradiotherapy and they were compared to a total of 39 patients with conventional sequential teletherapy and brachytherapy. Results: In the experimental arm all the patients had complete response to treatment whereas, 24 patients (85.7%) in the conventional arm had complete response [P = 0.08]. At the last follow up 28 patients (73.68%) in the study arm and 17 patients (43.58%) in the control arm were free of disease. The failure rate in the conventional control arm was significantly higher [P = 0.035]. Test of proportion derived from data also showed that the proportion of patients with no evidence of disease at the time of last follow-up was significantly higher in the study arm compared to the control arm [P < 0.05] and the proportion of patients with persistent disease was significantly less in the stuwdy arm compared to the control arm [P < 0.05]. The probability of disease-free survival in percentage according to the curve at the time of median follow-up was approximately 70% for study arm and 60% for control arm [log-rank test, P = ]. Conclusion: we should hence minimize treatment time and avoid any planned or unplanned interruptions or delays by timely integration of external beam and intra-cavitary irradiation that may yield a better local control in locally advanced cervical cancer. Key words: Brachytherapy, cervix cancer, radiotherapy, treatment duration INTRODUCTION An estimated 371,000 new cases of invasive cervical cancer are diagnosed worldwide each year, representing 10% of all cancers in women. In developing countries, cervical cancer has been the most frequent neoplastic disease among women especially in a rural area until date. [1,2] Worldwide; cervical cancer is the fifth most frequent cause of cancer deaths in women, causing about 9 deaths per 100,000/year. In Southeast Asia, cancer cervix has been a big challenge since long due to poor socioeconomic reason. Age adjusted incidence rates of cervical cancer range from 19 to 44 per 100,000 women in various cancer registries in India. It has been estimated that about 120,000 women in India newly develop cervical cancer and approximately 80,000 die of the disease every year. [3] Nearly 80% of cervical cancers are diagnosed in our country at stage III or above when there is very little scope of definitive therapy. Locally advanced cervical cancer, that is, stages IIB; III and IVA are treated with radiotherapy alone or with a combination of chemotherapy and radiotherapy. Radiotherapy duration could be the most independent treatment related prognostic factor in cervical cancer. It has been suggested that the mechanism for patients with longer treatment durations exhibiting a greater risk of local relapse could be the accelerated repopulation of tumor clonogens surviving a course of radiotherapy. Though concomitant chemo radiotherapy is currently recommended as the standard treatment protocol for advanced stages of cervical cancer on the basis of results of some randomized trials as per 85 Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2

2 National Cancer Institute (NCI) alert, [4 8] in our institution, like many other institutions in India locally advanced cervical cancer patients had been treated with radiotherapy alone instead of concomitant chemo radiotherapy in early part of first decades of this century. This is due to the following reasons: Nearly 90% of our advanced cervical cancer patients present in stage IIIB. The benefit of concomitant chemo radiotherapy in stage IIIB cancer of the cervix is not yet convincingly proved [9] Poor in nutritional status to tolerate chemo radiotherapy for the full course Non affordability to the cost of chemotherapy and supportive therapy such as granulocyte colony stimulating factor, etc. Chemotherapy purposefully was not included in this study due to its potential to aggravate the toxicities of concomitant telebrachytherapy and affect the outcome. It is recommended that radiation therapy for cervical cancer patients should be delivered in the shortest possible overall time. [10] External beam radiotherapy (EBRT) if inter phased with intracavitary radiotherapy (ICRT), the total duration of treatment can be drastically reduced. The total duration of treatment in the conventional radiation protocol of EBRT followed by ICRT is around 9 weeks. If ICRT is given concomitantly with EBRT, the duration can be brought down to approximately 5 weeks. From radiobiological point of view, the second approach is likely to be more effective, and there is ample evidence that this approach is radiobiologically acceptable. The rational for using concomitant EBRT and ICRT is to shorten the overall duration of treatment by radiotherapy. If the surviving tumor clonogen doubled every 3 days during the latter 3 weeks of treatment, as they do, for example in irradiated squamous cell carcinomas of head and neck [11 13] the effective number of cells to be eradicated would increase by a factor 27. This roughly 100 fold increase in cell number is equivalent, for example, to about a 2 or even 3 unit increase in T stage. Lanciano et al. had analyzed an increase in actuarial 4 year infield recurrence from 5% to 20% occurred when total treatment time increased from <6 weeks to 10+ weeks (P = ) as well as significantly decreased survival too (P = ). [14] Ferrigno et al. [15] performed a retrospective analysis of 138 patients to report results of patients with cancer cervix treated by EBRT and interdigitated high dose rate ICRT. Overall 5 year survival and local control rates were 81.5% and 84% versus 44.6% and 53% for patients with treatment duration up to 50 days and those with treatment duration >50 days, respectively. Objectives The two therapeutic modalities were compared in terms of the following parameters as response to treatment, acute toxicities, disease free survival, and long term complications. MATERIALS AND METHODS The retrospective case control study was performed at Chittaranjan NCI, Kolkata from September 2005 to May Patients with histologically confirmed cervical cancer belonging to stage IIB to IVA having minimum Karnofsky Performance Score of 70 were assigned to Study arm and Control arm (natural selection). The study compared concomitant EBRT and ICRT (Study Arm) with sequential EBRT, followed by ICRT (Control Arm). Treatment protocol for study arm (concomitant external beam radiotherapy and intracavitary radiation therapy) Patients received external beam radiation to the whole pelvis up to a total dose of 50 Gy, delivered in 25 fractions over 5 weeks. Teletherapy was delivered to the pelvis by AnteroPosterior PosteroAnterior (AP PA) fields by Tele cobalt ( 60 Co). The borders for the AP PA fields were superiorly the junction of the L 4 L 5 vertebra, inferiorly 1 cm below the lower border of obturator foramen and laterally 1 cm lateral to the pelvic wall. If the inter field distance (IFD) was >18 cm, two lateral fields were added in spite of two AP PA fields only. The superior and inferior borders for the lateral fields were the same as for the AP PA fields. The anterior border was at the level of the symphysis pubis and the posterior border at the junction of the S 2 S 3 vertebral body. High dose rate brachytherapy was delivered with Ir 192 point source by remote after loading system under short anesthesia. Applicators used were intra uterine tandems (IUT) and rings of various sizes and angles selected according to the patient s geometry. Bladder was marked by putting a Foley s catheter and inflating the balloon with 7 ml of radio opaque dye. Rectum was marked by putting into it a radio opaque flexible marker. Simulation was done using Mecaserto Axsim II simulator to individualize each patient s treatment. Doses to bladder point, rectal point, and Point A were defined according to ICRU 38 recommendations. 60 Simulation and planning was carried out on the day of each ICRT application. During the first 2 weeks of therapy, EBRT was administered only and was given from Monday to Friday. From 3 rd week onwards, ICRT was administered and was given on Thursday and EBRT was given from Monday to Wednesday and on Friday and Saturday. Second and third fractions of ICRT were given during the 4 th and 5 th week of treatment with EBRT. Dose of radiation given by ICRT was 7 Gy per fraction weekly for 3 such fractions. Treatment protocol for control arm (sequential external beam radiotherapy followed by intracavitary radiotherapy) Patients received external beam radiation to the whole pelvis up to a total dose of 50 Gy, delivered in 25 fractions over 5 weeks. The machines, field sizes and other details were same as followed in the study arm. In this arm, intracavitary brachytherapy was started 2 weeks after the completion of teletherapy. The dose and Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2 86

3 procedure of brachytherapy was same as described in the study arm. Here, the average duration for completion of therapy came to about 9 weeks. During radiotherapy, patients were assessed weekly, and complications were graded according to the Radiation Therapy Oncology Group Cancer Therapy Evaluation Program 8 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS. [16] Follow up After the completion of therapy, patients were evaluated 2 weeks and 6 weeks after the completion of therapy and 3 monthly thereafter. Patients response was classified as per RACIST criteria. If any growth was found in the cervix on follow up, its size and extent were noted with obtainment of a punch biopsy and time calculation was noted. Total duration of treatment included both the external beam and intracavitary components of therapy and was calculated in calendar days starting from the day of first fraction of EBRT. RESULTS Intracavitary radiotherapy inter phased with EBRT was delivered to 38 patients (Study Group) and ICRT following EBRT was delivered to 39 patients (Control Group). The mean age of the patients was 50.1 ± 9.8 years. The median age at marriage of the cervical cancer patients was 16 year, and the median age at first childbirth was 19 year. The mean parity was 3.9 ± 1.9. In the study group, 55.3% were postmenopausal and in the control group the proportion was 66.7% (P = 0.22). Majority of the patients in the study were in stage IIIB (74.0%), and the rest were in stage IIB (26.0%) (P = 0.41). The most common histopathological diagnosis was squamous cell carcinoma in either of the groups (P = 0.60). The morphological characteristics of the tumors did not have any significant difference (P = 0.59). Pretreatment evaluation of the patients The pretreatment performance status was similar (P = 0.60). The pretreatment mean hemoglobin levels of the patients in the study group and in the control group were 11.1 ± 1.2 g/dl and 11.2 ± 1.0 g/dl, respectively, (P = 0.69). On ultra sonography, 11.7% of the total patients had significantly enlarged pelvic lymph nodes. The percentage of patients having enlarged pelvic nodes was similar in the study group (10.5%) and the control group (12.8%). Radiation therapy details Majority of the patients in either treatment group completed the EBRT within 6 weeks. Treatment was completed as per protocol in 34 patients of the study group and 31 patients in the control group. In the study group, 3 patients had incomplete EBRT and no ICRT at all. In the same group, 1 patient had incomplete EBRT and only a single insertion of ICRT. In the control group, 6 patients received incomplete EBRT and no ICRT. In the same group, 1 patient completed EBRT, but received no ICRT and 1 patient received 2 insertions of ICRT after complete EBRT (P = 0.50). The most commonly used IFD was cm in either treatment group (P = 0.19). Mean dose of radiation given by EBRT till the time of first ICRT insertion to patients in the study arm was Gy (range Gy), and the mean dose of radiation given by EBRT till the time of 2 nd and 3 rd ICRT were Gy (range Gy) and Gy (range Gy), respectively. ICRT was given to all patients in the control arm after the completion of EBRT, and thus they had received a full dose of 50 Gy with EBRT before ICRT was given. Overall 3 patients in the study group and 7 patients in the control group did not receive any ICRT. Majority of the patients in either of the groups had ICRT using an IUT of size 60 mm. Rest of the patients were treated using the IUT of size 40 mm. The details of size of IUT used are shown in Table 1 (P = 0.68). The vaginal Table 1: Uterine tandem size used IUT size Study Control Total 40 mm mm Total IUT: Intra uterine tandem Table 2: Vaginal ring used Ring size Study Control Total 26 mm mm Total Table 3: Radiation dose to the urinary bladder Bladder dose (percentage Study Control Total of dose to point A) < and above Total Table 4: Radiation dose to the rectum Rectal dose (percentage Study Control Total of dose to point A) < Total Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2

4 ring size used depended on the pliability of the vagina and the space available for insertion. The most commonly used size was 30 mm, followed by 26 mm. The details of the ring size used are given in Table 2 (P = 0.40). The calculated radiation dose to the bladder mucosa was <80% of the dose to point A in 76.4% of patients (77.8% in study group and 75% in control group) shown in Table 3 (P = 0.37). The calculated radiation dose to the rectal mucosa was < 80% of dose to point A in 98.2% patients (100.0% in study group and 96.4% in the control group) shown in (P = 0.38) Table 4. The duration of therapy was calculated in days starting from the day of first fraction of EBRT till the last dose of radiation (EBRT or ICRT as applicable) and was converted to weeks. Due to concomitant use of EBRT and ICRT nearly all patients in the study group could complete therapy within 7 weeks (33/34; 97%). In the control Table 5: Duration of treatment arm wise Duration of therapy Study Control Total 4 weeks weeks weeks weeks weeks weeks weeks weeks weeks Total patients in study group and 8 patients in the control group did not complete treatment Table 6: Treatment interruption arm wise Duration of interruption Study Control Total 1-5 days days days days days Total group due to application of ICRT after completion of EBRT the proportion of patients completing radiation therapy within 7 weeks was significantly less (2/33; 6.1%) (P = 0.00) [Table 5]. Treatment was interrupted in 9 patients of the study group and 10 patients of the control group. In the majority of the patients, the interruption did not exceed 10 days (P = 0.36) [Table 6]. The level of difficulty of insertion was noted during each ICRT application and was graded according to a scale of 1 5 (1 = very easy, no difficulty at all; 5 = extremely difficult, procedure abandoned). During the first insertion level 3 or worse difficulty was encountered in 31 patients in the study group (88.6%) and 26 patients in the control group (81.3%) (P = 0.61). During second insertion same level of difficulty (level 3 or worse) was encountered in 11 patients (32.4%) and 4 patients (12.5%) in the study group and the control group, respectively, (P = 0.05). The number of patients in whom level 3 or worse difficulty was observed came down to 3 (8.8%) in study group and 0 in control group during the 3 rd insertion of ICRT (P = 0.09) [Table 7]. The recruited patients were periodically examined and investigated for the occurrence of any acute toxicity. Intestinal obstruction developed in two patients (1 in each arm of the study) after 5 days and 8 days of starting radiation, respectively. The intestinal obstruction was attributed to the disease process rather than to the treatment and was not considered as toxicity. Both these patients died within a week of diagnosis of intestinal obstruction. The most commonly encountered toxicity was drop in hemoglobin (P = 0.80). Compared to anemia the other hematological toxicity, leucopenia was observed much less frequently (P = 0.51). Grade 1 or 2 anorexia was observed in a significant number of patients treated by either modality (P = 0.41). Radiation induced dermatitis (grade 2 3) was observed more frequently in the study group (P = 0.58). The other frequently encountered dermatological toxicity was the pruritus that was mild in most of the cases and was similar in both the arms (P = 0.09). Dysuria and urinary frequency and urgency were the common bladder related toxicities encountered (For Table 7: Levels of difficulty encountered during different ICRT applications Study group Control group Level 1 Level 2 Level 3 Level 4 Level 5 Total Level 1 Level 2 Level 3 Level 4 Level 5 Total 1 st ICRT nd ICRT rd ICRT ICRT: Intra cavitary radiotherapy Table 8: Arm wise comparison of complications Symptom Study (n=33) Control (n=28) Grade 1 (%) Grade 2 (%) Grade 3 Total (%) Grade 1 (%) Grade 2 (%) Grade 3 Total (%) Proctitis 2 (6) 1 (3) 0 3 (9) 3 (11) 1 (4) 0 4 (14) Diarrhoea 3 (9) 2 (6) 0 5 (15) 4 (14) 3 (11) 0 7 (25) Bladder 3 (9) 1 (3) 0 4 (12) 2 (7) 1 (4) 0 3 (11) Vaginal stenosis 2 (6) 1 (3) 0 3 (9) 4 (14) 2 (7) 0 6 (21) Genital edema 4 (12) 1 (3) 0 5 (15) 2 (7) 1 (4) 0 3 (11) Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2 88

5 dysuria P = For frequency/urgency: P =0.12). Among the gastro intestinal toxicities, diarrhea and proctitis were observed in both the groups (For diarrhea: P = For Proctitis: P =0.92) [Table 8]. Follow up after therapy The patients were followed up at 2 weeks, 6 weeks and subsequently every 3 months after completion of radiation therapy. The median duration of follow up for the patients completing therapy (n = 65) was 312 days from the initiation of treatment (minimum 75 days; maximum 541 days). Of the total 77 patients recruited in the study, 65 completed treatments. Of them, 61 patients came for at least one follow up visit and in these patients response to treatment could be evaluated. Treatment could not be completed only in 2 patients (1 in each arm) due to intestinal obstruction developing within 10 days of initiation of treatment. It is likely that the complication was due to advanced disease process rather than due to therapy. In the study arm, all the patients had a complete response to treatment. In contrast to that, 24 patients (85.7%) in the control arm had complete response (P = 0.08). The late complications (complications observed after 180 days of starting of treatment) are listed in Table 8. In the study group, there were total 20 instances of late complications where in the control group was 23. At the last follow up, 28 patients in the study arm and 17 patients in the control arm were free of disease. There were 2 pelvic recurrences and 2 metastatic diseases in the study arm. The corresponding values in the control arm were 6 and 0, respectively. One patient in study arm and 1 patient in control arm had combined pelvic and distant failures. The failure rate in the control arm was significantly higher (P = 0.035). Test of proportion derived from the above data also showed that the proportion of patients with no evidence of disease at the time of last follow up was significantly higher in the study arm compared to the control arm (P < 0.05). The proportion of patients having persistent disease was significantly less in the Figure 1: Test statistics for equality of survival distributions study arm compared to the control arm (P < 0.05). There was no significant difference for pelvic recurrence, metastatic disease and pelvic recurrence with metastatic disease (P > 0.05). The disease free survivals in the study and control arm are shown by Kaplan Meier analysis in Figure 1. The probability of disease free survival in percentage according to the curve at the time of median follow up was approximately 70% for study arm and 60% for control arm (log rank test, P = ). DISCUSSION Radiation therapy is the treatment of choice for patients with stage IIB, and III carcinoma of the uterine cervix (dose to point A is Gy delivered by combining brachytherapy and EBRT). It is believed that in the treatment of cancer, an improvement in loco regional control should lead to improved disease free survival. [17,18] In radiotherapy, increment of the local dose can improve the local control but at the cost of increased frequency of complications. [19] Loco regional control of primary cancer also depends on the duration in which the entire course of radiotherapy is given. It was very well demonstrated by Denekamp [20] that proliferation of the epithelium of the skin or mucosa accelerates 2 or 3 weeks after initiation of radiation. Withers et al. [13] experimentally documented the acceleration of repopulation of tumor cells after fractionated radiation therapy and Fowler [21] emphasized the importance of rapid proliferation of malignant cells as a factor influencing tumor control probability. Baumann et al. [22] reported in a series of experiments in nude mice bearing a human squamous cell carcinoma, a progressive increase in TCD 50 with longer periods of treatment time ranging from 2 to 10 weeks, with radiation doses ranging from 43 to 102 Gy: The loss of tumor control dose was 1 Gy/day with prolongation of time. Oka et al. [23] observed that radiation doses of 5.4 Gy to 9 Gy increase the number of cycling squamous tumor cells in G 1 or G 2 phase and that transient increase was attributable to the combined effects of recruitment of the cycling cells and G 1 or G 2 block. Keane et al. [24] was the first to report decreased pelvic tumor control in carcinoma of the cervix for stages I and II as 0.7%/day and for stages III and IV as <1.2%/day due to the above effect. Fyles et al. [25] demonstrated the adverse effect of increased treatment duration on pelvic tumor as loss of tumor control of 1%/day of treatment prolongation beyond 30 days, and it was predominantly observed predominantly in stages III and IV. Suguwara et al. [26] also noted a significant increase in pelvic recurrences in 97 patients with stage III IV disease receiving doses of 93 Gy or greater to Point A when overall treatment time was longer than 42 days (40 41%) compared with patients treated in shorter times (10 18%). Girinsky et al. [27] in a study of 386 patients with stage IIB to III carcinoma of the cervix treated with irradiation also observed a loss of tumor control and overall survival when the treatment time exceeded 52 days. A 1.1% loss of pelvic tumor control per day was observed. 89 Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2

6 According to Kapp et al. [28] stage of the disease as a pretreatment factor was found to be significantly correlated with incidence and severity of late sequelae. In the early stage IB disease, a favorable anatomy permits optimal placement of applicators with maximum sparing of normal tissues. In advanced stages eccentric growth or shrinkage of initially large tumors often result in uni or bilateral flattening of the vaginal fornices or cause vaginal narrowing, which impede optimum placement of applicators thus causing over exposure of normal tissues and more complications. Thus, the point of significance is the volume of normal tissue irradiated to high doses with brachytherapy rather than the maximum doses calculated at specified points. While considering EBRT, the factors that came into play were varying external beam doses, treatment position, choice of energy, 2 versus 4 field technique, number of fields treated per day, fractionation and daily dose, customized blocking, use of mid line shield or side wall boost influenced the nature and likelihood of complications. For brachytherapy, the different factors had been the choice of isotope, applicator design, combination of IUT with ring applicators, cylinders, shielded or nonshielded ovoids, loading technique, treatment plans standardized or individualized according to the patient, dose specifications, isodose distribution and maximum doses to adjacent normal tissues. The practical conclusion is that in the treatment of patients of carcinoma of the uterine cervix with radiation therapy, we should minimize treatment time and avoid any planned or unplanned interruptions or delays by timely integration of external beam and intracavitary irradiation. REFERENCES 1. 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Expedience of conventional radiotherapy in locally advanced cervix cancer: A retrospective analysis. Onc Gas Hep Rep 2015;4: Source of Support: Nil, Conflict of Interest: None declared. Oncology, Gastroenterology and Hepatology Reports Jul-Dec 2015 Vol 4 Issue 2 90