Concurrent chemoradiation in locally advanced carcinoma cervix patients

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1 Original Article Free full text available from Concurrent chemoradiation in locally advanced carcinoma cervix patients ABSTRACT Purpose: To investigate the feasibility of concurrent chemo radiation in locally advanced carcinoma cervix patients in our clinical setting. Materials and Methods: From Sept. 1 st 2005 to Aug. 31 st 2006, 102 patients of carcinoma cervix belonging to stage IIA to IV A were enrolled in the study. External beam radiation therapy was administered using Cobalt 60 teletherapy machine. Cisplatinum (40 mg/m 2 ) and 5 Fluorouracil (500 mg /m 2 ) continuous infusions with radiotherapy on D2-D5 in first and last 5 # of radiation therapy were administered. Results: Response to treatment and toxicities were monitored and analyzed in 102 patients (50 study group and 52 control group). All 102 patients completed treatment. Out of 50 patients in the study group, 30, 10 and 4 patients had complete, partial and progressive disease, respectively. While out of 52 patients in the control group, 26 had complete and 12 showed partial response. No difference in overall renal, hematological and cutaneous toxicity was seen between two groups. Conclusion: This study did not show any benefit of concurrent chemo radiation as compared to radiotherapy alone in locally advanced cervical cancer patients. This could be due to more bulk of tumor stage per stage, poor nutritional status, less number of patients in both arms, not enough to pick up statistically significant small difference in outcome. KEY WORDS: Carcinoma cervix, concurrent chemo radiation, cisplatin & 5-FU R. R. Negi, Manish Gupta, Muninder Kumar, M. K. Gupta, R. Seam, Madhup Rastogi Department of Radiotherapy & Oncology, I.G.M.C, Shimla, HP, India For correspondence: Dr Manish Gupta, Senior Resident, Department of Radiotherapy & Oncology, I.G.M.C, Shimla , HP, India. mg9122@ rediffmail.com INTRODUCTION Cervical carcinoma is the second most frequent cancer among women worldwide and most frequent cancers among women in Africa, South America and Asia including India. [1] Presently, the age adjusted incidence rate of cervical carcinoma ranges from 19 to 44 per 1,00,000 women in various cancer registries of Madras, Bangalore and Bombay. Lowest incidence is seen in Bombay with an incidence of 19.3 per 1, 00,000 women. [2] In our center, carcinoma of uterine cervix accounts for approximately 58.66% of all gynecological malignancies and about 17.08% of all the malignancies in female patients registered in the department. Overall, 80-90% patients present with advance stage with bulky central disease. Radio therapy is the main stay of treatment for locally advanced cervical cancer. The ability of radio therapy to cure locally advanced cervical cancer is limited by the size of the tumor, because the doses required to treat large tumors exceed the limit of radiation tolerance in normal tissue, [3] and the results of radiotherapy treatment are poor with high failure rates. Therefore, need arises to increase the radio responsiveness of primary tumors. Many methods have been tried to improve the radioresponsiveness of the tumor such as treatment of patient with hyper baric oxygenation along with radiation, or use of radio sensitizing agents such as mesonidazole but with no significant outcome. Other methods such as hyper fractionation with increased dose, hypo fractionation and variation in treatment time did not produce any significant outcome. For improving the results of treatment in advanced stage disease, chemotherapeutic agents also have been used for last 2-3 decades. It has been used as neo adjuvant, concurrent chemo radiation and adjuvant. But only concurrent chemo radiation with cisplatin alone or in combination with other agents like 5 fluorouracil have recently been proven to give better response rates, disease free survival and overall survival in carcinoma cervix. [2,4-6] Most of the studies conducted on concurrent chemo radiation in carcinoma cervix are in the western literature and it is not clear whether the same result can be reproduced in Indian patients. In our center, about 90% patients present with locally advanced disease and performance status is relatively poor. So the purpose of the present study is to analyze the effect of concurrent chemo radiation in patients with advance cervical cancer stage II A stage IV A in our clinical setting and to study its effects and complications. MATERIALS AND METHODS We conducted a prospective randomized study for a DOI: / PMID: ***** J Cancer Res Ther - April-June Volume 6 - Issue 2 159

2 period of one year from Sept to Aug 2006 in 102 patients, in our center, with histological proven invasive squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma. Patients with stages IIA IVA (FIGO 2001) with normal hematological, renal and hepatic function, karnofsky performance status >50, and no prior chemotherapy, radiotherapy or surgery were eligible. All patients were aged equal to or less than 70 years. All patients gave written informed consent according to institutional regulation. A detailed medical history and clinical examination were performed before enrolment. All the patients were subjected to a thorough physical and pelvic examination. Base line investigations like complete blood count, blood biochemistry, urine for routine and microscopic examination and base line audiometry were done. In radiological examination, X-ray of chest, ultrasound of abdomen and pelvis were done in all patients. Cystoscopy was done only in patients with clinical suspicious of bladder involvement and/or ultrasonography suggestive of bladder involvement. CT scan of abdomen and pelvis was done in selected patients where metastatic disease was suspected. Patients were staged according to FIGO staging Randomization was carried out by stratification and the treatment assignment was stratified according to clinical stages of disease. Patients were randomized into two groups: Study group - patients who were subjected to concomitant chemoradiation therapy. Control group - patients who were subjected to radiation therapy alone. Patients were further divided according to involvement of parametrium, unilateral or bilateral parametrial involvement. External beam radiation therapy was administered using cobalt 60 teletherapy machine. A dose of 45 Gy in 20 fractions in 4 weeks was given at a dose of 225 centigrays per fraction daily, for 5 days in a week. After a gap of 3 to 4 weeks, patients were reassessed for response and patient with good local response and preserved local anatomy were subjected to intracavitary brachytherapy using Selectron remote controlled LDR system, 137 Cs based, giving a dose of 35 Gy to point A. Patients with poor response or when local anatomy was not preserved and not fit for intracavitary brachytherapy were given external beam radiation therapy in the form of supplement radiation therapy, a dose of 20 Gy in 10 fraction over two weeks. Patients were treated either using two fields by SSD techniques at 80 cm. The 4 field box technique (by SAD techniques) was adopted in obese patients with separation more than 20 cm. Pelvic radiation was delivered by anteroposterior and posteroanterior parallel portals or a four-field box technique (anteroposterior, posteroanterior, and two lateral fields). Minimum margins were the upper margin of L4-5(superiorly), the lower margin of the obturator foramen or the lowest extension of the disease (inferiorly), and cm beyond lateral margins of true bony pelvis. For the lateral fields, the anterior margin was the anterior edge of symphasis. The posterior margins at the S2-S3 interspaces were used. The irradiated volume was to include the whole uterus, cervix and the part of vagina depending upon the lower extent of tumor, the paracervical, parametrium, uterosacral regions as well as external iliac, hypo gastric and obturator lymph nodes. Planned duration was 8-9 weeks. Radiotherapy was withheld if the patient had a leukocyte count less than 4000 per cubic millimeter, and delays of one week were also allowed in the event of radiation-related gastrointestinal or genitourinary toxicity. Cisplatin and 5 Fluorouracil were the chemotherapeutic agents administered. Cisplatin was given in a dose of 40 mg/m 2 of body surface area (total dose not exceeding 70 mg). The drug was given in an infusion over a period of 90 minute after adequate hydration and antiemetic followed by diuresis, on D1 and D21, 1-4 h before radiotherapy. If the patient is not fit for I/C brchytherapy, same dose of cisplatin was also given on D1of supplementary RT. 5-fluorouracil was given in a dose of 500 mg/m 2 continuous infusion along with radiotherapy on D2-D5 and D22-D25 of radiotherapy. Patients who underwent supplement radiotherapy were given similar dose along with first 5# of Radiotherapy. Patients were assessed in every 2 weeks during treatment for disease response and every week for toxicities. Weekly hemograms and complete blood biochemistry for liver and renal function were done in all patients. ECOG toxicity criteria were used for monitoring and documentation of hematological toxicities. The RTOG toxicity criteria were used for radiation-induced toxicities. Patients were assessed in every 2 weeks during treatment for disease response and patients were categorized into following response groups. Complete response: - If there was complete regression of lesion. Partial response: - If there was more than 50% regression in lesion in maximum diameter. No response: - If lesion regressed less than 50% in maximal diameter. Performance status was evaluated by Karnofsky score. First follow up was done at six weeks after completion of treatment. A complete gynecological examination accompanied with systemic examination was performed and subsequent follow-up was done at every two months. Patients were examined apart from local examination, for any late toxicity. Late toxicities were graded according to RTOG criteria. Patients who had persistent tumor on completion of treatment were considered for salvage surgery if resectable. Chemotherapy was administered in patients with unresectable disease. Response rate was the primary end point for analysis. The various prognostic factors affecting response were analyzed with the statistical software (SPSS, Version-14). The Chi-square 160 J Cancer Res Ther - April-June Volume 6 - Issue 2

3 test was used to compare proportions. A two-tailed probability (P) value of less than 0.05 was considered as statistically significant. RESULTS From 1 st September 2005 to 31 st August, 2006, 102 patients of carcinoma cervix belonging to stage II A to IV A were enrolled in the study. After all relevant investigations and staging (described in materials and methods), all patients were assigned to receive treatment by stratified randomized sampling. Of 102 patients, 50 were assigned to study group and 52 to control group. Response to treatment and toxicities were monitored and analyzed in 102 patients. The age of patients ranged from 25 to 70 years with median age of presentation being 51 years in control group and 46 years in study group. Majority of the patients were between 36 and 55 years of age in both arms. Majority of the patients belonged to stage IIIB (52% in study and 53.8% in control group). Majority of our patients had bilateral parametrial involvement both in study (58.3%) and control group (68.4%), in stage IIB. 61.5% of patients had unilateral para involvement up to LPW (lateral pelvic wall) in study group as compared to 35.7% of patients in control group. Similarly, the percentage of patients having bilateral para involvement up to LPW was 38.5% and 64.3% in study and control group in stage III B, respectively [Table 1]. Majority of the patients were having SCC histology in both the arms. Number of patients with SCC in study arm was 45 (90%), while it was 51 (99.02%) in control arm. Both the arms of this study were balanced in regard to histology of the disease. Majority of the patients had ulceroproliferative growth (UPG). 39 (78%) patients in study group and 32 (61.54%) patients in control group had UP growth. Most of the patients had (KPS) karnofsky performance status 70 or above in both arms. Brachytherapy was successfully performed in 13 patients in study group and 09 in control group, respectively. Of the 102 patients who completed treatment, at first follow up at 6 weeks [Table 2], 41 patients [82%] achieved complete response in study group and 38 patients (73%) in control group. The difference in complete response in the study and control group was statistically not significant (P value 0.736). Partial response was achieved in 9 patients [18%] in study arm and 14 patients (27%) in control group The difference in partial response in the study and control group was also not statistically significant (P value 0.297). At a median follow up of 36 months [Table 3], a total of 56 patients were disease free i.e. 30 (60%) in study group and 26 (50%) in control group whereas 22 patients had residual disease; 10 (20%) in study group and 12 (23.1%) in control group. This difference is not statistically significant. J Cancer Res Ther - April-June Volume 6 - Issue 2 Table 1: Patients characteristics Characteristics Study group Control group Median age 46 years 51 years Histology SCC Adeno Adenosq Type of growth UPG NPG Infiltrative Nodular infiltrative Stage of disease IIA IIB IIIA IIIB IVA Bulk of disease IIB U/L B/L IIIB U/L B/L Treatment duration (week) Brachytherapy done Yes No 45 (90) 04 (8) 01 (2) 39 (78) 9 (18) 1 (2) 1 (2) 0 24 (48) 0 26 (52) 0 10 (41.7) 14 (58.3) 16 (61.5) 10 (38.5) 2 (4) 43 (86) 5 (10) 13 (26) 37 (74) Table 2: Response at first follow-up 51 (98.07) Nil 01 (1.93) 32 (61.5) 14 (26.9) 1 (1.92) 5 (9.6) 1 (1.9) 19 (36.5) 3 (5.7) 28 (53.8) 1 (1.2) 6 (31.6) 13 (68.4) 10 (35.7) 18 (64.3) 1 (1.92) 45 (86.5) 6 (11.5) 9 (17.3) 43 (82.69) Response to treatment Study Control Total P value No % No % No % Complete response Partial response There was a direct correlation between stage of the disease and complete response. As stage increases from stage IIB to IIIB, complete response went down in both arms. Fifteen (62.5%) out of the 24 patients of stage IIB had complete response in study arm and 12 patients (63.2%) out of 19 patients had complete response in control arm. In stage IIIB, 15 patients (57.7%) out of 26 patients had complete response in study arm and 13 patients (46.4%) out of 28 patients had complete response in control arm, respectively. The difference in outcome is not statistically significant. The tumor bulk had direct influence on response to treatment within the same stage, less tumor bulk (as measured from the degree of parametrial involvement) showed better response in both groups. As the disease bulk increased, the response rate dropped down. However, this pattern was not seen with stage IIB patients in control group. All patients in stage IIA had complete response. In stage IIB [Table 4] with U/L parametrial involvement, complete response was seen in 60% in study group and 66.6% patients in control group. In stage IIB with B/L parametrial involvement, complete response was seen in 64.3% in study group and 61.5% patients in control group. There were only 161

4 3 patients in stage IIIA in control group and all had showed complete response. In stage IIIB with U/L parametrial involvement, complete response was seen in 56.2% patients in study group and 60% patients in control group. In stage IIIB [Table 5] with B/L parametrial involvement, complete response was seen in 60% patients in study group and 38.9% patients in control group. There was only 1 patient in stage IVA in control group and had shown partial response. The difference in outcome as per bulk of the disease was also not statistically different in both the groups. Of the 15 patients who had treatment failure in study group, 24% had local failure [Table 6] and 4% had failure in the form of paraaortic LAP. similarly 24 failures were seen in control group, out of which 38.5% had local failure and 7.7% had distant in the form of metastasis in lung and liver respectively. There were no treatment-related deaths. Hematotoxicity [Table 7] was noted in 5 (10%) patients in study group and 4(7.6%) patients in control group. Only grade I toxicity was seen. No grade II, III or IV toxicities were observed. Cutaneous toxicity [Table 8] was noted in a total of 55 (53.92%) patients (30 in study group and 25 in control group). Grade I, Table 3: Response at 36 months median follow-up Status of disease Study Control P-value CR 30 (60) 26 (50) PR 10 (20) 12 (23.1) PD 4 (8) 6 (15.4) Relapse 6 (12) 8(15.4) Total Table 5: Disease response as per bulk of the disease, Stage IIIB Para-Metrium Study Control CR PR CR PR No % No % No % No % Unilateral 9/16 (56.3) 7/16 (43.8) 6/10 (60) 4/10 (40) Bilateral 6/10 (60) 4/10 (40) 7/18 (38.8) 11/18 (61.1) P-value was not found to be significant (P>0.05) II and III toxicity in study group were 4 (8%), 24 (48%) and 2 (4%), respectively. There was no grade IV cutaneous toxicity in study arm. Whereas grade I and II toxicity noted in control group were 8 (15.38%) and 16 (30.77%) patients, respectively. There was one grade III toxicity (1.92%). No grade IV cutaneous toxicity was noted in control arm. Gastro Intestinal (GI) toxicity [Table 9] was noted in a total of 80(78.43%) patients (41 in study group and 39 in control group). Grade I, II and III toxicity in study group were 27(54%), 12(24%) and 2(4%), respectively. There was no grade IV GIT toxicity. Grade I and II toxicity noted in control group were 20(38.4%) and 8(15.4%), respectively. There was only one patient who had grade III toxicity (1.9%) in control group. No grade IV toxicity was reported. Renal toxicity [Table 10] was noted in 3(6%) patients in study group. All were grade I toxicities. There were no grade II, III and IV toxicities. There was no renal toxicity in control arm. No ototoxicity was noted either in study or control group. DISCUSSION Radiation therapy alone to the pelvis fails to control the local Table 4: Disease response as per bulk of the disease, Stage IIB Parametrium Study Control (CR) PR CR PR No % No % No % No % Unilateral 6/10 (60) 4/10 (40) 4/6 (66.6) 2/6 (33.3) Bilateral 9/14 (64.3) 5/14 (35.7) 8/13 (61.6) 5/13 (38.5) P-value was not found to be significant (P>0.05) Table 6: Site of treatment failure at 36 mths Site of failure Study Control P-value Local 12 (24) 20(38.5) Distant 3(6) 4 (7.7) Total 15(30) 24 (46.2) Table 7: Hematotoxicity Hematotoxicity Study Control P-value Grade I 5 (10%) 4(7.6%) Grade II Grade III Grade IV No toxicity 45 (90%) 48 (92.4%) Table 9: GI toxicity GI toxicity Study Control P-value Grade I 27 (54) 20 (38.4) Grade II 12 (24) 8 (15.4) Grade III 2 (4) 1 (1.9) Grade IV No toxicity 9 (18) 23 (44.2) Table 8: Cutaneous toxicity Cutaneous toxicity Study Control P-value Grade I 4 (8) 8 (15.38) Grade II 24 (48) 16 (30. 77) Grade III 2 (4) 1 (1.92) Grade IV No toxicity 20 (40) 27 (51.93) Table 10: Renal toxicity Renal toxicity Study Control P-value Grade I 3 (6%) 0 - Grade II Grade III Grade IV No toxicity 47 (94%) 52 (100%) J Cancer Res Ther - April-June Volume 6 - Issue 2

5 disease in cervical cancer. The radiation therapy failure rates in stage IIB are 20-50%, for patients with more extensive stage III disease failure rate ranges from 50% to as high as 75%. [7,8] Despite improvements in radiation equipment and techniques, in approximately two-third of the cases, progression occurs in the area irradiated i.e. the pelvis. The major cause of local failure is the inability to deliver high dose in the pelvis due to critical organs i.e. the urinary bladder and rectum, in proximity of cervix. [9] Several means of improving local control have been tried including use of hyperbaric oxygen, particle therapy, hyperthermia and sensitizers like mesonidazole. [10] But all these have shown only marginal improvement in local control or survival. Thus some mechanism to improve loco regional control was required and researchers attempted concurrent chemo radiotherapy to locally advanced carcinoma cervix. A higher rate of survival and progression free survival were reported among patients treated with radiotherapy and either cisplatin alone or cisplatin and fluorouracil, and hydroxyurea than patients who are treated with radiotherapy and hydroxyurea alone. Cisplatin is believed to augment the effects of radiation by inhibiting the repair of radiationinduced sub lethal damage and by sensitizing hypoxic cells to radiation. [11,12] Because of cytotoxic effect, the drug reduces the bulk of tumors, which leads to reoxygenation of the tumor and entry of the cells into a radiation-sensitive phase of the cell cycle. In February 1999, the US National Cancer Institute (NCI) issued an alert that chemo radiation should be considered for all patients with cervical cancer based on five randomized trials. The five randomized trials of cervical cancer involved different stages of the cervical cancer and a combination of treatment, but they shared a common result, all studies found that a concomitant treatment with cisplatin containing schedules (cisplatin, cisplatin and 5FU, cisplatin, 5FU and HU) and radiation therapy led to a better outcome than radiation therapy alone or in combinations with treatments that did not include cisplatin. This remarkable consistency offers compelling reason to consider cisplatin therapy in combination with radiation therapy as a new standard of care for patients with bulky stage IB disease, stage IIB through IVA and high risk cervical cancer cases. But these studies had several drawbacks; of four of these cisplatin containing regimens, only two were compared directly. [13,14] It is unclear from the results which regimen achieves the most favorable therapeutic ratio and whether the inclusion of 5FU in several of the studies contributed importantly to the results. Further, all of these studies excluded patients with paraaortic lymph node metastases, poor performance status or impaired renal functions. Meta-analysis by Vale et al. showed a significant survival benefit for both the group of trials that used platinumbased (HR = 0.83, P = 0.017) and non platinum-based (HR = 0.77, P = 0.009) chemo radiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemo radiotherapy also reduced local and distant recurrence and J Cancer Res Ther - April-June Volume 6 - Issue 2 progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. [15] Clinicians are challenged to determine how these favorable results can be generalized to those patients not included into these prospective randomized trials and which are more commonly seen in developing nations where invasive cervical cancer is epidemic, including our country. The radiation protocol we used allowed a total dose of 81 Gy to be delivered to point A and an anticipated total treatment time of 8 to 10 weeks. Several studies have suggested that total length of treatment influences the efficacy of radiotherapy. [9,16-18] In our study, duration of radiotherapy and dose of radiation were similar among two arms, implying that the difference in response rate, progression free survival and overall survival were related to chemotherapy. Two of the cisplatin based trials delivered 81 Gy to point A allowing up to 70 days for treatment. Both the trials had a median treatment time of 63 days. Total treatment for each arm in these trials was identical, suggesting that the survival benefit seen was the result of intervention, cisplatin-based chemotherapy and not a difference in treatment time. And they defined optimal radiation therapy as having more than 85% of the prescribed dose without any substantial delay (median time 57 days, ranging from days). Lastly, a significant benefit to chemotherapy and radiation was seen in radiation therapy oncology group (RTOG) trial 9009 which used a more optimal radiation schedule of 89 Gy in 58 days. The optimal scheduling and timing of cisplatin and radiation is not well understood. Lelieveld et al. showed that small doses of cisplatin and lower serum levels produce maximal effect. [18] Interactions leading to increased cell kill, namely radio sensitization of hypoxic cells and inhibiting repair of sub lethal damage, require the presence of cisplatin prior to and after radiation therapy. Continuous infusion of the drug fulfills this requirement. Majority of randomized trials have given cisplatin few hours prior to radiation therapy. In our trial, we gave cisplatin few hours (1 to 4) before radiotherapy. We conducted this study to evaluate the feasibility and tolerability of concurrent CRT in our clinical setting, where patients usually report very late with poor general condition and usually they are anemic. Further, the tumor bulk is a very important prognostic factor among each stage and usually our patients, stage per stage, have more tumor bulk as compared to patients in western world. Our results with concurrent CRT in patients of stage IIB, IIIA, IIIB were not significantly different compared with patients treated with RT alone. At a three year follow up, there was 60%CR and 20% PR in CRT arm. In RT alone, arm CR was 50% and PR was 23%. Tumor response was higher in CRT arm, though the difference was not statistically significant. Our results with CRT and RT alone are comparable to the results seen in major randomized trials. The difference 163

6 in tumor response was evident after completion of treatment i.e. at first follow up (at 6week). Response rates decreased at first follow up (at 6 weeks) to follow up at three years from 82% to 60% in study arm, 76% to 50% in control arm. No significant difference in outcome with concurrent CRT in our study is consistent with the results reported by Pearcy et al. [19] They conducted a prospective randomized trial comparing RT with weekly cisplatin with standard pelvic RT alone in 259 patients (stages IB2 -IVA). Surgical staging was not considered mandatory and pelvic and para aortic nodes were assessed by CECT, and positive para aortic cases were excluded from the analysis. No significant difference was seen in DFS (60% for CRT arm versus 56 % for RT alone arm) and OS (66% for CRT versus 58% for RT alone) at 5 years. This trial could not find any benefit of CRT over RT alone. Although this study fails to demonstrate significant difference in progression free and overall survival, outcomes like OS and DFS slightly favored cisplatin chemo radiation. Similarly, our study does not show significant difference in disease response but the outcome marginally favors the chemo radiation arm. Similar results were observed in a phase 2 study done by Saibish Kumar EP et al from PGIMER, Chandigarh. [20] The overall survival, disease free survival and pelvic control with CRT at 5 years (45.6%, 43.9% and 57.9%) were similar to RT alone arm (47.4%, 45.5% and 61.3%). They concluded that with CRT, there were no significant differences in the outcomes. Similarly in a study by M. Garipa et al, tolerability and efficacy of the continuous infusion of cisplatin during radiotherapy was studied by tumor response, survival and pelvic control, in carcinoma of the cervix. [21] 44 patients with stage IIB IIIB cervical carcinoma were prospectively randomized into two groups: radiation alone versus radiation plus cisplatin. Tumor responses were no different at the end of the treatment and 3 months after completion of treatment. Five-year pelvic control rates were 69.4% and 63.9% (P=0.7), survival rates were 52.0% and 48.9% (P=0.7), and disease-free survival rates were 67.5% and 58.7% (P=0.3) for the RT and the CRT groups, respectively. Although the continuous infusion of cisplatin during radiotherapy was well tolerated, this additional treatment in form of CRT did not appear to show an improvement in pelvic control, survival, or disease-free survival. In trials by Whitney et al, Morris et al and Rose et al, 60% or more of the patients belonged to stage I-II and in a trial by Pearcy et al nearly 50% belonged to stages up to IIB. In our study out of 102 total patients, 101 belonged to stage IIB to IVA. Not only had this, the patient in stage IIB had bilateral parametrial involvement in more than 50% of the cases. Similarly about 50% of stage IIIB cases had bilateral parametrial involvement up to lateral pelvic wall. No benefit of concurrent CRT in our study may be due to this factor. Apart from this, another important factor could be the stringent criteria of inclusion in other trials. In trials by Whitney et al and Rose et al, they excluded patients if para aortic were positive on sampling. In Morris et al study, only 25% patients underwent lymph node sampling and rest underwent lymphangiography. In studies by Pearcy et al and Wong et al also, CT scans were done routinely to exclude para aortic node involvement. In our study, USG abdomen was mainly used to evaluate para aortic nodal status which is an inferior modality to lymphangiography and CT scans. CT scan was done in few patients. In our set up, it is difficult to carry out extensive work up like laprotomy, lymphangiography and CT scans due to financial and time constrains. Many patients may have had para aortic nodes that are not picked by USG abdomen adding to our inferior results. Similar to the finding of other authors, we also found that the tumor stage was an important prognostic factor. The complete response in stage IIA was 100% compared to only 60% in stage IIIB B/L. In major randomized trials, the benefit of CRT is more marked in early stages than advanced stages. Meta analysis by Green et al suggested that benefit of CRT is more apparent in early stages and when disease is confined to the pelvis. [22] The patients in our set up present with bulky disease with high tumor burden. Another reason of not finding benefit from concurrent CRT by Pearcy et al was anemia which was more in cisplatin-treated patients. The failure to correct anemia in chemotherapy arm may have accounted for up to 8--10% decrement in survival as reported in this study. In contrast, the analysis of hemoglobin levels just before each chemotherapy administration in GOG 120 yielded very similar average hemoglobin levels at week 5 of therapy. Majority of patients in our trial had Hb 10 to 10.5gm% reflecting poor nutritional status of our patients, translating into poorer outcome. Another reason for poor results in our study as compared to other randomized studies is that in our patients the tumor burden is higher even for the same stages. The FIGO staging does not take into account the variation in tumor burden within a given stage e.g. stage IIB includes patients with minimal invasion of parametrium to disease reaching just short of lateral pelvic wall. Stage IIIB includes patients with single parametrial involvement as well as the ones with both parametrial involvements up to lateral pelvic walls. Since the tumor bulk is a prognostic factor for outcome, the results for the same stage with variable tumors bulk will be different. Bulk of the disease stage per stage may vary between Indian and western patients. There is a lack of surveillance programs leading to detection of disease at an advanced stage in our country. Though overall response in our patients is acceptable considering the fact that majority of patients had locally advanced cancer of cervix Stage IIB-IIIB (98%), it has not shown improved response with concurrent CRT as compared to RT alone. Meta-analysis by Vale et al also suggested a decreasing relative effect of chemo radiotherapy on survival with increasing tumor stage, with estimated absolute survival benefits of 10% (stage Ia to IIa), 7%(stage IIb), and 3%(stage III to IVa) at 5 years. Another factor contributing to our inferior results may be the small sample size which may not have picked the difference in response in two treatment arms. The trial by Pearcy et al also had the smallest number of patients among all prospective randomized trials. Majority of treatment failures were seen in the pelvis in the irradiated area. An analysis of pattern of failure reveals that 29.4% of those who failed had pelvic tumor 164 J Cancer Res Ther - April-June Volume 6 - Issue 2

7 as a component of first site of failure. In our study, the local failure in study arm was 24% and in control arm was 38.5%. In our study, the complete response was higher in stage IIB patients in control group as compared to study group, but this may be due to inadequate number of patients and may be a chance finding. All patients had a median follow-up of 36 months, and disease free survival was 74% in study group and 50% in control group, which was not statistically significant. It is unclear whether longer follow-up will show any survival difference, but it is evident that concurrent CRT does not show any survival advantage. Cutaneous toxicity and GIT toxicity were the principal adverse effects in our trial. The frequency of grade II and III cutaneous and GIT toxicities was significantly higher in the study arm. Even though acute toxicities were more in CRT arm, they were manageable. In majority of the patients, the GI toxicity was vomiting and diarrhea which were infrequent in RT alone group. The Haematotoxicity was noted in 9 patients (5 in CRT 4 in RT alone). Compared to other randomized trials using cisplatin, we had less hematological complications which may be due to lesser dose of cisplatin and 5-Fluorouracil that we have used. The other factor leading to higher hematoxicity in other trials is incorporation of hydroxyurea in the treatment arms. Another factor leading to less hematoxicity in our study was that radiotherapy was confined to pelvis and no paraaortic field was used, thus exposing less bone marrow to radiation. The most important adverse effect with cisplatinum was emesis, but it was successfully managed by one of the 5-hydroxytryptamine antagonists. In our trial renal toxicity grade I occurred in 3 patients (6%) in CRT arm. No renal toxicity was noted in the control arm. There was no patient deaths solely attributed to concurrent cytotoxic drug therapy. Grade 3-4 gastrointestinal toxicity was higher in patients in cisplatin arm in a trial by Whitney et al (8%) as compared to HU arm. There was no grade 4 nephrotoxicity. Grade 3 and 4 of other toxicities were encountered less (<2%). In a study by Saibish Kumar et al comparing CRT to RT alone arm, (11.6 %) severe acute toxicities (grade 3 RTOG criteria) were significantly higher in CRT arm (31.6 %) (P < 0.001). More late rectal toxicities were encountered in CRT arm (22.8%) compared to RT alone (12.5 %) (P = 0.01), but the incidence of severe late rectal toxicities grade 3) was similar; 1.8 % in CRT versus 1.1 % in RT arm in his study. Thus our study showed that concurrent CRT, though tolerated well, failed to show any difference in outcome. SUMMARY AND CONCLUSION We did not find any statistically significant difference in complete response (60 % vs. 50%) between 2 arm of concurrent CRT and RT alone. Most important factor affecting the CR in our study was stage of the disease. The CR decreases from 100% in IIA to 62.8% in IIB to 51.8% in stage IIIB. Our study did not J Cancer Res Ther - April-June Volume 6 - Issue 2 show the advantage of concurrent CRT in any of the stage of the disease. However, this may be due to less number of patients in different stages. At median follow-up of 36 months, the present study did not show any difference in the disease free survival (60% vs. 50%) in the both arms. However, large follow-up is required for any form of conclusion. The regimens of concurrent CRT are well tolerated by our patients and none of our patients had treatment delay because of toxicity. More bulk of tumors stage per stage, poor nutritional status, low hemoglobin level etc. make our patients different from patients in developed countries and this may be the reason for lack of any advantage of concurrent CRT in our study. REFERENCES 1. Parkin DM, Pisani P, Ferlay J. 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8 Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17: Vale C, Tierney JF, Stewart LA, Brady M, Dinshaw K, Jakobsen A, et al. 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;35: Girinsky T, Rey A, Roche B, Haie C, Gerbaulet A, Randrianarivello H, et al. Overall treatment time in advanced cervical carcinomas: A critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys 1993;27: Perez CA, Grigsby PW, Castro-Vita H, Lockett MA. Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32: Lelieveld P, Scoles MA, Brown JM, Kallman RF. The effect of treatment in fractionated schedules with the combination of X-irradiation and six cytotoxic drugs on the RIF-1 tumour and normal mouse skin. Int J Radiat Oncol Biol Phys 1985;11: Bush R. The significance of anaemia in clinical radiation therapy. Intl J Radiat Oncol Biol Phy 1986;12: Saibishkumar EP, Patel FD, Sharma SC. Results of a phase II trial of concurrent chemoradiation in the treatment of locally advanced carcinoma of uterine cervix: An experience from India. Bull Cancer 2005;92:E Garipağaoğlu M, Kayikçioğlu F, Köse MF, Adli M, Gülkesen KH, Koçak Z, et al. Adding concurrent low dose continuous infusion of cisplatin to radiotherapy in locally advanced cervical carcinoma: A prospective randomized pilot study. Br J Radiol 2004;77: Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358: Source of Support: Nil, Conflict of Interest: None declared. Dispatch and return notification by The journal now sends notification to its members on dispatch of a print issue. The notification is sent to those members who have provided their address to the association/journal office. The alerts you about an outdated address and return of issue due to incomplete/incorrect address. If you wish to receive such notification, please send your along with the membership number and full mailing address to the editorial office by J Cancer Res Ther - April-June Volume 6 - Issue 2