Comparative Study of External Beam Radiotherapy with Cisplatin Verses Paclitaxel In Locally Advanced Cervical Carcinoma

Objective: The purpose of the study was to identify the value and response of four field radiotherapy, combined with concurrent chemotherapy (cisplatin vs. paclitaxel) as radio a sensitizer. Method: Fifty patients with diagnosis of Carcinoma of Cervix were consecutively enrolled in this study 25 assigned in each group. Gr 1 was assigned for Cisplatin as sensitizer and Gr 2 received Paclitaxel. Radiation fields were similar. The response and adverse effects were evaluated in fixed interval or at the time when it occurred. Result: Fifty patients were enrolled. FIGO stage of disease were stage IIB (n=33) and stage IIIB (n=14). The most commonly used field size for anterior / posterior field 15 x 15 cm and 15 x 18 cm. The lateral field size from right and left are 15 x 7 cm and 15 x 6 cm. Cisplatin 30 mg /m2 or Paclitaxel 230mg/m2 were used as assigned in each group of 25. During weekly assessment of chemo-irradiation, the reaction was seen from second week to fifth week of the treatment which were mild to moderate in severity. Vesico-Vaginal Fistula were seen in 8.0% of patient. Eighteen patients came for one follow up, 15 patients attended two follow up, and 17 patients attended all three scheduled follow up. Complete response was evaluated in 25 patients (p=0.002), partial response in 14 patients (p=0.03) and poor response in 11 patients (P=0.50). Conclusion: There are no significant differences in cisplatin or paclitaxel as a sensitizer in concurrent radiotherapy in response for cancer of uterine cervix. Rate of side effects were also similar. Further large scale studies may evaluate the difference in response of concurrent chemo-radiotherapy of these two drugs to confirm the optimal duration and schedule of concurrent chemotherapy. Introduction Carcinoma of the uterine cervix is one of the most common malignant neoplasms among women in Asia. Globally, it is second commonest neoplasia in women.3 It is the commonest neoplasia in women of the developing countries including Nepal. Carcinoma Cervix ranks fifth most common cancer in women of developed countries. In Nepal, according to the data of National Cancer Registry Program-2012, Kathmandu, Kaski, Morang, Chitwan, Sunsari, Jhapa, Nawalparasi, Rupandehi, Saptari and Dhanusha were found the top ten districts where the cancer cases were reported and the distribution is almost the same among the Hindus and the Muslims. Among them carcinoma of cervix (25%) was the number one cancer site followed by breast (15%)and lung (10%). Locally advanced cervical Cancer (LACC) are very common. The standard treatment modalities, advised in different stages of carcinoma of the cervix are surgery, radiotherapy and chemotherapy. Pelvic irradiation plays a major role in the standard, definitive therapy for these LACC, with overall 5 years survival rate between 25% and 55% depending on the extent of the disease.20 The conventional two main modalities of irradiation to cervix are external photon beam with or without weekly concomitant chemotherapy and brachytherapy. Not all the radiotherapy centers in other part of the nation have this facilities, so the patients are given radiotherapy alone


Introduction
Carcinoma of the uterine cervix is one of the most common malignant neoplasms among women in Asia. Globally, it is second commonest neoplasia in women. 3 It is the commonest neoplasia in women of the developing countries including Nepal. Carcinoma Cervix ranks fifth most common cancer in women of developed countries. In Nepal, according to the data of National Cancer Registry Program-2012, Kathmandu, Kaski, Morang, Chitwan, Sunsari, Jhapa, Nawalparasi, Rupandehi, Saptari and Dhanusha were found the top ten districts where the cancer cases were reported and the distribution is almost the same among the Hindus and the Muslims. Among them carcinoma of cervix (25%) was the number one cancer site followed by breast (15%)and lung (10%). Locally advanced cervical Cancer (LACC) are very common. The standard treatment modalities, advised in different stages of carcinoma of the cervix are surgery, radiotherapy and chemotherapy. Pelvic irradiation plays a major role in the standard, definitive therapy for these LACC, with overall 5 years survival rate between 25% and 55% depending on the extent of the disease. 20 The conventional two main modalities of irradiation to cervix are external photon beam with or without weekly concomitant chemotherapy and brachytherapy. Not all the radiotherapy centers in other part of the nation have this facilities, so the patients are given radiotherapy alone Keywords: External beam radiotherapy, Concurrent chemotherapy, locally advanced cervical cancer, Radio-sensitizer.

Correspondence
Suresh Shrestha, MD., Department of Radiation Oncology, B.P.Koirala Memorial Cancer Hospital,Bharatpur, Chit wan, e-mail:-drsureshshrestha@yahoo.com or radiotherapy plus concurrent chemotherapy with out brachytherapy. Technique wise, four field box technique and two anterior-posterior fields were applied. The first technique is considered superior in terms of radiation related morbidity. 3 The ability of Radiotherapy to treat LACC is very much limited by the size of the tumors, because the doses required to treat large tumors exceed the limit of toxicity in normal tissue. 12 Concurrent chemotherapy inhibits the repair of sub lethal damage from radiation, synchronizes cells to a particularly radiosensitive phase of the cell cycle. This method aims at enhancement of tumor cell kill and possible improvement in the sensitivity of the cancer cells to radiation. 3 The Cisplatin and Paclitaxel are the widely used molecules as a radio-sensitizing agents. Cisplatin is found to be the most active agent in this tumor and act as a good radiosensitizer and hypoxic cell sensitizer resulting in higher progression-free survival. When cisplatin and irradiation are used concomitantly, substantial enhancement of cell killing is observed. Paclitaxel has demonstrated a radiosensitizing effect because of its ability to block cells in the G2M phase of the cell cycle with a novel mechanism of action that involves stabilization of the mitotic spindles in micro-tubular polymer complex and cell replication. 21

Materials and Method
This is a prospective study undertaken in the Department of Radiotherapy of Bir Hospital Kathmandu. This Cohort recruited subjects of age > 25 years in open label randomized fashion in which radio-sensitizing dose of active drugs were used. The study parameters included Pathological/Radiological / Biological / Histopathological/Cytological-parameters.

Study Population and Sampling Techniques
This study included all sexually active, non-pregnant women presenting to the OPD with diagnosis of cancer of Cervix. Patient Written consents were taken, confidentiality will be maintained. Long term and short term effect of treatments were explained.

Methodology
Total of 50 patients were selected according to inclusion criteria. Patients were subjected to clinical examination including per speculum examination. Internal pelvic examination was done for proper staging according to the FIGO Classification (Table.1). The patients were divided into two groups, using box technique, 25 patients in each group. First group, treated with Radiotherapy plus cisplatin 30 mg/m 2 .Second group treated with Radiotherapy plus paclitaxel 30mg.
Radiotherapy-External beam radiation treatment (EBRT) was delivered using a telecobalt machine(Theratronics, Canada). A four-field box technique was used to treat all these 50 patients in Anterior/posterior portals and two lateral portals as shown in Figure 1 and Figure 2. The field size used is given in Table 4. The total dose of 6000 cGy was given in 30 fractions over 6 weeks, daily delivering 200 cGy per fraction per day for five days a week for six weeks. The planning and surface marking were done manually according to the anatomical landmark and by the help of the Aluminums wire are placed on the surface mark, and a check x-ray films were taken to see the actual field size matching. The upper border of the Anterior-posterior field passes through the upper border of the sacro-iliac joint (extended from the middle of L5-S1 or L4-L5), laterally covers the pelvic brim with a margin of 1.5 cm and inferiorly to cover the obturator foramen and the lower  figure 1. In the lateral field, the upper border and the lower border are same as in Anterior-posterior field, the anterior border taken from mid-symphysis and the posterior border taken from mid rectum as shown in figure 2. Figure.1 Field -Anterior-Posterior portals Figure.2. Field -Lateral port (Diagrammatic) (Diagrammatic) Chemotherapy: The concurrent chemotherapy was given intravenous before EBRT. In group-1, injection cisplatin 30 mg/m 2 , mixed in injection normal saline 250ml and infused over 30 minute, once a week for total 6 weeks. In group-2, injection paclitaxel 30mg was mixed in injection normal saline 250ml and infused over 30 minute, once a week for total 6 weeks. The patients were evaluated for complications using the Common Toxicity Criteria (CTC) of the National Cancer Institute (CTC.NCI, 1999) and RTOG/EORTC acute radiation scoring criteria -Skin (1995). Statistical methods: Data were expressed as mean, SEM and median. Chi-square tests were performed to compare two categorical variables. p value of <0.05 was considered statistically significant.
Evaluation: Response to chemo irradiation were evaluated at the end of the treatment. Complete response was registered when no clinical or cytological evidence of disease existed at the end of treatment. Partial response was registered when there was an equal or more than 50% reduction of the disease. Poor response was registered when they're clinically or cytological evidence of disease exist, less than 25% of the disease or more than 25% increase of the disease or the appearance of new lesion.

Results
This study was conducted in the outpatient unit of Department of Radiotherapy. All patients were previously untreated and histology proved. All patients were stage IIB to IIIB according to the FIGO classification of cancer of uterine cervix.
The details of 50 patients enrolled which were divided into 2 groups is elaborated in table 1.    As shown in Table 4 during weekly assessment of reaction, it was mainly seen in the second week to fifth week of the treatment which were mild to moderate. On the second week of the treatment skin reactions were mild to moderate in cisplatin group 55.6% (n=5) to 22.2% (n=2) and in the paclitaxel group 16.7% (n=1) to 50.0% (n=3) and GI,GU/Rectal reaction were mild to moderate in cisplatin group 22.2% (n=2) and in paclitaxel group 33.3% (n=2) during GI reaction. Where as in the third week of the treatment in the cisplatin group reaction were mild -Skin 57.1% (n=8), OC, pharynx 42.9% (n=6), GI 28.6% (n=4), GU/rectal 42.9% (n=6) and in paclitaxel group were mild to moderate, skin 38.5% to 23.1% (n=5 and n=3), OC, pharynx 38.5% (n=3), GI 23.1% to 15.4% (n=3 and n=2), GU/rectal 15.4% (n=2). On the fourth week of treatment there was no skin reaction in the cisplatin group but mild skin reaction in the paclitaxel group 28.6% (n=2) and other site also shows mild reaction during treatment in cisplatin group -OC, pharynx and GU/rectal 50.0% (n=2) and in paclitaxel group -OC, pharynx 28.6% (n=2). And finally on the fifth week of the treatment only mild skin reaction was observed in cisplatin group 33.3% (n=2) and in paclitaxel group 75.0% (n=3).

Discussion
Cervical cancer continues to be a major public health problem in developing countries. A substantial number of women are still dying of cervical cancer because majority of the affected patients present at late stage. Carcinoma of the cervix is one of the most common malignant neoplasms among women in Asia. 3 In this study, four field box techniques with concurrent chemotherapy weekly with cisplatin was preferred to avoid maximum rectal and bladder complication. In this four field box technique study, the most common effective field size was 15 x 15 cm and 15 x 18 cm in anterior / posterior portal and 15 x 7 and 15 x 6 in the lateral portal. In a study done by B.E.Greer et al. 20 reported, that the median length and width of the anterior / posterior fields were 20cm and 17.5cm respectively. Lateral fields had a median width of the 16.5cm and the posterior border encompassed the entire sacral silhouette and G. A. Perez et al. 1 has also written in a book Principles and Practice of Radiation Oncology that for patients with stage IIA, IIB, III and IVA carcinoma, somewhat larger portals (18 x 15 cm at the surface) are required to cover all of the common iliac nodes in addition to the cephalad half of the vagina. So comparing with this study the field size did not show any statistically significant. In this study, Cisplatin and Paclitaxel are used as concurrent chemotherapy weekly along radiotherapy as a radiosensitizer. The response rate of cisplatin was very