Original Article
Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: A phase II study ABSTRACT Background: Cervical cancer is the most common gynecological cancer in Indian women. This study was initiated to assess whether the combination of paclitaxel and cisplatin with radiation was feasible in Indian women. Aims and Objectives: The aim of this study was to assess the immediate tumor response and toxicity of weekly cisplatin and paclitaxel along with radiotherapy in the treatment of cervical cancer. Materials and Methods:Women with primary untreated squamous cell carcinoma of the cervix with FIGO stages IB2 to IIIB were treated with weekly injections of cisplatin 30 mg/m2and paclitaxel 40 mg/m2 for 4 weeks along with radiotherapy. A total of 25 patients were enrolled in this study. Disease was assessed prior to treatment by pelvic examination and contrast enhanced computed tomography scan of the abdomen and pelvis. Response was assessed 6 weeks after completion of treatment using the same parameters. Clinical and radiological response was documented. The toxicity was assessed and was graded using the common toxicity criteria Version 3.0. Intention to treat analysis was used when reporting results. Results: A total of 23 patients completed the intended treatment. There was a complete response rate of 88%, 12% were not available for response assessment. The major toxicity was Grade 3 diarrhea (48%). The mean duration of treatment was 58 days. Conclusions: Combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of cervix had a high incidence of acute toxicity. There was no increase in immediate tumor response and progression free survival with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemo radiation with cisplatin alone. KEY WORDS: Cervical cancer, cisplatin, concurrent chemotherapy, paclitaxel, radiotherapy
INTRODUCTION Carcinoma of the uterine cervix is the seventh most common cancer world‑wide.[1] Cervical cancer is the most common cancer in South Indian women with incidence of 19.4‑43.5/100,000/year.[2] Invasive disease can present as early stage, locally advanced and metastatic.[3] In the past, treatment for locally advanced carcinoma of the cervix has been radical radiotherapy. In 1999, five randomized studies including nearly 2,000 patients were published demonstrating that the survival rate with radiation plus concomitant chemotherapy with cisplatin based regimen was superior to that obtained with radiation alone.[4‑8] Subsequently, a meta‑analysis based on 19 trials including 4,580 patients concluded that chemo irradiation with Cisplatin offers an absolute survival benefit
330
of 12% at 5 years.[9] Since then, cisplatin based chemo irradiation has been accepted as the standard of care for all patients with cervical cancer stage greater than IB1.[3] Subsequently various chemotherapeutic agents have been combined with cisplatinum to evaluate whether there is any added benefit. Paclitaxel, a microtubule stabilizing chemotherapeutic agent, has broad activity against a number of solid tumors including cancers of the ovary, breast, lung, and endometrium[10‑14] and it blocks cells in the G2‑M phase of the cell cycle, which is the most radiosensitive phase of the cell cycle.[15] Thus, Paclitaxel has a rationale as a radiation sensitizer.[16‑19] The combination of cisplatin and paclitaxel was tried in recurrent and metastatic carcinoma of the cervix and was found to be safe and effective.[20‑23] Moore et al. reported that this combination gave 36.2%
Sunitha Susan Varghese, Thomas Samuel Ram, Simon Pradeep Pavamani, Elsa Mary Thomas1, Visalakshi Jeyaseelan2, Peringulam Narayan Viswanathan Departments of Radiation Oncology Unit I, 1Radiology, and 2 Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India For correspondence: Dr. Sunitha Susan Varghese, Department of Radiation Oncology Unit I, Christian Medical College, Vellore, Tamil Nadu, India. E‑mail: sunithasusan @cmcvellore.ac.in
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.136621 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Varghese, et al.: Study of cisplatin, paclitaxel and radiation in cervical cancer
overall response rate in patients with recurrent and metastatic carcinoma cervix.[23] The same combination was also tried as radio sensitizer in cervical carcinoma and was found to be tolerable and feasible with high response rates.[24‑29] Chen et al.[27] did a phase I study where weekly paclitaxel was combined with 3 weekly cisplatin. The maximum tolerated dose (MTD) of this trial was reported as paclitaxel 50 mg/m2/week with cisplatin 50 mg/m2 once in 3 weeks. There was another phase I study by Pignata et al.,[26] which reported cisplatin 30 mg/m2 and paclitaxel 50 mg/m2 as the MTD. Both these studies reported tumor response rates more than 90%. Disilvestro et al.[29] did a phase I/ phase II study where cisplatin and paclitaxel where used as radio sensitizers in cervical cancer. The MTD reported was cisplatin 40 mg/m2/week and paclitaxel 40 mg/m2/week. The phase II part of this study reported a complete response rate of 89.4% with acceptable toxicity profile. There was another phase II study by Miglietta et al.[28] where cisplatin 75 mg/m2 and paclitaxel 175 mg/m2 was given once every 3 weeks for four cycles. First cycle was given as neoadjuvant chemotherapy, second and third cycles where given along with external radiotherapy and the fourth cycle was given with brachytherapy. They reported a complete response rate of 100%. A phase I study was carried out in India to find out the MTD of the combination of cisplatin and paclitaxel as concurrent chemotherapy in women with locally advanced squamous cell carcinoma of the cervix.[25] This study concluded that cisplatin 30 mg/m2/week and paclitaxel 40 mg/m2/week for four cycles along with radiation was well‑ tolerated and this dose was recommended for further phase II trials. The present phase II study used the Indian phase I MTD to find out the efficacy and toxicity of combined cisplatin and paclitaxel along with radiation in the treatment of locally advanced squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS The study was initiated after obtaining clearance from the Institutional Review Board. Patients were included in the trial after getting a written informed consent. We decided to accrue 25 patients who fulfill the inclusion criteria. The inclusion criteria were women with squamous cell carcinoma of the uterine cervix with stages 1B2 to III B, with good performance score (Eastern Cooperative Oncology Group 0, 1 or 2) and an informed consent. Patients were excluded from the trial if they have any histopathology other than squamous cell carcinoma, any history of previous treatment for cervical cancer, hepatic, renal or cardiac dysfunction, poor hematological reserve (hemoglobin
Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: A phase II study ABSTRACT Background: Cervical cancer is the most common gynecological cancer in Indian women. This study was initiated to assess whether the combination of paclitaxel and cisplatin with radiation was feasible in Indian women. Aims and Objectives: The aim of this study was to assess the immediate tumor response and toxicity of weekly cisplatin and paclitaxel along with radiotherapy in the treatment of cervical cancer. Materials and Methods:Women with primary untreated squamous cell carcinoma of the cervix with FIGO stages IB2 to IIIB were treated with weekly injections of cisplatin 30 mg/m2and paclitaxel 40 mg/m2 for 4 weeks along with radiotherapy. A total of 25 patients were enrolled in this study. Disease was assessed prior to treatment by pelvic examination and contrast enhanced computed tomography scan of the abdomen and pelvis. Response was assessed 6 weeks after completion of treatment using the same parameters. Clinical and radiological response was documented. The toxicity was assessed and was graded using the common toxicity criteria Version 3.0. Intention to treat analysis was used when reporting results. Results: A total of 23 patients completed the intended treatment. There was a complete response rate of 88%, 12% were not available for response assessment. The major toxicity was Grade 3 diarrhea (48%). The mean duration of treatment was 58 days. Conclusions: Combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of cervix had a high incidence of acute toxicity. There was no increase in immediate tumor response and progression free survival with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemo radiation with cisplatin alone. KEY WORDS: Cervical cancer, cisplatin, concurrent chemotherapy, paclitaxel, radiotherapy
INTRODUCTION Carcinoma of the uterine cervix is the seventh most common cancer world‑wide.[1] Cervical cancer is the most common cancer in South Indian women with incidence of 19.4‑43.5/100,000/year.[2] Invasive disease can present as early stage, locally advanced and metastatic.[3] In the past, treatment for locally advanced carcinoma of the cervix has been radical radiotherapy. In 1999, five randomized studies including nearly 2,000 patients were published demonstrating that the survival rate with radiation plus concomitant chemotherapy with cisplatin based regimen was superior to that obtained with radiation alone.[4‑8] Subsequently, a meta‑analysis based on 19 trials including 4,580 patients concluded that chemo irradiation with Cisplatin offers an absolute survival benefit
330
of 12% at 5 years.[9] Since then, cisplatin based chemo irradiation has been accepted as the standard of care for all patients with cervical cancer stage greater than IB1.[3] Subsequently various chemotherapeutic agents have been combined with cisplatinum to evaluate whether there is any added benefit. Paclitaxel, a microtubule stabilizing chemotherapeutic agent, has broad activity against a number of solid tumors including cancers of the ovary, breast, lung, and endometrium[10‑14] and it blocks cells in the G2‑M phase of the cell cycle, which is the most radiosensitive phase of the cell cycle.[15] Thus, Paclitaxel has a rationale as a radiation sensitizer.[16‑19] The combination of cisplatin and paclitaxel was tried in recurrent and metastatic carcinoma of the cervix and was found to be safe and effective.[20‑23] Moore et al. reported that this combination gave 36.2%
Sunitha Susan Varghese, Thomas Samuel Ram, Simon Pradeep Pavamani, Elsa Mary Thomas1, Visalakshi Jeyaseelan2, Peringulam Narayan Viswanathan Departments of Radiation Oncology Unit I, 1Radiology, and 2 Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India For correspondence: Dr. Sunitha Susan Varghese, Department of Radiation Oncology Unit I, Christian Medical College, Vellore, Tamil Nadu, India. E‑mail: sunithasusan @cmcvellore.ac.in
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.136621 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Varghese, et al.: Study of cisplatin, paclitaxel and radiation in cervical cancer
overall response rate in patients with recurrent and metastatic carcinoma cervix.[23] The same combination was also tried as radio sensitizer in cervical carcinoma and was found to be tolerable and feasible with high response rates.[24‑29] Chen et al.[27] did a phase I study where weekly paclitaxel was combined with 3 weekly cisplatin. The maximum tolerated dose (MTD) of this trial was reported as paclitaxel 50 mg/m2/week with cisplatin 50 mg/m2 once in 3 weeks. There was another phase I study by Pignata et al.,[26] which reported cisplatin 30 mg/m2 and paclitaxel 50 mg/m2 as the MTD. Both these studies reported tumor response rates more than 90%. Disilvestro et al.[29] did a phase I/ phase II study where cisplatin and paclitaxel where used as radio sensitizers in cervical cancer. The MTD reported was cisplatin 40 mg/m2/week and paclitaxel 40 mg/m2/week. The phase II part of this study reported a complete response rate of 89.4% with acceptable toxicity profile. There was another phase II study by Miglietta et al.[28] where cisplatin 75 mg/m2 and paclitaxel 175 mg/m2 was given once every 3 weeks for four cycles. First cycle was given as neoadjuvant chemotherapy, second and third cycles where given along with external radiotherapy and the fourth cycle was given with brachytherapy. They reported a complete response rate of 100%. A phase I study was carried out in India to find out the MTD of the combination of cisplatin and paclitaxel as concurrent chemotherapy in women with locally advanced squamous cell carcinoma of the cervix.[25] This study concluded that cisplatin 30 mg/m2/week and paclitaxel 40 mg/m2/week for four cycles along with radiation was well‑ tolerated and this dose was recommended for further phase II trials. The present phase II study used the Indian phase I MTD to find out the efficacy and toxicity of combined cisplatin and paclitaxel along with radiation in the treatment of locally advanced squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS The study was initiated after obtaining clearance from the Institutional Review Board. Patients were included in the trial after getting a written informed consent. We decided to accrue 25 patients who fulfill the inclusion criteria. The inclusion criteria were women with squamous cell carcinoma of the uterine cervix with stages 1B2 to III B, with good performance score (Eastern Cooperative Oncology Group 0, 1 or 2) and an informed consent. Patients were excluded from the trial if they have any histopathology other than squamous cell carcinoma, any history of previous treatment for cervical cancer, hepatic, renal or cardiac dysfunction, poor hematological reserve (hemoglobin
