INTRODUCTION. J. Radiat. Res., 53, (2012)

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1 J. Radiat. Res., 53, (2012) The Effects of Two HDR Brachytherapy Schedules in Locally Advanced Cervical Cancer Treated with Concurrent Chemoradiation: A Study from Chiang Mai, Thailand Ekkasit THARAVICHITKUL 1 *, Pitchayaponne KLUNKIN 1, Vicharn LORVIDHAYA 1, Vimol SUKTHOMYA 1, Somvilai CHAKRABHANDU 1, Nantaka PUKANHAPHAN 1, Imjai CHITAPANARUX 1 and Razvan GALALAE 2 Cervix carcinoma/hdr/brachytherapy/schedules. Efficacy of different schedules of HDR brachytherapy in concurrent chemoradiotherapy was evaluated. The study compared the effectiveness of the two HDR brachytherapy schedules which have the same Biological Effective Dose (BED) in locally advanced cervical carcinoma that was treated with concurrent chemoradiotherapy. Included in the study were 377 randomly selected patients with advanced carcinoma of the cervix uteri who were treated during the period Patients were divided into : 7.2 Gy 3 fractions and : 6 Gy 4 fractions. With a median follow-up time of 35 months, local control, disease-free survival and overall survival rates were 80.8%, 63.4%, 98.8% in group I and 86.7%, 63.8%, 97.3% in group II, respectively. There was no statistical significance in terms of local control, disease-free survival, overall survival and complication rates between the two treatment schedules which could be observed. Seven patients in group I developed acute grade 2 4 GI toxicities and two patients in group II. In GU toxicities, there were three patients in group I and three patients in group II who developed grade 2 4 toxicities. In late toxicity, no patient developed grade 3 4 GU toxicities in group I while two patients developed grade 3 4 GU toxicities in group II. In GI toxicities, there were five and six patients in group I and group II, respectively, who developed grade 3 4 severity. Both HDR schedules seem to be safe and effective for the treatment of locally advanced cervical cancer. INTRODUCTION Radiotherapeutic treatment of cervical cancer has mainly consisted of External Beam Radiotherapy (EBRT) and Intracavitary Brachytherapy (ICBT). The goal of brachytherapy was to augment the dose of a paracentral point to the dose of Gy. 1) Doses of ICBT were still controversial according to institutional experience but maintained the principles of the International Commission of Radiological Units (ICRU). 2) In ICRU #38, the methods of determining the measurement of bladder and rectal dose points were *Corresponding author: Phone: , Fax: +66/ , paan_31@hotmail.com 1 The Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 2 Paul Schrer Institute, Zurich/Villingen, Switzerland and Medical Faculty, Christian- Albrechts-University of Kiel, Germany. Competing interests: The authors declare that they have no competing interests. doi: /jrr identified and the limitations of the dosage at these points noted. High-Dose-Rate (HDR) brachytherapy began in 1958 and has become highly developed during the past 30 years. Iridium-192 (Ir-192) usage was developed utilizing small units which could be applied in many techniques and sites of treatment. The advantages of HDR were rigid immobilization, outpatient treatment, patient convenience, and potential cost savings. 3) In carcinoma of cervix uteri, ICBT with HDR brachytherapy has been administered for many years. The confirmation of meta-analysis showed that there was no difference in efficacies and toxicities between LDR and HDR. 4) Although the usage of HDR brachytherapy in cervical cancer nowadays is agreed without question, the optimal dosage schedule is still controversial. The practical use of HDR brachytherapy varies according to the experiences of individual institutions. The American Brachytherapy Society (ABS) published a recommended dosage schedule of ICBT in cervical cancer in ) The recommended dosage of Gy in 4 6 fractions combined with EBRT Gy was considered acceptable. From the guidelines of the Japan Society of Gynecologic Oncology, the Japanese standard schedule (with the dose of Gy in 3 4 fractions

2 282 E. Tharavichitkul et al. combined with EBRT Gy) has a lower total radiation dose compared with those in the United States. 6) With the standard dose guidelines, the Biological Effective Dose (BED) at point A (α/β = 10) was Gy 10 in ABS recommendations and Gy 10 in the Japanese schedule. So, the optimal HDR-fractionation schedule for the treatment of cervical cancer remained under debate. Various fractionation schemes have been used experimentally in search of the optimal technique. 7) Presently, completed data has confirmed that the results of combined modality therapy (especially with a platinum-containing regimen) can lead to a prolonged time before disease recurrence and an increase in overall survival in locally advanced cervical cancer. 8 10) However, little comparative study between HDR dose schedules has been performed in locally advanced cervical cancer treated with concurrent chemoradiotherapy. This study was performed to evaluate the efficacy of a different schedule of HDR brachytherapy in concurrent chemoradiotherapy. Two HDR brachytherapy schedules were compared utilizing the same Biological Effective Dose (BED) to point A (α/β = 10) for locally advanced cervical carcinoma treated with concurrent chemoradiotherapy. MATERIALS AND METHODS Patient characteristics After approval from the ethics committee, patients with locally advanced carcinoma of the cervix uteri who were treated from 2004 to 2006 were included in the study. All patients had the following characteristics: stage IIB-IVA by FIGO staging, ages years, histology proven carcinoma of cervix uteri, Estern Cooperative Oncology Group (ECOG) performance status scale 0 1, no uncontrolled medical conditions, no previous pelvic surgery or irradiation and had signed the consent form for treatment protocol. Patients who had stage IVB (metastatic disease), allergy were excluded from the study due to their different management. Radiation techniques In External Beam Radiotherapy (EBRT), 6 10 MV photons by PRIMUS linear accelerators were used to treat the whole pelvis. The daily fraction of 2 Gy, five days per week was used to a dose of 50 Gy. Central shielding was applied after 40 Gy regardless of stage. Parametrial boost was used to build up the dose of parametrium to 56 Gy. All patients were treated with concurrent chemoradiotherapy with cisplatin (40 mg/m2 weekly, totally 6 cycles) or mitomycin-c (10 mg/m2 wk 1 and wk 6). The first ICBT was started at the fourth week of radiation therapy. The Fletcher-Suit applicator (Asia-Pacific version) was used in this treatment. In cases of extensive vaginal involvement, intra-vaginal cylinders were used in tandem to treat the primary lesion and vaginal extension. Patients were prospectively randomized into two treatment schedules as follows: : Gy : 4 6 Gy Application of ICBT was performed on an outpatient basis with non-narcotic analgesics. For ICBT simulation, orthogonal films of antero-posterior and lateral views were taken with the applicators inserted, and the position of point A, bladder and rectal points were defined according to the Manchester method and ICRU 38 recommendations. 2) The Linear Quadratic equation was used to calculate the dose to point A which can be calculated as in the following: Biologically effective dose (BED) to the point A (α/β = 10) BED = D (1 + d/α/β) For whole pelvis RT, the BED 10 was 40(1 + 2/10) = 48 Gy 10. For ICBT group I (21.6 Gy/3 Fr), the BED 10 was 21.6( /10) = 37.2 Gy 10. For ICBT group II (24 Gy/4 Fr), the BED 10 was 24(1 + 6/10) = 38.4 Gy 10. So the total BED 10 of was 85.2 Gy 10 and total BED 10 of group II was = 86.4 Gy 10. Evaluation During treatment, patients were appointed to visit the physician to evaluate the toxicities according to the National Cancer Institute; Common Terminology Criteria of adverse event (CTCAE) version ) After the treatment was completed, patients were appointed to visit for a vaginal examination (PV exam) in a follow-up program. A vaginal examination was performed to evaluate the disease status according to the World Health Organization (WHO) criteria. 12) Late toxicities were evaluated according to the Radiation Therapy Oncology Group/ European Organization of Research and Treatment of Cancer (RTOG/EORTC) late toxicity criteria. 13) Statistical analysis All data were inputed to SPSS software version Tumor response rate, local control, disease-free survival, and Overall survival rates were evaluated between the two groups by the chi-square test. Survival data were calculated by the Kaplan-Meier method and log-rank test to identify any statistical significance between the two groups. 14,15) RESULTS Patient data A total of 377 patients were included in this study. Seventeen patients were excluded due to poor compliance. Therefore, 172 Patients were randomized in group I (3 7.2 Gy) and the others were randomized in group II (4 6 Gy).

Comparison of Two HDR Schedules in Cervix 283 The total treatment time was 49 days in both groups. All data are shown in Table 1. a) Local control rate (p = 0.

3% in group II, respectively. All data of both groups are shown in Table 2 and Fig. 1. Analysis was performed on stage IIB and stage IIIB which had the largest populations in these groups.

3 Comparison of Two HDR Schedules in Cervix 283 The total treatment time was 49 days in both groups. All data are shown in Table 1. a) Local control rate (p = 0.146) Treatment results With the median follow-up time of 35 months, local control, disease-free survival and overall survival rates were 80.8%, 63.4%, 98.8% in group I and 86.7%, 63.8%, 97.3% in group II, respectively. All data of both groups are shown in Table 2 and Fig. 1. Analysis was performed on stage IIB and stage IIIB which had the largest populations in these groups. In stage IIB, local control, disease-free survival and overall survival rates were not statistically significant between both groups. In stage IIIB, the tendency was the same except local control rates in stage IIIB (p = 0.065). All data of both groups are shown in Table 3 and Figs Toxicity profiles In the toxicity profiles, seven patients in group I developed acute grade 2 4 gastrointestinal toxicities and two patients in group II. In genitourinary toxicities, there were b) Disease-free survival rate (p = 0.971) Table 1. Patient characteristic data between two groups Parameters (3 7.2 Gy) N = 172 (4 6 Gy) N = 188 P-value Age 49 (30 69) 50 (31 69) Stage IIB IIIA 2 2 IIIB IVA 0 2 Histology SCCA ACA Others 5 7 Chemotherapy Cisplatin Mitomycin-C c) Overall survival rate (p = 0.336) Table 2. The three year local control rate, disease-free survival rate and overall survival rate between group I (3 7.2 Gy) versus group II (4 6 Gy) Parameters (N = 172) (N = 188) Local control rate 80.70% 86.10% Disease-free survival rate 67.60% 68.10% Overall survival rate 98.40% 96.70% Fig. 1. Kaplan-Meier curve showing a) local control rate b) diseasefree survival rate and c) overall survival rate of group I (blue line) versus group II (green line).

284 a) Local control rate in stage IIB (p = 0.763) E. Tharavichitkul et al. a) Local control rate in stage IIIB (p = 0.065) b) Disease-free survival rate in stage IIB (p = 0.

Kaplan-Meier curve showing a) local control rate b) diseasefree survival rate and c) overall survival rate group I (blue line) versus group II (green line) in stage IIB of carcinoma of the

4 284 a) Local control rate in stage IIB (p = 0.763) E. Tharavichitkul et al. a) Local control rate in stage IIIB (p = 0.065) b) Disease-free survival rate in stage IIB (p = 0.525) b) Disease-free survival rate in stage IIIB (p = 0.327) c) Overall survival rate in stage IIB (p = 0.602) c) Overall survival rate in stage IIIB (p = 0.447) Fig. 2. Kaplan-Meier curve showing a) local control rate b) diseasefree survival rate and c) overall survival rate group I (blue line) versus group II (green line) in stage IIB of carcinoma of the cervix uteri. Fig. 3. Kaplan-Meier curve showing a) local control rate b) diseasefree survival rate and c) overall survival rate of group I (blue line) versus group II (green line) in stage IIIB of carcinoma of the cervix uteri.

5 Comparison of Two HDR Schedules in Cervix 285 Table 3. The three year local control rate, disease-free survival rate and overall survival rate of group I (3 7.2 Gy) versus group II (4 6 Gy) according to stage Stage IIB (N = 106) (N = 109) Local control rate 84.50% 87.60% Disease-free survival rate 73% 74.30% Overall survival rate 98.80% 97.90% Stage IIIB (N = 64) (N = 75) Local control rate 73% 82.20% Disease-free survival rate 58.80% 57.40% Overall survival rate 97.40% 94.50% Table 4. Acute toxicity of group I (3 7.2 Gy) versus group II (4 6 Gy) Acute toxicities (N = 172) (N = 188) GI toxicities grade % 46.30% grade % 1.10% 0.09 GU toxicities grade % 21.80% grade % 1.60% Table 5. Late toxicity profiles of group I (3 7.2 Gy) versus group II (4 6 Gy) Late toxicities (N = 172) (N = 188) GI toxicity grade % 10.10% grade % 2.70% GU toxicity grade % 5.30% grade % 0 three patients in group I and three patients in group II who developed grade 2 4 toxicities. No statistical significance could be observed in both GI (0.123) and GU (0.991) toxicities. In late toxicity, no patient in group I developed grade 3 4 GU toxicities while two patients in group II developed grade 3 4 GU toxicities. In GI toxicities, there were six and five patients in group I and group II, respectively, who developed grade 3 4 severity. All data are shown in Tables 4 and 5. DISCUSSION Intracavitary brachytherapy is one component of the radiotherapeutic treatment of carcinoma of cervix uteri. The dosage schedule of brachytherapy in cervical cancer is controversial. High-dose-rate brachytherapies are used worldwide due to the short treatment time, outpatient basis and better radiation protection for hospital staff. 16,17) The optimal fractionation schedules for HDR brachytherapy are still controversial. Orton et al. showed an increase of morbidity when the dose per fraction at point A was higher than 7 Gy. 18) Petereit et al. reported the results of HDR brachytherapy for cervix cancer using different regimens, however, this study failed to identify the optimal fractionation. 4) Consequently, the study of the fractionation schedule of HDR brachytherapy continues to have a lack of data support. A few studies tried to compare the effectiveness of the different schedules and the results revealed no statistical significance. From the study of Wong et al., the retrospective study reported the results of 7 Gy 3 fractions versus 6 Gy 4 fractions in 220 patients. They found that the two HDR fractionation schedules were not a significant prognosticator in the prediction of disease control and complications. 19) In the study from Korea by Nam et al., 46 patients were included in a comparison between 3 Gy 10 fractions (group A) versus 5 Gy 5 fractions (group B). The three year disease-specific survival rates of group A and B were 90.5% and 84.9%, respectively (p = 0.64). No difference of the three-year pelvic control was observed (p = 0.92). The incidences of late complications of the rectum or bladder of grade 2 or greater in group A and group B were 23.8% and 9.1%, respectively (p = 0.24). It showed comparable results between the both fractionation schedules. 20) In this study, the results of 7.2 Gy 3 fractions versus 6 Gy 4 fractions were comparable. No difference was observed in local control, disease-free survival and overall survival rates in group I versus group II. In stage IIB, local control, disease-free survival and overall survival rates between group I and group II were not statistically significant. In stage IIIB, no statistical significance in all parameters could be observed although there was an improvement of local control in group II (73% vs. 82.2%). In toxicity profiles, the grade 2 4 acute toxicities were equal between the two groups in terms of gastrointestinal toxicities and genitourinary toxicity aspects. In late toxicities, no statistical significance between the two groups in terms of grade 3 4 gastrointestinal toxicities and genitourinary toxicities was observed. The patient characteristics of both groups were not statistically significant in age, stage and histology. The median treatment time between group I and group II was 49 days which might be one of the factors. For the chemotherapy schedules (cisplatin vs. mitomycin- C), the analysis from our institution was published by

6 286 E. Tharavichitkul et al. Kamnerdsupaphon et al. At the median follow-up time of 17.5 months, the overall survival of these concurrent nonplatinum chemoradiation were not inferior to the standard cisplatin-based regimen (p = 0.19), although the disease-free survival showed a significant difference favoring the cisplatin arm (p = 0.006). 21) Our results showed that the acute side effects are tolerable in patients who are treated with concurrent chemoradiotherapy and late complications were similar. This study showed comparable results of the two fractionation schedules of high-dose-rate brachytherapy in carcinoma of cervix uteri. In stage IIIB, the dose of 4 6 Gy was better than the dose of Gy in terms of local control rates but not in disease-free survival and overall survival rates. For the BED 10, our study showed the BED 10 of 85.2 Gy 10 in group I and 86.4 Gy 10 in group II which related to the recommended dose of ABS. 5) When compared with the Japanese schedule (Nakano et al.) which showed the BED 10 of Gy 10 in locally advanced disease (stage II/ III), our BED 10 was higher. 22) In comparison with our routine schedule reported by Lorvidhaya in 2003, the BED 10 was around 87.6 to Gy 10. Although the BED 10 was high, the overall rate of Grades 3 and 4 RTOG complications was 4.2%. 23) Interestingly, the study for Toita et al. showed the cumulative BED Gy 10 at point A is appropriate for uterine cervical cancer patients treated with a combination of EBRT and HDR-ICBT. Moreover, the study reported patients who received treatment with 86.4 Gy 10 at point A suffered both proctitis and enterocolitis which equalled to the BED10 of our study in group II (4 6 Gy). 24) However, our study in this group showed only 2.7% of grade 3 4 GI late complications. In summary, our study showed that no statistical significance in terms of local control, disease-free survival, overall survival and complication rates between the two treatment schedules could be observed. The two HDR schedules seem to be safe and effective for the treatment of locally advanced cervical cancer. ACKNOWLEDGEMENTS The authors wish to thank Dr. Apichart Panichchewalak, Dr. Pimkhuan Kamnerdsupaphon and all staffs of The division of therapeutic radiology and oncology, faculty of medicine, Chinag Mai University for their initial findings which provided the foundation of this study. REFERENCES 1. Perez CA, et al (1986) Radiation therapy alone in the treatment of carcinoma of the uterine cervix: a 20-year experience. Gynecol Oncol 23: ICRU report 38 (1985) Dose and volume specification for reporting intracavitary therapy in gynecology. Bethesda, MD: International Commission on Radiation Units and Measurements: Ferrigno R, et al (2001) High-dose rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications. Int J Radiat Oncol Biol Phys 50: Petereit DG and Pearcey R (1999) Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: Is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 43: Nag S, et al (2000) The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carinoma of the cervix. Int J Radiat Oncol Biol Phys 48: Toita T, et al (2009) Current status and perspectives of brachytherapy for cervical cancer. Int J Clin Oncol 14: Viani GA, et al (2009) Brachytherapy for cervix cancer: lowdose rate or high-dose rate brachytherapy-a meta-analysis of clinical trials. J Exp Clin Cancer Res 28: Whitney CW, et al (1999) A Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17: Morris M, et al (1999) Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for highrisk cervical cancer. N Engl J Med 340: Rose PG, et al (1999) Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340: National Cancer Institute (2003) Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events. Version 3.0. DCTD, NCI, NIH, NHHH Miller AB, et al (1990) Reporting results of cancer treatment. Cancer 47: Cox JD, Stetz J and Pajak TF (1995) Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 31: Kaplan EL and Meier P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: Orton C (1991) HDR: forgot not time and distance. Int J Radiat Oncol Biol Phys 20: Speiser B (1991) Advantages of high dose rate remote afterloading systems: physics or biology. Int J Radiat Oncol Biol Phys 20: Orton CG, Seyedsadr M and Somnay A (1991) Comparison of high and low dose rate remote afterloading for cervix cancer and the importance of fractionation. Int J Radiat Oncol Biol Phys 21: Wong F, et al (2003) Treatment results of high-dose-rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimens. Int J Radiat Oncol Biol Phys 55: Nam TK and Ahn SJ (2004) A prospective randomized study on two dose fractionation regimens of high-dose-rate brachytherapy for carcinoma of uterine cervix: comparison of effica-

7 Comparison of Two HDR Schedules in Cervix 287 cies and toxicities between two regimens. J Korean Med Sci 19: Kamnerdsupaphon P, et al (2008) Cisplatin vs. mitomycin in concurrent with radiotherapy for locally advanced cervical cancer. J Thai Soc Ther Radiol Oncol 14: Nakano, et al (2005) Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix. Cancer 103: Lorvidhaya, et al (2003) Concurrent mitomycin c, 5-fluorouricil, and radiotehrapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 55: Toita T, et al (2003) Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cervical cancer: analysis of dose and fractionation schedule. Int J Radiat Oncol Biol Phys 56: Received on March 8, 2011 Revision received on May 29, 2011 Accepted on June 2, 2011

High-Dose-Rate Orthogonal Intracavitary Brachytherapy with 9 Gy/Fraction in Locally Advanced Cervical Cancer: Is it Feasible??

DOI 10.1007/s13224-015-0812-8 ORIGINAL ARTICLE High-Dose-Rate Orthogonal Intracavitary Brachytherapy with 9 Gy/Fraction in Locally Advanced Cervical Cancer: Is it Feasible?? Saptarshi Ghosh 1 Pamidimukalabramhananda