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ORIGINAL ARTICLE
Year : 2010  |  Volume : 6  |  Issue : 4  |  Page : 482-486

Treatment results of radical radiotherapy of carcinoma uterine cervix using external beam radiotherapy and high dose rate intracavitary radiotherapy


Department of Radiotherapy, Regional Cancer Centre, Dr. B. R. A. M. Hospital, Raipur - 492 001, India

Date of Web Publication24-Feb-2011

Correspondence Address:
S K Azad
G/10, Pink City, Gayatrinagar, Raipur (CG) - 492 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.77108

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 > Abstract 

Aim: To report the outcome of carcinoma cervix patients treated radically by external beam radiotherapy and high dose rate intracavitary radiotherapy.
Material and Methods: From January 2005 to December 2006, a total of 709 newly diagnosed cases of carcinoma cervix were reported in our department. All cases were staged according to the International Federation of Gynecologist and Oncologist staging system. Out of 709 cases, 342 completed radical radiotherapy and were retrospectively analyzed for the presence of local residual disease, local recurrence, distant metastases, radiation reaction, and disease free survival.
Results: There were 11(3.22%), 82(23.98%), 232(67.83%), and 17(4.97%) patients in stages I, II, III, and IV, respectively. The median follow up time for all patients was 36 months (range 3 -54 months). The overall treatment time (OTT) ranged from 52 to 69 days (median 58 days). The 3 year disease free survival rate was 81.8%, 70.7%, 40.08%, and 11.76% for stages I, II, III, and IV, respectively. There were 91 (26.6%) cases with local residual diseases, 27(7.9%) developed distant metastasis, and 18(5.26%) pts had local recurrence.
Discussion: The results of this study suggest that radical radiotherapy with HDR brachytherapy was appropriate for the treatment of early staged cancer of uterine cervix. For locally advanced cancer of cervix addition of concurrent chemotherapy, higher radiation doses, reduction of overall treatment time to less than 8 weeks, and use of latest radiotherapy techniques such as IMRT is recommended to improve the results.

Keywords: Brachytherapy, carcinoma cervix, chemotherapy, radical radiotherapy


How to cite this article:
Azad S K, Choudhary V. Treatment results of radical radiotherapy of carcinoma uterine cervix using external beam radiotherapy and high dose rate intracavitary radiotherapy. J Can Res Ther 2010;6:482-6

How to cite this URL:
Azad S K, Choudhary V. Treatment results of radical radiotherapy of carcinoma uterine cervix using external beam radiotherapy and high dose rate intracavitary radiotherapy. J Can Res Ther [serial online] 2010 [cited 2019 Nov 12];6:482-6. Available from: http://www.cancerjournal.net/text.asp?2010/6/4/482/77108


 > Introduction Top


Cervical cancer continues to be a significant health burden in developing countries such as India, Latin America, Southern and Eastern Africa where the majority of cases are locally advanced at diagnosis; hence, radiation remains the most frequently used modality of treatment. In the treatment policy evolved by Fletcher, initial external beam radiotherapy [EBRT] is given to the whole pelvis to induce primary tumor shrinkage and to sterilize microscopic disease within the pelvic nodes. Intracavitary brachytherapy is then used to boost the dose to primary tumor after completion of EBRT when the tumor volume is considerably smaller and brachytherapy dose distribution to residual tumor is improved. [1] The success of brachytherapy requires delivery of a high radiation dose to the tumor while sparing the surrounding normal tissue. Carcinoma of cervix is the most common malignancy at our center. Our hospital has facility of one telecobalt unit (Theratron 780 E), one HDR remote afterloading brachytherapy unit (Microselectron HDR), and a computerized treatment planning system (Plato). This study aimed to evaluate the overall outcomes of the carcinoma of cervix cases treated radically by external beam radiation and high dose rate intracavitary radiotherapy.


 > Materials and Methods Top


A total of 709 newly diagnosed cases of carcinoma of cervix were reported in the department of radiotherapy from January 2005 to December 2006. Out of this, only 342 patients completed their scheduled EBRT + HDR ICRT treatment and were analyzed retrospectively for residual disease, local recurrence, distant metastases, radiation reactions, and disease-free survival. Two hundred patients were not given ICRT due to large residual growth. These cases were given only EBRT with reduced field size with a total dose of 60-66 Gy. These 200 cases were excluded from study. 167 cases discontinued their treatment during EBRT. These patients are also excluded from the study. Histopathological confirmation was done for all patients. All cases were investigated with routine hematological and biochemical examination, X-ray chest, and sonography of abdomen and pelvis before starting radiotherapy treatment. All patients were examined and staged clinically according to the FIGO staging system. Patient characteristics are shown in [Table 1].
Table 1: Patient profile

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EBRT was administered to the whole pelvis to a total dose of 4600 cGy in 23 fractions over a period of 4.5 weeks (Monday to Friday of every week) using a Cobalt-60 machine (Theratron 780 E) at a source-skin distance of 80 cm by parallel opposing antero-posterior and postero-anterior fields. The upper margin of the EBRT port was the L4-L5 junction and the lower margin was 2 cm below the bottom edges of lesions. Lateral margins were 1 cm lateral to the bony pelvis. Patient was instructed to keep the urinary bladder full during radiation so as to minimize the intestinal toxicities.

After completion of external radiotherapy all the cases were examined for fitness to brachytherapy. Patients were planned for brachytherapy within 7 to 14 days. All cases were given three fractions of HDR-ICRT with a week's interval. Applicator insertion was done under general anesthesia. The vagina was packed with regular betadine-soaked gauze packs to push the bladder and rectum away and to stabilize the applicator. A Foley's catheter was inserted and the balloon was inflated with 7 cc of diluted urograffin to allow identification of the bladder neck region. A rectal marker was inserted in to rectum to visualize the rectal mucosa for rectal points. After applicator insertion AP and lateral semi-orthogonal marker x ray films were taken for pelvic dosimetry. Planning was done with the help of the Plato computerized treatment planning system. The dose was prescribed to point A. Point A is described as a point 2 cm up from the cervical os point of the uterine tube (tandem) and 2 cm lateral to the uterine source on both sides. Bladder reference points were marked on the anterior radiograph at the center of the balloon; on the lateral radiograph an anteroposterior line was drawn through the center of the Foley's catheter balloon and the bladder reference point was taken on the line at the posterior surface of the balloon as per the recommendations given in Report 38 of the International Commission for Radiation Units (ICRU). [2] For rectal reference points we used the rectal marker. Multiple rectal reference points were delineated on the lateral radiograph. For R1 rectal point in the lateral radiograph, an anteroposterior line was drawn through the lower end of the uterine source to a point 5 mm anterior to the rectal marker. Four more rectal points R2, R3, R4, and R5 were taken above and below the R 1 point at a distance of 1 cm one from another. All points were in the line of the rectal marker. The doses of urinary bladder and rectum were calculated on bladder and rectal reference points. [3] Dose delivered was 19.5 Gy to point A in three fraction at weekly interval (per fraction dose was 6.5 Gy). Bladder and rectal doses were limited to 80% of the prescribed point A dose as per the ICRU 38 recommendations. [2] Brachytherapy treatment was delivered by HDR 0 remote after loading unit in which a single high stepping iridium source was used. The Fletcher suit applicator was used in all patients. No procedural complication was seen. The total equivalent dose delivered to point A was 76 Gy of EBRT. The median cumulative point A dose (sum of EBRT mid line dose and point A dose of HDR-ICRT) was 65.5 Gy. The median cumulative bladder and rectal doses were 61.5 Gy and 59.3 Gy, respectively. The total duration of treatment was approximately 8.5 +/- 1 week. Treatment particulars are shown in [Table 2].
Table 2: Treatment profile

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All the patients reviewed monthly after completion of treatment for 6 months for the assessment of treatment response and treatment-related complications. After this they were reviewed every 2 months for 1 year and 3 monthly for next 3 years. On follow up, patients were examined clinically and routine pelvic examination was done in each patient. Investigations such as X-ray, sonography, and CT were done based on the patients complains and examination findings to rule out any locoregional and distant metastasis. Late complications were graded in accordance with the radiation therapy oncology group (RTOG) criteria especially for bladder, rectum, and bowel complications. Disease-free survival was calculated from the date of completion of treatment till the last follow up in August 2009. The follow up period was 3-54 months.

Patients who did not have either local residual/recurrent lesion or distant metastases till the last follow up were counted as disease free. The different results were analyzed using simple statistical values like mean, mode, and median. Med Calc 11.1.0 is used for statistical analysis. For overall survival, disease-free survival, and pelvic control, the duration was calculated from the date of completion of radiotherapy to the time of event. All losses to follow up were considered as an event for survival analysis.


 > Results Top


Three hundred forty two patients were the subjects for this retrospective analysis. Median cumulative dose to point A was 65.5 Gy. Bladder and rectal doses were 61.5 Gy and 59.3 Gy, respectively. Biological effective dose (BED) to point A was 87.4 Gy for tumor and 138.6 Gy for late responding tissue. BED doses for bladder and rectal reference points were 80.9 Gy, 77.1Gy, 126.2Gy, and 118.9 Gy for early and late responding tissues, respectively. Follow up period ranged from 3 months to 54 months with a median of 36 months. Overall, 45 (13.15%) patients were lost to follow up after completion of radiotherapy and 161 (47.07%) patients were disease free. The overall pelvic control rate was 47.07%. In stage I there were only 11 patients: 2 patients were lost to follow up and the other 9 (81.8%) were disease free till the last follow up. In stage II there were 82 patients: 58 (70.7%) were disease free till the last follow up and 4 patients were lost to follow up. In stage III there were 232 patients, out of which 37 patients were lost to follow up and only 92 (40.08%) were disease free. In stage IV there was 17 patients, out of which 2 patients was lost to follow up and only 2 (11.76%) were disease free. Details of disease free survival and pattern of failure according to disease stage are shown in [Table 3].
Table 3: Disease-free survival with patterns of failure according to disease status after radiotherapy

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The 3 year disease-free mean survival rate was 81.8%, 70.7%, 40.08%, and 11.76% with 95% confidence interval of 64.33-100.68 , 54.52-88.44, 28.58-54.47, and 5.49-19.68 for stages I, II, III, IV respectively. Overall survival rate was 81.8%, 78%, 54.3%, and 41.1% for stages I, II, III, and IV, respectively, at the end of third year. Kaplan Meier survival curve is shown in [Figure 1].
Figure 1: Disease-free survival

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Univariate and multivariate analyses showed that FIGO staging and OTT (overall treatment time) had a significant effect on survival in locally advanced carcinoma of cervix. The disease-free survival rate was 72.04% and 37.75% for early (stage I and II) and locally advanced carcinoma (stages III and IV A) with P value of 0.0001. DFS was 51.6% when OTT exceeded 56 days in comparison to 70.9 % when OTT was less than 56 days with P value of 0.001. Age and histology had no significant effect on survival. Details of multivariate analysis are shown in [Table 4].
Table 4: Univariate and multivariate analysis

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In the most of the patients recurrence was at the primary site and this tented to occur within 2 years of completion of treatment. Out of the 342 patients in the study group, 91 (26.6%) had local disease on routine monthly follow up in the initial 6 months. 45 (13.15%) patients were found to have recurrence/metastasis in subsequent follow ups. Distant metastasis was detected in 27 (7.87%) patients. Out of which nine had local disease also. The remaining 18 (5.26%) patients had only local recurrence. No significant difference was seen in metastatic pattern among different histology. Details of the recurrence pattern and metastasis sites are shown in [Table 5].
Table 5: Various sites of metastases

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We have not come across any severe acute treatment-related complications with EBRT and HDR ICRT. Late complications involving the bowel and bladder according to RTOG criteria were found in 62 (18.12%) patients. Bladder complications were seen in 21 (6.14%) patients, and rectal complications in 32(9.35%) patients. One patient had grade 3 radiation cystitis and two had grade 3 proctitis. [4],[5] All the patients were managed symptomatically with stool softeners and steroid enemas for proctitis and urinary analgesics, bladder irrigations, and plenty of oral fluids for cystitis. Rectal toxicities appeared within 3-20 months and bladder toxicities appeared between 6 and 36 months. Details of late radiation toxicities are shown in [Table 6].
Table 6: Late complication with radiotherapy

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 > Discussion Top


Radiotherapy is an effective treatment modality for all stages of carcinoma cervix. American Brachytherapy Society recommends multiple HDR insertions to allow progressive tumor volume reduction, allowing more effective disease coverage with subsequent applications. [6],[7] The results of the present study were more or less equal to results reported by other authors with respect to survival rate and were shown in [Table 7] and [Figure 2]. In this study, DFS was only 37.75% for locally advanced disease (stage III and IV A) in comparison to early staged cancer (72.04%). In most of the studies disease-free survival was less than 50% in locally advanced carcinoma cervix (stage III and IV). [8],[9],[10],[11],[12],[13],[14] In our study FIGO staging and OTT were the important prognostic factors which affect the response, [15] disease-free survival and pelvic control rate in locally advanced cervical cancer with P value of 0.0001 and 0.001, respectively. Out of 249 patients with locally advanced cancer only 94 (37.75%) patients were disease free till last follow up. In this study OTT was more than 56 days in 136 cases with 51.6% disease free survival in comparison to 70.9% in 206 patients with OTT less than 56 days and was responsible for poor outcome. Several studies estimate that survival and pelvic control decreases by < 1% per day with prolongation of radiation treatment beyond 7 to 8 weeks. [16] Pretreatment hemoglobin was less than 10 g% in 97 patients (28.3%) and had no significant effect on outcome (P = 0.194) in our study. Although Girinski et al., has reported that hemoglobin reading of less than 10 g% before or during radiation therapy was associated with reduced cause specific survival and locoregional control. Other factors such as age, gross feature and histology were also evaluated but no significant effects were seen in outcome.
Table 7: Five-year survival rate for cervix cancer

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Figure 2: Comparison of five-year survival among different studies

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Various chemotherapeutic agents have been tried concurrently with radiotherapy in different studies to improve the survival in stages III and IV of carcinoma cervix, and cisplatin has produced an absolute increase in the 5 year survival rate of 12% compared with radiotherapy alone in the treatment of locally advanced cervical carcinoma. [17],[18] Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by NCI after results of five randomized trials and positioned it as the standard agent to be used to sensitize cancer cells to radiation in cervical cancer treatment but despite these significant achievements, therapeutic results are far from optimal and other chemotherapeutic agents need to be assayed for best results. [17],[18]

CT and MRI based 3 D CRT (three-dimensional computerized radiotherapy) and IMRT (intensity-modulated radiotherapy) has shown improved results in locally advanced cases of carcinoma cervix but routine use in developing countries like India is limited. [19]

In this retrospective study on outcomes in carcinoma cervix treated radically with EBRT and HDR- ICRT we came to following conclusions.

  1. Concurrent chemotherapy should be used along with radical radiotherapy in locally advanced carcinoma cervix to improve the outcome.
  2. Overall treatment time (OTT) should be kept less than 8 weeks for better results.
  3. Use of the latest radiotherapy techniques such as IMRT can further improve the survival in locally advanced carcinoma of cervix.


 
 > References Top

1.Hemberger AD. Squamous cell carcinoma of the uterine cervix. In: Fletcher GH, editor. Text book of radiotherapy. 3 rd ed. Philadelphia: Lee and Febiger; 1980. p. 720-31.  Back to cited text no. 1
    
2.ICRU.org [internet] Bathesda, USA; International Commission on Radiation Units and measurement Report 38. Dose and volume specification for intracavitary, Inc 1985 Available from http://www.icru.org [Last accessed on 2009 Nov 09].  Back to cited text no. 2
    
3.Chen SW, Liang JA, Yeh LS, Yang SN, Shiau AC, Lin FJ. Comparative study of reference points by dosimetric analyses for late complications after uniform external radiotherapy and high-dose-rate brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2004;60:663-71.  Back to cited text no. 3
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4.Stryker JA, Bartholomew M, Velkey DE. Bladder and rectal complications following radiotherapy for cervix cancer. Gynecol Oncol 1988;29:1-11.  Back to cited text no. 4
    
5.Saibishkumar EP, Patel FD, Sharma SC. Evaluation of late toxicities of patients with carcinoma of the cervix treated with radical radiotherapy: An audit from India. Clin Oncol 2006;18:30-7.  Back to cited text no. 5
    
6.Shakespeare TP, Lim KH, Lee KM, Back MF, Mukherjee R, Lu JD. Phase II study of the American Brachytherapy Society guidelines for the use of high-dose rate brachytherapy in the treatment of cervical carcinoma. Int J Gynecol Cancer 2006;16:277-82.  Back to cited text no. 6
    
7.Nag S, Erickson B, Thomadsen B, Orton C, Demanes JD, Petereit D. The American Brachytherapy society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 2000;48:201-11.  Back to cited text no. 7
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8.Kosary CL. Cancer of cervix uteri. In: Ries LA, Young JL, Keel GE, Eisner MP, Lin YD, Horner MJ, editors. SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics. NIH Pub.No.07-6215. Bethesda, MD: National Cancer Institute, SEER Program; 2007. p. 111-22.  Back to cited text no. 8
    
9.Eilic S, Ristic B. Five year results with HDR after loading in cervix cancer: Dependence on fractionation and dose. Strahlenther Onkol 1988;82:139-46.  Back to cited text no. 9
    
10.Arai T, Nakano T, Morita S, Sakashita K, Nakamura YK, Fukuhisa K. High dose rate remote after loading intracavitary radiation therapy for cancer of the uterine cervix. Cancer 1992;69:175-80.  Back to cited text no. 10
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11.Shelke P, Roman TN, Souhami L, Freeman CR, Clark BG, Evans MD, et al. Treatment results of high dose rate brachytherapy in patients with carcinoma of the cervix. Int J Radiat Oncol Biol Phys 1993;27:803-9.  Back to cited text no. 11
    
12.Jain VS, Singh KK, Shrivastava R, Somsundaram KV, Sarje MB, Jain SM. Radical radiotherapy treatment (EBRT+HDR-ICRT) of carcinoma cervix: Outcome in patients treated at a rural center in India. J Cancer Res Ther 2007;3:211-7  Back to cited text no. 12
    
13.Ito H, Kutuki S, Nishiguchi I, Shigematsu N, Kuribayashi T, Uematsu M, et al. Radiotherapy for cervical cancer with high-dose rate brachytherapy, correlation between tumor size, dose and failure. Radiother Oncol 1994;31:240-7.  Back to cited text no. 13
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14.Annual report on the results of treatment on the gynecological cancer. In: Patterson F, editor. Twentieth volume statements of results obtained in patients treated in 1979-1981. Inclusive 5 year survival up to 1986. Stockholm: International Federation of Gynecology and Obstretics; 1987. p.52.  Back to cited text no. 14
    
15.Kapp KS, Stuecklschweiger GF, Kapp DS, Poschauko J, Pickel H, Lahousen M, et al. Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and Ir 192 high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1998;42:531-40.  Back to cited text no. 15
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16.Fyles A, Keane TJ, Barton M, Simm J. The effect of treatment duration in the local control of cervix cancer. Radiother Oncol 1992;25:273-9.  Back to cited text no. 16
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17.King M, McConkey C, Latief TN, Hartley A, Fernando I. Improved survival after concurrent weekly cisplatin and radiotherapy for cervical carcinoma with assessment of acute and late side effects. Clin Oncol 2006;18:38-45.  Back to cited text no. 17
    
18.Greek 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 analyses. Lancet 2001;358:781-6.  Back to cited text no. 18
    
19.Kavanagh BD, Schefter TE, Wu Q, Tong S, Newman F, Arnfield M, et al. Clinical application of Intesity- modulated radiotherapy for locally advanced radiotherapy for locally advanced cervical cancer. Semin Radiat Oncol 2002;12:260-71.  Back to cited text no. 19
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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