Journal of Cancer Research Reviews & Reports

Introduction

Cervical cancer is the eighth most common cancer in women, and the seventh overall, with an estimated incidence of 528,000 new cases and 266,000 deaths from the disease worldwide in 2012 [1]. Cervical cancer also contributed nearly 8% of all cancers among women and around 4% in all population. However, global cervical cancer incidence increased from 378,000 cases per year in 1980 to 454,000 cases per year in 2010, a 6% annual rate of increase [2]. approximately 1.6% c all cancer deaths in women and 13% of deaths from gynecologic cancers. However, for women aged 20 to 39 years cervical cancer remained the second leading cause of cancer deaths after breast cancer [3].

Cervical cancer is highly prevalent in developing nations. There exist wide geographic variations. Cervical cancer is more common in Latin America and less frequent in Jewish and European women and Fiji Islanders [4]. International incidences of cervical cancer tend to reflect differences in cultural attitudes toward sexual promiscuity and differences in the penetration of mass screening programs. Countries that have well-advanced screening programs (e.g., the United States and the countries of western Europe) or strict religious regulation of sexual behavior (e.g., Muslim countries of the Middle East or Asia) tend to have low rates of invasive disease [5]. The highest: incidences tend to occur in populations that have low screening rates combined with a high background prevalence of human papillomavirus (HPV) infection and relatively liberal attitudes toward sexual behavior [6]. Although there is no national cancer registry in Bangladesh, the hospital- based cancer registry of National Institute of Cancer Research and Hospital for the period of 20082010 showed that 43.95% of all registered cases were female. The male female ratio was 1.28:1. The report also revealed that cervical cancer ranks the third among all malignancies during this period an.: the second most common cancers in female (Cancer Registry Report; NICRH, 2013). The treatment of cervical carcinoma requires multimodality approaches and depends largely on the stage of disease. Radiotherapy plays a major role in the management of locally advanced cervical cancer. Currently, the two main modalities of irradiation are external photon beam and brachytherapy. Both EBRT and ICRT are used, often in combination with chemotherapy. External irradiation is used to treat the whole pelvis and the parametrium including the common iliac and para- aortic lymph nodes, whereas cervix and parametrium is primarily irradiated with intracavitary sources. The techniques described applied, with some individualization, to most patients with cervical carcinoma. To achieve local control, and subsequently patient cure, very high doses have to be delivered to patients with locally advanced cervical cancer. Traditionally this treatment has been rather toxic and it has been reported that up to 20 - 25 % of the patients experience adverse side effects [7]. To optimize the treatment of locally advanced cervical cancer it is important to establish a firm knowledge about dose response relationship in cervical tumours as well as in OARs those are in close vicinity of the uterus. The urinary bladder and the rectum stand for most important OARs in radiation therapy of carcinoma cervix due to their anatomical position. For ICRT it is usual to prescribe treatment a dose point (the Manchester point A, in Manchester System, the dose is specific at point A) or isodose (reference isodose surface). In 1985 the ICRU published report 38 making recommendations on dose and volume specifications in intracavitary brachytherapy. Two points were defined for reporting the dose respectively the rectum and the urinary bladder. Traditionally, High Dose Rate after loaders has been based on Ir¹⁹² radionuclide. The high specific activity of iridium allowed very small sources to be used interstitially despite its short half- life period. Typically, Ir¹⁹² source exchange is required each 4-6 months to keep the treatment times within the limits required by clinical practice. A few years ago, new HDR after loaders have been introduced using Co⁶⁰ instead of Ir¹⁹²; which are provided with sources having the same size as the Ir¹⁹² ones and have been already implemented in some institutes which shows a clear tendency to increase their number. In fact, these sources have been considered in the recent AAPM-ESTRO Report [8] with recommendations about dosimetry methodology and consensus datasets have been presented for the two commercially existing sources. The Co⁶⁰ introducers claim important economic advantages because of the larger half-life period and the improved technology. At present there is no clear position on advantages or disadvantages of both HDR modalities, to be taken into account in future HDR facility implementation.

In this thesis acquired data from study subjects, diametrical as well as clinical data ware used to elucidate the comparison between dose distribution of two HDR brachytherapy radionuclides in the tumour and organs at risk during ICRT for cervical cancer.

Research Methodology

The study was designed as prospective observational study. This study conducted in the Department of Clinical Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka; Lab Aid Specialized and Cancer Hospital, Green Road, Dhaka; and Delta Hospital Ltd. Mirpur, Dhaka were done during the period of July 2021 to December 2022. Target population was patients with histopathologically proven cervical cancer having FIGO stage I1B - IVA disease, at these above-mentioned hospitals during the period of July 2021 to December 2022. They were convinced to participate in the study after giving written informed consent and satisfying inclusion and exclusion criteria and enrolled in the study.

Study population and sample were patients with locally advanced cervical cancer & received EBRT with concurrent chemotherapy. The objective this study was to compare the radiation dose distribution among tissue including reference point “A”, urinary bladder points and rectum point.

All patients were received EBRT 50 Gy in 25 fractions at 2 Gy per fraction with concurrent chemotherapy with low dose weekly Cisplatin 40 mg/m2 weekly. Followed by 3 insertions of intracavitary HDR brachytherapy at a dose of 7 Gy per insertion weekly. This hospital based comparative study in used histologically diagnosed 98 patients of cervical carcinoma. All the patients received external beam radiotherapy at a total dose of 50 Gy in 25 fractions, at a rate of 200 Gy per fraction, each fraction per day; five fractions per week. The EBRT treatment period was 5 weeks. All the patients also received concurrent chemotherapy with inj. Cisplatin 40 mg/m2 weekly. The 98 patients who enrolled in this study were divided in two arms. 30 patients for Arm-A and 30 patients for Arm-B. Arm-A were treated with Ir¹⁹² HDR Brachytherapy and Arm-B treated with Co⁶⁰ HDR Brachytherapy.

Results

In this chapter the results of the data analysis of the study are presented. The data were collected and then processed in response to the study question. This study set out to investigate comparison of dose distribution in organs at risk and reference point “A” in treatment of carcinoma cervix using Co⁶⁰ and Ir¹⁹² HDR Brachytherapy. The principal goal is to investigate the clinical feasibility of the two aforesaid radionuclides in treatment of advanced stage carcinoma cervix by HDR brachytherapy. The objectives were accomplished. The findings presented in this chapter demonstrate the potential for merging theory and practice.

This hospital based comparative study have done on the basis of histopathologically diagnosed 60 patients of cervical carcinoma. All the patients received external beam radiotherapy at a total dose of 50 Gy in 25 fractions, at a rate of 200 Gy per fraction, each fraction per day; five fractions per week. The EBRT treatment period was 5 weeks. All the patients also received concurrent chemotherapy with inj. Cisplatin 40 mg/m2 weekly. The 60 patients who enrolled in this study were divided in two arms. 30 patients for Arm-A and 30 patients for Arm-B. Arm-A were treated with Ir¹⁹² HDR Brachytherapy and Arm-B treated with Co⁶⁰ HDR Brachytherapy. All patient in both arm completed treatment. No drop out was noticed during treatment (Tables 1-6).

Table 1: Distribution of the Patients by Stage of the Disease

Table 2: Distribution of the Patients by types of Irradiation and Stage of the Disease

Table 3: Distribution of the Patients by Histopathological types of Cancer

Table 4: Dose Distribution at Urinary Bladder Point of the Patients

Table 5: Dose Distribution at Rectum Point of the Patients.

Table 6: Distribution of the Toxicities by Group of Irradiation

Discussion

Patients with locally advanced cervical cancer in stage IIB to IVA are treated with irradiation including external beam and brachytherapy combined with concurrent chemotherapy. Traditionally LDR brachytherapy was used to treat cervical cancer. But the advent remote after loader HDR brachytherapy ensures some realistic benefit over LDR. From the early ages of HDR, Iridium¹⁹² was very much popular as radionuclide. Recently Cobalt⁶⁰ radionuclide has been introduced with equivalent structural and physical properties.

The objective this study was to compare the radiation dose distribution among the site of tissue including reference point “A”, urinary bladder points and rectum point. 60 patients were enrolled in the study with an age range from 35 to 63 years. Arm A was formed comprising 30 patients who were treated by Ir¹⁹² HDR brachytherapy and Arm B formed with equal number of 30 patients who received HDR brachytherapy treatment with Co⁶⁰ radionuclide.

The patients of different stages were enrolled in this study. Most of the patients presented with stage IIB disease, consisting of 39 patients (65.3%). The next leading stage was IIIA with 11 (17.35%) and 9(15.31%) patients were suffering from stage IIIB disease and stage IV was 1 patient (2.04%).

The study subjects were included as histopathologically diagnosed carcinoma cervix. Different histopathological types were found. Among them 60 patients had squamous cell carcinoma (80.60%), adenocarcinoma trailing with 9 patients (15.3%) and rest were adenoid- squamous carcinoma 2 and small cell carcinoma 1.

In this study radiation dose distribution in tissues by HDR brachytherapy using Ir¹⁹² & Co⁶⁰ radionuclides were compared among carcinoma cervix patient. All the patients were biopsy proven, locally advanced between stages of IIB - IVA. The brachytherapy was completed with the insertion of central uterine Tandem and two vaginal ovoids. The treatment planning being done with optimizing dose to reference point “A” to a dose of 7 Gy per insertion. Each patient received 3 insertions of intracavitary brachytherapy, to total dose 21Gy contributing to reference point “A”. After computerized planning, 100% dose distribution was confirmed to point “A”. Thus, all the patients received 7 Gy at point ‘A’ in both arm of the study subjects.

In this study radiation dose distribution at OARs in consideration i.e., urinary bladder and rectum were compared between Arm A and Arm B. Independent sample t test were done to find whether any significant difference is existing or not. In all three insertions, urinary bladder dose distribution was slightly smaller by HDR Co⁶⁰ irradiation than HDR Ir¹⁹² exposure. These differences were statistically significant in first two insertions but not in third one. The analysis of data reveals that radiation dose distribution in case of rectum points, the mean dose distribution was significantly lower in all three insertions of Co⁶⁰ exposure than Ir¹⁹² exposure (p<0.001). Richter compared a Co⁶⁰ and Ir¹⁹² source of identical dimension and construction and discussed [9] tissue absorption, geometry function and integral dose of the two sources and revealed that the dose for Co⁶⁰ sources in fat tissue is 0.4 percent higher and 0.8 percent lower for the rectum than for Ir¹⁹² sources. Islam [10] has also showed no significant advantages or disadvantages found in dosimetry aspect comparing with two sources.

The study was set out to explore the comparison of dose distribution of two radionuclides used in remote after loading HDR brachytherapy, Ir¹⁹² and Co⁶⁰ respectively, at reference point ‘A’ and OARs in the treatment of locally advanced carcinoma cervix. EBRT followed by HDR-ICRT is considered as standard radiation treatment strategy for patients with locally advanced carcinoma cervix. Especially in developing country like Bangladesh; where high number of patients with cervical cancer requires the brachytherapy service, low-cost sustainable technology is utmost need.

In this study, ICRT treatment planning dose was prescribed and normalized at reference point ‘A’. So, both radionuclides contributed the same dose as prescribed and achieved 100% coverage.

Therefore, both the radionuclides are identical at this point. Hence difference would be at OARs. Normal tissues like rectum and urinary bladder remain as organs at risk for HDR brachytherapy treatment of locally advanced carcinoma cervix due to their close vicinity.

Conclusion

In this study radiation dose distribution at OARs i.e., urinary bladder and rectum were compared between Arm A and Arm B. In all three insertions in urinary bladder the mean dose distribution was slightly smaller in HDR Cobalt⁶⁰ irradiation than HDR Iridium¹⁹² exposure. These differences were statistically significant in first two insertions but not in third one. In case of rectum point, the mean dose distribution was significantly lower in all three insertions of Co⁶⁰ exposure than Ir¹⁹² exposure.

Recommendation

This observational study concerned with radiation dose distribution to OARs. Taking into the account of long half-life of Co⁶⁰ and subsequent economic considerations (low cost), distribution by the two radionuclides are comparable and Co⁶⁰ can be the acceptable alternative radionuclide used in HDR brachytherapy.

Conflict of interest:

There was no conflict of interest in this study.

References

1. GLOBOCAN Database (2012) International Agency for Research on Cancer Cancer Incidence and Mortality.
2. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, et al. (2011) Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378: 1461-1484.
3. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer CA Cancer J Clin 61: 212-236.
4. Hochman A, Ratzkowski E, Schrieber H (1955) Incidence of carcinoma of cervix in Jewish women in Br J Cancer 9: 358-364.
5. DeVita VT, Rosenberg SA, Lawerence TS (2015) Devita, Heilman & Rosenberg’s cancer. Principles & practice of oncology 1037-1040.
6. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, et (1995) Prevalence of human papillomavirus in cervical cancer: worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 87: 796-802.
7. Pedersen D, Bentzen SM, Overgaard J (1994) Early and late radiotherapeutic morbidity in 442 consecutive patients with locally advanced carcinoma of the uterine cervix. Int J Radial Oncol Biol Phys 29: 941-952.
8. Perez-Calatayud J, Ballester F, Das RK, De Wera LA, Ibbot GS, et (2012) Dose calculation for photon-emitting brachytherapy sources with average energy higher than 50 keV: Report of the AAPM and ESTRO. Med Phy 39: 2904- 2929.
9. Richter J, Baier K, Flentje M (2008) Comparison of Cobalt⁶⁰ and Iridium^l92 sources in high dose rate afterloading Strahlenther Onkol 184: 187-192.
10. Islam MA, Akramuzzaman MM, Zakaria CA (2012) Dosimetric comparison between the micro Selectron HDR Ir¹⁹² v2 source and the BEBIG Co⁶⁰ source for HDR brachytherapy using the EGSnrc Monte Car o transport J Med Phys 37: 219-225.