Motepalli Pandu Ranga Kumari has graduated from the Osmania Medical College of NTR University of Health Sciences, Andhra Pradesh. She obtained her MBBS degree from the VMMC of Pondicherry University and is presently working as an Assistant Professor in the Department of Radiotherapy, the Government General Hospital, Kurnool, Andhra Pradesh.
Introduction: In carcinoma of cervix, if overall treatment time (OTT) is prolonged beyond 6 weeks, then the total dose required to achieve a given probability of tumor control is to be increased by 0.6 Gy for each day of prolongation, to control the accelerative repopulation of the cells, i.e., 1 % loss of tumor control, and to avoid increased treatment delays and drop outs due to the prolonged gap between EBRT and intracavitary brachytherapy (ICBT).
Objectives: To evaluate local disease control and early complications of concomitant HDR-ICBT with EBRT and thereby decrease the OTT in I B–III B stage carcinoma cervix.
Methods: Fifty patients of carcinoma cervix (FIGO-I B/III B) were randomly divided into two groups: the study group treated with concomitant EBRT and HDR-ICBT (EBRT = 50–50.4 Gy/25–28 Fr, HDR 7 Gy in 3 Fr during the 3rd, 4th, and 5th weeks), EBRT and weekly cisplatin were not given on the day of HDR-ICBT; and the control group treated with EBRT followed by HDR-ICBT and weekly cisplatin. Acute reactions and local disease response were compared after treatment and at 6-month follow-up.
Results: Medians of OTTs were 42 and 63 days in the study and the control groups, respectively. Dysuria and diarrhoea incidences were more in the study but manageable. At the completion of the treatment, there were 92 and 80 % complete responses; 4 and 4 % partial responses; and 4 and 16 % stable diseases in the study group and the control group, respectively. DFSs (disease free survivals) at 6-month follow-up were, respectively, 96 and 84 %, and most of the stable diseases were observed in stage III B.
Conclusions: Response was better in the study group but statistically insignificant, acute reactions were manageable, and there was decrease in drop outs due to completion of treatment at a stretch, but larger number of patients and longer follow-up are required to arrive at concrete conclusions.
Keywords : Cervical cancer, Concurrent EBRT and HDR, Decreasing OTT, Local response, Early reactions, Preventing drop outs
Cervical cancer is the third most common malignancy in women worldwide, and it remains the leading cause of cancer-related deaths in women in developing countries, with an estimated 5.3 million new cases and 2.7 million deaths in 2009. About 86 % of the cases occur in developing countries, with 13 % of them accounting for the female cancers. Worldwide mortality rates of cervical cancers are substantially lower than the incidence. The projected incidence-to-mortality ratio is about 52 % (IARC, GLOBOCON 2008).
More than 80 % of cervical cancers are found to occur in developing countries. The cervical cancer risk is 1 % during the life of a woman living in a developed country, whereas the corresponding value for a woman living in a country without preventive programs is 5 %, and around 20 % of the global burden of cervical cancer risk falls within India
Latest estimates indicate that every year 134, 420 women are diagnosed with cervical cancer, and 72,825 die from the disease. Cervical cancer ranks to be the top most frequently occurring cancer among women in India and the top most frequently occurring cancer among women between 15 and 44 years of age. Around 7.5 % of the women in general population are estimated to harbor cervical HPV infection at a given time, and 82.5 % of invasive cervical cancers are attributed to HPV 16 or 18 (IARC, GLOBOCON 2008).
At our institute (MNJIO & RCC), about 30–55 % of female out-patients constitute those with carcinoma cervix.
Before the introduction of radiotherapy, surgery was the only available method for the treatment of cervical cancer. Soon after of the discovery of radium by Madam Curie in 1998, Margaret Cleaves first inserted radium into a malignant uterus. Since then advances in radiotherapy have resulted in achieving the preferred loco-regional control and increased rates of disease free survival (DFS).
The radiotherapy of cervical cancer involves a judicious use of teletherapy and brachytherapy. Teletherapy has evolved from conventional to more conformal, and Intracavitary therapy has evolved from manual insertions of radioactive sources—techniques of manual after-loading— to remotely controlled after-loading techniques, to minimize radiation exposure to health personnel. Interest in the applications of high dose rate intracavitary (HDR) brachytherapy compared with low dose rate (LDR) brachytherapy , has increased considerably over the last 20 years because of advantages such as
HDR brachytherapy is advantageous as it maintains spatial relationships between the treatment applicator and the dose-limiting normal structure over the short treatment time of ,say, minutes as opposed to hours or days.
Concurrent administration of the chemotherapy could increase the chance of the local control and survival. Local control is necessary for long-term DFS. It is in this context, various methods of combination of single, multiple chemotherapeutic agents have been integrated with radiotherapy as neo-adjuvant or adjuvant therapy. Recent studies by (GOG-85, 120, 123, SWOG-8797, RTOG-9001) have shown that this method is particularly appropriate for bulky and locally advanced cervical cancers.
The risk of death from cervical cancer has decreased by 30–50 % with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.
In carcinoma cervix, if overall treatment time (OTT) is prolonged beyond 6 weeks, total dose required to produce a given probability of tumor control is to be increased by 0.6 Gy for each day of prolongation. This is to control the accelerative repopulation of the cells. Increasing dose to control accelerated repopulation is not possible due to dose-limiting structures around cervix.
If HDR is given after EBRT as in conventional method, the total treatment time will be around 10 weeks, and moreover, giving HDR 1 week after EBRT with three continuos weekly visits to hospital results in lot of drop outs either due to sociofinancial problems or due to perceived phobia about HDR procedure.
In this study, the authors have analyzed the results in terms of local control and DFS by reducing the OTT by simultaneously administering external radiotherapy and intracavitary radiation and there by preventing drop outs in treatable cancer like cervix.
Target Population
In this prospective two-arm study, the study has been conducted on a total of 50 patients with 25 patients in each arm registered at MNJIO & RCC, with confirmed diagnosis of squamous cell carcinoma of cervix. The objectives were to integrate HDR-ICA with external RT in the treatment of locally advanced carcinoma of cervix, and thereby study the effect of reduction of OTT on survival, and to evaluate local control rates and radiation toxicity to the surrounding structures especially bladder and rectum.
Study period: From November 2011 to April 2013. Follow- up till November 2013.
Patient Selection
Inclusion Criteria:
Exclusion Criteria
Lanciano et al.’s [4] study of cervical cancer on 837 patients treated with radiation therapy showed that local recurrence within 4 years of completion of treatment increased from 6 to 20 % when the OTT was increased to 6–10 weeks (P = 0.0001). This translated into significantly decreased rate of survival.
Girinsky et al. [5] studied 386 patients of cervical cancer treated with radiation therapy. They reported relative risk of local recurrence has increased by a factor of 2.4 when OTT was increased up to 62 days. 1.1 % of loss of pelvic tumor control per day prolongation of treatment time is observed. 10 year-recurrence-free survival rate also decreased.
Perez et al. [6] studied 1,227 patients of cervical cancer treated with radiation therapy. They showed a strong correlation between OTT and clinical tumor stage except for patients with stage I A tumor size being\3 cm (Tables 8, 9).
OTT has a strong correlation with pelvic tumor control and survival in stages I B, II A , and II B. Performance of all ICR insertions within 4–5 weeks from the initiation of the irradiation yielded lower pelvic failure rate.
Local failure rate was 8.8 % versus 18 % in stage I B disease P <= 0.1 (Figs. 8, 9) Delaloye et al. [7] studied 360 patients of cervical cancer stages I B to III B treated with external RT and Brachytherapy. They observed 5-year survival rate of 61 % when OTT was < 60 days compared with 53 % when OTT was more than 60 days (P = 0.03) and 50 % increase in death rates for longer therapy group. It is finally concluded that the shorter treatment duration is a factor associated with the longer survival in cervical cancer.
AU Mayer et al. [8] studied 210 patients cervical cancer stages II A to III B treated with EBRT and HDR-ICA. Two regimens were compared.
Sequential Radiation Therapy with 4 9 8 Gy. HDR BT to point A was followed by EBRT. Continuous Radiation Therapy was given as 5 9 6 Gy. HDR BT to point A. One session per week was integrated into EBRT. No EBRT was given on the day of HDR BT. Total dose given was 68–70 Gy. to point A Median follow-up was 3.4 years (Table 10). Preterit et al. [9] retrospectively studied the relation of OTT with pelvic control and overall survival. They studied 209 patients of cervical cancer stages I B–III B disease. 5-year survival rate—65 % when OTT < 55 days 54 % when OTT > 55 days For stages I B and II A, the effect of OTT was significant.
Survival rate has decreased by 0.6 % per day. Pelvic control decreased by 0.7 % per day for each additional day beyond 55 days. There was no significant difference in late complications. Aravind Kumar Patidar et al. [10] studied 55 patients of early-stage carcinoma by integrating HDR with EBRT and found that response rates were better with the increased acute skin reaction and diarrhea in the study group. All the trials shown above proved that prolonged treatment time had an adverse affect on outcome because of accelerated repopulation of tumor cells. In patients treated with radiation therapy, OTT should be as short as possible, and any planned or unplanned interruptions or delays should be avoided. Timely integration of EBRT and ICA in patients with carcinoma of uterine cervix and thereby decrease of OTT is an important factor in improving pelvic tumor control and to prevent drop outs for HDR-ICA. In this study, patients were examined at the first visit, and the patients with proliferative tumours and squamous histology were taken into consideration. External RT was planned on simulator with 1.8–2 Gy per fraction. After completion of treatment with 3,000 cGy, patients were assessed for suitability of intracavitary application, and two fractions of HDR were given, while the patient was on external RT, and the last fraction was given 1 week after completion of external RT. Thus, the total treatment time was completed within 5–6 weeks, and the entire treatment from initiation to completion of radiation was completed during single stay of the patient in the hospital,
In this study, HDR brachytherapy was used which has two distinct features:
From LQ model, the larger the fraction size, the greater the potential for late tissue damage compared with tumor control. The practical advantages of HDR may counterbalance its radiobiological disadvantages. Each application lasts only for 10–15 min and thus eliminates the morbidity arising from prolonged bed rest. Applicator movement during treatment is minimized making dosimetric calculations more representative of actual treatment.
The dose distribution can be optimized using computer controlled variable dwell times. Finally, out-patient HDR brachytherapy may be well tolerated if given along with external RT. Chemotherapy is not given on the day of integrated HDR-ICA
Out of 25 patients treated with integrated ICA therapy in this study with OTT less than 6 weeks, 24 patients, i.e., 96 %, had local control and DFS at the end of follow-up compared with 21 patients: 84 % treated with standard protocol of EBRT followed by HDR of total OTT of more than 9 weeks with a loss of 12 % LC and PFS when OTT is increased from 6 to 9 weeks which is in comparison to A.U. Mayer et al.’s study which showed a PFS of 56 % for OTT of 5 weeks and 71 % for OTT of 8 weeks with a loss of PFS 15 % when OTT is increased
In this study LC and PFS decreased by 0.57 % per day prolongation of treatment which is in comparison with Preterit et al.; study which showed a decrease in survival by 0.6 % when OTT is increased.
In this study, there was an increase in acute rectal and bladder toxicities of Gr-I, II during integration HDR with EBRT which were easily managed medically and there were no treatment interruptions or delays. There were no Gr III,IV acute toxicities or chronic toxicities
MNJ Institute of Oncology is the only tertiary cancer center and referral hospital in A.P with an annual registry of 9,000–9,500 new cancer cases among which cervical cancer constitutes 30–40 % of cases. The majority of the patients coming to the hospital are below poverty line, who cannot afford 4–5 times of hospital visit for treatment, which resulted in high rate of drop outs after EBRT for ICA. By integrating HDR with EBRT, the treatment time will be reduced, and whole treatment will be given in one visit itself, thereby reducing the financial burden to the patient and hospital.
The long-term survival and late rectal and bladder toxicities cannot be assessed because of short follow-up period. However, a randomized study with a large number of patients and longer follow-up period has to be done to show consistent and long-term results in terms of the benefits of concurrent EBRT and HDR brachytherapy
