|LETTER TO THE EDITOR
|Year : 2020 | Volume
| Issue : 6 | Page : 1541-1545
A comparative analysis of different fractionation schedules used in the treatment of postmodified radical mastectomy carcinoma breast patients
Surabhi Gupta1, Laxman Pandey2, Mridul Chaturvedi3, Prashant Prakash3
1 Department of Radiation Oncology, Sarojani Naidu Medical College, Agra, Uttar Pradesh, India
2 Department of Radiation Oncology, AIIMS, Rishikesh, Uttarakhand, India
3 Department of Medicine, Sarojani Naidu Medical College, Agra, Uttar Pradesh, India
|Date of Submission||27-Jul-2019|
|Date of Acceptance||19-Dec-2019|
|Date of Web Publication||18-Dec-2020|
Senior Resident, AIIMS, Rishikesh, Uttarakhand
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gupta S, Pandey L, Chaturvedi M, Prakash P. A comparative analysis of different fractionation schedules used in the treatment of postmodified radical mastectomy carcinoma breast patients. J Can Res Ther 2020;16:1541-5
|How to cite this URL:|
Gupta S, Pandey L, Chaturvedi M, Prakash P. A comparative analysis of different fractionation schedules used in the treatment of postmodified radical mastectomy carcinoma breast patients. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1541-5. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1541/303896
The frequency of advanced breast carcinoma is 10%–25% in the developed countries and 40%–50% in developing countries like India. Micrometastasis or systemic spread control can be achieved by chemotherapy and hormonal therapy.
As breast carcinoma is considered a systemic disease, and hence, multimodality treatment is generally required in every patient. Radiotherapy is given to the breast after conservative surgery and to the chest wall after mastectomy to complete locoregional treatment. This may be followed by a boost to the tumor bed over a further 1–2 weeks in some patients, who have breast conservation. For breast carcinoma, patients having primary breast conservation surgery or mastectomy, the most common schedule used internationally involves 50 Gy/25#@2 Gy per fraction (additional 16 Gy in BCS).
Radiation treatment, in which the total dose of radiation is divided into small doses and treatments are given more than once a day is called hypofractionated radiotherapy. In a developing countries like ours where there are not sufficient government hospitals with proper machinery resources, patients have to wait for 3–4 months for radiation treatment and patients economic status does not allow them to afford treatment at private set up, and hence, it is not feasible to give radiation timely to all the patients. Few patients get defaulted due to long waiting list for radiation treatment. The main purpose of this study was to assess the reduction of the burden of the patients on the machine with comparison in terms of efficacy and toxicities, so that more number of patients could get radiation treatment on time. Different schedules have been developed to minimize the burden on machines and operators, for example, 3000 cGy in 10 fractions, 3000 cGy in 8 fractions, 2000 cGy in 4 or 5 fractions, or 800 cGy single fractions. Due to these encouraging data, there has been increasing interest of the world about using hypofractionation in curative setting also. It has been tried quite extensively in breast conservation setting (BCS) and a lot of data are now available which shows very good local control with acceptable toxicity and equivalent cosmetic outcomes.
This study compared the conventional radiation protocol with two hypofractionated protocols treating chest wall and nodal areas in post mastectomy carcinoma breast patients in terms of the relative efficacy of hypofractioned protocols in controlling the locoregional disease, disease-free survival, and overall survival in carcinoma breast as adjuvant modality. Apart from this, it also compared the early and late toxicities of radiation in these patients and compared the expenditure load during treatment for patients and work load for the hospital's staff. This study was conducted on 91 histopathologically proven patients of carcinoma of breast, treated surgically with modified radical mastectomy. These patients were randomized into three treatment arms.
- ARM I (30 patients) – 5000cGy/25#/[email protected] Gy per fraction in 33 days
- ARM II (30 patients) – 4250cGy/17#/[email protected] per fraction in 23 days
- ARM III (31 patients) – 4000cGy/15#/[email protected] per fraction in 19 days [Table 1].
All patients received external beam radiotherapy to chest wall and regional lymph nodes, respectively. These hypo fractionated protocols were radiobiologically equivalent to 5000 CGy in 5 weeks in 25 fractions and thus to each other.
Female patients of; age >18 to <70 years with primary lesion-pT2, pT3, or pT4 nodal status of pN0, pN1, pN2, and pN3 were included in this study. Metastatic workup including isotope bone scan, X-ray chest, and abdominal ultrasound were done in each patient. Adjuvant chemotherapy was completed before radiation [Table 2].
All patients were planned on two-dimensional planning system and were treated on Co-60 teletherapy machine. Two tangential portals for the chest wall, direct anterior filed to the supraclavicular and axillary areas were planned with 0.5 cm gap junction from tangential fields. The head of humerus was shielded. A posterior axillary boost was added to compensate the midline dose twice a week, treated at 80 cm skin to source distance (SSD). Written consent was obtained before starting the treatment. Following expected toxicities of radiation along with local control and workload were compared:
- Skin reactions were categorized according to the RTOG recommendations
- Some risk of bone marrow suppression were expected with shorter protocols, so complete blood counts were done according to the protocol before starting radiation, at completion, at 1 week, 4 weeks, and 6 months after the completion of treatment. The hematological depression in any of the components were graded as mild (10%–20%), moderate (20%–30%), and severe (>30%)
- Lymphedema was taken as a clinical finding. The arm circumference was measured at 20 cm above and below the olecranon process of ulna. Measurements were taken at 1 week, 4 weeks, 8 weeks, 4 months, 6 months, 8 months, 10 months, and 1 year after the completion of treatment and were categorized as G0 (no change in circumference), G1 (0–1 cm), G2 (1–2 cm), and G3 (>2 cm)
- The echocardiography of all the patients was done before radiation and at 2 months after radiation. A fall of >10% in ejection fraction was taken as significant reduction in the left ventricular ejection fraction (EF) whether symptomatic or not. The patients who had a base line EF of <55% were not included in the trial
- X-ray chest was performed before starting radiation and at 4 weeks and 6 months after completion of treatment for assessing any pulmonary toxicity
- Any injury to the brachial plexus causing its damage and weakness of the arm was documented.
Standard curative schedules of radiotherapy to the breast deliver 25 fractions of 2.0 Gy per fraction per day over 5–6 weeks. Considerable recent literature suggests that hypo-fractionation may be advisory in breast cancer. Over the past several years, there has been renewed interest in the use of hypofractionation for whole-breast irradiation. It is certain that some forms of hypofractionations are unsuitable for treating the axilla and supraclavicular fossa by virtue of the sensitivity of brachial plexus to fraction size. However, interest in hypofractionation is based on two postulated clinical benefits. The first is that breast cancer is more sensitive to fraction size than formerly thought, and hence that fewer larger fractions maintain current levels of anti-tumor effect without increasing late adverse effects. The second is that shorter overall treatment times (accelerated hypofractionation) may be more effective in patients with rapidly proliferating tumours.
At Christie Hospital Manchester, there has been a routine to deliver 5000–5500 CGy in 15–16 fractions for most of the tumors for decades and they have shown equivalent results in most of the settings. For breast cancer, they use 4000 cGy in 3 weeks, i.e., 15 fraction with good results.
The UK START trial B has randomized 2215 patients to 40 Gy in 15 fractions and 50 Gy standard in 25 fractions in 5 weeks and concluded that radiotherapy schedule delivering 40 Gy in 15 fractions over 3 weeks seems to offer local regional tumor control and rates of late normal tissue effects at least as good as the accepted international standard of 50 Gy in 25 fractions over 5 weeks.
Shelley et al. reported results of the effectiveness of the schedule 40 Gy in 16 fractions in 294 patients. Overall 5-year survival and disease-specific survival were 87.8% and 92.1%, respectively. Recent randomized trials have confirmed that hypofractionation in whole breast irradiation is equivalent to conventional whole-breast irradiation with respect to local recurrence and cosmetic outcome.
In breast conservation, there is now a lot of data in the support of hypofractionation. Yarnold et al. randomized 1410 patients into three arms, i.e., 50 Gy in 25 fr, 39 Gy in 13 fr and 42.9 Gy in 13 fr. The aim was to compare a 13 fraction schedule to 40 Gy in 25 fractions as far as late radiation changes and local control in early breast cancer after local excision is concerned. The cosmetic effect was equal for 50 Gy in 25 fr and 42.9 Gy in 13 fr. Whelan randomized, 1234 patients in BCS into two fractionation programs, i.e., 42.5 Gy in 16 fr and 50 Gy in 25 fr and showed comparable results.
The present study allowed female patients from 20 to 70 years to be included in the protocols. Most of the patient falls in 40–49 years age group. This data showed that the incidence of carcinoma breast moves more toward younger age group. This distribution shows that the three arms were very well balanced as far as the age distribution was concerned (P = 0.9640).
Disease laterality again shows fairly similar prevalence among the three arms with P value of 0.3068. Arm I, II, and III were very well balanced as far as the stage grouping and menopausal status was concerned (P = 0.4269 and 0.4677, respectively).
Abhilash et al. conducted his study on 60 histopathologically proven patients of carcinoma of the breast, treated surgically with modified radical mastectomy. Group I patients received dose of 39 Gy/13 fractions/3.1 weeks and Group II patients were given 50 Gy/25 fractions/5 weeks. Locoregional control after the completion of radiotherapy in Group I versus Group II was 26/30 (86.7%) versus 27/30 (90%), respectively.
When we compared our data of locoregional failures in all the three arms, we observed that the results were almost similar that is 0%, 6.66%, and 3.23%, respectively, and distal recurrence were 13.33%, 20%, and 12.9% consecutively and there are no statistically significant differences in three arms (P = 0.7769).
Similarly, when we analyzed the data for disease-free survival at 2 years in all the three arms, theses were 86.66%, 73.33%, and 83.87%, respectively, with a value of P = 0.0310 (statistically significant) and mortality (10%, 20%, and 9.67%) with P = 0.9236. Two years overall survival was 90%, 80%, and 93.33% in Arms I, Arm II, and Arm III, respectively [Table 3]. Hence from this discussion, we can very well conclude, that the efficacy of all three protocols were equal in controlling the locoregional disease [Table 3].
The second objective of the study was to compare the acute and chronic toxicity of both the protocols. When we compared our data for skin reaction in hypofractionated and conventional arms, we saw that there was comparable, Grade 3 skin reactions in all the three arms (3.33%, 6.66%, and 6.45%) with statistically nonsignificance difference (P = 0.5283). The reactions normally settled in 1–2 weeks with excellent healing [Table 4].
We were very much concerned about the issue of bone marrow suppression. However in spite of very close watch on the blood counts as recommended by the protocol, we did not notice even a single case of fall in any of the blood components in any arm.
Radiation pneumonitis is well-known toxicity of the chest wall and supraclavicular radiation. In a study, Plataniotis et al. evaluated radiation pneumonitis in hypofractionation setting (42.5 Gy/16 Fr) by high-resolution computed tomography in early breast cancer patients and reported minimal and minor effect on the underlying lung parenchyma. We experienced symptomatic radiation pneumonitis in only one patient (3.22%) in Arm III (P = 0.9420), which was well managed with steroids and antibiotics. These values were well in line with international data, as when we compared with prospective randomized trials done by Amin Akhtar et al., where 4% in Arm A, 5% in Arm B, and 5% of patients in Arm C showed radiation pneumonitis.
Lymphedema is a well-known complication of both axillary lymph node dissection and axillary radiotherapy. The incidence varies in different series. In our study, we had categorized lymphedema into four grades depending on the increase in arm circumference. Grade 1, 2, and 3, lymphedema was seen in 10%, 3.33%, and 3.33% (in Arm I) patients, 13.33%, 3.33%, and 3.33% (in Arm II), 9.67%, 3.22%, and 3.22% (in Arm III)(P = 0.9945) patients [Table 4]. These data, thus, prove the safety of shorter protocols.
There has always been an increased concern for left-sided breast cancer as far as chest wall radiation is concerned. Some portion of the heart has to be included in the tangential portals due to chest wall contour. Another important factor in this regard is the administration of anthracyclines which again cause cardiotoxicity [Table 5]. Data from different studies are controversial. In our study, mild cardiotoxicity was seen in 3.33%, 6.66%, and 6.45% patients in Arm I, II, and III (P = 0.9420).
The third objective of the study was to assess the reduction in workload of the institute and reduction of the radiation waiting list of breast patients, as a whole by reducing the total span of treatment.
At the moment, we are registering about 1200 new cancer patients each year. Female patients constitute about 550 of which 200 new breast cancer patients enrolled [Table 6]. A good number of these patients require radiotherapy. We have got one Cobalt-60 machine (THERATRON PHOENIX model no. 223). That is why one patient of carcinoma breast who needs four field radiotherapy, can take about 30 min for the whole treatment. A shorter breast RT schedule would be more convenient for patients (especially those coming from remote areas to RT facilities) and for health-care providers, as it would increase the turnover in RT departments. The use of 15-fractions, instead of a 25-fractions regime, for instance, would save 240 treatment sessions per 24 patients (600–360 = 240). This corresponds to an additional 16 (240/15) patients who could be treated with the same number of fractions. This would result in substantial decrease in institution workload and radiation waiting list, as well as economic benefit as breast cancer patients, represents the majority of patients treated in RT departments. On an average, two technologists work on the machine for 6–8 h. Of course, they have to go in to set each field and then come out and start the machine. The whole process of setting one field and starting the machine may take 2–5 min. As we are treating breast cancer patients with four fields in 25-fractions protocol, 100 fields have to be treated in total.
In contrast to 15 fractions, the number of fields comes down to 60 only. Thus saving about 120 min (80–200 min) if the average time for setting one field is taken as 3 min. Hence if we are treating three patients of breast cancer in 1 day, we can save 9–10 precious working hours in this respect. In addition to time-saving less number of field applications also saves the labor and hard work for the technologists.
During radiotherapy, the patients routinely visit their treating physician once or twice a week for radiation reaction. This makes about 10 visits if 25 fractions protocol is used and 6 visits if 15 fraction protocols is used, thus it greatly reduced the burden on the physicians.
In this study, 25% of patients in 3 weeks protocol required remarking, whereas about 60% of patients in 5 weeks protocol.
The nonentitled or paying patients have to pay according to the number of fractions. The payment includes daily radiation charges. Cost at our institute for daily fraction Rs. 35. Hence that for 25 fractions the total cost will be 875 and for 15 fractions, the total cost will be 525 Rs. This will reduce the cost of radiation by 350 Rs. in the study arm. This small amount of money is also worth a lot for poor people. Those patients who stay in hospital in the private rooms have to pay Rs. 500/- per day for a room. The cost for a 5 weeks protocol would be Rs. 16500/-. This will be reduced to 9500/- for 3 weeks protocol. The same statistics hold true for those patients residing in nearby hotels falling in this reference range. Those patients who are accompanied by their husbands, fathers or brothers, and their companions stay with them for the whole-treatment period have to sacrifice their businesses. If a person earning Rs. 20,000/- per month stays for 3 weeks and quits his business, and he will suffer a loss of Rs. 22,000/- while this loss will be reduced to Rs. 12,667/- for 3 weeks protocol.
Interest in hypofractionation is based also on the practical advantages to patients and health services. Treatment given with the fewest possible fractions over the shortest possible time (reduced number of visits) offers several advantages in terms of convenience, time, cost, and quality of life for patients. Given the high incidence of breast cancer in our society, a shorter fractionation schedule would also produce savings to the health-care budget and decrease waiting lists in busy radiotherapy centers.
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospital breast conservation trial: An update at 8 years from inception. Clin Oncol (R Coll Radiol) 1993;5:278-83.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al
. The UK Standardisation of Breast Radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-41.
Shelley W, Brundage M, Hayter C, Paszat L, Zhou S, Mackillop W. A shorter fractionation schedule for postlumpectomy breast cancer patients. Int J Radiat Oncol Biol Phys 2000;47:1219-28.
Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220-9.
Abhilash G, Dhull AK, Atri R, Dhankha R, Kaushal V, et al
. Comparison of hypofractionated radiation therapy versus conventional radiation therapy in post mastectomy breast cancer. J Evid Based Med Health 2016;3:1177-81.
Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, et al
. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: Long-term results of a randomised trial. Radiother Oncol 2005;75:9-17.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]