Adjuvant radiation therapy in breast cancer: Recent advances & Indian data.

Breast cancer is the most common cancer among women in India, and adjuvant radiotherapy is an integral part of curative treatment in most patients. The recent decades have witnessed several advances in radiation therapy delivery. Several advances in radiation oncology have been identified which include technological advances, change in fractionation used, use of cardiac-sparing radiotherapy as well as efforts to personalize radiotherapy using accelerated partial breast irradiation or avoidance of radiotherapy in certain subpopulations. Indian data are available in most areas which have been summarized. However, increasing emphasis on research in these areas is needed so that effectiveness and safety in our setting can be established. Advances in breast cancer radiotherapy have resulted in improved outcomes. Data published from India suggest that these improved outcomes can be replicated in patients when appropriate treatment protocols are followed.

Breast cancer is the most common cancer among women in India, and about 160,000 cases are diagnosed annually1. It is also the most common cause of cancer-related mortality and disability in India2. Adjuvant radiotherapy plays an important role in the breast cancer management paradigm. Results from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis in patients undergoing breast conservation surgery showed that the risk of use of adjuvant radiotherapy resulted in a 50 per cent relative reduction in the risk of a locoregional recurrence at 15 years3. Similarly, in node-positive patients undergoing mastectomy, the use of adjuvant radiotherapy translated into a relative risk reduction in locoregional recurrence at 10 yr to the tune of 69 per cent4. More importantly, in the patients undergoing breast conservation, one breast cancer death was avoided at 15 yr for every four locoregional recurrences avoided, while in patients who had undergone a mastectomy4, one breast cancer death was avoided at 20 yr for every 1.5 locoregional recurrences avoided3.

Over the past couple of decades, advances in technology, as well as our understanding of breast cancer biology, coupled with an increasing emphasis on early detection, have resulted in improved outcomes for breast cancer patients. A larger proportion of patients now undergo breast conservation surgery, and the issues related to the quality of life and survivorship care are receiving much-needed attention. Here, an attempt was made to review the recent advances made in adjuvant radiotherapy of breast cancer and also to look at the Indian data in these areas. After internal discussion among ourselves, as well as the experience with a recently concluded expert consensus meeting in breast cancers, the following areas were identified: (i) Technological advances in dose delivery: better dose homogenization and development of simultaneous-integrated boost (SIB) techniques; (ii) widespread use of altered fractionation, e.g., hypofractionation; (iii) avoidance of morbidity of radiation therapy, especially cardiac morbidity; (iv) customization of irradiation volume, e.g., avoidance of whole-breast irradiation; and (v) avoidance of radiation therapy in certain low-risk populations.

Technological advances

Intensity-modulated radiotherapy (IMRT): Radiation to the breast is complicated by the anatomy and the relationship of the primary target volume (i.e., chest wall or breast) as well as the elective nodal volumes with the underlying organs at risk. Furthermore, given the relatively favourable prognosis of breast cancer, restricting the irradiated volume to reduce the risk of contralateral breast and lung cancers is an important planning target. Hence, the most common beam arrangement used to ensure optimal dose delivery is a tangential beam pair for the breast/chest wall along with en face portals for regional nodes. Most modern radiotherapy trials have avoided axillary radiotherapy after adequate axillary dissection as isolated axillary recurrence rates are low and lymphedema risks are high56. Use of forward planned IMRT, has been investigated in several randomized controlled trials. In the earliest reported trial by Donovan et al7, the use of IMRT reduced the incidence of change in breast appearance. Pignol et al8 demonstrated a significantly reduced risk of moist desquamation after radiotherapy. Two and five-year follow up results of the Cambridge Breast Forward-Planned IMRT Trial reported a significant reduction in the risk of developing telangiectasia as well as improved cosmesis in patients undergoing IMRT910.

Prabhakar et al1112 reported a significant reduction in contralateral breast dose with the use of IMRT as compared to standard wedged tangential fields. Kataria et al13 reported a lower incidental dose to the axilla with the use of forward-planned IMRT and three-dimensional conformal radiotherapy (3DCRT) as compared to the standard technique. No clinical studies comparing outcomes in IMRT and 3DCRT have been reported from India. Several dosimetric studies have examined the feasibility of using volumetric modulated arc therapy (VMAT) instead of tangents and have reported better coverage of the breast/chest wall target volume1415. Of these, an in silico trial reported a significant increase in the contralateral breast dose with the use of these techniques14. None of these studies have reported comparative clinical outcomes.

Simultaneous Integrated Boost: Incorporation of the tumour bed boost after conventional breast irradiation results in prolongation of the overall treatment time by almost one and a half weeks, stretching the total treatment time to around six and a half weeks. As a result, several studies have attempted to incorporate the tumour bed boost along with the course of whole-breast irradiation - a technique of treatment delivery called simultaneous integrated boost (SIB). Table I shows a summary of the results obtained from prospective studies that have evaluated the outcomes of a SIB strategy in breast cancers1617181920. Good cosmesis and local control were reported across all these studies. The largest trial investigating a SIB strategy in breast cancers with a higher risk of recurrence (IMPORT High) has demonstrated that the use of a SIB strategy with a dose schedule of 48 Gy delivered to tumour bed results in no significant difference in grade 3/4 adverse events as compared to a sequential boost strategy21.

Table I

Treatment techniques and outcomes of studies investigating simultaneous integrated boost

Author (year)	n	Technique	FU	Local control (%)	Good cosmesis (%)
Franco et al16, 2014	82	Tomotherapy (whole breast + boost)	12	100	91
Cooper et al17, 2016	400	Prone tangential + IMRT boost	45	99	80
De Rose et al18, 2016	144	VMAT (whole breast + tumor bed)	37	100	NA
Shin et al19, 2016	45	Prone 3 field IMRT	36	100	85
Cante et al20, 2017	178	Tangential+direct photon boost	117	97.3	87.80

Studies which reported medium to long-term outcomes included. FU, follow up in years; RT, radiotherapy; IMRT, intensity modulated RT; VMAT, volumetric-modulated arc therapy

In two studies on SIB from India, IMRT using a VMAT technique or a seven-field IMRT technique was utilized to irradiate the entire breast and regional nodes with tumour bed boost. An electron boost was used by Jalali et al22. The largest study reported by Dewan et al23 had 223 patients treated to a total dose of 59.92 Gy in 28 fractions (#) with a non-standard dose fractionation regimen for the whole-breast/regional nodes (46 Gy in 28 fractions). They reported grade 2-3 acute skin toxicity in 31 per cent patients, while chronic grade 2-3 fibrosis was reported in 16 per cent of the patients. Only one patient had a local recurrence at a median follow up of 18 months. Two other studies explored the use of helical tomotherapy for treatment of the bilateral breast cancers with an SIB to the tumour bed2425. However, the use of rotational or multi-field IMRT techniques can result in a higher dose to contralateral breast and lung as shown by Joseph et al26.

To combine the advantages of tangential breast radiation with the dose conformity obtained by using IMRT, our team developed a SIB class solution27. This technique emphasizes conformal avoidance of normal tissues, especially contralateral lung and breast, while improving conformity of the high-dose region in the breast. To achieve this, a tangential field-in-field forward-planned IMRT technique is used for whole-breast irradiation to homogenize the dose distribution. The tumour bed boost is delivered using a pair of short VMAT arcs of 25°-30° offset at an angle of 10°-15° from the tangents27.

Dosimetric comparison between a traditional sequential boost class and SIB class solution shows improved target dose conformity (conformity index 0.52 in SIB vs. 0.31 with sequential boost) while maintaining conformal avoidance of contralateral organs at risk (Table II).

Table II

Comparison between simultaneous integrated boost (SIB) and sequential (SEQ) plans for various volumes

Volume	Dosimetric parameter	SIB technique	SEQ technique	P
BTV	D98* (%)	95.5 (94.7-96.4)	94.9 (94.0-95.9)	0.38
	D2† (%)	103.2 (102.5-103.9)	102.9 (102.0-103.8)	0.85
	Conformity index	0.52 (0.47-0.56)	0.31 (0.28-0.35)	<0.01
	Homogeneity index	0.08 (0.07-0.08)	0.08 (0.07-0.09)	0.44
	V95‡ (%)	97.9 (96.9-98.9)	97.7 (97.0-98.7)	0.88
Contralateral breast	Dmean# (Gy)	0.25 (0.17-0.32)	0.12 (0.10-0.15)	<0.01
	V0.5∥ (%)	14.1 (10.5-17.8)	7.7 (5.8-9.6)	<0.01
Contralateral lung	Dmean# (Gy)	0.16 (0.13-0.19)	0.14 (0.12-0.17)	<0.01
	V0.5∥ (%)	4.9 (3.4-6.4)	3.4 (2.0-4.8)	<0.01
Heart	Dmean# (Gy)	0.90 (0.73-1.07)	0.87 (0.69-1.04)	0.01
	V0.5∥ (%)	56.5 (48.8-64.1)	53.5 (43.6-63.4)	0.03
Ipsilateral lung	V12§ (%)	15.8 (13.1-18.4)	15.6 (12.9-18.4)	0.12
	Dmean# (Gy)	6.64 (5.80-7.49)	6.66 (5.79-7.54)	0.81

Figures represent the mean and 95 per cent confidence interval. *Dose to 98 per cent volume; †Dose to 2 per cent volume; ‡Percentage volume receiving 95 per cent prescribed dose; #Mean dose to volume; ∥Percentage volume receiving 0.5 Gy dose; §Percentage volume receiving 12 Gy. BTV, boost target volume

Altered fractionation

Moderate hypofractionation: Conventional breast radiotherapy is delivered over a period of 5-6 wk using a dose fractionation of 1.8-2 Gy per fraction in the USA28. This stemmed from the belief that breast cancer had fraction sensitivity similar to that of other cancers, notably squamous cell carcinomas. Unfortunately, the prolonged duration of radiation was a significant hindrance in the uptake of breast conservation in breast cancer28 and was associated with a limited access to radiotherapy with consequent increase in the risk of local recurrence29. Research on alternate fractionation schedules where a higher dose of radiation was delivered over a shorter period of time (known as hypofractionation) was first undertaken at the Royal Marsden Hospital and Gloucestershire Oncology Center, UK in 199830. The results showed that breast cancer behaved similar to late reacting normal tissues - with the implication that a higher than conventional dose fractionation was likely to result in the similar local control without excess toxicity if the total dose was appropriately adjusted31. Following this trial, three seminal trials were reported from Canada and the UK in which various hypofractionated radiotherapy schedules were investigated in nearly 8000 women3032. Taken together, the trials demonstrated the safety and effectiveness of hypofractionated radiotherapy delivered over 15-16 fractions with appropriate reduction in total radiation dose. The results from the START B trial demonstrated that use of the 40 Gy/15#/three-week regimen was associated with a significantly reduced risk of late normal tissue complications30. Another study of hypofractionated radiotherapy after mastectomy also demonstrated non-inferiority of the hypofractionated radiotherapy schedule33.

The results of studies on moderate hypofractionation from India are summarized in Table III. The largest study reported is by Chatterjee et al34, who have reported outcomes of more than 900 patients treated with a uniform protocol of 40 Gy/15#/three-week regimen with an excellent local control comparable to results obtained in the START trial30. The acute toxicity reported by the same group was also comparable with end of treatment grade 2 toxicity being reported by six per cent of patients who had undergone mastectomy and 23 per cent in patients who had undergone breast conservation41. Late effects of use of moderate hypofractionation have been reported by Yadav et al42. Overall results from the Indian subcontinent showed similar outcomes with moderately hypofractionated radiotherapy as compared to stage-matched patients from the West34.

Table III

Compilation of results of hypofractionated radiotherapy in breast cancer reported from India

Author (year)	n	Dose fractionation	Follow up (months)	Local control (%)	Overall survival (%)
Chatterjee et al34, 2016	925	40 Gy/15#	22	97.1*	93
Mishra et al35, 2016	56	42.4 Gy/16#	11	96.5	NA
Chelakkot et al36, 2017	308	40 Gy/15#	60	99.45	81
Yadav and Sharma37, 2018	50	34 Gy/10#	39	100	96
Rastogi et al38, 2018	50	42.72 Gy/15#	20	100	100
Yadav et al39, 2020	254	42.4 Gy/16#	46	97*	NA
Vijayaraghavan et al40, 2020	67	42.5 Gy/16#	9	98.5	NA

*Studies have reported locoregional recurrence-free survival instead of local recurrence-free survival. NA, not available

Extreme hypofractionation: Given the results of hypofractionated radiotherapy, it has been reported that earlier further hypofractionation with compression of treatment intervals to one week may be appropriate4344. Two studies were published till date where a five-fraction regimen was compared to a conventional regimen. The UK FAST study reported 10 yr outcomes of a five-fraction schedule delivered over one week and showed that the regimen of 28.5 Gy in five fractions was well tolerated and associated with similar rates of late toxicity4344. However, the patient population studied in the trial was primarily of early breast cancers, and the relevance of this study in the Indian settings remains doubtful as the overall treatment time extends to five weeks45. Moreover, the trial45 was not designed to test for difference in relapse rates between the two arms, but overall local relapse rate was only 1.3 per cent in the 917 patients recruited in the study. The larger FAST Forward Trial compared two-dose schedules of 26 and 27 Gy (over five fractions in one week) against the standard 40 Gy/15# regimen (delivered over three weeks)46. Acute toxicity results reported from the study suggested no increase in acute skin toxicity with 26 Gy schedule as compared to the 40 Gy schedule46. Long-term outcome data suggest that the use of this schedule is non-inferior in properly selected early-stage low-risk breast cancer patients47.

None of the studies form India compared a five-fraction regimen against a standard treatment approach. However, an ongoing study HYPORT Adjuvant (CTRI/2018/12/016816/Clinical Trials: NCT03788213) is testing a 26 Gy/5#/one-week regimen against a 40 Gy/15#/three-week standard schedule4348. In addition, patients who have undergone breast conservation are also being treated with an SIB to give a one-week treatment regimen.

Cardiac sparing

In the past decade, increasing attention has been focussed on the importance of avoiding cardiac morbidity (and mortality) in patients with breast cancer. Cardiovascular disease is a major contributor towards morality in breast cancer patients and among women between 70 and 79 yr and accounts for 22 per cent of the deaths (while breast cancer itself accounts for 17 per cent of the deaths by 10 yr)49. Darby et al50 have reported that each Gy increase in the mean heart dose raises the risk of major cardiac events by 7.4 Gy, with no apparent lower threshold. Radiotherapy-induced heart disease (RIHD) is a complex, multifactorial disorder, and currently, the primary pathophysiology is believed to be radiation-induced endothelial injury resulting in microvascular occlusion and consequent myocardial ischemia. It is believed that the inflammatory response due to endothelial injury accelerates macrovascular atherosclerosis51. A dose relationship for the left anterior descending artery was proposed where a mean dose greater than 20 Gy was shown to be associated with an increased risk of developing coronary stenosis (odds ratio of 5.23)52.

Modern radiation techniques have been developed to allow safer cardiac-sparing radiotherapy53. The two most commonly used techniques include prone breast radiotherapy and deep inspiration breath-hold (DIBH). A recent survey of radiation oncologists in the USA showed that the DIBH was most commonly used to spare the heart54. DIBH is a form of radiotherapy delivery where radiation is delivered while the patient breathes in deeply and holds the breath. As a consequence, the heart rotates inwards inside the thorax and becomes more tubular as the diaphragm moves down, reducing cardiac dose. Analysis of results collated in a systematic review shows a weighted average absolute reduction of 2.1 and 5.9 Gy in the mean cardiac dose and mean left anterior descending artery dose, respectively, when DIBH is used55. This corresponds to halving of the dose as compared to that received in the free-breathing plans.

All of the eight studies on cardiac sparing from India were dosimetric studies which reported a mean heart dose reduction ranging between 50 and 60 per cent as compared to free-breathing plans5657585960616263. Chatterjee et al60 quantified the resource utilization and the cost-effectiveness of using DIBH for all left-sided breast cancers. They found that the use of DIBH resulted in a reduction of 0.95 yr of life lost (YLL) per 100 patients treated (0.09 per patient). These estimates were relatively similar to those reported by Simonetto et al64 from the Netherlands who reported that the use of DIBH resulted in a reduction of YLL between 0.09 and 0.02 per patient. DIBH was found to be cost-effective in the Indian setting even when higher estimates of salary as prevalent in the private sector were taken into the account60.

New treatment volume concepts

Partial breast irradiation (PBI): While whole-breast radiotherapy improves outcomes after breast conservation surgery, prolonged treatment is often a concern. As a consequence, patients with poor socio-economic status and those residing in countries with limited access to radiotherapy will often forego breast conservation6566. As most recurrences after breast conservation surgery are usually confined within the original quadrant6768, there is a rationale to treat a small volume of breast hence, the name partial breast irradiation (PBI). Given the volume effects associated with radiotherapy, the small target volume allows accelerated hypofractionated radiotherapy schedules to be used with radiation being delivered to a small volume in 1-2 wk often treating twice a day69. This type of radiation is known as APBI. Various techniques have been used including 3DCRT2170, single and multi-catheter brachytherapy7172, as well as intraoperative radiotherapy7374.

Clinical outcomes of several randomized controlled trials have been reported which have utilized various techniques for delivery of APBI making cross-trial comparisons difficult69. Comparison of outcomes in randomized controlled trials that have investigated PBI against whole-breast irradiation suggests that local recurrence rates may be higher7576. However, a meta-analysis showed that external beam radiotherapy-based PBI techniques might be associated with the lowest margin for non-inferiority76. Further risk of fat necrosis was also found to be higher in patients undergoing APBI76. Overall, the results of these studies suggest that careful case selection and attention to quality are essential for safe implementation of APBI in clinical practice.

While 23 studies were identified which reported results of PBI, mature clinical outcome data were available from one institute (Wadasadawala & colleagues)7778 where a multi-catheter PBI technique was followed. Clinical, cosmetic and patient-reported outcomes were favourable, with better outcomes reported for cosmesis and patient-reported outcomes with APBI as compared to whole-breast irradiation777879. Perioperative implant placement was generally favoured. Five- and seven-year local control rates were 97 and 92 per cent80. Excellent-to-good cosmesis was reported in 77 per cent of women80. Dosimetric comparison of an external beam-based APBI technique against whole-breast irradiation has been reported by Kumar et al81 who reported that the use of 3DCRT APBI approach resulted in improved conformity as compared to whole-breast tangents. The key issues with implementing these treatment techniques in most centres in India are lack of expertise for brachytherapy-based PBI, as well as the necessary caseload of patients eligible for APBI. Further, the role of multi-catheter APBI (especially the perioperative technique) has not been well studied in patients undergoing oncoplastic breast surgery82.

Radiation avoidance: With improvement in outcomes of patients with breast cancer, the risk of locoregional recurrence has declined. As a result, increasing attention is now being focussed on avoidance of adjuvant radiotherapy in selected patients with a low risk of recurrence. Two randomized controlled trials have investigated omission of adjuvant radiotherapy in elderly patients undergoing breast conservation8384. In both these studies, a favourable population of elderly patients, with T1-T2 tumours and luminal type A disease subtype, were selected. The results of these trials are summarized in Table IV. As can be seen, there was a significant increase in the local recurrence rate with the avoidance of radiotherapy in these studies. While the results of these two studies8384 show that there is no detriment in overall survival with avoidance of adjuvant radiotherapy in subset of patients with low-risk disease, the applicability of these findings in the Indian setting needs to be seen where the prevalence of such early-stage low-grade disease is low and adherence to long-term follow up may be a problem. Furthermore, with increasing adoption of hypofractionated radiotherapy and cardiac-sparing techniques, the primary concerns with adjuvant radiotherapy usage even in this population may be rendered moot85.

Table IV

Summary outcomes of two trials evaluating avoidance of adjuvant radiotherapy

Study	n	Age (yr)	T size (cm)	N+	FU	LRFS (%)	OS (%)
CALGB 934383	636	≥70	≤2	No	10	RT: 98 No RT: 90	RT: 67 No RT: 66
PRIME II84	658	≥65	≤3	No	5	RT: 98.7 No RT: 95.9	RT: 93.9 No RT: 93.9

Superscript numerals denote reference numbers. n, number; T size, tumour size; N+, node positive allowed; FU, follow up in years; LRFS, local recurrence-free survival; OS, overall survival; RT, radiotherapy

Conclusion

Most institutes that have adopted hypofractionated radiotherapy have been able to report good outcomes. This has important implications for India, where radiotherapy resources are limited. Further adoption of hypofractionation results in significant cost savings for the patient. Institutional practice varies widely with respect to more sophisticated techniques such as cardiac-sparing radiotherapy, SIB, and APBI, but centres that have adopted these techniques in a systematic manner have reported comparable outcomes as in West. There is need for developing multi-centric collaborative research studies to identify gaps in knowledge where such research would be most useful.