Hypofractionation in postmastectomy breast irradiation. How safe are we in using standard tangentials?

Introduction

Breast cancer is the second most common cancer in India and leading cancer in women worldwide. Radiotherapy is an integral part of its multimodal treatment with a proven survival advantage for patients undergoing breast-conserving surgery and those patients with high-risk pathological features following modified radical mastectomy.^1,2

The past few decades have seen dramatic changes in the approach to radiotherapy delivery and technique as well as the concepts of fractionation. Hypofractionated schedules have become the standard in the United Kingdom and many centers in Canada and gaining popularity in other parts of the world including India. Four major randomized trials involving nearly 7000 patients have updated results to suggest that hypofractionated schedules can provide an equivalent survival benefit and local control to the earlier standard of care 50 Gy delivered in conventional 2 Gy per fractions over a period of 5 weeks.^3,4 The most popular regimes that have been adopted are 42.5 Gy in 16 fractions as well as 40 Gy in 15 fractions. The START A, START B, and Ontario trials have >10 years of follow-up to suggest favorable cosmesis. Although the incidence of cardiac morbidity was not significantly different, this parameter was less well analyzed and documented. The fact that <15% of patients involved in these trials had undergone mastectomy compromises the extrapolation of safety to this category of patients. Regarding the efficacy of hypofractionation in the postmastectomy setup, a few prospective trials do show equivalence. However, there are insufficient mature data to suggest the same as regards the late toxicity of heart and lung.⁵ The extrapolation of the currently available data to the postmastectomy setup faces several unaddressed issues. Patients undergoing mastectomy usually have more aggressive disease necessitating cardiotoxic neoadjuvant or adjuvant chemotherapy that can contribute to cardiac morbidity. The postmastectomy planning target volume (PTV) is inclusive of the chest wall and will be associated with a larger volume of heart and lung in the high-dose frame.

The most common technique of radiotherapy delivery to the postmastectomy chest wall is two-dimensional (2D) TW-based beams. However, in the past few decades, better radiotherapy techniques have evolved. There is evidence to suggest that 3D conformal radiotherapy field in the field (3DCRT FIF), tangential (inverse planning) intensity modulated radiotherapy and multifield intensity modulated radiotherapy may have dosimetric advantages over conventional tangentials in terms of heart and lung sparing.⁶

The current study was carried out with the objective of evaluating the dosimetric benefit of considering 3DCRT FIF over standard 2D TW when using hypofractionation in the postmastectomy setup.

Materials and Methods

Twenty-six patients with locally advanced breast cancer planned for postmastectomy irradiation were considered for this study. Eleven patients (42%) had left-sided lesions and 20 patients (76%) required supraclavicular irradiation. The study was performed with approval of the institutional ethics committee.

Results

The PTV and OAR parameters achieved and observed are represented in Table 1.

Plan A represents the 3DCRT FIF plan and the values achieved for the 2D TW plan by plan B.

Plan comparison and structure parameters

The PTV parameters evaluated were Dmax (maximum dose), V_47.5 (percentage of PTV receiving 95% of the prescribed dose) V_52.5 indicating the dose hotspot area that received 107% of the prescribed dose, HI was calculated as (D2%–D98%)/D50%. CI as:

The parameters evaluated for OAR were Dmean, average dose delivered to an organ and V_{x gray} which was the percentage of the organ receiving ‘x’ Gy y or higher. We used paired sample, ‘t’-test, to compare normally distributed data between PLAN A and PLAN B.

Discussion

The radiotherapeutic management of breast cancer has significantly evolved over the past few decades both in terms of wider availability, application of newer technology and a better understanding of biological response and toxicity to the breast tissue and other OAR associated with breast irradiation.

Hypofractionation in the adjuvant setup offers local control and adverse effects comparable to conventional fractionation. Four large randomized control trials have provided evidence to support its application following breast conservative surgery. Canadian, START A, START B, Royal Marsden Hospital and Gloucestershire oncology center.^4,7 All these have conclusively shown equivalent roles of survival and local relapse as well as acceptable cosmesis with moderate hypofractionation. The advantage of using a shorter fractionation schedule includes better patient compliance, lower treatment cost-related to stay and travel, as well as better resource utilization. However, gray areas persist that prevent it from being the standard of care or being used routinely in the postmastectomy setup. Less than 15% of patients in START A, 8% in START B trial and none in the START pilot or Ontario trials had undergone modified radical mastectomy. The toxicities that have been addressed with the available follow up have mainly concentrated on cosmesis. In the postmastectomy set-up, there is the invariably larger amount of normal breast and lung volumes in the high dose cloud on account of including the chest wall as a part of the CTV. Majority of the patients undergoing postmastectomy radiation have the locally advanced disease and will receive chemotherapy that would contribute to anticipated cardiac and pulmonary toxicities.

In most centers in India as well as other parts of the world, postmastectomy irradiation is mainly delivered with two tangential wedge fields with additional supraclavicular fields when required. Although there are a number of prospective studies that provide insights into more sophisticated radiation techniques for treatment delivery to the intact breast, very few have addressed the issue in the postmastectomy setup.

We conducted this analytic study of dosimetric comparison of the treatment plans using 26 consecutive postmastectomy breast cancer patients to evaluate this issue. Several ongoing trials in breast radiotherapy are focusing on increasing conformity with intensity modifications with gated techniques.⁸ However, such facilities and options are not available to the majority of patients in India. In this study, we have focused on a practical alternative to standard 2D TW based plans that can provide better sparing to the heart and lungs and can be safely executed for patients considering hypofractionated treatment.

In our study, the 3DCRT plan showed a dosimetric advantage in terms of PTV coverage that was statistically significant. An earlier trial conducted by Cavey et al. evaluating 12 patients with these two treatment techniques also observed the same statistical benefit of PTV coverage (P < 0.001) as well as HI (P = 0.023).⁹ In our study, the 3DCRT FIF plans were more homogenous (HI) 0.37+/-0.05 versus 0.4+/-0.06. However, this was not statistically significant. The most significant results from our study were pertaining to the sparing of heart and lungs. The 3DCRT FIF plans clearly showed that the cardia could be better spared with nearly three times less exposure compared to the 2D TW technique, Dmean 6.45 ± 0.02 versus 22.5 ± 2.1(P < 0.001).

The relative proportionate risk of ischemic related cardiac events and mortality has been clearly established in several studies. In a population-based study considering 2168 women who underwent radiotherapy for breast cancer, Darby et al. observed a dosimetric correlation of mean dose received to the whole heart to the risk of major coronary events. They observed a risk of 7.4% per Gy (95% confidence interval 2.9–14.5, P < 0.001) with no apparent threshold.¹⁰ The increase incidence of ischemic events started at 5 years and continued to the third decade. Considering the same, the results of the current study would suggest a significant clinical impact.

Pulmonary toxicity in terms of dose received to the ipsilateral lung as well as both lungs was also significantly less V₂₀, V₃₀, and V₅ (both lungs) P < 0.001. Besides pneumonitis, a higher incidence of second primary lung cancer has been associated with incremental exposure of the lung. Grantzau et al. in a population-based study involving 23,627 early breast cancer patients observed a linear association of second lung cancers with 8.5% per Gy (95% confidence interval = 3.1%–23.3%; P < 0.01).^11,12

The other OAR that can be better spared with the 3DCRT FIF is the opposite breast. In our study, the Dmean in the 3DCRT FIF was nearly half of the value observed with the 2D TW plan 3.5 ± 0.43 versus 8.8 ± 0.94.

Conclusion

3DCRT FIF is dosimetrically more advantageous in terms of PTV coverage and sparing of the heart and lungs. It may not be practical to suggest this technique for all patients undergoing postmastectomy irradiation, as it is labor intensive for planning. However, it can be strongly recommended for patients undergoing hypofractionation and especially for left sided tumors when respiratory gating and image guidance is not an available option.