Hypofractionated adjuvant radiotherapy in breast cancer is now considered the standard of care and is recommended by most major cancer societies and guidelines worldwide. The results of the UK Standardization of Breast Radiotherapy (START) trials A and B suggested that moderate hypofractionation is non-inferior in terms of locoregional control and is also associated with lower acute toxicity. Existing data from India by Chatterjee et al. suggest that moderately hypofractionated radiotherapy can be delivered safely with results comparable to those published in the West. The major impact of hypofractionated radiotherapy is on health care systems with limited radiotherapy resources. By shortening the treatment time, the indirect costs of treatment are also curtailed.
The late effects of the radiation dose on the heart translate into a higher cardiac mortality. A meta-analysis by Taylor et al. suggested that cardiac events (in the form of ischemic heart disease) are the most common cause of non-cancer deaths amongst breast cancer survivors. However, overall event rates remain low—with only 1253 events identified in 40,781 women.
The concern is higher with hypofractionated radiotherapy, as theoretically, a higher dose per fraction translates to a higher risk of late complications. Clinical trials to date have shown no excess of cardiac mortality or morbidity amongst patients who had received hypofractionated radiotherapy for breast cancer. At the same time, it needs to be acknowledged that further research is sorely required. The cumulative number of events observed in trials investigating hypofractionated radiotherapy remains quite low—considering that in a recent meta-analysis, 8189 participants were identified across 13 trials. For example, in the START trials, a total of 73 ischemic heart disease events were reported across 4451 patients with no difference apparent between the conventional fractionation and hypofractionated radiotherapy arms. The number of confirmed events was even lower at 42 events. Symptomatic lung fibrosis was observed in a total of 61 patients only. Numerically, the rates of both events were higher in the conventional fractionation arm in both trials.
In this issue of the journal, Saha et al. report a rare randomized controlled trial which focused on evaluating the cardiopulmonary toxicity of hypofractionated radiotherapy. They report a study in which 59 patients with left breast cancers were treated with a usual conventionally fractionated radiotherapy regimen of 50 Gy in 25 fractions over 5 weeks versus a hypofractionated regimen of 39 Gy in 13 fractions over 3 weeks. Radiotherapy was delivered on a telecobalt unit and regional nodal radiation was performed including to the supraclavicular fossa for most patients and the axilla for a few patients. Cardiac toxicity was evaluated using the decline in left ventricular ejection fraction on echocardiography while pulmonary toxicity was measured using pulmonary function tests.
There are several methodological limitations of the study like the lack of prospective study registration, limited information available on the data collection and storage methods, limited reporting of the endpoint definitions for the primary and secondary outcomes, as well as a sample size calculation method better suited to calculate the error of a single proportion rather than compare two proportions. The correct method for analysis of this kind of longitudinal continuous data would involve a comparison of the values between the two arms with adjustment for the baseline values using the analysis of the covariance (ANCOVA) test.
Despite these limitations, the authors need to be congratulated for choosing to go ahead with a randomized design in the first place despite the complete lack of funding. Other strengths of the study include proper subject selection (left breast cancers), the use of measures of cardiac and pulmonary functions which are easily accessible and have direct relevance to patient outcomes and management, as well as good follow-up, despite the lack of funding. Even more important is the fact that this study was conducted in a state government-funded institute where arguably the poorest of the patients receive treatment.
This is very important when we consider how difficult it is for the patients with cancer to access clinical trials relevant to their condition in India. As reported by us, there is a drastic disparity in geographical access to clinical trials in India. Disparity in access to government and intramurally funded research is also apparent. For example, for breast cancer, for each 1000 incident cases, a median of 2.38 patients can potentially get enrolled in a clinical trial. However, there are whole states where there are no clinical trials running for patients. As can be appreciated in the face of such disparity, equity in access to clinical trials is a challenge, and therefore the poorest of the Indian patient population is likely to be severely underrepresented in clinical trials.
Therefore, it is heartening that the eastern part of India is taking an active interest in conducting randomized controlled trials for hypofractionated radiotherapy in breast cancer. One of the largest randomized controlled trials investigating an even further abbreviated hypofractionated course of radiotherapy is being coordinated by the Tata Medical Center in Kolkata. When published, the results of this study will inform the adoption of a one-week hypofractionated radiotherapy schedule in patients with breast cancer with more advanced disease. In addition, the study will also be reporting on the use of a modern simultaneous integrated boost approach for treating the breast tumor bed after breast conservation.
There is another important reason why these studies are needed from India. The younger demographic pattern of India is probably the reason why we tend to see patients with breast cancer at a younger age as compared to the West. Most patients present with advanced disease and receive systemic therapy as well as regional nodal irradiation as a part of their adjuvant therapy. This was demonstrated in the study by Saha et al. too in which only 1% of the patients in the hypofractionated radiotherapy arm were pathologically node negative. The ischemic heart disease burden in women in India is increasing rapidly and between 2000 and 2017, the mortality has nearly doubled. Along with this, risk factors like diabetes, obesity, and tobacco use have increased disproportionately amongst women. Thus, the lifetime risk of developing cardiac events in Indian women may be even higher as the increase in cardiac toxicity is typically observed 10–15 years after radiotherapy. When viewed from this perspective, the importance of the study by Saha et al. is immediately apparent.
In conclusion, the report of the randomized controlled trial by Saha et al. demonstrates the stark need for more equitable access to public clinical trial funding in India. The intention to conduct a pragmatic randomized trial instead of a cohort study or a case-control study is a testament to the scientific forethought in the group. Ongoing trials are indicative of the fact that the talent required to conduct such trials exists in the Eastern part of the country. The question remains as to whether the funders will now step up to the plate.
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