|Year : 2021 | Volume
| Issue : 1 | Page : 41-44
Advances in radiotherapy in 2020: Hypofractionation - less is more in times of COVID-19
Hari Mukundan, Pankaj Vats
Department of Radiation Oncology, Oncology Centre, INHS Asvini, Colaba, Mumbai, Maharashtra, India
|Date of Submission||14-Dec-2020|
|Date of Decision||18-Dec-2020|
|Date of Acceptance||25-Dec-2020|
|Date of Web Publication||24-Mar-2021|
Department of Radiation Oncology, Oncology Centre, INHS Asvini, Colaba, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mukundan H, Vats P. Advances in radiotherapy in 2020: Hypofractionation - less is more in times of COVID-19. Indian J Cancer 2021;58:41-4
The main focus of medicine in 2020 has been the COVID-19 pandemic. As we move forwards with eyes pinned to various vaccine researches, oncologists have slowly gotten used to the fact that we will have to resume our usual patient treatments irrespective of when a viable vaccine is available. Even so COVID-19 infection poses a great risk to cancer patients with a heightened risk of adverse events like ICU admission, mechanical ventilation, and mortality. Hypofractionated radiotherapy; by virtue of decreasing total treatment time, reduces the time often immuno-compromised cancer patients spend in hospitals and thereby decreases the risk of getting COVID-19 infection. In this article, we have tried to look at some of the important papers published this year that used hypofractionation or stereotactic delivery methods.
In breast cancer treatment, UK START trials brought the use of hypofractionated radiotherapy into the mainstream. Further, the UK FAST trial showed that once a week treatment over five weeks was non-inferior to the standard START fractionation schedule. The results of FAST-Forward Trial published in Lancet this year are bound to have a major impact on the treatment as well as economic factors world over. Early breast cancer patients needing whole breast or chest wall radiotherapy following initial surgery were studied in this trial. The estimated absolute difference in 5-year incidence of ipsilateral breast cancer recurrence for 26Gy (5# in one week) arm versus 40Gy (15# in 3 weeks) arm was –0.7% (P = 0.00019). Normal tissue effects were similar between these two arms. Another very promising Phase I/II trial has been published in Brachytherapy by Jean-Michel et al. They have reported outcomes after a 5-year median follow-up of elderly (age >70 years) breast cancer patients treated with single fraction (16 Gy) treatment with intra-operative catheter implant. They report 100% local control and a 100% cancer-specific survival; no long-term toxicities more than grade 2 were reported and 81% patients reported an excellent cosmetic outcome. This approach can be adopted into mainstream especially for the elderly patients who often have difficulty completing the lengthy conventional treatment course.
The other primary site which has generated quite a bit of interest with regards to hypofractionation is prostate. Recent studies have estimated the α/β ratio to be 2.5 to 4.9 for prostate cancer. The efficacy and toxicity profile of the multi-cohort DELINEATE study published in the Red Journal show that it's possible to deliver hypofractionated (60Gy in 20#) image-guided radiotherapy to prostate with an integrated boost of up to 67 Gy to lesions visible on multiparametric magnetic resonance imaging. No late grade 3 rectal or genitourinary toxicities were reported. Macias et al. delivered 43.8–45.2 Gy in 8# over 3 weeks with tomotherapy in unfavorable intermediate- and high-risk prostate cancer patients. They reported 5-year biochemical disease-free survival for the whole series of 154 patients to be 94.3%. While the control rates are similar to historical controls, the toxicity profile was reported as milder when compared to external beam radiation therapy (EBRT)/brachytherapy combination treatments. 7-year outcomes of HYPRO trial were also published in the Red Journal this year. Fractionation schedule of 64.6 Gy in 19# was used in the study arm in this trial for treating patients with intermediate or high-risk localized prostate cancer (EQD2 of 90.4Gy). However, even in the 7-year outcomes, as was seen with 5-year outcomes, the difference in relapse-free survival was not significantly different between the conventional (67.6%) versus hypofractionated (71.7%) arms. Patrick et al. published results of interim analysis of their prospective trial studying role of stereotactic body radiation therapy (SBRT) in delaying systemic therapy in oligometastatic prostate cancer. They achieved the desired goal of avoiding systemic therapy for at least 2 years in more than 50% of patients, with median escalation-free survival being 27.1 months. They report equal outcomes when treating 1-3 lesions or 4–5 lesions. No late grade three toxicities were reported with their fractionation schedule of 50Gy in 10#, showing efficacy and good tolerability of this approach. Murthy et al. had in 2018 published their experience with extreme hypofractionation in high-risk, very high-risk, and node-positive prostate cancer using SBRT, which showed acceptable toxicity profiles and promising overall survival as well as biochemical control results. Following this experience, Murthy et al. have started a multi-centric PRIME TRIAL which includes the above-mentioned subset of patients, who are being randomized to receive 68Gy/25# over 5 weeks versus 36.25Gy/5# over 7 to 10 days by SBRT. The authors aim to prove that the markedly shorter regimen would prove to be therapeutically efficacious and also cost-effective. Another study, the HOPE Trial, assessing the role of hypofractionated radiotherapy (25Gy/5#) for whole pelvis radiotherapy in conjugation with brachytherapy, is also ongoing.
This year certain important reviews and trials were published dealing with radiotherapy in the brain. The Cochrane Database Systematic Review studies various fractionation schedules against the standard conventional regimen. An important finding with regard to hypofractionated schedules was that they have similar efficacy for survival as compared to conventional schedules, especially so in patients with glioblastoma and in those aged more than 60 years. This finding has an important implication in geriatric patient management with these aggressive histologies and resultant poor prognosis. The abbreviated schedules would entail much less time spent in hospital setting without any compromise on tumor control or survival. With COVID-19 pandemic headlining every medicine related issue this year and having widespread implications, less time spent in hospitals by these high-risk patients is surely an added advantage. With regards to pituitary tumors, a meta-analysis of Stereotactic Radiosurgery (SRS) was published in World Neurosurgery. The mean radiation marginal dose was 19.6Gy which provided an overall tumor control rate of 95% in the total 2315 analysed patients. Benefit was seen in both secretory as well as nonsecretory tumors. The review mentioned only a few minor side effects. Though no randomized controlled trials were included in the analysis, it nonetheless supports continued use of SRS for pituitary tumors. With regards to brain metastasis; Zarique et al. published their meta-analysis in the Green journal. They studied 3458 patients for the role of postoperative SRS following excision of brain metastasis. Very promising local control (at 1 year) of 83.7% was seen, with patients receiving fractionated SRS faring even better (87.3%). Review showed no benefit of adding margins to the tumor bed. The approach was considered safe with radiation necrosis rate of only 6.9%. However, distant brain control at 1 year was found to be 52.8%. Even so, the authors concluded that post-operative SRS to the resection cavity is an effective treatment option. Results of a prospective phase 3 trial studying the dose and fractionation schedule in whole brain radiotherapy (WBRT) following surgical excision were published in the Red Journal. Most commonly used schedule of 30Gy/10# was compared against 37.5Gy/15#. Lung primaries were more commonly treated with the protracted schedule. No benefit of the extended schedule in terms of reduced risk of cognitive deficit, surgical bed control, distant brain disease control or overall survival was seen; furthermore, a statistically significant increase was seen in the risk of grade >3 toxicity with the 37.5 Gy schedule. These results further solidify the stance of shorter more hypofractionated WBRT regimen.
Also published this year were the results of a single-arm phase 2 study evaluating the role of stereotactic ablative radiotherapy (SABR) in delivering local EBRT boost in locally advanced carcinoma cervix, in patients who were medically unfit or refused brachytherapy. The authors correlated the grade >3 toxicities with the increasing volume of tumor/planning target volume (PTV). They reported lower than expected local control and overall survival; however, authors suggest continued use of SABR in patients with smaller tumors who are unfit for standard brachytherapy. SBRT is now widely accepted treatment modality for local treatment of unresectable hepatocellular carcinoma. Won et al. treated patients with 45 to 60 Gy in 3# with the primary endpoint being to assess treatment-related toxicity at 1 year, which was reported as 3% for severe toxicities. At 3 years local control was 95% and overall survival was 76%. Shao et al. reported their experience in the Princess Margaret institute, with hypofractionated radiotherapy (2.4Gy/fraction) alone for treating head and neck cancers. They did a retrospective analysis of patients treated with hypofractionated radiotherapy (60Gy/25#/5 weeks) versus accelerated radiotherapy (70Gy/35#/6 weeks) versus conventional concurrent chemoradiotherapy. They analyzed patients based on 7th edition TNM classification and presence or absence of human papillomavirus (HPV) infection. For HPV positive cases, they identified T1-3N0-2c cases as having similar locoregional (LRC) as well as distant control (DC) rates with all three treatment modalities. In HPV negative cases, the only RT arms were similar to concurrent chemoradiotherapy (CCRT) arm in terms of LRC and DC only in T1-2N0 cases. Hence the authors propose use of hypofractionated radiotherapy for head and neck cases falling into the above subsets showing similar results as prolonged conventional CCRT. For medically inoperable early-stage lung cancers, SBRT has become somewhat of a standard norm; to add to the abundant experience from western countries, Agarwal et al. published their experience with the same in an Indian tertiary care hospital. They reported 94% 2-year local control rates with a promising 68% cancer-specific survival in their cohort of medically inoperable patients with a median age of 71 years and median Charlson comorbidity index of 3.
A review analyzing the role of very interesting concept of FLASH radiotherapy was also published this year. The authors give thought-provoking points about the ultra-high dose rate radiotherapy, which is largely experimental at this point though, has the feather of successfully treating one patient under its cap.
This is by no means an exhaustive review of the articles in 2020 or even of the ones on hypofractionation. While 2020 has ensured that it will forever be known as 'the year of COVID-19' in the annals of history, there has been enough worthwhile data published this year to help radiation oncologists continue to choose hypofractionated regiments with increasing confidence as well as increasingly explore applications of stereotactic treatment delivery systems to deliver these schedules.
This article was peer-reviewed by an external referee.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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