key: cord-1019261-kg9lf68b authors: Lewis, Shirley; Talapatra, Kaustav title: Radiotherapy management of rectal cancer in the backdrop of the COVID pandemic date: 2020-12-09 journal: Cancer Rep (Hoboken) DOI: 10.1002/cnr2.1320 sha: 6a2990bb47a949e5e55c8b18f7e066f62da3f16a doc_id: 1019261 cord_uid: kg9lf68b BACKGROUND: COVID‐19 outbreak was declared as a pandemic by the World Health Organization in March 2020. Over the last 3 months, the pandemic has challenged the diagnosis and treatment of all cancer, including rectal cancer. Constraints in resources call for a change in the treatment strategy without compromising efficacy. RECENT FINDINGS: Delivery of shorter treatment schedules for radiotherapy offers advantages like short overall treatment time, improved throughput on the machine, improved compliance and reduced risk of transmission of COVID 19. Other strategies include delaying surgery, reducing the intensity of chemotherapy and adoption of organ preservation approach. CONCLUSION: The curative treatment of rectal cancer should not be hindered during the COVID pandemic, and modifications in the multi‐modality treatment will help achieve quality care. COVID 19 pandemic is arguably the most extensive global healthcare emergency of this millennium. 1, 2 It has rapidly spread across the countries with over 34 205 913 cases and 1 019 605 deaths. Various hospitals have been paralyzed by the enormous needs of COVID 19 patients. 3, 4 The transmission of COVID in India is increasing with 6 312 584 cases and 98 708 deaths. However, with easing out of public restrictions, more patients will likely be affected. Cancer care during these difficult times is challenging and may lose its priority. 5, 6 Various aspects of care are put on a back burner. 7 There is a danger of high mortality both from COVID and inadequately treated cancer. [8] [9] [10] There are constraints on resources (particularly supplies and operating room) and hospital staff, which may make delivery of current standard approaches for the treatment of cancer difficult. 11 Demands on hospital infrastructure and staff lead to rationing of patient care services. The functioning of operating rooms is affected by short staffing of anesthesia personnel, risk of aerosol generation during surgery and inability to provide adequate postoperative care in intensive care units. The disinfection protocols in the operating room, or linear accelerator suite, impact the number treated per day with reduced staff. There is a shortage or low-quality personal protective equipment for these specialized services. Many frontline medical workers are getting infected, which causes reorganization of other healthcare professionals. Saving most lives receives maximum priority. 12 Thus, changes like shorter treatment times and telemedicine patient consults are favored. The pandemic has already transformed significant aspects of cancer care, and experts predict the changes in oncology treatment wrought upon by the epidemic may not be short-lived. 5 Radiation plays a vital role in the multi-modality treatment of rectal cancer. 13, 14 Rectal cancer patients with intermediate and high-risk factors on preoperative MRI and neoadjuvant radiotherapy are required for down-staging the disease before surgery. 15 During the COVID pandemic, radiation use for rectal cancer has been classified as medium priority. To maintain continuity of care without compromising outcomes, changes to optimize practice or delivery of multi-modality treatment are needed. "Less is more" is the newfound mantra, and the RADS framework by Zaorksy et al is very appropriate for all settings. 16, 17 The major changes proposed are shortening chemoradiation from 5 weeks to 1 week, delaying surgery from 4-6 weeks to 12 weeks, less intensive chemotherapy and organ preservation approach. These may yield the least chance of side effects while maintaining excellent outcomes and avoid the risk of contracting COVID 19 infection. In this paper, we shall review the evidence for these approaches and their applicability during the COVID pandemic. There has been a resurgence of short-course radiotherapy (SCRT) in recent years. SCRT is shown to be safe, effective and allows treatment in a short time, thereby reducing patient visits. 18 Despite similar outcomes to long course RT (LCRT), the adoption of SCRT in routine practice is low with concerns for increased late toxicity and poor down-staging in case of locally advanced cases. 19 The Swedish rectal cancer study reported late gastrointestinal effects. 20 However, the portals used for radiotherapy in this study were more extensive than currently used, which spare significant dose spillage to the bowel. rates were low in SCRT arms; however, no difference was seen in patients requiring APR in distal cancers (<5 cm). 22, 23 Similarly, in locally advanced and advanced cancers, SCRT with integrated consolidation chemotherapy in waiting period to surgery has the advantage of better down-staging, improved compliance and reduced risk of distant metastases, and studies exploring this approach have shown excellent results. Bujko et al compared SCRT and consolidation chemotherapy (3 cycles FOLFOX 4) with oxaliplatin-based LCRT in 515 cT4 or fixed T3 rectal cancer patients. 24 The R0 resection rates (primary endpoint), pCR rates, local recurrence and distant metastases were similar in both arms at a median followup of 35 months. The OS was higher in SCRT arm (73% vs 65%), and the acute preoperative toxicity was lower in SCRT arm. The updated results of this trial, with a median follow-up of 8 years, show similar 8-year OS of 49% in both arms with no difference in late grade 3+ toxicity between the arms (11% vs 9%). 25 The major drawbacks of this trial are that MRI was not used for staging (with a possibility of under staging), nonstandard oxaliplatin-based concurrent chemotherapy in the control arm and was not designed based on survival endpoints. These factors are being addressed in the RAPIDO trial, comparing SCRT followed by chemotherapy with LCRT ± adjuvant chemotherapy in locally advanced rectal cancer with DFS as the primary endpoint. 26 The early results show compliance of over 80% with SCRT + chemotherapy (6 cycles of CAPOX) at the expense of higher grade 3+ toxicity. 27 The results of RAPIDO in abstract form was presented at ASCO 2020 by Hospers et al, which showed low 3-year diseaserelated treatment failure (23.7% vs 30.4%; P = .02), distant metastasis (19.8% vs 26.6% P = .004) and high pathological completed response (27.7% vs 13.8%; P < .001) with SCRT and chemotherapy. 28 The locoregional failure rates (8.7% vs 6.0%; P = .10) and quality of life were similar between the two arms. The full manuscript of the RAPIDO trial and results of the STELLAR trial are awaited. 29 During the COVID pandemic, while the patient awaits surgery after SCRT, consolidation chemotherapy may be added and, to reduce toxicity, dose reductions may be considered. SCRT is a cost-effective treatment strategy, compared to LCRT, based on an economic modeling study by Raldow et al. 30 They showed that SCRT was associated with an incremental costeffectiveness ratio of $133 495 per quality-adjusted life-year. SCRT plus chemotherapy is also a cost-effective approach, as demonstrated by Wang et al. 31 Although cost-effectiveness is not proven in LMIC, it is logical that 1 week of radiotherapy would reduce the financial burden in terms of stay and reduce exposure to COVID in the hospital setting. Based on these studies, the adoption of shorter fractionation schedules is strongly recommended by the international expert panel and ESMO. 32, 33 This change is being adopted in major cancer centers, including the United States and Europe, during the pandemic. 34, 35 Rosenblatt et al (IAEA trial with 55% patients from India) and Chakrabarti et al show the feasibility and improved compliance of SCRT in the low middle-income country (LMIC). 36, 37 This change in practice in a resource-constrained setting would benefit the patient greatly during the prolonged pandemic times and beyond. The usual practice is to consider surgery within 3 to 7 days or 4 weeks of SCRT and 6 weeks of LCRT. A delay after radiation has benefits in COVID scenario where scheduling of surgery may be difficult due to resource and staff constraints. 38 The delay will help in down-staging, particularly in cases of distal cancers (< 5 cm from the anal verge), as shown in the Stockholm trial. The Stockholm trial compared SCRT with immediate surgery vs SCRT with delay and found no difference in the local recurrence rates, recurrence-free survival and OS between the two arms. 39 The pCR rates were 11.8% and fewer postoperative morbidity in the delayed group. 40 In a real-world scenario, the United Kingdom population-based study, in a cohort of 3469 patients, showed no difference in postoperative outcomes with delayed surgery. 41 In a meta-analysis by Huang et al, there was no difference in OS in LCRT with late surgery, SCRT with immediate surgery and SCRT with delayed surgery. 42 However, the authors also conclude that larger studies are required to come to a more convincing conclusion. In patients who have completed chemoradiation, and awaiting surgery, postponing surgery to 11 weeks can be considered based on GRECCAR 6 trial. 43 There was no difference in 3-year OS, or DFS, however, the complications were higher at 11 weeks vs 6 weeks. 44 Higher postoperative complications seen in GRECCAR trial have not been seen in RAPIDO trial, or trials using total neoadjuvant approach. 27, 45 The response to radiation could be used to tailor the type of surgery (local excision in place of TME) during the pandemic with ongoing triage and rationing of cancer surgeries. GRECCAR 2 trial is a multicentric randomized trial, which compared local excision with TME in 148 down-staged (residual <2 cm) bulky low rectal cancer (good responders to LCRT in T2-T3 disease). 46 Completion of TME was performed in local excision group if pathological stage revealed T2/T3. At a median follow-up of 60 months, there was no difference in local recurrence rates, DFS, OS, distant metastases or cancerspecific mortality. A total of 35% in local excision required TME for completion. 47 Few patients who are in early stage, and get operated upfront, may be upstaged after surgery and may need adjuvant chemoradiotherapy. As per ESMO guidelines, adjuvant radiotherapy is indicated in pT4, margin positivity, N2, especially with low tumors and poor-quality surgery. 15 Postoperative radiotherapy has shown in randomized trials and meta-analyses to reduce local recurrence rates significantly. 48 The decision to treat should be carefully weighed and may be deferred in low-risk cases. In case of high risk, LCRT is to be favored. Chemotherapy has the risk of myelosuppression, and early reports from China and Italy suggest higher complications from COVID, in patients, after chemotherapy. 10, 49 Thus, changes in the regimens of chemotherapy to minimize myelosuppression should be considered. Intensive regimens can be substituted with lesser ones, and oral drugs may replace intravenous, where feasible, to reduce hospital visits. 50 Avoidance of severe grade 3-4 reactions necessitating emergency room visits can be tried with upfront dose reductions up to 25% and optimal use of growth factors to prevent neutropenia. The role of chemotherapy in rectal cancer after neoadjuvant chemoradiation in the adjuvant setting is controversial and has not shown survival benefit. 15 The evidence for adjuvant chemotherapy is primarily extrapolated from colon cancer, and the prospective trials are flawed due to low patient numbers. There is a small disease-free survival benefit, especially in nonresponders after neoadjuvant chemoradiation and node-positive patients with no overall survival benefit. 51 There is wide variation in the use of adjuvant chemotherapy worldwide with oncologists from the United States recommending it, and those from Europe negating it. While deciding adjuvant chemotherapy, risk vs benefit should be assessed based on the patient's comorbidities and impact of the pandemic, and the same to be communicated with the patient. For low-risk patients, omitting adjuvant chemotherapy may be considered. In high-risk patients, requiring doublet chemotherapy, initiation of oxaliplatin may be delayed or omitted as it adds very little to single-agent 5FU/Capecitabine. 50 The use of oral capecitabine is to be preferred as it is proven to be equivalent to 5FU and should replace intravenous 5FU. Dosing of capecitabine may be reduced (fixed dosing 1500 mg twice daily 5 days a week or 7 days on and 7 days off) to reduce the risk of severe mucositis and diarrhea. Following neoadjuvant SCRT, in cases where there is a delay to surgery due to pandemic, chemotherapy may be considered. Studies exploring the total neoadjuvant treatment (TNT) approach have shown significant response rates and are safely tolerated. 52 Although the TNT approach generally uses LCRT, the use of SCRT has demonstrated promising results. 24, 53 These regimens involve the use of doublet chemotherapy, which is FOLFOX based. In addition to the modifications suggested, skipping the bolus 5FU and delaying each cycle by 2 to 3 weeks may help balance toxicity with benefit. The use of telemedicine consults to inform blood reports performed at local should be encouraged to avoid hospital visits. Organ preservation approach may be considered in patients with a complete response after neoadjuvant radiotherapy. 54 Studies have shown that wait and watch after complete response has similar outcomes compared to those undergoing surgery. The international wait and watch database of 1009 patients from 15 countries showed that the local regrowth rate is 25% with over 80% occurring within 2 years. 55 The regrowths are limited to bowel wall in 97% and amenable for salvage with a 5-year OS of 85%. Salvage surgery is feasible in 83% of cases with regrowth. 56 Radiological down-staging was achieved in 73% with 12% showing a complete response. 82% underwent surgery with a pCR of 9%, and local recurrence rates were 8% at a median follow-up of 30 months. Bujko et al showed 20% complete clinical response after SCRT and delay. 58 In complete responders, nonoperative management may be proposed, especially in frail, unfit elderly patients who are at high risk during COVID. This approach needs diligent monitoring with imaging and follow-up assessments, especially in LMIC's, where patients are often lost to follow-up. It can be considered in educated and wellinformed patients who will adhere to follow-up assessments. The modifications discussed are backed by evidence to ensure curative treatment of rectal cancer during the COVID crisis. Table 1 summarizes the approaches. This is particularly applicable for LMIC like India where the existing challenges of access to cancer care, economic burden, are further compounded by the pandemic. Both patient-and healthcare-related factors contribute to delays in treatment in these times. 59 Experts believe 50 to 60% of surgeries have been postponed in the first 12 weeks of the pandemic. 60 Patients are hesitant to come to hospital due to COVID restrictions and are likely to present in late stage. Adoption of these changes enables continuity of care while adhering to the new norms of physical distancing with short and few patient visits. The curative treatment of rectal cancer should not be hindered during the COVID pandemic and is a priority. Modifications in the multimodality treatment will help achieve quality care. These include transition to SCRT in appropriately selected patients, optimally delay in surgery, less intensive chemotherapy and making room for a wait and watch strategy where feasible. The authors declare no conflicts of interest. Not applicable. visualization; writing-original draft; writing-review and editing. Data sharing is not applicable to this article as no new data were created or analysed in this study. https://orcid.org/0000-0001-5306-1649 Abbreviations: LCRT, long-course radiotherapy; SCRT, short-course radiotherapy. WHO declares COVID-19 a pandemic Responding to Covid-19-a once-in-a-century pandemic? Challenges for NHS hospitals during covid-19 epidemic COVID-19 pandemic: perspectives on an unfolding crisis Managing cancer care during the COVID-19 pandemic: agility and collaboration toward a common goal Provision of cancer care during the COVID-19 pandemic Urgent dental care for patients during the COVID-19 pandemic SARS-CoV-2 transmission in patients with cancer at a Tertiary Care Hospital in Wuhan, China Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Caring for patients with cancer in the COVID-19 era Fair allocation of scarce medical resources in the time of Covid-19 Radiotherapy for colorectal cancer: current standards and future perspectives Rectal cancer: multimodal treatment approach Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Radiotherapy in the time of the coronavirus pandemic: when less is better Prostate cancer radiotherapy recommendations in response to COVID-19 Should we favour the use of 5x5 preoperative radiation in rectal cancer Use of Neoadjuvant Short-Course Radiotherapy for Rectal Adenocarcinoma in the United States: Insights into Patterns of Practice and Outcomes. Diseases of the Colon & Rectum Adverse effects of preoperative radiation therapy for rectal cancer: long-term followup of the Swedish rectal cancer trial Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer Randomized trial of shortcourse radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: trans-Tasman radiation oncology group trial 01.04 Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized polish II study Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer -the RAPIDO trial Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer -results of the international randomized RAPIDO-trial Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: the randomized RAPIDO trial The updated results for the phase 3 study of 5× 5 Gy followed by chemotherapy in locally advanced rectal cancer (STELLAR trial) Cost-effectiveness of shortcourse radiation therapy vs long-course chemoradiation for locally advanced rectal cancer Cost-effectiveness analysis of long-course oxaliplatin and bolus of fluorouracil based preoperative chemoradiotherapy vs. 5x5Gy radiation plus FOLFOX4 for locally advanced resectable rectal cancer Recommendations for the use of radiation therapy in managing patients with gastrointestinal malignancies in the era of COVID-19 International expert consensus statement regarding radiotherapy treatment options for rectal cancer during the COVID 19 pandemic Management of locally advanced rectal cancer during the COVID-19 pandemic: a necessary paradigm change at Memorial Sloan Kettering Cancer Center Treatment approach in locally advanced rectal cancer during coronavirus (COVID-19) pandemic: long course or short course? Short-course radiation for locally advanced rectal cancer: an IAEA randomized trial Long-course chemoradiation in carcinoma rectum; is it really worth it? Perspectives from a developing nation Caring for patients with rectal cancer during the COVID-19 pandemic Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, noninferiority trial Tumour regression in the randomized Stockholm III trial of radiotherapy regimens for rectal cancer Time to surgery following shortcourse radiotherapy in rectal cancer and its impact on postoperative outcomes. A population-based study across the English National Health Service Early versus delayed surgery after short-course radiotherapy for rectal cancer: a network meta-analysis of randomized controlled trials Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6) Does a longer waiting period after neoadjuvant radio-chemotherapy improve the oncological prognosis of rectal cancer? three years' follow-up results of the Greccar-6 randomized multicenter trial Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: young oncologists' perspective Colorectal cancer care in the age of coronavirus: strategies to reduce risk and maintain benefit Oxaliplatin-based adjuvant chemotherapy for rectal cancer after preoperative chemoradiotherapy (ADORE): long-term results of an open-label, multicentre, phase 2, randomised controlled Adoption of total neoadjuvant therapy for locally advanced rectal cancer Sequential short-course radiation therapy and chemotherapy in the neoadjuvant treatment of rectal adenocarcinoma Watch-and-wait as a therapeutic strategy in rectal cancer Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study Salvage surgery following "watch and wait" for rectal cancer after neoadjuvant therapy: a systematic review MRI response rate after short-course radiotherapy on rectal cancer in the elderly comorbid patient: results from a retrospective cohort study The feasibility of short-course radiotherapy in a watch-and-wait policy for rectal cancer Treatment delays in oncology patients during COVID-19 pandemic: a perspective How to cite this article: Lewis S, Talapatra K. Radiotherapy management of rectal cancer in the backdrop of the COVID pandemic