Impact of COVID -19 pandemic on Gynaecological cancer radiation during complete nationwide lockdown: Observations and Reflections from Tertiary care institute in India.

ABSTRACTPURPOSE

To report real world compliance to radiation in gynecological cancers during the complete lockdown phase of COVID 19 pandemic.

METHODS

From 23rd March, 2020 until 30th June, 2020 complete lockdown was imposed in India. During this period there was restructuring of cancer care and radiation oncology department due to operational policies prevalent in the institution, and the care for gynaecological cancer was based on the evolving international recommendations. Institutional review board approval was obtained to audit patterns of care during complete lockdown phase. Descriptive variables were used to report on patient characteristics, compliance, delays, toxicity and observed deviations in recommended care.

RESULT

During the lockdown period spanning 100 days, treatment of 270 and telephonic follow-up of 1103 gyneconcological cancer patients was undertaken. Of 270 new patients, due to travel restrictions, 90 patients were referred to the facilities in vicinity of their residence. Of the remaining 180 patients, 138 were planned for complete treatment at our institution and 42 were referred to our centre for brachytherapy. Of 138 patients, only 106 (76%) completed the planned external radiation. Twenty four (26%), patients completed full course of concurrent chemotherapy, 11 (12%) received chemotherapy dose reduction and 57 (62%) received no concurrent chemotherapy. Treatment delay of upto 3 weeks noted in 8.6% patients due to COVID infection. No grade IV-V acute sequelae were observed. No excess adverse effects were observed in high risk population. Low rate of symptom burden was observed amongst 1103 patients on telephonic follow-up. with 100 (9.6%) patients reporting symptoms Amongst these, (54/100) 54% had complete resolution of symptoms within 4 weeks of teleconsultation, while 10% had disease progression.

CONCLUSION

Low compliance to planned treatment was observed for radiation and concurrent chemotherapy due to lockdown and fear of contracting COVID, will likely lead to increased risk of cancer related mortality. Rapid restructuring of care is needed to prevent the same as COVID pandemic further evolves.

Summary

The current article provides a real world audit of treatment for gynecological cancers during the complete lockdown phase of COVID Pandemic within tertiary cancer centre in India. Unacceptable treatment delays were noted within the health care system primarily due to societal restrictions posed due to lockdown. No untoward adverse effects were noted as a direct result of COVID infection. Treatment was overall well tolerated by patients

IntroductionThe year 2020 has been affected by the pandemic caused by 2019-20 SARS-Cov2 novel coronavirus (COVID-19). Due to increasing cases in India in March,2020, a complete nationwide lockdown was imposed from 23rd March,2020Covid-19 pandemic in india.. The lockdown was imposed in 4 phases which was planned to be phased out from 1st June 2020, by selectively releasing restrictions in each phase. The city of Mumbai reported the highest cases in any city in India, crossing 50,000 cases till the 1st week of June and around 93,000 by 15th July, constituting around 20% of all cases across the country. Expectedly, overall cancer care and delivery of fractionated radiation treatment was affected due to compounded impact of fear of attending hospitals, no access to public transport and limited availability of paid accommodation in the city of Mumbai. As a vast majority of patients with gynaecological (cervical cancer) are from lower socioeconomic status the impact of many of these changes were anticipated to be higher.During this period there was also a change in operational workflow of the hospital, that included reduced staffing and re-designation of inpatient beds for COVID care. This led to reduced staff and bed capacity for administering concurrent chemotherapy or admitting patients for brachytherapy. In keeping with the evolving recommendations for radiation for gynaecological cancers during COVID -19 pandemic

Elledge CR, Beriwal S, Chargari C, et al. Radiation therapy for gynecologic malignancies during the covid-19 pandemic: International expert consensus recommendations. Gynecologic Oncology 2020.

the policy for delivery of care was reorganized both for patient treatment and follow up. However, due to prolonged lockdown the implementation of COVID guidelines at ground level had distinct challenges.Methods

Consecutive patients who were planned for treatment of gynecological cancers with radiation and those scheduled for routine follow-up within the gynecological radiation oncology group of the institution from 23rd March, 2020 to 30th June, 2020 during which complete lockdown was imposed in the country were included. All patients > 18 years of age were included in this audit.

During this period broad principles that governed the delivery of care within the gynaecological radiation oncology unit. The existing staff (staff radiation oncologists, specialists and in training residents, physicists and dosimetrists, nurses, support staff) services were reorganised such that at a given time only 50% of the staff were functional to handle operations of outpatient department, treatment planning and brachytherapy applications. This was based on institutional recommendations to ensure patient care at all times, in case a staff tests positive and the need of other contacts to be quarantined which would introduce challenges in operations and functionality. Institutional review board approval was obtained (XXX-IRB Project No. XXX), to audit patterns of care during the complete lockdown phase. While the institution was part of guidelines development for prioritization for radiation and brachytherapy for gynaecological cancers

Elledge CR, Beriwal S, Chargari C, et al. Radiation therapy for gynecologic malignancies during the covid-19 pandemic: International expert consensus recommendations. Gynecologic Oncology 2020.

, following additional decisions were made by the physician multidisciplinary group based on evolving and continued review of local and national impact of pandemic and evolving recommendations on COVID testing: a) Temporary suspension of all concurrent chemotherapy for cervical, endometrial, vulvo-vaginal during radiation as most of the patients on treatment were from geographical locations identified as “COVID hotspots” b) Preferential use of hypo fractionated external beam treatment schedules for very elderly patients (age >75 years) to minimise need for travel on multiple days for treatment c) Increase in referral for external radiation to nearby facilities when feasible d) COVID testing for only symptomatic patients on external radiation as per institutional and national guidelines

Indian Council of Medical Research NDI. Indian council of medical research, new delhi [internet] 2020.

between March and April,2020, d) COVID testing for all patients prior to admission for brachytherapy or inpatient care with effect from May, 2020 e) To delay definitive external radiation or brachytherapy in case a patient tests positive or needs to be isolated f) Retesting of patients tested positive or quarantined on 14th day for resumption of treatment g) Use of extra physical barrier shielding during general anaesthesia to minimize aerosol generation during initial days of pandemic followed by planned transition to spinal anaesthesia for all brachytherapy procedures to minimise aerosol generation h) Preferential use of single application multiple fractions of intracavitary interstitial brachytherapy, and multiple applications with reduced time interval to prevent multiple inpatient admissions and procedures i) Due to the anticipated impact of policy revision on institutional and international clinical trials, in a planned way recruitment on interventional trials was temporarily suspended. j) No modifications were made on choice of treatment technique or use of imaging for treatment execution.

In addition, complete cessation of planned physical follow up was done and telephonic follow up facilities were set up by the institution. A structured telephonic interview was performed to assess patients for the following symptoms 1) Any discharge from vagina 2) Abdominal pain or pain in the back radiating to lower limbs 3) Vomiting 4) Blood in urine/stools. Due to sociocultural reasons and anticipated emotional and psychological impact of ongoing pandemic questions related to sexual functioning were not enquired. The results of the telephonic follow up were reviewed by radiation oncology staff consultant to identify symptomatic patients for whom further video calling was organised by staff radiation oncologist or in case of non resolution of symptoms a physical follow up to nearest facility was advised.

An expediated institutional review board permission was sought to report on the “real world pattern of care” during the lockdown period of COVID-19 pandemic. The gynaecology radiation oncology database, electronic medical records (EMR) and radiation oncology information system (ROIS) was reviewed to summarize the patterns of care during this period of COVID-19 pandemic including the observed COVID infection rate in patients and gynaecology unit health care workers. These patients are planned to be followed up to 36 months and will be assessed for local control, disease free survival, overall survival, late radiation associated toxicities.

Compliance to treatment

Out of a total of 180 patients who were considered for treatment at our institution, radical external radiation and/or brachytherapy was considered for 107 patients (59.4%), postoperative adjuvant radiation was planned for 23 (12.8%) patients. While 13 patients were planned for salvage radiation for recurrence after surgery (either external or in combination with brachytherapy) and 37 were planned for palliative radiation.

A summary of treatment flow of the patients is depicted in Fig 1. Of the 180 patients, 138 were planned for complete treatment at our institution and 42 were referred from outside institutions for performing brachytherapy. Of 138 patients who started on external radiation in our institution (101 radical/adjuvant or salvage radiation and 37 palliative intent treatment) only 106 completed the planned external radiation. Of these, 80 patients were in definitive, adjuvant or salvage setting and 26 in palliative setting. Of the 80 patients who were planned for combination of external radiation and brachytherapy, 22 decided not to go ahead with brachytherapy treatment due to either fear of contracting covid or travel restrictions. Therefore, overall only 58/80 (72.5%) patients who were planned for full course external radiation and brachytherapy managed to complete their entire treatment. Of those undergoing palliative treatment 26/37 (70.2%) completed their planned treatment. Of the 42 patients referred for brachytherapy from outside institutions, 5 did not complete brachytherapy (12%). (Table 2)Figure 1:

Figure 1Study patient inclusion workflow.

Also as noted in Table 2, asignificant proportion of patients had brachytherapy delivered through one or two intracavitary applications and with the same application 2 or more fractions were delivered to complete brachytherapy treatment, , . Those who received multiple applications were either part of an ongoing trial or treated through the early phase of lockdown where policies regarding brachytherapy were still being defined.Despite intention for treatment acceleration, treatment could be completed in 60 days. The details of overall treatment time are depicted in Table 2. Overall the patients who had delay beyond 70 days, the major contributing reason was the social milieu as the result of pandemic related fear and lockdown. During this lockdown period only 5/138(4.7%) patients tested positive for novel coronavirus that led to > 2 weeks delay in delivery of planned treatment.It is noteworthy that in this entire period, no grade IV-V acute sequelae of treatment were observed. Grade II-III toxicities were also reduced to 8 (4.4%) and 2 (1.1%) (Table 2), compared to previous studies from the institution. This could possibly be attributed to omission of concurrent chemotherapy in a vast majority of patients. The present cohort had 25% patients with age > 60 years but no increase in adverse effects was noted in this population.Within the treated cohort discussed above 13 patients were treated for either local relapse (8/13) or locoregional relapse (5/13) following surgery (8/13) or radiation (5/13). All the patients completed salvage treatment. Of the 37 patients considered for palliative treatment, 26 completed planned treatment. The reason for offering palliative radiation are summarised in Table 4.

Of the 90 patients referred to other treatment facilities, 57 (63%) patients were able to start the planned treatment within the referred facility within 2-3 weeks, while 25 (28%) were unable to reach to the referred cancer care facility due to the practical difficulties caused by lockdown. At the time of submitting this publication, no contact could be made with 8/90 (9%) patients.

DISCUSSIONNationwide lockdown due to COVID-19 pandemic posed distinct challenges to delivery of uninterrupted care for patients with solid tumours where fractionated radiation constituted the backbone of curative treatment. Various international societies published their recommendations on prioritising care of patients with cervical cancer including brachytherapy whereas adjuvant treatments could hold a relatively lower priority

Uwins C, Bhandoria GP, Shylasree TS, et al. Covid-19 and gynecological cancer: A review of the published guidelines. International Journal of Gynecologic Cancer 2020:ijgc-2020-001634.

,Chargari C Chopra S Viswanathan AN et al.Brachytherapy issues and priorities in the context of the coronavirus disease 2019 (covid-19) outbreak.. Furthermore, special issues of various journals had rapid publications related to organisational and structural changes in patient care, follow ups, physician and resident trainings in the institute,

Indian Council of Medical Research NDI. Indian council of medical research, new delhi [internet] 2020.

. While there have been publications related to increased risk of adverse effects following surgery and systemic chemotherapy, didactic “real world reports” of “on the ground” implementation of radiation oncology priority procedures is limitedThe impact of the covid-19 pandemic on cancer patients.,Risk of covid-19 for patients with cancer..Mumbai was the worst affected city during the COVID 19 pandemic in India. In the first phase of the pandemic, also corresponding to nationwide lockdown, the gynaecology radiation oncology unit treated at one-third of its capacity which is similar to the rate reported in cancer hospitals in the west as a result of reorganisation of infrastructural and human resourcesSlotman BJ Lievens Y Poortmans P et al.Effect of covid-19 pandemic on practice in european radiation oncology centers.Wakefield DV Sanders T Wilson E et al.Initial impact and operational responses to the covid-19 pandemic by american radiation oncology practices.Srinivasa GY Dey T Suri V et al.Rationalizing treatment for gynecological cancers during the covid-19 pandemic: An indian experience.ElMajjaoui S Ismaili N Benjaafar N. Covid-19, brachytherapy, and gynecologic cancers: A moroccan experience.Malicki J Martenka P Dyzmann-Sroka A et al.Impact of covid-19 on the performance of a radiation oncology department at a major comprehensive cancer centre in poland during the first ten weeks of the epidemic.. During this period as seen in our results approximately 25-30% patients decided not to receive further treatment due to fear of infection and challenges posed due to nationwide lockdown reducing patients’ ability to travel for 8-week treatment. During this phase interstate and intrastate transportation was stopped. Also, many residential hotels were transformed into either quarantine centres or were asked to remain closed during lockdown, causing unavailability for travellers to stay in the city causing logistical problems. The compliance rate to radiation therapy dropped down to 66% during this period, which was inferior to non-COVID times, which was recorded 85% for the full course of concurrent chemoradiation and brachytherapy. Similar responses have been observed in other major cities that became epicentre of COVID within their countries

Sindhu K, Gupta V. Fear in the age of covid-19 2020.

. However, unlike India, Europe and United States of America the functionality of radiation departments continued to exist at an almost similar level in Hong Kong, a country that had previous experience with dealing with SARS virus in 2003Lee AWM Xu Z-Y Lin L et al.Advocacy to provide good quality oncology services during the covid-19 pandemic – actions at 3-levels.. The anticipatory fear response throughout the world is likely to have an untoward impact on cancer specific survival as a result of delayed and interrupted care. Therefore, it's important that as pandemic is evolving we report the “real world outcomes” which can help in rapidly shaping treatment policies and response in the next few months also if a second wave or another pandemic in near future were to arise.During the lockdown period, we continued to treat patients using conventional fractionation (rather than hypofractionation) for external radiation despite recommendations to reduce hospital visits for patients. This decision was made to prevent patients from combined long term adverse impact of hypofractionated external radiation and brachytherapy, the impact of which on normal tissues was hitherto unknown even from data of other pelvic malignancies (prostate and rectum)Ling D Vargo J Grimm R et al.Dose-response model for severe late laryngeal toxicity after stereotactic body radiation therapy for previously irradiated head and neck cancer.. Furthermore, as cervical cancer has higher alpha/beta ratioThe impact of the covid-19 pandemic on cancer patients. than rectal or prostate malignancies extreme hypofractionation may not be associated with equivalent tumour response/control. Nevertheless, to reduce the impact of omission of concurrent chemotherapy and to reduce hospital stay we decided to accelerate the treatment to

Song S, Rudra S Fau - Hasselle MD, Hasselle Md Fau - Dorn PL, et al. The effect of treatment time in locally advanced cervical cancer in the era of concurrent chemoradiotherapy.

Lin S-M Ku H-Y Chang T-C et al.The prognostic impact of overall treatment time on disease outcome in uterine cervical cancer patients treated primarily with concomitant chemoradiotherapy: A nationwide taiwanese cohort study.

Perez CA, Grigsby Pw Fau - Castro-Vita H, Castro-Vita H Fau - Lockett MA, et al. Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy.

, And also observations within EMBRACE study where reduced overall treatment time was associated with improved local control Pötter R Tanderup K Kirisits C et al.The embrace ii study: The outcome and prospect of two decades of evolution within the gec-estro gyn working group and the embrace studies.. Based on our institutional experience to treat patients with single application and multiple fractions within and outside clinical trials (CTRI/XXXX) we reduced the number of brachytherapy implants and increased the number of fractions delivered per implant. This reduced the need for repeated hospitalisations and risk of contracting COVID after hospital discharge and before the next procedure. This period also noted a transient reduction in advanced interstitial procedures (from 15% to 7%) as a result of reduced staff, reduction in availability of blood products if needed and reduced access to appointments for MRI. As seen in Table 3 close to 70% patients received single implant and multiple fractions including completing all brachytherapy in single application. Nevertheless, despite this attempt only 33% patients could complete treatment within 50 days and another 13% within 56 days. Inability to reach treatment facility due to lack of transport or fear of contracting COVID led to increase in treatment time. While the specific causes of prolonged overall treatment time are listed in Table 2, it's noteworthy that COVID infection itself or treatment induced toxicity led to delay in only 8.2% and 10% of patients respectively. All other delays happened due to organisational challenges (inability of patients to reach facility, reduced bed capacity, reduced brachytherapy capacity due to staff reorganisation). It is expected that this cohort of patients may have reduced local control (estimated 4%,8%,12%,16% in those completing within 61-70 days, 71-80,81-90 and 91-100 days)González Ferreira JA Jaén Olasolo J Azinovic I et al.Effect of radiotherapy delay in overall treatment time on local control and survival in head and neck cancer: Review of the literature.. This detriment may also be further magnified as concurrent chemotherapy was temporarily suspended due to operational reasons during the lockdown specifically paucity of day care and in-patient beds and blood products. Concurrent chemotherapy is known to have direct impact on disease free survival of cervix cancer across stagesGupta S Maheshwari A Parab P et al.Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage ib2, iia, or iib squamous cervical cancer: A randomized controlled trial.Shrivastava S Mahantshetty U Engineer R et al.Cisplatin chemoradiotherapy vs radiotherapy in figo stage iiib squamous cell carcinoma of the uterine cervix: A randomized clinical trial.

Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials.

and this cohort of patients will be at risk of local, nodal and distant relapse. Careful observation of this cohort may be needed with elective imaging including decisions for salvage hysterectomy and/or reirradiation, in cases of persisting residual disease within 5-6 months of follow up to prevent long term detriment.

Table 3Table depicting the reasons of non-compliance to radical or adjuvant radiotherapy.

Table 4Table depicting the details of patients offered palliative radiation during the complete lockdown period.

Traditionally, in radiation oncology transition to hypofractionation has been slow. In “normal times”structured prospective trials with rigorous endpoints and long observation period are needed for such transition. However, the pandemic led to fast paced changes and adaptations that had to be made. Few months before the initiation of COVID pandemic, the gynaecological radiation oncology unit had completed accrual towards phase II study of single application and multifraction brachytherapy study (CTRI/XXXX). In this study a vast majority of patients received combined intracavitary-interstitial MRI based brachytherapy and long term results would be needed for opening the next phase trials with anticipated full results after a decade. Also, as this transition was envisioned within advanced brachytherapy programmes it could be implemented only within settings of advanced brachytherapy programmes. However, due to the pandemic we had to transition to this fractionation within days of completing recruitment in the study also within the preview of standard intracavitary and CT based brachytherapy. Dose volume recommendations from ongoing prospective trials was rapidly adopted for “clinical practice”. While the present report focusses on lockdown period that had treatment delays, at the time of writing this study more than 150 patients have received brachytherapy treatment with altered fractionation scheme (also more recently completing treatment within 8 weeks) and will form an extremely important cohort that will shape cervix brachytherapy in future as long term outcomes mature. Similar experiences of rapid adoption of FAST forward breast protocol have been observed during COVID Pandemic whereas the earlier UK START B trial had very slow clinical adoption due to concerns related to toxicity despite availability of structured clinical dataColes CE Choudhury A Hoskin PJ et al.Covid-19: A catalyst for change for uk clinical oncology..During this phase of using radical radiotherapy alone we observed very few acute toxicities and no mortality suggesting that radical radiotherapy and brachytherapy is indeed a treatment that despite its intensity is very well tolerated. Amongst oncological treatments, radiation is a treatment modality that could be easily deployed and is more resilient in the phase of such pandemics where systemic response to surgery and chemotherapy (including targeted agents and immunotherapy) may be unknown

Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to sars-cov-2: A multicenter study during the covid-19 outbreak.

Mehta V Goel S Kabarriti R et al.Case fatality rate of cancer patients with covid-19 in a new york hospital system.Mei H Dong X Wang Y et al.Managing patients with cancer during the covid-19 pandemic: Frontline experience from wuhan.. Within our cohort of patients 17.8% and 2.8% patients were categorized ASA class II and III for brachytherapy. However, no increased adverse effects were observed. Furthermore, 25% of our patients had age > 65 years and no increase in adverse effects was noted.Palliative treatments during this phase could be completed in 70% of patients and overall 9/37 (24%) patients who still had symptoms and were on once monthly fractionation could not return to the treatment facility. Another 5 patients had complete relief of symptoms though treatment schedule could not be completed. As the pandemic evolves there is a clear need of rapid palliative schedules and are presently being tested in ongoing randomized trial in the institution.Continuation of radiation treatment including salvage reirradiations amongst patients who could not be offered surgery or chemotherapy is attributed to the experience of the clinical team. The institutional team has treated patients effectively during and after the HIV epidemic that taught important lessons about treatment tolerability in patients with viral coinfectionsShrivastava SK Engineer R Rajadhyaksha S et al.Hiv infection and invasive cervical cancers, treatment with radiation therapy: Toxicity and outcome.. All the patients who tested COVID positive during treatment were reinitiated on external radiation or brachytherapy within 2-3 weeks. At the time of writing this manuscript a policy of restarting treatment within 10 days of diagnosing COVID-19 infection has been introduced.Based on the early observations and lessons on tolerability of radiation during COVID pandemic we also reinitiated use of concurrent chemotherapy from August,2020. While the results are not part of this manuscript, the treating team has observed no increase in complications with concurrent chemotherapy during the pandemic. Similarly, recruitment to institutional and international trials has been reinitiated. While the pandemic continues to peak in India with >90,000 new cases per day in September 2020, the cancer care is slowly reverting back to normal. It is important to quickly reorganise and deliver appropriate care for cancers which are priority 1 treatment for radiation oncology and brachytherapy lest one public health crisis may turn into another health crisis. It is estimated that in India close to 80,000 women may annually need radiation for cervix cancer

Chopra SJ, Mathew A, Maheshwari A, et al. National cancer grid of india consensus guidelines on the management of cervical cancer.

. Delay of treatment due to fear or lockdown restrictions may lead to 10-12% excess risk of local recurrence as estimated. In India, this will put 8000-10,000 additional women at risk of relapse and death /annum. We believe that early reporting of our observations may help rapid shaping of treatment policies in India and in other countries where COVID-19 is still evolving.Despite the intention to slowly recover back to normalcy, our unit continues to see only 50% of the original number of patients at the time of submission of this manuscript due to restrictions on interstate travel and fear in patients and caregivers of acquiring COVID infection. During the lockdown period hospital and our unit offered free of cost teleconsultation services to close to 1100 patients who were scheduled for clinical follow up for cervix or endometrial cancer. In this cohort, a low rate of symptom burden was observed in those scheduled for follow up (9.6%). While these observations will require validation against clinical follow up in the near future, the results may open an opportunity to preferentially teleconsult in a vast majority of patients in future. The strategy of teleconsultations for follow up has been previously validated in lung and oral cancer patients in our institution

Malik A, Nair S, Sonawane K, et al. Outcomes of a telephone-based questionnaire for follow-up of patients who have completed curative-intent treatment for oral cancers. JAMA Otolaryngology–Head & Neck Surgery 2020.

. While a recently initiated ongoing trial in telephonic follow up in gynaecological cancers will provide structured information in future, this cohort of 1100 patients who were attended through teleconsultations during COVID 19 will allow shaping of follow up clinics in near future even as pandemic evolves. Similar insights into integrating telemedicine into radiation oncology have recently been reportedOrazem M Oblak I Spanic T et al.Telemedicine in radiation oncology post–covid-19 pandemic: There is no turning back..

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