|Year : 2020 | Volume
| Issue : 5 | Page : 40-48
Management of patients with gynecological cancers during the COVID-19 pandemic
Sampada Dessai1, Ankita Nachankar2, Pritam Kataria3, Anuja Abyankar4
1 Department of Surgical Oncology, Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Gunma University, Maebashi, Japan
3 Department of Medical Oncology, Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||05-Apr-2020|
|Date of Decision||06-Apr-2020|
|Date of Acceptance||08-Apr-2020|
|Date of Web Publication||25-Apr-2020|
Prarthana Samaj, Raja Rammohan Roy Road, Charni Road East, Khetwadi, Girgaon, Mumbai - 400 004, Maharashtra
Source of Support: None, Conflict of Interest: None
Coronavirus disease 2019 (COVID-19) pandemic is on the rise. There is an urgent need for triaging cancer patients for treatment. Gynecological malignancies require complicated surgical procedures, complex prolonged radiation techniques, and myelosuppressive chemotherapy. Therefore, judicious decision-making is required, balancing the risk of fatality because of COVID-19 infection with the benefit of therapy. The guidelines need to be tailored according to the local situation. These guidelines are specifically written with respect to the current situation in India. Some procedures are urgent, while some can be deferred. Surgeries for suspected ovarian cancer and early-stage cervical cancer are considered urgent. Surgeries for early-stage endometrium can be deferred for 4–6 weeks. Surgery for advanced ovarian cancer can be deferred by administering neoadjuvant chemotherapy. Chemoradiation for advanced-stage cervical cancer is considered urgent. Similarly, chemotherapy in gestational trophoblastic neoplasm, adjuvant chemotherapy for ovarian cancer, and neoadjuvant and concurrent chemotherapy for cervical cancer and germ cell tumor of the ovary is considered urgent. These guidelines will help us to provide effective treatment for gynecological cancers in the current situation.
Keywords: Cervical cancer, COVID-19, endometrial cancer, guidelines, gynecological cancer, India, ovarian cancer
|How to cite this article:|
Dessai S, Nachankar A, Kataria P, Abyankar A. Management of patients with gynecological cancers during the COVID-19 pandemic. Cancer Res Stat Treat 2020;3, Suppl S1:40-8
|How to cite this URL:|
Dessai S, Nachankar A, Kataria P, Abyankar A. Management of patients with gynecological cancers during the COVID-19 pandemic. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jun 3];3, Suppl S1:40-8. Available from: http://www.crstonline.com/text.asp?2020/3/5/40/283294
| Introduction|| |
As of April 04, 2020, more than 3000 cases of coronavirus disease (COVID-19) have been diagnosed in India, and the number is exponentially rising daily. Although we have fewer COVID-19 cases compared to the western world, this can be partly attributed to the limited testing. Hospitals are issuing directives to delay elective surgeries in order to prevent COVID-19 spread by maintaining social distancing and preventing the exposure of at-risk patients and staff within the hospital. This also helps to conserve the finite essential personal protective equipment (PPE) and to ensure adequate availability of hospital beds and ventilators in case the need arises. Health-care workers are at an increased risk of getting infected even from asymptomatic patients. Furthermore, the impact of aerosols that are generated during the surgical procedures is unknown.
Another problem faced at this time is the extreme difficulty in predicting how long this situation will prevail. This poses the question to the gynecologic oncologist as to how long it is possible to postpone the definitive treatment of our patients and what the impact will be on the clinical outcome. Cancer patients are at a 3.5 times higher risk of developing severe complications because of COVID-19 disease. Liang et al. provided outcomes of COVID-19 patients with and without cancer (n = 1,590). Cancer was associated with an increased risk of death and/or intensive care unit admission (odds ratio 5.4; 95% confidence interval [CI], 1.8–16.2). This study from China suggested that patients who underwent surgery or chemotherapy during the COVID-19 pandemic had a numerically higher risk of either requiring ventilatory support or death. Therefore, the authors suggested intentional postponement of surgeries and chemotherapy in clinically stable patients. Case fatality rates were also markedly higher among patients with comorbidities: 11% for cardiovascular disease, 7% for diabetes, 6% for chronic respiratory disease, and 6% for cancer. Hence, we need to weigh the benefit of cancer treatment against the risk of getting infected with the coronavirus.
| General Measures for the Oncology Units|| |
- Establishing a COVID-19 free unit: As most patients with cancer need anticancer therapy urgently, it is preferable to develop COVID-free hospitals or units. This hospital or unit can triage patients at the entry points and can restrict entry to patients with a low risk of COVID-19 infection and those without COVID-related symptoms
- Limit patient visits to the hospital: Only patients currently undergoing treatment need to be encouraged to attend the hospital. Follow-up visits can be avoided or done virtually. Screen the patients by audiovisual aids to determine whether they require to visit the hospital in person for a consultation
- All patients to be tested for COVID-19 before the initiation of any immunosuppressive treatment
- All healthcare workers in all specialties should use PPE all the time as there is a risk of transmission in asymptomatic and test-negative patients too
- Multidisciplinary board: Virtual meetings of multidisciplinary tumor boards should be conducted ensuring that a prompt decision is reached whenever possible
- High risk of COVID-19 infection-related fatality: patients who are >70 years old and with comorbidities should be considered as high-risk for COVID-19 related morbidity and mortality. The subsequent guidelines will provide specific recommendations for these patients
- Prophylaxis: Hydroxychloroquine prophylaxis is recommended in high-risk cases. However, its use should be judicious and should take into account the risk-benefit ratio. High-risk cases as defined by the Indian Council of Medical Research are health-care workers, patients with a history of international travel, and those with known contacts having COVID-19 disease [Figure 1]
- Comprehensive research related to the development of a triage strategy, prospective database, video-consultation, and prophylaxis for COVID-19 disease needs to be carried out
- Considering the American Cancer Surgery guidelines to triage a patient, oncological surgeries are categorized as IIIA, and the recommendation is to not postpone the oncological surgeries. Surgeries should preferably be performed by the open method, as we do not know the effect of carbon dioxide leakage on COVID-19 spread yet. Staging procedures should preferably use sentinel lymph node biopsy as a method of lymph nodal staging to reduce the postoperative morbidity.
|Figure 1: Detailed management flow chart of patients with gynecological cancers. COVID: Corona virus disease. PS: Performance status. PPE: Personal protective equipment; NCCT: Non-contrast CT scan|
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| Endometrial Cancer|| |
Early-stage and operable advanced endometrial cancer
Mariam et al. analyzed the national cancer database to investigate the impact of time to surgery (TTS) in endometrial cancer. Of the 284,499 patients included in the study, 83% had type I and 17% had type II endometrial cancers. A delay in surgery of more than 6 weeks was associated with the worst overall survival (OS) in type I endometrial cancers, with stages I and II only. However, in type II cancers of any stage, TTS had no significant impact on the OS. This may sound counterintuitive, but probably, the survival of patients with advanced-stage endometrial cancers and type II histology is more dependent on the tumor biology, and surgery has a small role to play in improving the outcomes. In other words, fast-tracking these surgeries may not improve the outcomes. In type I histology endometrial cancers, the cause for lower survival may not only be disease-related, but these patients might also have had comorbidities that had delayed their surgeries, in turn influencing the mortality. In another systematic review done in 2020 by Pergialiotis V, it was suggested that the time to wait for surgery should be limited to 6 weeks and the time to adjuvant therapy should be limited to 9 weeks. Going by the literature on the impact of survival in endometrial cancers, a delay of 6 weeks is acceptable in both type I and II endometrial cancers. The impact of delay in surgery beyond that is not known. High-dose progesterone has been shown to be effective in reversing the estrogenic effect on the endometrium in a good number of cases and has been used in fertility-preserving protocols. Most cases of type I histology are estrogen/progesterone-receptor-positive, and it would be worthwhile to start these patients on hormonal therapy to reduce progression if surgery is not possible within the 6 weeks' timeframe in today's resource-constrained settings.
Adjuvant therapy in completely staged patients could be avoided, especially if the patient has comorbidities and is elderly with a high risk of COVID-19 fatality. Endometrial patients should be “consented” for delays up to 9–12 weeks unless there is residual disease, positive resection margins, or aggressive histological subtype. Endometrial cancer is common in older patients (63%), those with hypertension (47%), diabetes (26%), and obesity (18%–69%)., Hence, the risk and benefit of adjuvant radiation should be discussed. Adjuvant radiotherapy even in the presence of high-intermediate risk factors (age >or = 60, poor grade, presence of lymphovascular emboli) decreases the local recurrence rate, but has no impact on OS, and hence can be deferred or omitted. Patients with high-risk factors (residual disease, positive resection margins, or aggressive histological subtype) should only be considered for vault brachytherapy or can be deferred or omitted. Adjuvant treatment is given to decrease the chance of recurrence over the next 5 years. If the disease recurs, it can be salvaged at a later date. This strategy will decrease the hospital visits of patients, thus limiting their exposure. Adjuvant chemotherapy has an OS benefit in carcinoma endometrium with high-intermediate risk and hence needs to be discussed further. In the PORTEC 3 trial, 4 cycles of paclitaxel-carboplatin led to an increase in the 5-year OS from 76.1% to 81.4%. Hence, this needs to be discussed.
Inoperable or metastatic cases
Symptomatic treatment with palliative chemotherapy with or without radiation should be offered. However, in patients in whom surgery and hormonal therapy are not possible because of patient morbidity, radiotherapy can be considered as an alternative. Intrauterine brachytherapy is used for early-stage disease; however, it is deferred until more resources are available. External beam radiotherapy can usually be deferred, or if required urgently, a hypofractionated approach is recommended.
Operable endometrial cancer surgery can be deferred for up to 6 weeks. Adjuvant radiation can be deferred in high-risk cases and omitted for the rest. In inoperable cases, either progesterone or radical radiation with brachytherapy can be administered. In advanced disease, palliative therapy with chemotherapy with paclitaxel-carboplatin should be offered, except in the COVID-19 high-risk fatality cohort; in them, progesterone or palliative radiation can be offered.
| Ovarian Cancer|| |
Suspected early-stage ovarian cancer
Adnexal masses suspected to be cancerous should undergo immediate staging laparotomy. They constitute only 10%–15% of all ovarian cancer cases. In addition, patients with imaging-confirmed pelvic-confined disease usually do not require extensive surgery, thus limiting the postoperative stay and reducing the surgical morbidity. Paraaortic lymph node dissection should be avoided, as this procedure is associated with increased adverse events but no survival benefit. Primarily resected ovarian cancer mandates adjuvant therapy as per the guidelines, except for grade 1 or 2 stage I disease. In a cochrane meta-analysis of 1277 women with early stage ovarian cancer, at 10 years the risk of death (relative risk [RR] 0.76, 95% CI, 0.62–0.94) and progression (RR, 0.72; 95% CI, 0.60–0.87) favored the adjuvant chemotherapy arm. The type of chemotherapy used in the 2 major studies was single-agent carboplatin or cyclophosphamide, doxorubicin and cisplatin combination treatment in the ICON-1 and platinum with paclitaxel in the EORTC-ACTION study. There is limited evidence of the benefits of the combination over single-agent carboplatin in early-stage ovarian cancer, and hence, in the current situation of the COVID-19 pandemic, single-agent carboplatin can be considered a suitable option. The number of cycles of adjuvant therapy was 6 in the ICON-1 study and 4 in the EORTC-ACTION study. Hence, if single-agent carboplatin is selected, 6 cycles need to be administered, while in case of combination, 4 cycles should be considered. In patients over 60 years of age with comorbidities, single-agent carboplatin can be considered to reduce the risk of neutropenia.
Newly diagnosed patients who have extensive disease on imaging or disease spread outside the adnexa, which will require prolonged and extensive surgeries, should undergo image-guided biopsy and neoadjuvant chemotherapy. Neoadjuvant chemotherapy followed by surgery has been shown to be noninferior to primary surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. During cytoreductive surgery, an optimal cytoreduction defined as no visible microscopic disease should be attempted., However, ultraradical surgery, paraaortic lymph node dissection, and extensive resection should be avoided., It is worthwhile to withhold hyperthermic intraperitoneal chemotherapy in the centers where it is practiced, as the additive benefit of this procedure is minimal, and it delays postoperative recovery considerably. The choice of adjuvant or neoadjuvant therapy should be paclitaxel and carboplatin administered once in 3 weeks. In patients at a high risk of COVID-19 infection, single-agent carboplatin or metronomic chemotherapy can be considered to reduce the risk of immunosuppression. Delaying chemotherapy has an adverse impact in carcinoma ovary, and the OS decreases by 4% for each week of delay in initiating adjuvant chemotherapy.
Patients presenting with acute conditions such as bowel obstructions are emergency conditions and should undergo treatment as required. All patients who undergo surgery or chemotherapy should undergo COVID-19 testing, and if positive, their treatment should be initiated after the completion of COVID-19 treatment.
In case of recurrent ovarian cancer, the intent of therapy based on the disease-free survival, the extent of disease and the symptoms of the disease will guide the promptness of therapy. The decision regarding the same must be taken after a thorough discussion with the patient and their caregivers by weighing the morbidity that might develop in case of a COVID-19 infection or due to the disease itself. In case of asymptomatic recurrences or only CA-125 elevation, delaying treatment is a valid option. In case of symptomatic recurrence, less intensive regimens such as single-agent carboplatin (platinum-sensitive disease) or single-agent paclitaxel or metronomic combination or poly (ADP-ribose) polymerase inhibitor with growth factor support can be considered to minimize the risk of neutropenia and thrombocytopenia. The selection of the regimen should be on the basis of the patient's preference and the risk of COVID-19 infection. In case of extensive disease, palliative care options must be discussed with the patient and the caregivers.
Early-stage ovarian cancer-staging laparotomy should not be delayed, and adjuvant chemotherapy should be offered with single-agent carboplatin – area under the curve 5 mg per ml (COVID-19 high-risk patient) or paclitaxel-platinum in others. For locally advanced disease, neoadjuvant therapy with single-agent carboplatin (COVID-19 high-risk patient) or paclitaxel-platinum in others, and cytoreduction should be performed after 3–6 cycles. If recurrent cases are symptomatic, only then systemic therapy should be offered. Single-agent therapy or metronomic combination should be preferred.
| Cervical Cancer|| |
Early-stage cervical cancer (International Federation of Gynecology and Obstetrics Stage IA, IB1, IB2–IIA1)
Cervical cancer requires early initiation of treatment, preferably within 4 weeks of diagnosis. A delay beyond this time leads to a 1%/day decline in local control. Hence, early treatment initiation is necessary. All diagnostic procedures, including colposcopy-guided biopsies, should be carried out as indicated as this will help in decision making.
Early-stage cervical cancer up to stage IIA1 (International Federation of Gynecology and Obstetrics [FIGO] 2018) should undergo surgery within 4 weeks of diagnosis. Both surgery and radiation have equivalent control rates in early-stage cervical cancer. However, in view of the frequent visits to the hospital, the need for concurrent therapy, and multiple intraoperative procedures for cervical brachytherapy, it is preferable to perform surgery in the current COVID pandemic. The surgical procedure should be radical hysterectomy with pelvic lymph node dissection. Adjuvant chemoradiation is recommended in the presence of lymph node metastasis and R1 resection. Adjuvant chemoradiation increases progression-free survival and OS by 17% and 10%, respectively. The corresponding hazard ratios for not using concurrent chemotherapy were 2.01 (P = 0.003) and 1.96 (P = 0.007) for progression-free survival and OS, respectively. Hence, this modality cannot be deferred. If the high-risk criteria are negative, but tumor size is >4 cm and depth of invasion is >1/3rd of the cervical stroma, adjuvant radiation is indicated. It can be deferred as adjuvant radiation in this situation is associated with a disease-free survival benefit, but not increased OS. However, if administered preoperatively, R0 resection seems difficult or if pelvic lymph nodes are present, it would be preferable to refer the patient for radical chemoradiation upfront as it would be required postsurgery.
For cervical cancers, pelvic radiotherapy with concurrent platinum-based chemotherapy remains the standard of care and should be initiated within 4 weeks, and treatment should be completed without any unnecessary delays or breaks., A minimum number of fractions should be used. Usually, 45 Gy in 25 fractions in node-negative cases and the use of simultaneous integrated boost to escalate doses to nodal region in node-positive cases is permitted. Less complex techniques such as three-dimensional conformal radiotherapy are preferred over intensity-modulated radiation therapy (IMRT), image-guided radiation therapy, and adaptive radiotherapy to avoid strain on the resources, as there is limited evidence to suggest their benefits. For patients ≤70 years of age, concurrent chemotherapy remains the standard of care; however, the decision is based on the risk versus benefit analysis. The use of concurrent cisplatin is associated with a 10% absolute improvement in the OS and hence should be administered even in the current pandemic in early-stage cervical cancer.
Locally advanced stage (IB3, IIA2, IIB–IVA)
Radical chemoradiation should be administered without any delay. In a large population-based analysis by Nandakumar et al., in 1,753 patients with locally advanced cancers, significantly better survival was observed with chemoradiation (70.2% vs. 47.3%; hazard ratio, 0.48; 95% CI, 0.41–0.56) over radiation alone. A similar absolute benefit of 9%–10% in the progression-free survival and OS at 5 years was confirmed in a randomized study from the Tata Memorial Hospital, Mumbai, India. Hence, concurrent cisplatin should be considered as an essential treatment and offered in the current pandemic.
Delay in brachytherapy procedures for cervical cancer patients may have a serious adverse effect on the outcomes and should not be delayed for patients without COVID-19 symptoms. In all cases, however, patients who have begun cancer treatment, including brachytherapy, and are not displaying COVID-19 symptoms should complete their treatment. Patients from centers that cannot deliver brachytherapy because of resource constraints due to COVID-19 situations should be referred appropriately to higher facilities and should seek expert opinion if deviating from the protocol. Considering the constraints of anesthesia, applicator insertion using a local anesthetic or sedation and delivery of two or three fractions 6 hours apart per insertion is recommended. Consider limiting the number of brachytherapy fractions to as few as 2–3 with the aim of limiting the combined external beam radiation therapy (EBRT) and brachytherapy high risk-clinical target volume dose biologically equivalent dose of 2 Gy (EQD2) >85 Gy., Decisions regarding image-based adaptive planning versus point “A” based planning should be made depending on the availability of trained staff. The overall treatment time should be minimum, however, patients with COVID-19 infection may need a few weeks delay in treatment until they recover. Under extreme circumstances, when brachytherapy cannot be delivered, EBRT boost might be considered to a dose of 16–20 Gy in 8–11 fractions.
Early-stage cervical cancer-If surgery alone can suffice, then radical hysterectomy with pelvic lymph node dissection should be performed. If not or in the presence of locally advanced cervical cancer, radical chemoradiation should be administered. The treatment should start within 4 weeks and should not be unnecessarily delayed. Concurrent cisplatin is necessary and should be administered unless the patient has a high risk of COVID-19 infection-related fatality. Palliative treatment in recurrent-relapsed cancer can be offered in single-fraction radiation schedules.
| Vulval Cancers|| |
Early-stage cancers (FIGO stage I–II) should preferably be operated within 6 weeks. Considerations should be given for sentinel node biopsy to avoid groin wound complications. Only 25%–30% of early-stage vulvar cancers have nodes harboring disease,,, and there is substantial morbidity associated with groin node dissection, like leg edema in 47%, lymphocele in 40%, and wound breakdown in 38.3%. [47,48] There is no need for adjuvant treatment in FIGO stage I–II disease.
In locally advanced-stage cancer (FIGO III), if operable, wide local excision with inguinofemoral dissection needs to be performed. Adjuvant radiation should be considered for 2 or more pathologically positive lymph nodes, the presence of perinodal extension, and in case of large lymph nodes.,, There is no evidence to routinely administer adjuvant radiation in lymph node-negative cases and single lymph node-positive disease. Neoadjuvant chemoradiation is recommended in some series; however, in the presence of COVID-19 pandemic, this modality can be avoided as there is no level 1 or 2 evidence supporting it., Patients who are not suitable for surgery due to large volume disease or metastatic disease (FIGO IV) should receive radical radiation or palliative radiation. Concomitant chemoradiotherapy is routinely used in this situation for long-term control; however, the evidence is limited. Most vulvar cancer patients are older and have multiple comorbidities; hence, concurrent chemotherapy can be omitted. Consideration should be given for using the IMRT technique to reduce skin toxicity,, and single-fraction regimen should be used for palliation to reduce hospital visits.
Early stage-Surgery can be avoided for 4–6 weeks, if required. Locally advanced disease-Surgery is urgent and should be performed as early as possible. Adjuvant radiation should be limited to settings with proven benefit as mentioned above. Locally advanced unresectable or metastatic disease-Palliative single-fraction radiation can be used.
| Gestational Trophoblastic Neoplasia|| |
Gestational trophoblastic neoplasia (GTN) is a rare tumor which originates from the placental tissues and includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Being a highly curable malignancy, immediate treatment is required, since a delay in the treatment may lead to the occurrence of tumor chemoresistance or even metastatic disease, necessitating multiple agent chemotherapy.
The choice of chemotherapy treatment is based on the combination of the anatomic staging and the World Health Organization scoring system based on risk factors.
Low-risk GTN should be first treated with a single agent, either methotrexate or actinomycin-D (ActD). High risk GTN can be treated with a regimen of choice, especially with EMA/CO (combining etoposide, methotrexate, ActD, cyclophosphamide, and vincristine) or EMA/EP (etoposide and cisplatin with etoposide, methotrexate, and dactinomycin)., In case of unavailability of resources, initial therapy with EP regimen can be considered in case of high-risk GTN.
GTN needs to be considered urgent, and treatment should be done in accordance with standard guidelines, irrespective of the COVID-19 pandemic situation.
| Germ Cell Tumor|| |
Germ cell tumors, though rare, require a special mention because of the heterogeneity and rapid doubling time of the disease. Being a disease of young individuals and being chemo-sensitive, the treatment must be considered urgent. Appropriate chemotherapy must be initiated as per the standard guidelines for treatment, and delay must be avoided. Surgery for residual disease should be delayed for 6–8 weeks postchemotherapy, but should be performed on an urgent basis if required.,
Recommendation-Germ cell tumor management needs to be considered urgent, and should be done in accordance with the standard guidelines irrespective of the COVID-19 pandemic situation.
| Ancillary Care|| |
- Surgery: Surgery should be performed with universal precautions in all cases. Elective surgery should be performed after COVID-19 testing in cases with a high risk of COVID-19 infection, as far as possible. If this is not possible or in case an emergency procedure has to be performed, precautions recommended for patients with acquired immunodeficiency syndrome should be taken
- Chemotherapy: All elective chemotherapies should be planned after taking informed consent for the risk of COVID-19 infection and its related complications. The use of Granulocyte-colony stimulating factor prophylaxis should be more liberal than usual to avoid the risk and decrease the duration of immunosuppression. In case of a patient developing pneumonia during treatment, COVID-19 must be considered as one of the differentials. Patients who are on prophylaxis for COVID-19 (hydroxychloroquine, or azithromycin) need to have a medication interaction check performed prior to prescribing any additional drugs. Chemotherapy selection should take in to account the risk-benefit ratio, COVID-19 pandemic situation and institution treatment preferences,,
- Radiation: Radiation treatment should be temporally managed so that the waiting period for therapy is reduced. Universal precautions should be performed after completing each radiotherapy session.
| Conclusion|| |
During the COVID-19 pandemic, patients with cancer should be treated with careful utilization of resources and with an effort to reduce the chance of progression and the risk of getting infected with COVID-19. It is reasonable to delay non-urgent cancer-directed therapies, but this needs to be individualized based on the prevailing pandemic situation and pattern of care at the treating center.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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