Background

The outbreak of the novel Coronavirus disease 2019 (COVID-19), consisting in a severe acute respiratory syndrome often associated to multiple organ dysfunction, has rapidly spread globally, being declared a pandemic by the World Health Organization (WHO) on 11 March (Coronavirus disease 2019).

The risk to develop a severe illness by COVID-19 increases by age, comorbidities, and presence of underling medical conditions influencing immune system. Based on early statistical data, the case-fatality rate (CFR) in the patients over 60 years old is much higher than overall rate: 14.8% in patients over 80 years, 8.0% in patients aged 70–79 years, and 3.6% in patients aged 60–69 years (Ramella et al. 2020). The proportion of deaths over 60 years old accounts for 81% of the total deaths in the national wide, which implicates aged people are more vulnerable to the SARS-CoV-2 (Verity et al. 2020). Moreover, the overall fatality rate is 3.8% for patients with cancer, as a comorbid condition was 7.6% (Zhang et al. 2020; Huang et al. 2020; Aggarwal et al. 2020). In general, cancer patients must be considered more exposed and frail, because of their immunologic state, directly due to the cancer and the need for immunosuppressive anti-cancer treatments.

In particular, patients with cancer recently undergone chemotherapy and surgery seems to have more risk of COVID-19, with more severe clinical events and rapid evolution; therefore, they need to be more intensively followed (Liang et al. 2020). Some limited data on immunosuppressed cancer patients indicated a 3.5 times higher risk of needing mechanical ventilation compared with patients without cancer (Zhang et al. 2020).

Therefore, a correct management of the risk related to the circulation of SARS-CoV-2 involves many specific implications in the particular context of the geriatric oncology.

A relevant geriatric branch of gynecological oncology concerns women suffering from vulvar carcinoma, more critical because typically older and frail due to comorbidities and physical performance often aging related. Moreover, the high aggressiveness of this cancer turns every choice risky, when proceeding with treatment delivery or deciding to postpone/omit them, according to the priorities (Ramirez et al. 2020).

Gemelli University Hospital is one of the larger COVID-19 referral centre in Italy and, at the same time, one of the larger Italian Oncological Centers. In our institution, a vulvar cancer multidisciplinary team (Vul.Can MDT) is responsible for personalized treatment strategies and management. It is structured in a core team, supplemented by a group of support specialists. The core team includes two dedicated members (one senior and one young) for seven central specialties: gynecologic oncologist, plastic surgeon, radiation oncologist, medical oncologist, radiologist, nuclear medicine physician, and pathologist. The group of support specialists includes one dedicated member for each complementary specialty: geriatric oncologist, infectivologist, general surgeon, urologist, nutritionist, pain therapy anesthesiologist, psycho-oncologist, physiatrist, and physiotherapist. Moreover, a midwife is dedicated to the case management and a nurse provides advanced wound care. A total number of about 260 cases are annually discussed within the multidisciplinary tumor board (MDTB): about 120 are addressed to surgical procedures, among which about 30 combined with plastic surgery, 50 to radiotherapy evaluation, 15 to chemotherapy, and 10 to electrochemotherapy (ECT).

Since COVID-19 is expected to remain a primary focus of the medical leadership for a very long time, in the full absence of vulvar cancer-specific guidelines oriented to the pandemic context, we are trying to respond to the urgent need to address the possible changes of resource allocation, clinical care, and treatment delivery for vulvar cancer patients.

The aim of this paper is to focus a proposal of a personalized workflow for vulvar cancer patients and to define the specific measures that can be adopted to reduce the ongoing risk of infection during treatments.

All the contents have to be considered as an expert opinion guidance, to be considered during the extraordinary period of the pandemic emergency and do not overcome the current available international guidelines, the national and regional recommendation as well as the clinical decision obtained after interdisciplinary discussion.

Methods

The project was designed and approved in the frame of Vul.Can MDT and three steps process were defined.

In the first step, a specific Interdisciplinary Task Group, coordinated by one gynecologist (SMF) and one radiation oncologist (VL), defined preliminary postulates and guiding principles of vulvar cancer patient workflow. In the second step, the proposal was subjected to the evaluation of the Senior Members of the Vul.Can MDT and in addition, considering the issues of the project, to the infectivologist and the geriatric oncologist (GG—gynecologist, LT—radiation oncologist, SG—plastic surgeon, GCol—geriatric oncologist, GCor—medical oncologist, ET—infectivologist) who also defined management protocols, stratified for disease prognostic categories and COVID-19 status. In the third step, final evaluation was supplied by a Master Team (GS, AF, MAG, and GM) for validation.

Postulates and definitions

Postulates were considered as the basic elements for the construction of renewed clinical/management pathways. Definitions were considered the way to classify elements and recognize priorities to propose targeted treatments for each category of patients (Table 1).

Table 1 Postulates and definitions
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Recommendations

The team produced two types of recommendations: one concerning safety regulations for patient flow management and hospital environments; in particular, these have been declined in Table 2, according to three categories of relevance, referring to care pathways, patients, and health care providers. The second section about personalized treatment protocols in the COVID-19 era.

Table 2 Guiding principles
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Since the outbreak of the pandemic, we have managed an outpatient flow of 80 patients with about 40 surgical procedures. We only recorded one case of SARS-CoV-2 infection in a patient’s family member. No patient showed signs of infection due to the strict protocols of social distancing and isolation initiated even before the lockdown for the frail patients such as those typically affected by vulvar cancer.

Vulvar cancer management

Several clinical conditions have been distinguished and analyzed below, taking into account in vulvar cancer patients the frailty condition, the COVID-19 status, the stage of disease and the available treatments including surgery, radiotherapy, chemotherapy, and electrochemotherapy. The risk–benefit ratio and morbidity of these approaches were afforded in the MDTB meetings that are a requirement of utmost importance for any personalized strategy.

COVID-19 symptomatic patients

No clear guidelines exist regarding this group of patients, however, in case of acute symptomatic syndrome, the care of the COVID-19 should be reasonably considered a priority compared to anti-cancer treatments. Therefore, in patients who are candidates for diagnostics, surgical or medical treatments, it should be advisable to postpone these procedures after the complete recovery from COVID-19. Concerning palliative treatments they should be performed only when acute, severe, and extremely urgent and should be faced with the least invasive treatment: for example, in case of acute and irreversible bleeding from a bulky proliferative lesion, hemostatic radiotherapy or embolization could be provided, paying attention to carefully trace and secure the hospital staff and pathways used for the urgency. The clinical pathways for the management of women with vulva cancer who are infected with Sars-CoV-2 are shown in Fig. 1.

Fig. 1
figure 1

Clinical pathways for management of patients with SARS-CoV2 infection and vulvar cancer. DACT diagnostic tests and anti-cancer treatments

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COVID-19 asymptomatic patients

Given the high risk of an unfavorable outcome from COVID-19, even treatments of asymptomatic or pauci-symptomatic cases, should be jointly discussed in the MDTB, strongly considering to postpone vulvar cancer cure after negative laboratory test are gained. Time interval for lab test repeat should be defined on the base of infectivologist’s opinion, usually 2 weeks from the first diagnosis. In case of negativization of laboratory tests, oncological care could safely continue; in case of persistence with no symptoms, the MDTB should decide whether to proceed with the treatments limited to cases deemed urgent (e.g. aggressive disease, severe cancer-related symptoms). However, in these cases, the least invasive treatments should be carefully chosen, considering consequences related to treatment delivery or delay. Moreover, any chosen treatment should be carried out in COVID-19 dedicated pathway.

Switching patients

Non-COVID patients may become positive for SARS-Cov-2 during administration of prolonged anti-cancer treatments, such as radiation therapy and chemotherapy. Continuous surveillance, repeating lab tests periodically (usually every 10–15 days), can favor early diagnosis of viral infection and prompt introduction to COVID-19 dedicated pathways, when disease is still pre- or pauci-symptomatic.

The possible decision to complete, discontinue or postpone the ongoing anti-cancer treatments requires a focused discussion in the MDTB, carefully considering risk–benefit balance, based on many contextual parameters, such as frailty, presence of COVID-19 symptoms, cancer aggressiveness and time to complete the ongoing therapies.

In case of discontinuation, treatments could potentially be resumed after recovery, whenever it is still possible and beneficial. Usually two consecutive negative laboratory tests (collected > 24 h apart), and a waiting time of at least 3–7 days from symptoms resolution and imaging restoration could be considered as adequate (Istituto Superiore della Sanità 2020).

In any case, we suggest to share as clearly as possible the benefits, risks, and final decisions with patient and possibly caregivers.

Patients negative for COVID-19

Work up

To minimize the exposure of patients to hospital-related risks, diagnostic procedures and patients’ access should be limited at most.

The work-up should follow a fast track protocol, included at the first access:

  • Integrated evaluation of the patient’s general conditions with the assessment of the potential frailty

  • Gynecologic exam and biopsy of the vulvar lesion, if required

  • Pelvic and inguinal lymph node ultrasound, with needle-aspiration/biopsy if required

  • Blood-chemical and serological investigations (including SCC tumor marker)

On the basis of this fast track protocol, the gynecologist should preliminarily assess the clinical stage and follow these advices:

Clinical early stage: if lymph nodes are negative at ultrasound assessment, given the accuracy of the ultrasound exam when performed by skilled examiner, considering the low risk for distant metastasis, we could suggest to omit additional imaging to complete systemic staging (Frumovitz et al. 2008; Gradishar et al. 2020).

Clinical advanced stage: if groin or pelvic lymph nodes show metastatic involvement at ultrasound or if infiltration of cutaneous bridges, urethra, anus, or vagina are evident or suspicious, considering the higher risk for distant metastases, a whole-body assessment should be performed by conventional radiologic imaging (CT, plus or minus pelvic MRI) or metabolic imaging (by 18FFDG-PET/CT) (Salani et al. 2017; Kataoka et al. 2010; Robertson et al. 2016; Viswanathan et al. 2013; Collarino et al. 2018, 2017; Fiorentino et al. 2019; Alongi et al. 2019).

In case of undefined clinical presentation, a case-by-case preoperative work-up should be planed after MDTB discussion.

Treatment

Several clinical conditions have been distinguished and analysed below, taking into account all potential treatments among the surgical, radiotherapy, and chemotherapy options.

Fit patients

Radical surgery on primary tumor site and groin lymph nodes should be highly supported but keeping in mind that impact of surgical burden should be limited as much as possible. If plastic surgery is required to repair tissue defects, techniques producing minimal impact should be favored (Gentileschi et al. 2016, 2017). Medical therapies (RT and CT) should be guaranteed, anyway favoring the least possible impact. In particular, neoadjuvant treatment has not been included among the available treatment options because of the high cumulative morbidity of RT–CT followed by radical surgery, in the absence of a strong evidence of benefit compared to exclusive RT regimen (Montana et al. 2000; Moore et al. 2012).

All these general principles fit for all stages. Possible modulations on the standard therapeutic choices are reported in Tables 3 and 4.

Table 3 Flowchart of surgical indications, stratified for clinical presentation
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Table 4 Flowchart of indications to radiotherapy stratified for intention
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Early stages

Standard radical surgery with negative surgical margins should be performed on primary tumor site if possible. Sentinel lymph node procedure has to be always provided in all clinically N0 patients that meet the standard criteria (primary unifocal tumor < 4 cm) (Frumovitz et al. 2008; Gradishar et al. 2020). The remaining clinically N0 cases, not fit for the standard selection criteria, should be addressed to radical lymphadenectomy, with high rate of morbidity and complications, often unnecessary. Nevertheless, considering the need for reducing the severe morbidity related to this surgical procedure (DiSaia et al. 1979; Carlson et al. 2018), a sentinel lymph node biopsy could be considered instead of standard radical lymphadenectomy always after discussion in MDTB. Recent preliminary evidences showed the safety of the procedure even in this setting only if provided that an accurate ultrasound and metabolic (PET/CT) assessment of the lymph node status is performed by expert examiners (Garganese et al. 2017, 2020). Possible modulation in radiation therapy approach is reported in Table 4.

Locally advanced stages

The standard treatment may include exclusive radio-chemotherapy (RT–CT) or radical surgery eventually followed by adjuvant RT.

Radical lymphadenectomy should be performed in all cases with proven or highly suspicious inguinal lymph node metastasis, taking care to completely harvest the superficial and deep lymph nodes of the inguino-femoral triangle.

Conversely, sentinel node biopsy of lymph node surgical staging could also be considered in selected clinically N0 cases, such as in FIGO stage III contralaterally to a metastatic groin or in FIGO stage II, beyond the standard selection criteria for SLN, limited to the conditions previously specified in early stage workflow. Moreover, complete omission of surgical staging could be considered after MDTB.

In case of perineal extensive disease, requiring large surgical demolition of structures bordering the vulva (urethra, vagina or anus), with possible functional impairment, and/or large plastic reconstruction, upfront radical RT should be considered, both in node negative or positive patients, after MDTB discussion. In this case, RT should be delivered with radical intent and surgery would be performed only on residual disease with debulking intent.

Local recurrence

The choice underlies the treatments previously carried out and the extent of disease. Surgery could still obtain radical results; radical RT–CT could be the favorite option in large relapses followed by debulking surgery in case of partial response. ECT or other palliative treatments for local control of disease (surgery or RT regimens) could take over if the radical intent can no longer be pursued (Certelli et al. 2020).

Metastastatic stage

Chemotherapy with or without palliative local treatments versus supportive palliative care programs are suggested. The MDTB choice should focus on possible benefits of proposed treatments (Weinberg and Gomez-Martinez 2019).

Frail patients

In this setting, the MDTB discussion is particularly required to define the most balanced and personalized treatment plan.

Early stage

Radical surgery has to be considered limited to cases requiring low surgical effort. In larger lesions, one option could be upfront palliative surgery, with minimally invasive approach on primary tumor site, even omitting sentinel node procedure in previous well staged cN0 cases. Another option could be the shift to other locoregional palliative treatments (e.g. RT regimens or ECT).

Locally advanced stages

The most recommended choice might be the primary RT–CT treatment with exclusive intent. In case of minimal residual disease debulking surgery could still play a role. In large volume residual disease, we suggest to consider to omit surgery, evaluating switch to alternatives such as chemotherapy, interventional miniinvasive local therapy (brachitherapy, stereotactic RT, ECT) or palliative care.

Moreover, palliative primary tumor site surgery and/or selective lymphadenectomy could be considered.

Local recurrences and metastastic stages

Decisions regarding initiation of additional chemotherapy or further local treatments should be based on clinical MDTB judgment and potential for benefit based on expected response of subsequent available therapies.

Follow-up

Any patient home management should be encouraged, including telemedicine and phone calls. It is well kwon than only visual and clinical inspection permits early detection of recurrence, preventing an incurable progression: thus, as a compromise, we suggest every 4 months follow-up evaluations alternating telemedicine and outpatient visits. Virtual consultation should provide questionnaires including specific items aimed to identify the early symptoms and signs of a possible recurrence. It would be very useful to ensure the presence of the care giver next to the patient, to collect advice from a person able to perform an elementary anatomical inspection and to offer additional information about the symptoms and disorders reported.

Results from each virtual consultation should be recorded and if any doubt arises about a possible relapse, a medical exam should be scheduled in a short time.

Conclusions

In this manuscript, we have summarized our internal guidelines to manage vulvar cancer in COVID-19 era.

Our model is focused on finding a compromise between the risks of SARS-CoV-2 infection and the need to ensure the best oncologic treatments.

In this scenario, the application of the current available guidelines still remains a priority.

Each deviation from standard or modulation of treatment options for particular conditions requires a critical approach, individually customized, within the frame of a MDTB discussion.

The experience of the referral centers with dedicated MDTBs needs to be shared and extended to other centers through the use of multimedia support.

This expert-opinion-based guideline could be considered as a resource in an unprecedented critical period, still evolving. Moreover, the suggestions provided have to be molded on national circumstances and existing health system regulations.