Strategies for care of patients with gastrointestinal stromal tumor or soft tissue sarcoma during COVID‐19 pandemic: A guide for surgical oncologists

Abstract The coronavirus disease‐2019 (COVID‐19) pandemic is deeply impacting the accessibility of cancer patients to surgery. In resource‐limited conditions, the standard of care might not be deliverable, but evidence to support alternative management strategies often exists. By revisiting available treatment options, this review provides surgical oncologists with an evidence‐based framework for treating patients with gastrointestinal stromal tumor, extremity/truncal soft tissue sarcoma, and retroperitoneal sarcoma to rapidly adapt their decision‐making to the constant evolution of the COVID‐19 pandemic.

high-volume expert centers; however, this poses an additional challenge in the pandemic landscape. [3][4][5][6] Documents briefly discussing prioritizing principles and alternative options for patients with STS have been released by the Society of Surgical Oncology, by the European Society of Medical Oncology, and by the French Sarcoma Group. [7][8][9] However, decision making under crisis/resource-limited conditions requires analysis of multiple variables that are interrelated and vary by jurisdiction. These variables include the local pandemic phase, availability of the full spectrum of medical resources; institutional policies, and prevailing cultural values related, as an example, to the perception of risk. Evidence-based guidelines for a rare tumor type are challenging to generate and follow at the best of times. In the face of an evolving pandemic or similar catastrophe, this challenge is compounded. Clinicians will benefit from guidance that is based on what applicable evidence exists, specialized expert opinion, and common sense.
In this article, we aim to provide data that illuminate the appropriate prioritization of STS surgery in times of crisis, and that support the selection of alternative multimodality management options, to assist surgeons in optimizing the care of patients with gastrointestinal stromal tumor (GIST) and STS in the context of the present COVID-19 pandemic, and beyond.

| APPROACH
In the majority of primary GIST and STS, surgery is the curative modality. As the benefit of surgery is limited in locally recurrent and metastatic patients, we focus on primary GIST and STS, highlighting risk stratification, the perceived impact of delayed surgery, the projected burden of resource utilization along with surgical morbidity, and restricted indications for urgent surgery. We review the evidence for alternative nonsurgical approaches that may be employed until definitive surgical management can be performed and highlight their known relevant limitations. Finally, a framework to prioritize patients for surgery in resource-limited conditions is provided for each disease site.

| GASTROINTESTINAL STROMAL TUMOR
The curative treatment for localized GIST is surgery. Indications for surgery for patients with GIST include curable primary tumor, limited focal progression of recurrent/metastatic disease on tyrosine kinase inhibitors (TKI), and treatment of complications.
The chance of tumor recurrence, and thus the chance of cure, after complete surgery depends upon tumor site, size, mitotic rate, F I G U R E 1 Prioritization of surgical intervention in elective patients with gastrointestinal stromal tumor (GIST). This framework is intended to guide prioritization for elective surgery in GIST patients. Surgical emergencies/urgencies (i.e., tumor bleeding, progressive unrelenting symptoms) are not covered. Patient categories represent the most common clinical scenarios. Patient priority and alternate treatments should be personalized and discussed in the context of multidisciplinary tumor boards. The different spacing between boxes on the priority line reflect a conceptual difference in patient prioritization as suggested by Hanna et al. 15 EUS, endoscopic ultrasound; GIST, gastrointestinal stromal tumor; PDGFRA, platelet-derived growth factor receptor alpha; PR, partial response; RFA, radiofrequency ablation; RT, radiotherapy; SD, stable disease; TKI, tyrosine kinase inhibitor CALLEGARO ET AL.

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and intraoperative tumor rupture. These factors are combined in risk-stratification tools such as the modified NIH criteria, the Miettinen and Lasota classification, the GIST nomogram, or the prognostic contour maps. [10][11][12][13] Some of these tools are categorical   and distinguish low-risk versus intermediate-risk versus high-risk   patients, who have a 10-year progression-free survival when treated with surgery alone of about 90% or higher versus 80%-90% versus 30%-60%, respectively. 12 These risk-stratification tools were developed based on series of patients treated with surgery to predict the chance of tumor recurrence after resection. Nevertheless, there is evidence suggesting that the progression rate of GIST left untreated might correlate with these same risk categories, with high-risk GIST progressing more rapidly. 14 Hence, risk stratification tools might be useful to inform the choice of alternative treatments to surgery.
Criteria for assigning priority for surgery in patients with GIST and alternative multimodality management options in the face of the COVID-19 pandemic are discussed in the following paragraphs and summarized in Figure 1 and Table 1.

| Surgical resources and anticipated morbidity
Resource utilization and postoperative morbidity associated with resection of GIST vary with tumor site and type of operation. Less complex procedures with lower morbidity include endoscopic resections of gastric or rectal GIST, partial gastrectomy (postoperative complications after wedge resection 4%-12%), local resection of the duodenum (90-day morbidity 24%, ≥grade 3 complications 5%), segmental small bowel resection, and local excision of rectal GIST (perioperative ≥3 complications related to the rectal repair 17%). [16][17][18][19][20] More resource-intensive procedures include multivisceral resections, total gastrectomy, pancreaticoduodenectomy (90-day morbidity 70%, ≥grade 3 complications 43%), and abdominalperineal resection. 19 In terms of surgical technique, outside the current pandemic laparoscopy was shown to be less resource intensive (shorter OR time, shorter hospital stay, limited blood loss) and safe (less overall complications) in patients with small bowel and gastric GIST, though there is likely an inherent selection bias. [21][22][23] In the specific scenario of the COVID-19 pandemic, concerns regarding the theoretical risk of viral transmission to healthcare workers via aerosolization during laparoscopy have been raised, especially at the pandemic outbreak.
Surgical societies have recommended modifications of the surgical practice to minimize this potential risk. Recommendations included the use of adequate personal protective equipment, enhancement of OR ventilation, use of lower CO 2 pressure, use of smoke extractors and CO 2 filters, minimization of the use of energy devices. In the lack of evidence about the laparoscopy-associated risk of SARS-CoV-2 transmission, the decision to pursue laparoscopy should be personalized weighting individual patient risk, safety of the operating room environment, and expected benefit from the minimally invasive approach. 24,25 Use of neoadjuvant imatinib does not appear to significantly increase perioperative morbidity, while surgery in patients on Sunitinib is associated with a complication rate as high as 54%. 26,27 Thus, the extent of intervention and anticipated use of resources is variable across GIST patients, and assessment of other key tumor features including risk category and local resource allocation will aid in determining if upfront surgery can be performed or if alternate strategies are necessary.

| Watchful waiting
Watchful waiting is a management option already routinely considered in patients with gastric GIST less than 2 cm, which are very low or low risk. 28,29 This approach may be considered for gastric GIST more than 2 cm or for smaller GIST in other locations, while being mindful of increasing risk of tumor progression associated with increasing risk category. If watchful waiting is pursued in patients who would otherwise have undergone upfront surgical resection in the pre-COVID era, a CT scan should be repeated early (i.e., in 1-3 months) to monitor for disease progression. The decision to pursue watchful waiting versus neoadjuvant imatinib as a delay strategy for patients with GIST that would normally be resected upfront should be based on several considerations. First, tumors close to EGJ, duodenal papilla, or anal sphincter, whose progression might upscale the surgical procedure from a local resection to a radical procedure, would benefit more from neoadjuvant imatinib as a temporizing strategy. Second, even if imatinib is overall well tolerated, patients are exposed to side effects such as myelosuppression (grade ≥ 3 experienced by up to a fifth of the patients) that might be worrisome if the patient acquires a SARS-CoV-2 infection. 30 Finally, initial watchful waiting would not preclude the chance of initiating imatinib upon tumor progression.

| Neoadjuvant tyrosine kinase inhibitors
Neoadjuvant imatinib is usually continued until the desired response or maximal response (according to Choi criteria) has been achieved or if the patient becomes intolerant. During this pandemic, surgery might not be feasible at the desired time, and patients who have already achieved the desired response might need to stay on imatinib longer than anticipated. Knowing that 40% of secondary resistance will appear before 2 years from imatinib initiation in advanced disease, caution should be taken when neoadjuvant imatinib T A B L E 1 Risk stratification, resources required, and impact of delay in surgical intervention in gastrointestinal stromal tumor (GIST) and soft tissue sarcoma (STS) patients

| Metastatic GIST
In patients with metastatic GIST, imatinib is the standard treatment and this should not be discontinued until progression, even in case of initial radiological complete response. Surgery may also be con- ference centers is 76%, 7%, and 25%, respectively. 36 Survival after wide excision is mainly related to tumor size, grade, and histology.
Quality of surgical margins and radiotherapy administration concur in defining the risk of local recurrence. [36][37][38][39] These factors have been combined in prognostic tools and two free-to-download apps-Sarculator and Persarc-include models to predict postresection OS, LR, and DM in patients with extremity STS. 40,41 Even though these tools were created for post-op use, they may have some utility to risk stratify patients by inputting data from imaging and biopsy. In particular, the key prognostic factors to predict survival (tumor size, histology, grade, and patient's age) are available preoperatively, with the caveat of a possible change in tumor grade at final pathology.
Criteria for prioritizing surgery and options available in extremity and truncal STS are summarized in Figure 2 and Table 1. A recent meta-analysis of 21 studies and more than 5,000 patients operated for extremity STS, identified an overall wound complication rate of 30% and a reoperation rate of 13%. [42][43][44] The type of surgical procedure strongly influences postoperative complications rate and resource burden. For example, in a study of 78 patients who underwent hindquarter amputation wound complication rate was 49%, in-hospital mortality was 6%, and median hospital stay was 24 days. 45 4.2 | Alternate nonsurgical approaches

| Watchful waiting
When surgery must be postponed due to resource limitations, watchful waiting can be considered in patients with ALT and DFSP.
They are typically slow growing and, in most locations, modest tumor growth would not alter the surgical plan. The outcome after surgery is excellent with disease-specific survival rates more than 95% at 5 years. 46,47 The probability of an ALT developing a dedifferentiated component is very low, close to 1%, and this is usually observed only after tumor recurrence. 48

| Neoadjuvant radiotherapy
Radiotherapy is usually considered in the multidisciplinary care of patients at high-risk of LR, bearing in mind that some particularly radiosensitive histological subtypes such as myxoid liposarcoma, angiosarcoma, myxofibrosarcoma, and synovial sarcoma have been described. 36 Preoperative and postoperative radiotherapy are equally effective in improving local control. Preoperative radiotherapy is associated with lower rates of late, irreversible toxicities but it portends a higher risk of acute wound healing complications. 43,52 In the neoadjuvant setting, RT is usually ad-

| Neoadjuvant chemotherapy
For adult-type STS, administration of chemotherapy varies across expert sarcoma centers. Histological subtypes that are more commonly treated with chemotherapy include synovial sarcoma, angiosarcoma, high-grade myxoid liposarcoma, undifferentiated pleomorphic sarcoma, and leiomyosarcoma. 36 The relative benefit associated with chemotherapy administration in patients with localized STS is unclear; however, higher risk tumors seem to benefit the most. 56 When cytoreduction is the main objective, combination chemotherapy of doxorubicin and ifosfamide is usually administered, for a total of 3-5 cycles.

| Recurrent STS of the extremity and trunk
Isolated LR from STS still has surgery as a potentially curative option.
Criteria for prioritization should be based on disease biology, tumor site (vicinity to critical structure) and chance of long-term disease control. In this sense, there are tools available to predict the personalized impact of LR on extremity STS survivor's prognosis. 61,62 Radiotherapy and chemotherapy should be considered as mitigating strategies when surgery needs to be delayed with the same principles discussed for primary STS of the extremity and trunk and taking into consideration treatments previously administered at primary surgery, disease-free interval, and expected functional outcome.

| RETROPERITONEAL SARCOMA
Surgery is the only potentially curative treatment for patients with primary retroperitoneal sarcoma (RPS). 63 The 5-year overall survival in primary localized RPS treated in expert centers is 67%. 64 From a biological perspective, RPSs are heterogeneous. In particular, their growth rate, metastatic potential, and prognosis differ widely ( Table 2). 64 In the setting of primary localized disease, prognosis is mainly related to patient's age, histological subtype, tumor grade, size, multifocality, and completeness of surgical resection.
These factors have been combined in a prognostic nomogram that predicts 7-year OS and DFS after surgery, a nomogram that is cited in the 8th American Joint Committee on Cancer staging system. 65 This prognostic tool was designed to be used in the postoperative setting. In the current scenario, it might be useful to provide a personalized rough estimation of the chance of long-term cure to assist surgical oncologists in patient prioritization and choice of alternative strategies, with the caveat that some of the variables (such as completeness of resection) will have to be inferred.
Criteria for case prioritization and mitigating strategies are summarized in Figure 3 and Table 1.
T A B L E 2 Expected growth rate and oncological outcomes in different retroperitoneal sarcoma histological subtypes

| Surgical resources and morbidity
Surgical resection of primary RPS is often more complex and resource intensive compared to resection of GIST or extremity/truncal STS. Preoperatively, patients might need nutritional and physical prehabilitation. 66 Multivisceral resection is required in about 70% of cases, 64

| DISCUSSION
This review synthesizes data that may aid in decision making and patient prioritization based on a comprehensive review of sarcoma care for GIST and STS and is presented by experts in countries that have been moderately to profoundly impacted by the current COVID 19 pandemic.
The international sarcoma collaborative community remains steadfast in its commitment to providing guidance in deferral of care and is resolved to synergize our collective experience so that the data and wisdom gained from the "new normal" imposed by a pandemic can be developed and refined with the goal of continuing to optimize care for cancer patients.
Collection of data regarding the impact of the pandemic on patient outcomes will be beneficial for advancing knowledge for future pandemic planning and will facilitate decision making when resources are no longer restricted, as we continue to strive for the best outcomes for patients with cancer within our global community.

CONFLICT OF INTERESTS
Cecile Le Péchoux received institutional honoraria for participation to advisory boards from Astra Zeneca, Nanobiotix, and Roche; institutional honoraria for participation to educational meetings from Amgen, Astra Zeneca, Medscape, and Lilly; and personal honoraria from PrimeOncology for participation to educational meetings. The other authors declare that there are no conflict of interests.

DATA AVAILABILITY STATEMENT
The data that support the findings of the study are available in the public domain and have been cited in the reference section.