key: cord-0760784-peo85pdn authors: Glehen, O.; Kepenekian, V.; Bouché, O.; Gladieff, L.; Honore, C. title: Treatment of primary and metastatic peritoneal tumors in the Covid-19 pandemic date: 2020-04-23 journal: J Visc Surg DOI: 10.1016/j.jviscsurg.2020.04.013 sha: 08531c5148e25ba1223465e47b2fb2d63b25a707 doc_id: 760784 cord_uid: peo85pdn Abstract The Covid-19 pandemic is profoundly changing the organization of healthcare access. This is particularly so for peritoneal neoplastic diseases, for which curative treatment mobilizes substantial personnel, operating room and intensive care resources. The BIG-RENAPE and RENAPE groups have made tentative proposals for prioritizing care provision. A tightening of the usual selection criteria is needed for curative care: young patients with few or no comorbidities and limited peritoneal extension. It is desirable to prioritize disease conditions for which cytoreduction surgery with or without associated hyperthermic intraoperative peritoneal chemotherapy (HIPEC) is the gold-standard treatment, and for which systemic chemotherapy cannot be a temporary or long-term alternative: pseudomyxoma peritonei, resectable malignant peritoneal mesotheliomas, peritoneal metastases of colorectal origin if they are resectable and unresponsive to systemic chemotherapy after up to 12 courses, first-line ovarian carcinomatosis if resectable or in interval surgery after at most six courses of systemic chemotherapy. Addition of HIPEC must be discussed case by case in an expert center. The prioritization of indications must consider local conditions and the phase of the epidemic to allow optimal peri-operative care. For several weeks now, France has been facing un unprecedented epidemic that is forcing its care systems to make rapid, far-reaching adjustments. The channeling of resources toward care for persons infected by SARS-CoV-2 has had to be balanced with ensuring continued provision necessary for other patients. This health emergency setting impacts the treatment of peritoneal cancer diseases, which is not clearly defined. In most cases, gold-standard curative treatment combines complete cytoreduction surgery (sometimes major and extensive) with hyperthermic intraperitoneal chemotherapy (HIPEC). The scant and still insufficient epidemiological data that we have reports an excess mortality risk in patients infected by SARS-CoV-2. For palliative care, pressurized intraperitoneal aerosol chemotherapy (PIPAC), alone or combined with systemic chemotherapy, is a therapeutic approach proposed by expert centers that also requires time in the operating room. PIPAC is still being evaluated and has not yet proved its efficacy in Phase III. For these cancer conditions, local and national governing bodies have mostly opted to de-schedule major surgery and prioritize systemic chemotherapy as a delaying strategy, without yet planning later care. The impact of these changes in therapeutic strategy on the prognosis of patients eligible for curative care, patients potentially eligible after neoadjuvant treatment or those receiving palliative treatment, can be marked and so deserves analysis. This is the aim of the CAIRN-carcinomatosis prospective observational study conducted by the BIG-RENAPE group, in which he first patient inclusions were made. A second French cohort, GCO-02 CACOVID-19, promoted by the French-speaking Cancer Federation (FFCD), collects data on patients with both cancer and Covid-19 to gain more knowledge on this disease association. While these data are being collected, the existing evidence must be considered. Some peritoneal cancers, such as pseudomyxoma peritonei, do not respond to systemic chemotherapy or only weakly. In other cancers, prolonged preoperative chemotherapy has a negative impact on prognosis (e.g. peritoneal mesothelioma) or is still controversial (e.g. resectable ovarian carcinomas). For still other cancer sites, the response to systemic chemotherapy is very uncertain (e.g. gastric and colorectal). To make progress in the difficult task of coping with the demands of this epidemic in terms of mobilizing resources and ensuring the continuity of the care we owe all our patients, the BIG-RENAPE group Page 5 of 19 J o u r n a l P r e -p r o o f 5 offers some proposals, as ways forward rather than guidelines, that can help practitioners and local and national governing entities make informed choices. -In the last decade major advances have helped optimize the selection of patients and set perioperative care, thereby markedly reducing morbidity (1, 2) . Efficient network organization, twice certified by the French National Cancer Institute (INCa) (RENAPE), has allowed these practices to be generalized nationwide. -One fundamental feature of this improved patient selection is the generalization of exploratory laparoscopy, an examination that offers a higher sensitivity for evaluating small intestine involvement, which is necessary to determine a patient's resectability. In the setting of the Covid-19 epidemic, suspending these interventions and preferring peritoneal MRI is an option that can be considered. -All the patients involved and infected by Covid-19 must have all anti-neoplasia treatment suspended, be closely monitored (not necessarily with hospitalization) and have their treatment reassessed every two weeks based on the proposals presented here, according to the evolution of their infection and their cancer. -The advent of this unprecedented situation has produced a highly uneven pattern of adaptation among different health centers across France. Our purpose here is not criticism, but rather to raise awareness of the need to ensure care provision for patients with peritoneal cancer to ensure continuity and equity of care. A process of narrowing therapeutic indications is now engaged, and it is right that healthcare authorities respond by setting in place an organization that clearly separates non-Covid-19 care facilities. The French National Digestive Cancer Thesaurus (TNCD) describes five phases in the Covid-19 epidemic that will influence our strategic choices according to their impact on our healthcare capacities (3). 6 In Phase 1, the de-scheduling of many surgical operations for peritoneal cancer seems excessive except for patients at risk of severe forms of SARS-CoV-2 infection. The buildup of patients awaiting care will cause an increase in time-to-surgery per-and post-epidemic, with a resulting loss of life chances for all these patients. In Phases 2 and 3, shortage of material and human resources will cause many deferrals of major surgery. These phases are probably those that most obviously justify suspending major surgery. However, forward-planned solutions for externalizing care to ringfenced non-Covid-19 centers can probably be implemented. In Phases 4 and 5, the constitution of specific Covid-19-positive and Covid-19-negative circuits, and more clarity on available and projected means, will enable delayed or de-scheduled cancer care to be prioritized over non-urgent care. This prioritization must be imposed by authorities and governing bodies to minimize loss of life chances caused by the modification of care strategy in Phases 2 and 3. At this stage, given the likely shortage of human resources, and the very gradual freeing up of beds in intensive care, means must be allocated as a priority to absorb the backlog of delayed or de-scheduled surgery. Whichever the epidemic phase, a restriction of the usual selection criteria is necessary. For this purpose, a new pre-operative assessment report with screening for a SARS-CoV-2 infection, a thoracoabdominopelvic CT scan and peritoneal MRI with reading by a designated expert radiologist (4-6) will help this stricter selection with the assessment of a new benefit/risk/means balance: de-scheduling of surgical exploration if the probability of non-resectability is deemed high, deferral if the risk of post-operative complications linked to the number of digestive resections seems too great, and screening for Covid-19-related pneumonia. -In Phases 4 and 5: give priority to resources for curative cancer surgery The international recommendations of PSOGI and EURACAN, drawn up using the same procedure as for pseudomyxoma, specify three pictures: (i) immediately resectable and operable patients, (ii) nonresectable and/or non-operable patients, and (iii) borderline-resectable patients (16) . The association of cytoreduction surgery and HIPEC is the gold-standard curative treatment when the condition is resectable. Systemic chemotherapy alone yields median survival times of one year, against more than 50 months after complete cytoreduction with HIPEC in expert centers. Rate of response to standard neoadjuvant chemotherapy is about 40%. Italian and French experiments report a negative effect of neoadjuvant chemotherapy on overall survival of resectable patients (17, 18) . Borderline resectability forms, usually identified by exploratory laparoscopy, are given bidirectional neoadjuvant treatment with systemic and intraperitoneal chemotherapy, which results in secondary resectability in half of cases (19) . In the current epidemic setting, in non-resectable or borderline-resectable cases and/or with poor prognosis factors (sarcomatoid or biphasic histological forms, Ki-67 > 9%) first-line systemic chemotherapy with cisplatin + Alimta is recommended. In immediately resectable cases, cytoreduction surgery-HIPEC must be the priority. -Propose cytoreduction surgery with HIPEC, the gold-standard treatment for resectable pseudomyxoma peritonei, as first-line treatment. -If local scheduling is impossible: -For low-grade asymptomatic PMP, propose deferral. -For high-grade PMP with signet-ring cells, propose systemic chemotherapy (FOLFOX or CapOx in this epidemic setting to reduce contacts). Since the French PRODIGE 7 randomized trial, complete cytoreduction surgery associated with perioperative systemic chemotherapy has been the gold-standard curative treatment for colorectal peritoneal metastases, giving a median survival time of more than 40 months (20) . HIPEC has not yet demonstrated any benefit for overall disease-free survival when associated with complete cytoreduction surgery. However, some monocentric studies have reported survival times longer than 60 months in cases of surgery plus HIPEC (21) . Systemic chemotherapy, even if it is less effective on peritoneal metastatic disease (especially when mucinous) than on liver or lung metastases (22) , can still control the disease to an extent. Median survival time with modern systemic chemotherapy protocols is 24 months (23). Histological analysis of resected peritoneal metastases showed that this chemotherapy achieved a significant tumor response in more than 30% of patients, of which 10% were complete responses on all the samples from the same patient (24) . It is difficult to predict poor response to chemotherapy. Factors such as RAS and BRAF mutations, location to the right of the primary tumor or a mucinous component accounting for >30% could help grade patients for this risk. Patients whose tumor presents microsatellite instability are potentially more sensitive to immunotherapy, which could be This condition is the one for which discussion of curative treatment strategies is most difficult in the current epidemic setting. There are three main reasons for this: (i) its poor prognosis with median survival times of 18 months in the latest study associating cytoreduction surgery and HIPEC (25) , (ii) the high risk of post-operative complications with this therapeutic association, and (iii) the difficulty pursuing the current recommended neoadjuvant chemotherapy, FLOT, for toxicity reasons. In cases of peritoneal metastases, systemic chemotherapy alone does not give median survival times of more than one year. A recent French multicentric study (25) reports a significant survival benefit for the cytoreduction-HIPEC association over surgery alone, irrespective of the subgroups studied in a population of strictly selected patients in whom there was a possibility of obtaining remissions in cases of limited disease (26) . Median survival was not attained at 5 years follow-up with this therapeutic association in the subgroup of patients with favorable histology (no independent signet-ring cells). -Complete cytoreduction surgery associated with perioperative systemic chemotherapy is the gold-standard treatment for resectable colorectal peritoneal metastases. -Systemic neoadjuvant chemotherapy, if effective and well-tolerated, can allow cytoreduction surgery to be delayed, and can be repeated up to 12 times, with appraisal, albeit difficult, of the risk of an evolution toward non-resectability during that time. -Give priority to cytoreduction surgery for resectable colorectal metastases that are unresponsive to systemic chemotherapy. -Discuss addition of HIPEC case by case in an expert center. It must not increase the risk of post-operative complications. 12 There is therefore a marked difference in prognosis between a major surgery strategy (with HIPEC) requiring intensive post-operative care and with high risk of severe post-operative complications and a strategy of systemic chemotherapy that soon meets problems of tolerance and efficacy. The patients involved are often young (mean age in the HIPEC group of the CYTO-CHIP trial was 51 years). If an immediately resectable ovarian metastasis of limited extension is diagnosed (with few or no digestive resections expected) in a patient with an uneventful medical history, primary surgical cytoreduction is the gold-standard treatment. It presents a prognostic advantage in terms of survival over neoadjuvant chemotherapy according to the recent recommendations of the French National Cancer Institute (INCa) (27) . In the epidemic setting it must therefore take priority according to local possibilities. The same picture in a patient with a major risk of post-operative complications (advanced age, obesity, severe cardiovascular pathology, ASA III or IV) would justify neoadjuvant chemotherapy. In cases of diffuse cancer requiring major cytoreduction surgery with potentially prolonged postoperative intensive care, the start of neoadjuvant chemotherapy can be discussed, as there was no difference survival rate between the two strategies in the main randomized trial that evaluated it (28) . This strategy must be discussed, in particular for patents with marked comorbidities. HIPEC with cisplatin to complete resection has recently shown its potential for survival benefit in a randomized study (29) , with no increase in postoperative complications being reported. However, the place of HIPEC remains largely controversial in the current context of intense development of targeted therapies. Delayed interval surgery (after at most six chemotherapy courses) must be discussed case by case in a multidisciplinary meeting, considering local conditions and chemotherapy response. Interval HIPEC must also be discussed case by case in expert centers. In cases of recurrence, a recent study has challenged the impact of surgery (30) relative to systemic chemotherapy alone with an anti-angiogenic. We await definitive results from the DESKTOP study evaluating the impact of complete surgery on platinum-sensitive recurrences with AGO selection criteria (31) . Although the results come out significantly in favor of surgery for disease-free survival, impact of overall survival is not yet known. HIPEC in platinum-sensitive recurrence is still being evaluated in randomized trials (CHIPOR in France -NCT01376752 et HORSE in Italy -NCT01539785) and so cannot be recommended outside those trials. In cases of platinum-resistant recurrence, the best reported results were obtained with the association of surgery and complete cytoreduction with HIPEC (32) . The results of the cytoreduction surgery-HIPEC association for certain rare indications in patients strictly selected in expert centers have been collected by the international PSOGI group. That work has revealed notably long survival times for some of these unusual indications (urachus, mucinous ovarian tumor, cholangiocarcinoma, liver cell carcinoma and others) (33) . The same prognostic factors were found in this population as in peritoneal metastasis of more frequent origin (complete cytoreduction surgery and PCI). The level of scientific proof given by these limited retrospective cohorts is admittedly not high, but the possibility must be considered of offering access to treatment for some of these patients with clearly resectable disease and favorable tumor biology, reflected in good, prolonged response to chemotherapy, that could result in long survival or even complete remission. -Prioritize primary complete cytoreduction surgery for immediately resectable ovarian metastases and of limited extension according to local possibilities. -Prefer neoadjuvant chemotherapy for immediately resectable peritoneal cancer if local scheduling of cytoreduction surgery is impossible or the cancer is more extensive. -Discuss delayed interval surgery (after six courses at most) in multidisciplinary meetings in the light of local conditions and response to chemotherapy. -Consider local conditions when prioritizing indications to ensure optimal perioperative care. -Prioritize systemic chemotherapy whenever it can control the disease with an acceptable tolerance until the epidemic has abated. Perioperative Clinical Pathway Can Dramatically Reduce Failure-to-rescue Rates After Cytoreductive Surgery for Peritoneal Carcinomatosis: A Retrospective Study of 666 Consecutive Cytoreductions Prehabilitation of patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancy COVID-19 epidemic: proposed alternatives in the management of digestive cancers : A French Intergroup clinical point of view (TNCD). Dig Liver Dis Evaluation of the peritoneal carcinomatosis index with CT and MRI Peritoneal MRI in patients undergoing cytoreductive surgery and HIPEC: History, clinical applications, and implementation Concerning CT features used to select patients for treatment of peritoneal metastases, a pictoral essay Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis in the Elderly: A Case-Controlled, Multicenter Study A War on Two Fronts: Cancer Care in the Time of COVID-19 Strategy for the practice of digestive and oncological surgery during the Covid-19 epidemic Risk of COVID-19 for patients with cancer Risk of COVID-19 for patients with cancer SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1000 patients with perforated appendiceal epithelial tumours Early-and longterm outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Diffuse malignant peritoneal mesothelioma: Evaluation of systemic chemotherapy with comprehensive treatment through the RENAPE Database: Multi-Institutional Retrospective Study Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7 Progression following Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin Pathological response to neoadjuvant chemotherapy: a new prognosis tool for the curative management of peritoneal colorectal carcinomatosis Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire / Synthèse.: Institut National du Cancer (INCa) Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20 Peritoneal carcinomatosis treated with cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients Complete cytoreductive surgery plus HIPEC for peritoneal metastases from unusual cancer sites of origin: results from a worldwide analysis issue of the Peritoneal Surface Oncology Group International (PSOGI)