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Systemic Treatment of Patients With Gastrointestinal Cancers During the COVID-19 Outbreak: COVID-19-adapted Recommendations of the National Cancer Institute of Milan

      Abstract

      The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak poses a major challenge in the treatment decision-making of patients with cancer, who may be at higher risk of developing a severe and deadly SARS-CoV-2 infection compared with the general population. The health care emergency is forcing the reshaping of the daily assessment between risks and benefits expected from the administration of immune-suppressive and potentially toxic treatments.
      To guide our clinical decisions at the National Cancer Institute of Milan (Lombardy region, the epicenter of the outbreak in Italy), we formulated Coronavirus-adapted institutional recommendations for the systemic treatment of patients with gastrointestinal cancers. Here, we describe how our daily clinical practice has changed due to the pandemic outbreak, with the aim of providing useful suggestions for physicians that are facing the same challenges worldwide.

      Keywords

      Introduction

      In December 2019, Chinese authorities firstly reported a cluster of cases of severe pneumonia in Wuhan (Hubei province). The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was deemed responsible for coronavirus disease 2019 (COVID-19) and the pandemic outbreak. This highly infectious disease is usually associated with flu-like symptoms but may rapidly evolve to severe interstitial pneumonia and even death, particularly in older patients with comorbidities, including cancer. As of April 4, 2020 Italian authorities reported 124,632 SARS-CoV2 confirmed cases and 15,362 deaths, thus representing the highest number of COVID-19-related deaths in the world.
      A Chinese single-institution cohort study showed that patients with cancer may be at higher risk of SARS-CoV-2 infection compared with the general population,
      • Yu J.
      • Ouyang W.
      • Chua M.L.K.
      • Xie C.
      SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China.JAMA Oncol 2020 Mar 25;e200980.
      and a nationwide study associated a history of cancer with higher risk of severe events, defined as intensive care unit admission, invasive ventilation, or death.
      • Liang W.
      • Guan W.
      • Chen R.
      • et al.
      Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
      Additionally, because nosocomial transmission was identified in up to 41.3% of hospitalized patients,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      hospital admissions or repeated clinic visits clearly represent a crucial source of contagion. On top of their disease, patients with cancer face several threats related to their frequent hospital accesses: the presence of cancer-related and treatment-related immune suppression and coexisting comorbidities.
      The risk of hospital transmission of SARS-CoV-2 may be reduced, thanks to the screening of patients and staff and by minimizing face-to-face interactions.
      National Institute for Health Care and Excellence
      Coronavirus (COVID-19).
      Furthermore, Hanna et al provided a general framework to prioritize the use of systemic chemotherapy or radiotherapy during this global emergency, taking into account the magnitude of treatment benefit and the potential negative impact of treatment delays/interruptions on outcomes.
      • Hanna T.P.
      • Evans G.A.
      • Booth C.M.
      Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic.
      However, there is no cancer-specific recommendation yet, particularly for curable disease, on how to choose less toxic or more easy-to-administer treatments without jeopardizing survival outcomes.
      The National Cancer Institute of Milan (INT) is a comprehensive cancer center located in the Lombardy region, which accounts by itself for more than a half of the COVID-19-related deaths in Italy so far. In February 2020, INT faced the challenge of profoundly reorganizing its daily routine and procedures at an unprecedented pace to maintain its patients with cancer as safe as possible from COVID-19 and, at the same time, guarantee adequate levels of care. In few weeks, our Gastrointestinal Oncology Unit has elaborated Coronavirus-adapted treatment guidelines and regimens, measures for patient information and support and procedures for dynamic up- and downscaling of clinical activities and research.
      Here, we describe how our daily clinical practice has changed due to the COVID-19 outbreak, with the aim of providing useful recommendations for physicians that are facing the same challenges worldwide.

      Methods

      Since the beginning of the Lombardy outbreak in February 2020, a Gastrointestinal Oncology task force drafted the new Coronavirus-adapted institutional guidelines for gastrointestinal cancers. The multidisciplinary panel also included an external consultant (C.C.), member of the steering committee of the Italian Association of Medical Oncology (AIOM) Guidelines and based in a less impacted Italian region, with the aim to minimize the potential bias related to physicians’ stress condition and burnout.
      Treatment decisions were discussed on an individual basis, and, whenever necessary, multidisciplinary meetings were held as routinely via video or call conference. Phone screening surveying patients’ conditions, symptoms, latest radiologic evaluation, and contact with potential infected subjects was carried out on a daily basis.
      Table 1 summarizes our recommendations according to disease subtype.
      Table 1Summary of Coronavirus-adapted Institutional Guidelines at the National Cancer Institute of Milan, Lombardy Region, Italy
      Gastric and gastroesophageal cancer
       Pre (peri)-operative treatmentMSI-high cancer and R0 resectable or age > 70 years:

      Not recommended

      Node-positive or cT3N0 tumors with adverse prognostic/technical features:

      CAPOX

      cT4 stage or high-risk of R1/R2 resection:

      FLOT

      CRT for gastroesophageal junction cancers (including Siewert 1-2):

      Not recommended
       AdjuvantMSI-high cancer:

      Not recommended

      Based on pathologic stage and individual risk of relapse:

      capecitabine

      CAPOX
       First lineHER2-negative:

      CAPOX

      HER2-positive:

      CAPOX + trastuzumab for 6 cycles followed by trastuzumab maintenance
       Second linePaclitaxel + ramucirumab (modified biweekly regimen: mRAINBOW)

      Ramucirumab contraindicated or not available:

      Three-weekly irinotecan/docetaxel
       >Third lineNot recommended
      Pancreatic cancer
       Pre (peri)-operative treatmentResectable cancer:

      Upfront resection

      Borderline resectable cancer:

      Multidisciplinary discussion (evaluating age, ECOG PS, comorbidities, and risk factors)
       AdjuvantECOG PS 0, < 70 years old patients, based on pathologic stage, individual risk of relapse/toxicity, and comorbidities:

      Consider modified FOLFIRINOX (consider delaying treatment up to 12 weeks after surgery).
       First lineNab-paclitaxel + gemcitabine, biweekly

      BRCA-mutated disease:

      Oxaliplatin-based doublets with a stop-and-go approach

      Olaparib maintenance only if residual grade ≥ 2 neuropathy after oxaliplatin-based induction

      ECOG PS ≥ 2 patients and/or extensive comorbidities:

      Consider best supportive care alone
       >Second lineOnly in highly selected cases, ECOG PS 0-1
      Biliary tract cancers
       AdjuvantBased on pathologic stage, individual risk of relapse/toxicity, and comorbidities:

      Capecitabine (consider delaying treatment up to 16 weeks after surgery)
       First lineECOG PS 0-1 patients:

      CAPOX
       >Second lineOnly in highly selected cases, ECOG PS 0-1
      Hepatocellular carcinoma
       First lineOnly in ECOG PS 0-1 and Child A:

      sorafenib or lenvatinib
       Second lineOnly in highly selected cases:

      cabozantinib or regorafenib
      Colorectal cancer
       Preoperative treatment (rectal cancer)For cT3b and/or cN+ tumors in the lower rectum and any cT4 tumors:

      Long-course capecitabine-based chemoradiation

      For all other locally advanced tumors:

      Short-course radiotherapy
       AdjuvantThree-weekly capecitabine-based regimen preferred

      Stage III MSS tumors:
      • pT3 and pN1: CAPOX for 3 months
      • pT4N1 or anyTN2: CAPOX for 6 months
       First lineLeft-sided, RAS and BRAF wild-type, MSS and HER2-negative and age < 75 years:FOLFOX + bi-weekly anti-EGFRsRight-sided and/or RAS mutated and age <75 years:CAPOX + bevacizumabBRAF mutated, right-sided/KRAS mutated with high disease burden. AND age < 70 years:Modified FOLFOXIRI + bevacizumabUnfit or elderly patients:Capecitabine ± bevacizumabStrongly consider treatment holidays following 4 to 6 months induction.Capecitabine-based maintenance in case of RECIST response and aggressive disease
       Second lineFOLFIRI + bevacizumab

      MSI-high:

      Six-weekly pembrolizumab

      BRAF mutated:

      Bi-weekly cetuximab plus oral encorafenib
       Third lineBi-weekly anti-EGFR agents if not used in the first-line and only for left-sided, RAS and BRAF wild-type, HER2-negative tumors.

      Consider best supportive care or regorafenib with alternative schedules
      Anal cancer
       Curative therapyCapecitabine-based chemoradiation or radiotherapy alone for unfit patients
       Palliative therapyCarboplatin plus paclitaxel
      Advanced neuroendocrine neoplasms
       First lineWell differentiated GEP-NETs:

      SSAs

      Poorly differentiated NECs:

      Carboplatin plus oral etoposide
       Second lineWell/moderately differentiated pNETs:

      Sunitinib

      Well-differentiated small intestinal NETs:

      High-dose SSAs or PRRT

      Poorly differentiated NECs:

      Consider best supportive care or capecitabine + temozolomide
      Abbreviations: CAPOX = capecitabine and oxaliplatin; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; FLOT = docetaxel, oxaliplatin, and fluorouracil/leucovorin; FOLFIRI = folinic acid, 5-fluorouracil, and irinotecan; FOLFIRINOX = folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin; FOLFOX = folinic acid, 5-fluorouracil, and oxaliplatin; FOLFOXIRI = folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan; GEP-NET = gastroenteropancreatic neuroendocrine tumor; HER2 = human epidermal growth factor receptor 2; MSI = microsatellite instable; MSS = microsatellite stable; NEC = neuroendocrine carcinoma; NET = neuroendocrine tumor; PNET = pancreatic neuroendocrine tumor; PRRT = peptide receptor radionuclide therapy; RECIST = Response Evaluation Criteria in Solid Tumors; SSAs = somatostatin analogues.

      Gastric and Gastroesophageal Cancer

      For perioperative or adjuvant chemotherapy of patients with locally advanced gastric or gastroesophageal junction adenocarcinoma, the choice of multimodality treatment over surgery alone was made after careful evaluation of each individual risk-benefit profile. First, microsatellite instability (MSI) testing was performed for all patients to avoid perioperative/adjuvant treatments in those with MSI-high, R0 resectable cancers.
      • Pietrantonio F.
      • Miceli R.
      • Raimondi A.
      • et al.
      Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer.
      Based on a multidisciplinary team assessment, preoperative chemotherapy was recommended only for patients with age < 70 years and resectable high-risk disease. Oxaliplatin-based doublets were the treatment of choice for patients with node-positive disease assessed by both fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scan and endoscopic ultrasonography and for selected patients with cT3N0 tumors with adverse prognostic features (ie, diffuse histotype) or technical risks of incomplete resection (ie, gastroesophageal junction cancers). FLOT (docetaxel, oxaliplatin, and fluorouracil/leucovorin) triplet chemotherapy, which is associated with increased survival at the cost of a higher risk of toxicity,
      • Al-Batran S.E.
      • Homann N.
      • Pauligk C.
      • et al.
      FLOT4-AIO Investigators
      Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
      was recommended only for cT4 tumors and in those cases with unacceptable risk of positive (R1/R2) tumor margins. For patients with gastroesophageal junction adenocarcinoma, the use of neoadjuvant chemoradiation was discouraged even for Siewert 1 and 2 tumors. Regarding postoperative chemotherapy, we carefully assessed the patient’s health condition and nutritional status after gastrectomy, and the choice between adjuvant single-agent fluoropyrimidines (capecitabine) or CAPOX (capecitabine plus oxaliplatin) was made based on pathologic stage and individual risk of relapse.
      • Kattan M.W.
      • Karpeh M.S.
      • Mazumdar M.
      • Brennan M.F.
      Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma.
      ,
      • Noh S.H.
      • Park S.R.
      • Yang H.K.
      • et al.
      CLASSIC trial investigators
      Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.
      For patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic gastric cancer (mGC), the most commonly used first-line chemotherapy regimens are represented by combinations of fluoropyrimidines and platinums, with or without a third chemotherapy agent. Given the limited overall survival advantage provided by triplet chemotherapy at the cost of significant toxicity, doublet regimens are usually preferred in the clinical practice. Moreover, the administration of cisplatin requires protracted hydration and may cause severe vomiting, nephrotoxicity, and grade 3 to 4 neutropenia worthy of hospital admissions or intravenous supportive treatments. Several studies demonstrated the non-inferiority of oxaliplatin compared with cisplatin as part of combination regimens.
      • Cunningham D.
      • Starling N.
      • Rao S.
      • et al.
      Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom
      Capecitabine and oxaliplatin for advanced esophagogastric cancer.
      ,
      • Al-Batran S.E.
      • Hartmann J.T.
      • Probst S.
      • et al.
      Arbeitsgemeinschaft Internistische Onkologie
      Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie.
      Therefore, the choice of CAPOX regimen was preferred over FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) thanks to its 3-weekly schedule and the oral administration of fluoropyrimidine, with no need for infusion pumps and central venous catheters.
      • Cunningham D.
      • Starling N.
      • Rao S.
      • et al.
      Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom
      Capecitabine and oxaliplatin for advanced esophagogastric cancer.
      • Al-Batran S.E.
      • Hartmann J.T.
      • Probst S.
      • et al.
      Arbeitsgemeinschaft Internistische Onkologie
      Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie.
      • Wagner A.D.
      • Syn N.L.
      • Moehler M.
      • et al.
      Chemotherapy for advanced gastric cancer.
      For dysphagic patients needing nutritional support, initial treatment with FOLFOX infusional regimen was shifted to CAPOX as soon as the symptoms’ resolution allowed it.
      For patients with HER2-positive mGC, phase II non-randomized trials of trastuzumab added to standard CAPOX demonstrated an advantageous safety profile of this chemotherapy backbone and efficacy outcomes in line with those achieved with cisplatin-based regimens in the phase III ToGA registration trial.
      • Bang Y.J.
      • Van Cutsem E.
      • Feyereislova A.
      • et al.
      ToGA Trial Investigators
      Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
      • Rivera F.
      • Romero C.
      • Jimenez-Fonseca P.
      • et al.
      Phase II study to evaluate the efficacy of trastuzumab in combination with capecitabine and oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial.
      • Ryu M.H.
      • Yoo C.
      • Kim J.G.
      • et al.
      Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer.
      Therefore, we selected CAPOX-trastuzumab for 6 cycles followed by maintenance with single-agent trastuzumab as the strategy of choice.
      Even if irinotecan, taxanes, or the anti-vascular endothelial growth factor receptor 2 (VEGFR-2) monoclonal antibody ramucirumab represent evidence-based second-line treatment options,
      • Ford H.E.
      • Marshall A.
      • Bridgewater J.A.
      • et al.
      COUGAR-02 Investigators
      Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial.
      • Fuchs C.S.
      • Moore M.R.
      • Harker G.
      • Villa L.
      • Rinaldi D.
      • Hecht J.R.
      Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer.
      • Thuss-Patience P.C.
      • Kretzschmar A.
      • Bichev D.
      • et al.
      Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
      the absolute survival benefit is quite limited and should be carefully evaluated based on the relevant toxicity risk and individual patients’ life expectancy.
      • Pietrantonio F.
      • Barretta F.
      • Fanotto V.
      • et al.
      Estimating survival probabilities of advanced gastric cancer patients in the second-line setting: the gastric life nomogram.
      The optimal candidates for second-line therapy may be identified based on Eastern Cooperative Oncology Group performance status (ECOG PS), tumor response to first-line treatment, and a first-line treatment-free interval of at least 3 months.
      • Catalano V.
      • Graziano F.
      • Santini D.
      • et al.
      Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?.
      Noteworthy, the combination of weekly paclitaxel and ramucirumab achieved an unprecedented median overall survival (OS)
      • Wilke H.
      • Muro K.
      • Van Cutsem E.
      • et al.
      RAINBOW Study Group
      Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
      and is frequently used in several countries as the standard second-line treatment in absence of contraindications to anti-angiogenics. We selected the modified RAINBOW (mRAINBOW) bi-weekly simplified regimen (paclitaxel 110 mg/m2 plus ramucirumab 8 mg/kg every 2 weeks) as our standard according to the MD Anderson study.
      • Rogers J.E.
      • Xiao L.
      • Amlashi F.G.
      • et al.
      Ramucirumab and paclitaxel administered every 2 weeks (mRAINBOW Regimen) in advanced gastroesophageal adenocarcinoma.
      Whenever ramucirumab was contraindicated or not available, second-line chemotherapy consisted of 3-weekly courses of docetaxel or irinotecan (provided pharmacogenomic testing results were available).

      Pancreatic Cancer

      For patients with resectable pancreatic adenocarcinoma (PAC), we recommended upfront resection. For borderline resectable disease, neoadjuvant chemotherapy was indicated only after multidisciplinary discussion and careful evaluation of age, ECOG PS, comorbidities, and risk factors. Regarding postoperative treatments, given the survival advantage of adjuvant mFOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin),
      • Conroy T.
      • Hammel P.
      • Hebbar M.
      • et al.
      Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group
      FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer.
      this triplet regimen was recommended only for patients with ECOG PS 0 and age < 70 years—a more selected patient population compared with the pivotal study. Furthermore, we chose to delay the treatment start as much as possible and up to 12 weeks after resection.
      As far as unresectable or metastatic PAC is concerned, the 2 standard first-line regimens are standard-dose FOLFIRINOX
      • Conroy T.
      • Desseigne F.
      • Ychou M.
      • et al.
      Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup
      FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
      and nab-paclitaxel plus gemcitabine.
      • Von Hoff D.D.
      • Ervin T.
      • Arena F.P.
      • et al.
      Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
      Even in the absence of a randomized comparison between the 2 options, the toxicity profile of the triplet regimen is clearly worse
      • Pusceddu S.
      • Ghidini M.
      • Torchio M.
      • et al.
      Comparative effectiveness of gemcitabine plus nab-paclitaxel and FOLFIRINOX in the first-line setting of metastatic pancreatic cancer: a systematic review and meta-analysis.
      and may represent a challenge even for fit and younger patients. Therefore, we chose nab-paclitaxel plus gemcitabine as the preferred upfront regimen, with a modified bi-weekly schedule instead of the classical 3 weeks on/1 week off schedule.
      • Kokkali S.
      • Drizou M.
      • Tripodaki E.
      • et al.
      Updated results of biweekly gemcitabine/nab-paclitaxel as first-line treatment for advanced pancreatic cancer.
      ,
      • Rogers J.E.
      • Mizrahi J.D.
      • Shroff R.T.
      • et al.
      Dose-modified gemcitabine plus nab-paclitaxel front-line in advanced pancreatic ductal adenocarcinoma with baseline hyperbilirubinemia.
      When the triplet was deemed necessary (ie, for selected patients with locally advanced or borderline resectable disease), we used the modified FOLFIRINOX schedule that is commonly used in the adjuvant setting (irinotecan dose reduced to 150 mg/m2 and omission of the 5-fluorouracil bolus), due to better tolerability.
      • Tong H.
      • Fan Z.
      • Liu B.
      • Lu T.
      The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis.
      For BRCA-mutated disease, our standard strategy was initial oxaliplatin-based doublet chemotherapy for at least 4 months followed by treatment breaks in case of disease control (stop-and-go approach). Maintenance treatment with oral olaparib was taken into account mostly for patients who had platinum-induced neuropathy of grade 2 or more. For patients with an ECOG PS ≥ 2 and/or extensive comorbidities, we strongly advised best supportive care based on a home-delivery model.
      Even if no standard second-line treatment is defined yet, there is evidence on effectiveness and manageable toxicity of such regimens defined according to what was given as first-line and ECOG PS.
      • Pelzer U.
      • Schwaner I.
      • Stieler J.
      • et al.
      Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.
      • Wang-Gillam A.
      • Li C.P.
      • Bodoky G.
      • et al.
      NAPOLI-1 Study Group
      Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.
      • Gill S.
      • Ko Y.J.
      • Cripps C.
      • et al.
      PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy.
      However, given the very poor prognosis of metastatic PAC in this extremely palliative setting, we recommended that a second-line treatment was offered only to patients with a good ECOG PS and chemosensitive disease.

      Biliary Tract Cancers and Hepatocellular Carcinoma

      Although the only curative treatment for biliary tract cancer (BTC) is surgery, adjuvant oral capecitabine is recommended for patients with resected BTC based on the results of the BILCAP trial.
      • Primrose J.N.
      • Fox R.P.
      • Palmer D.H.
      • et al.
      BILCAP study group
      Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
      However, this study was criticized due to its failure to meet the primary endpoint (OS) in the intention-to-treat population, with a relapse rate as high as 60%. Considering such issues, we decided to: (1) delay treatment start as much as possible, giving the patient time to fully recover from surgery and (2) discuss each case according to the risk-benefit profile with regard to ECOG PS, age, comorbidities, and patients’ preferences.
      As far as metastatic or unresectable disease is concerned, the standard initial treatment for patients with a good ECOG PS is the combination of cisplatin and gemcitabine, which achieved superior OS compared with gemcitabine alone.
      • Valle J.
      • Wasan H.
      • Palmer D.H.
      • et al.
      ABC-02 Trial Investigators
      Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
      However, the schedule of the regimen by Valle et al (on days 1 and 8 every 21 days) requires multiple accesses to the hospital and abundant hydration and may cause relevant grade 3 to 4 toxicities, including hematologic ones.
      The gemcitabine-based GEMOX (gemcitabine and oxaliplatin) regimen is considered a reasonable alternative and safer option, also when considering single-day courses given every 2 weeks.
      • Li J.
      • Merl M.
      • Lee M.X.
      • Kaley K.
      • Saif M.W.
      Safety and efficacy of single-day GemOx regimen in patients with pancreatobiliary cancer: a single institution experience.
      Furthermore, CAPOX was non-inferior to GEMOX in terms of 6-month progression-free survival (PFS) rate in a recent phase III trial, with a better toxicity profile and less frequent hospital visits.
      • Kim S.T.
      • Kang J.H.
      • Lee J.
      • et al.
      Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.
      Therefore, CAPOX was recommended as the first-line treatment of choice for ECOG PS 0 to 1 patients with metastatic or unresectable BTC. For patients with liver-limited unresectable disease, we discussed, in a multidisciplinary setting, the chance for locoregional therapy (eg, yttrium-90 radioembolization), when feasible.
      • Hyder O.
      • Marsh J.W.
      • Salem R.
      • et al.
      Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      For patients with an ECOG PS ≥ 2 and/or extensive comorbidities, we strongly advised best supportive care based on a home-delivery model.
      Regarding second-line treatment, the same considerations expressed for patients with PAC were valid.
      • Lamarca A.
      • Hubner R.A.
      • David Ryder W.
      • Valle J.W.
      Second-line chemotherapy in advanced biliary cancer: a systematic review.
      For IDH1-mutated or FGFR2 translocated intrahepatic cholangiocarcinoma, patients’ access to orally administered selective inhibitors was recommended, whenever feasible.
      • Lowery M.A.
      • Burris 3rd, H.A.
      • Janku F.
      • et al.
      Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit Busset M.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      For patients with advanced and unresectable hepatocellular carcinoma (HCC), oral treatments were prescribed via web-based telemedicine and continued until symptomatic deterioration or radiologic progression, whichever occurred first. The tyrosine kinase inhibitors sorafenib or lenvatinib
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      were recommended in the first-line setting only in patients with ECOG PS 0 or 1 and Child-Pugh score A. Second-line treatment with cabozantinib
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.L.
      • et al.
      Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
      or regorafenib
      • Bruix J.
      • Qin S.
      • Merle P.
      • et al.
      RESORCE Investigators
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      was recommended only in highly selected patients with good prognostic features. Enrollment in clinical trials with immunotherapy agents was discouraged.

      Colorectal Cancer

      For patients undergoing adjuvant treatment for colon cancer, 3-weekly capecitabine-based regimens were preferred over biweekly infusional 5-fluoruracil-based schedules in order to limit the accesses to hospital. When oxaliplatin was indicated (mainly in the case of stage III MSS tumors), the limitation of treatment duration to 3 months was highly recommended in stage III low-risk (pT3 and pN1) tumors.
      • Grothey A.
      • Sobrero A.F.
      • Shields A.F.
      • et al.
      Duration of adjuvant chemotherapy for stage III colon cancer.
      In the same perspective, for locally advanced rectal cancer, the indication to neoadjuvant capecitabine-based long-course chemoradiation was carefully pondered and mainly applied to tumors arising in the lower rectum and staged ≥ cT3b and/or node-positive, or for cT4 cancers located in any part of the rectum. Short-course radiotherapy was preferred in all other cases of locally advanced rectal cancer.
      In the metastatic setting, the impact of the first-line therapy is the most relevant, both on patients’ long-term outcome and on the potential subsequent steps of treatment, including surgical and other locoregional approaches. The relative additional benefit from second and further lines of therapy is much less important, and their intent is definitely palliative in most of cases.
      Therefore, when choosing of the “best” upfront treatment, every effort was made to limit toxicity while offering the most efficacious therapy to each individual patient. In patients unfit for a combination of chemotherapy, the opportunity to start a first-line regimen was properly evaluated and discussed, with capecitabine ± bevacizumab as the preferred option.
      When an anti-epidermal growth factor receptor (EGFR) monoclonal antibody was chosen as first-line targeted agent (mainly in fit patients with a left-sided, RAS and BRAF wild-type, MSS, and HER2-negative tumors), it was combined with a 5-fluorouracil-based doublet. In the case of cetuximab, we used the bi-weekly schedule, now widely adopted in clinical trials and in the daily practice because of its equivalent efficacy and safety compared with the weekly schedule.
      • Cremolini C.
      • Antoniotti C.
      • Lonardi S.
      • et al.
      Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial.
      With regard to the choice of the upfront chemotherapy, in fit patients, the triplet FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) provides survival benefit as compared with both oxaliplatin- and irinotecan-based doublets at the price of increased gastrointestinal and hematologic toxicities.
      • Cremolini C.
      • Antoniotti C.
      • Rossini D.
      • et al.
      GONO Foundation Investigators
      Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.
      The choice of this intensive and highly active regimen was suggested only for patients with aggressive cancers, such as those with BRAF mutation, or with right-sided primary tumor/KRAS mutation and high tumor burden, or whenever conversion to liver surgery was foreseen in borderline resectable liver metastases. Because in patients aged 70 to 75 years the risk of grade 3 and 4 diarrhea and neutropenia is increased, we carefully weighted the use of the triplet in this age subgroup.
      • Marmorino F.
      • Rossini D.
      • Lonardi S.
      • et al.
      Impact of age and gender on the safety and efficacy of chemotherapy plus bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies.
      To minimize the risk of neutropenia, the use of granulocyte-colony stimulating factor (G-CSF) as primary prophylaxis, which is not routinely recommended, was considered, as well as modified schedules of FOLFOXIRI, with reduced doses of 5-fluorouracil (2400 mg/m2 instead of 3200 mg/m2) and irinotecan (150 mg/m2 instead of 165 mg/m2).
      • Cremolini C.
      • Antoniotti C.
      • Lonardi S.
      • et al.
      Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial.
      If an oxaliplatin-based doublet plus bevacizumab was chosen as an upfront option, the use of capecitabine instead of 5-fluorouracil was preferred to reduce the frequency of in-hospital infusional procedures.
      • Simkens L.H.
      • van Tinteren H.
      • May A.
      • et al.
      Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.
      The duration of the induction therapy was limited to 4 to 6 months. If locoregional treatments were not pursuable, de-intensifying the treatment to maintenance with fluoropyrimidine and the biologic agent used during induction is generally recommended. However, because the actual benefit of maintenance with fluoropyrimidine and bevacizumab as compared with treatment holiday is modest,
      • Stein A.
      • Schwenke C.
      • Folprecht G.
      • Arnold D.
      Effect of application and intensity of bevacizumab-based maintenance after induction chemotherapy with bevacizumab for metastatic colorectal cancer: a meta-analysis.
      whereas bevacizumab alone does not provide any advantage,
      • Aparicio T.
      • Ghiringhelli F.
      • Boige V.
      • et al.
      PRODIGE 9 Investigators
      Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9).
      we suggested treatment breaks as a reasonable clinical option. With regard to anti-EGFRs, although continuing 5-fluorouracil with panitumumab improves PFS when compared with panitumumab alone,
      • Pietrantonio F.
      • Morano F.
      • Corallo S.
      • et al.
      Maintenance therapy with panitumumab alone vs panitumumab plus fluorouracil-leucovorin in patients with RAS wild-type metastatic colorectal cancer: a phase 2 randomized clinical trial.
      the magnitude of benefit from maintenance as compared with treatment holiday has not been assessed yet. In general, in an effort to adequately assess the cost/effectiveness balance of each treatment choice, the opportunity to administer maintenance therapies was limited to patients with high tumor burden (when a rapid disease progression may deeply impair subsequent chances of therapy) and/or those who experienced objective response rather than disease stabilization in previous disease assessments.
      With regard to second-line chemotherapy, minimizing toxicity was our primary aim, given the outbreak situation. As a consequence, if the inhibition of angiogenesis beyond progression was the preferred strategy, bevacizumab was chosen over aflibercept and ramucirumab owing to the increased incidence of gastrointestinal and hematologic chemotherapy-related adverse events observed with aflibercept
      • Van Cutsem E.
      • Tabernero J.
      • Lakomy R.
      • et al.
      Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.
      and the higher occurrence of neutropenia with ramucirumab.
      • Tabernero J.
      • Yoshino T.
      • Cohn A.L.
      • et al.
      RAISE Study Investigators
      Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
      In patients bearing BRAF V600E-mutated tumors, the combination of cetuximab and encorafenib was considered a valid option with manageable toxicity profile in the second and third line, based on results of the phase III BEACON trial.
      • Kopetz S.
      • Grothey A.
      • Yaeger R.
      • et al.
      Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer.
      Though in the absence of data in this specific setting, the bi-weekly schedule of cetuximab appears safe and therefore preferable.
      Finally, in the patients who were chemorefractory, we carefully evaluated the option of best supportive care based on the assessment of individual patients’ life expectancy
      • Pietrantonio F.
      • Miceli R.
      • Rimassa L.
      • et al.
      Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the colon life nomogram.
      and comorbidities. Two guideline-recommended third-line oral therapies are available: the multikinase inhibitor regorafenib is associated with fatigue, hand and foot skin reaction, skin rash, hypertension, and aspartate aminotransferase/alanine aminotransferase elevation as the most frequent adverse events, whereas neutropenia and anaemia more frequently occur with the novel fluoropyrimidine trifluridine/tipiracil. Therefore, though the safety profile of trifluridine/tipiracil seems to affect patients’ quality of life much less than regorafenib and thus its use is more frequently favored, in the frame of the COVID-19 outbreak, avoiding neutropenia and its consequences was regarded as of paramount importance, thus leading to widen the potential indications for the use of regorafenib. The registrative schedule (160 mg/daily 3 weeks on/1 week off) was not recommended, although other schedules of dose escalation, developed to reduce the toxicity burden, were implemented.
      • Bekaii-Saab T.S.
      • Ou F.S.
      • Ahn D.H.
      • et al.
      Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.
      Out of the frame of clinical trials, therapies supported by low levels of evidence (ie, anti-EGFR rechallenge or chemotherapy reintroduction, anti-HER2 strategies, alkylating agents in MGMT methylated tumors) were not administered.

      Anal Cancer

      Concomitant chemoradiation using 5-fluorouracil plus mitomycin is the standard approach for most patients with localized anal squamous cell carcinoma (ASCC) and is able to achieve long-term disease cure in up to 82% of patients. Even if randomized trials showed the superiority of chemoradiation over radiotherapy alone in terms of disease-free survival, local control, and colostomy-free survival, no OS differences were observed.
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      Thus, we considered radiation treatment alone in patients with lower risk of local relapse, such as those with cT1-2N0 disease. For patients with locally advanced disease, we weighed up the use of oral capecitabine as a radiosensitizer as a reasonable treatment alternative to infusional 5-fluorouracil.
      • Oliveira S.C.
      • Moniz C.M.
      • Riechelmann R.
      • et al.
      Phase II study of capecitabine in substitution of 5-FU in the chemoradiotherapy regimen for patients with localized squamous cell carcinoma of the anal canal.
      Finally, HIV-associated patients with ASCC are at higher risk of developing toxicities from chemoradiotherapy,
      • Oehler-Janne C.
      • Huguet F.
      • Provencher S.
      • et al.
      HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy.
      and, due to their comorbidities, have augmented risk of severe COVID-19. Hence, we carefully assessed a de-escalation of anticancer treatment in this peculiar and frail patient category, whereas patients not able to receive effective highly active antiretroviral therapy (HAART) or those with CD4+ cell counts less than 200/μL were treated with radiotherapy alone.
      In the setting of metastatic disease, the combination of cisplatin plus 5-fluorouracil is regarded as the treatment of choice.
      • Ajani J.A.
      • Carrasco C.H.
      • Jackson D.E.
      • Wallace S.
      Combination of cisplatin plus fluoropyrimidine chemotherapy effective against liver metastases from carcinoma of the anal canal.
      Nevertheless, the recent phase II InterAACT randomized trial of cisplatin plus 5-fluorouracil versus reduced-dose carboplatin plus weekly paclitaxel showed superior survival outcomes and reduced treatment-related toxicity in favor of the experimental arm.
      • Rao S.
      • Scafani F.
      • Eng C.
      • et al.
      InterAACT: a multicentre open label randomised phase II advanced anal cancer trial of cisplatin (CDDP) plus 5-fluorouracil (5-FU) vs carboplatin (C) plus weekly paclitaxel (P) in patients (pts) with inoperable locally recurrent (ILR) or metastatic treatment naïve disease - An International Rare Cancers Initiative (IRCI) trial.
      Based on these data, the combination of carboplatin/paclitaxel has entered the clinical practice and was recommended at our hospital.

      Gastroenteropancreatic Neuroendocrine Neoplasms

      We recommended the use of somatostatin analogues (SSAs) as one of the mainstay treatments of well-differentiated gastoenteropancreatic neuroendocrine tumors (NETs).
      • Garcia-Carbonero R.
      • Sorbye H.
      • Baudin E.
      • et al.
      Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas.
      Both octreotide and lanreotide have very low toxicity and may be administered at patients’ homes. Notably, because lanreotide does not require reconstitution, it can be injected by a trained individual (either the patient or a trusted “partner”) without concern of variability in drug preparation. High-dose SSAs were used after progression on standard doses. For small intestinal NETs, we recommended the standard second-line treatment with peptide receptor radionuclide therapy (PRRT) only after a careful patients' selection based on high 68Ga-DOTATATE-PET-TC uptake, high tumor burden, or the presence of tumor-related symptoms, adequate bone marrow function, young age, and good ECOG PS. Of note, severe lymphopenia occurred in less than 10% of patients in the pivotal phase III study, and PRRT requires a short hospitalization every 8 weeks.
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      NETTER-1 Trial Investigators
      Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors.
      In patients with advanced progressive G1-2 pancreatic NETs (pNETs), we chose to administer further therapy in case of symptomatic progression and to prefer sunitinib over everolimus due to the lower risk of immune suppression and interstitial pneumonia.
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • et al.
      RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ,
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      For patients with advanced poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (NEC G3-4), etoposide-platinum combinations are the most commonly used upfront regimens and are able to achieve high tumor response rates (30%-50%)
      • Garcia-Carbonero R.
      • Sorbye H.
      • Baudin E.
      • et al.
      Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas.
      ,
      • Sorbye H.
      • Welin S.
      • Langer S.W.
      • et al.
      Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.
      and potential symptom relief. Although the quality of the available evidence is relatively low, the Nordic NEC trial did not show differences in terms of efficacy between cisplatin- versus carboplatin-based regimens. Therefore, we chose the short infusion of carboplatin plus 3 days of oral etoposide with granulocyte-stimulating factor support for up to 4 to 6 cycles. Second-line chemotherapy after platinum-containing regimens has not been established nor compared with best supportive care. Even if oxaliplatin- and irinotecan-based doublets showed some activity, temozolomide-based regimens showed a promising response rate.
      • Welin S.
      • Sorbye H.
      • Sebjornsen S.
      • et al.
      Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy.
      • Hadoux J.
      • Malka D.
      • Planchard D.
      • et al.
      Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma.
      • Hentic O.
      • Hammel P.
      • Couvelard A.
      • et al.
      FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3.
      Therefore, we chose CAPTEM (capecitabine plus temozolomide) as our reference second-line regimen to be adopted for fit patients with chemosensitive disease, thanks to its 4-weekly schedule and fully oral administration.

      Microsatellite Instability-high Advanced Solid Tumors

      “Universal” MSI testing was performed for all patients with advanced gastrointestinal adenocarcinomas, and, after failure of at least 1 prior treatment line, those with MSI-high cancers were treated as early as possible with off-label use of immune checkpoint inhibitors.
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      Our treatment of choice was the 6-weekly schedule of pembrolizumab at the flat dose of 400 mg, which was recently approved by the United States Food and Drug Administration (FDA) for several indications.
      • Lala M.
      • Li M.
      • Sinha V.
      • et al.
      A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.

      Pharmacogenetic Testing

      Pharmacogenetic testing for DYPD and UGT1A1 genotypes was recommended in all patients to personalize the starting dose of fluoropyrimidines and irinotecan, respectively, thus reducing the risk of hematologic and gastrointestinal toxicities.
      • Falvella F.S.
      • Cheli S.
      • Martinetti A.
      • et al.
      DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.

      Maintenance of Central Venous Catheters

      Routine maintenance of central venous catheters (CVCs), as well as the potential complication of such devices, are among the most common reasons for hospital accesses, particularly for patients with gastrointestinal cancers. Even if the standard schedule recommended by several guidelines is a 4-week locking with saline solution plus or minus heparin, delayed schedules (every 8 or 12 weeks) did not increase the risk of complications in 2 studies.
      • Diaz J.A.
      • Rai S.N.
      • Wu X.
      • Chao J.H.
      • Dias A.J.
      • Kloecker G.H.
      Phase II trial on extending the maintenance flushing interval of implanted ports.
      ,
      • Solinas G.
      • Platini F.
      • Trivellato M.
      • Rigo C.
      • Alabiso O.
      • Galetto A.S.
      Port in oncology practice: 3-monthly locking with normal saline for catheter maintenance, a preliminary report.
      Based on these data, despite the absence of randomised trials, the delayed schedule of CVCs maintenance was recommended at our hospital.

      Thromboprophylaxis

      COVID-19 has been associated with a hypercoagulable state due to cytokine release syndrome,
      • Guo T.
      • Fan Y.
      • Chen M.
      • et al.
      Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020 Mar 27;e201017.
      together with prolonged bed rest and invasive ventilation, which may result in a higher risk of thromboembolic events and disseminated intravascular coagulation. Treatment with low molecular weight heparin (LWMH), namely enoxaparin administered at therapeutic dosages (1 mg/kg twice a day), has shown initial evidence of reducing mortality in hospitalized patients with COVID-19 and is recommended as a support treatment in these cases.
      Also, it is well-recognized that patients with cancer are at major risk of thromboembolic events.
      • Ay C.
      • Pabinger I.
      • Cohen A.T.
      Cancer-associated venous thromboembolism: burden, mechanisms, and management.
      Of note, patients with gastrointestinal malignancies, especially advanced gastric and pancreatic cancers, are at the highest risk, so that thromboprophylaxis is almost universally recommended in these patients when an anticancer treatment is initiated.
      Given these considerations, we recommended proper thromboprophylaxis for patients with advanced gastrointestinal cancers. As these patients are also at higher risk for bleeding complications,
      • Kraaijpoel N.
      • Di Nisio M.
      • Mulder F.I.
      • et al.
      Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE cancer study.
      LMWH should be considered as the preferred agent over direct oral anticoagulants in this phase.

      Conclusions

      The current COVID-19 pandemic represents an unprecedented challenge to our health care systems. As the Gastrointestinal Oncology Unit of a referral comprehensive cancer center, we were faced with the need of changing our day-by-day clinical practice to cope with the pandemic. Our adaption of standard-of-care treatment regimens was guided mainly by 2 needs: (1) to minimize the number of hospital visits and hospitalizations, and (2) to prevent anticancer treatment-induced complications of COVID-19. COVID-19 created a reality where we needed to decide almost immediately on what is important and what is of less importance, instead of making very careful decisions based on large trials and thoughtful discussions as we, like most oncologists, are used to doing. Therefore, even if we tried to set up a rigorous method, inevitably, most measures are based on educated assumptions and expert opinions, influenced or supported by extrapolated information.
      Despite their limits, we hope that our guidelines might be of interest for gastrointestinal oncologists who are now beginning to face the outbreak all over the world.

      Disclosure

      F.Pi. received honoraria for speaker activities and participation in advisory boards from Sanofi SA, Amgen, Inc, Bayer AG, Merck-Serono, Roche, and Servier Laboratories. F.M. received honoraria from Servier Laboratories. M.N. received honoraria from EMD Serono. C.C. received honoraria for speaker activities and participation in advisory boards from Roche, Amgen, Inc, Bayer AG, and Servier Laboratories and research grants from Merck-Serono . S.P. received honoraria from Ipsen, Novartis, AAA, Pfizer, Italfarmaco. F.d.B. received honoraria for speaker activities and participation in advisory boards from Amgen, Inc, Roche, and Novartis International AG, EMD Serono. M.D.B. received honoraria for speaker activities and participation in advisory boards from Amgen, Inc, Roche, Eli Lilly and Company, Servier Laboratories. Incyte Corp, and Celgene Corporation. All other authors state that they have no conflicts of interest.

      References

      1. Ministero della Salute. Novel coronaviris.
        (Available at:)
        • Yu J.
        • Ouyang W.
        • Chua M.L.K.
        • Xie C.
        SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China.JAMA Oncol 2020 Mar 25;e200980.
        (Online ahead of print)
        • Liang W.
        • Guan W.
        • Chen R.
        • et al.
        Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
        Lancet Oncol. 2020; 21: 335-337
        • Wang D.
        • Hu B.
        • Hu C.
        • et al.
        Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
        JAMA. 2020; 323: 1061-1069
        • National Institute for Health Care and Excellence
        Coronavirus (COVID-19).
        (Available at:)
        https://www.nice.org.uk/guidance/ng161
        Date accessed: April 3, 2020
        • Hanna T.P.
        • Evans G.A.
        • Booth C.M.
        Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic.
        Nat Rev Clin Oncol. 2020; 17: 268-270
        • Pietrantonio F.
        • Miceli R.
        • Raimondi A.
        • et al.
        Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer.
        J Clin Oncol. 2019; 37: 3392-3400
        • Al-Batran S.E.
        • Homann N.
        • Pauligk C.
        • et al.
        • FLOT4-AIO Investigators
        Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
        Lancet. 2019; 393: 1948-1957
        • Kattan M.W.
        • Karpeh M.S.
        • Mazumdar M.
        • Brennan M.F.
        Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma.
        J Clin Oncol. 2003; 21: 3647-3650
        • Noh S.H.
        • Park S.R.
        • Yang H.K.
        • et al.
        • CLASSIC trial investigators
        Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.
        Lancet Oncol. 2014; 15: 1389-1396
        • Cunningham D.
        • Starling N.
        • Rao S.
        • et al.
        • Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom
        Capecitabine and oxaliplatin for advanced esophagogastric cancer.
        N Engl J Med. 2008; 358: 36-46
        • Al-Batran S.E.
        • Hartmann J.T.
        • Probst S.
        • et al.
        • Arbeitsgemeinschaft Internistische Onkologie
        Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie.
        J Clin Oncol. 2008; 26: 1435-1442
        • Wagner A.D.
        • Syn N.L.
        • Moehler M.
        • et al.
        Chemotherapy for advanced gastric cancer.
        Cochrane Database Syst Rev. 2017; 8: CD004064
        • Bang Y.J.
        • Van Cutsem E.
        • Feyereislova A.
        • et al.
        • ToGA Trial Investigators
        Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
        Lancet. 2010; 376: 687-697
        • Rivera F.
        • Romero C.
        • Jimenez-Fonseca P.
        • et al.
        Phase II study to evaluate the efficacy of trastuzumab in combination with capecitabine and oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial.
        Cancer Chemother Pharmacol. 2019; 83: 1175-1181
        • Ryu M.H.
        • Yoo C.
        • Kim J.G.
        • et al.
        Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer.
        Eur J Cancer. 2015; 51: 482-488
        • Ford H.E.
        • Marshall A.
        • Bridgewater J.A.
        • et al.
        • COUGAR-02 Investigators
        Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial.
        Lancet Oncol. 2014; 15: 78-86
        • Fuchs C.S.
        • Moore M.R.
        • Harker G.
        • Villa L.
        • Rinaldi D.
        • Hecht J.R.
        Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer.
        J Clin Oncol. 2003; 21: 807-814
        • Thuss-Patience P.C.
        • Kretzschmar A.
        • Bichev D.
        • et al.
        Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
        Eur J Cancer. 2011; 47: 2306-2314
        • Pietrantonio F.
        • Barretta F.
        • Fanotto V.
        • et al.
        Estimating survival probabilities of advanced gastric cancer patients in the second-line setting: the gastric life nomogram.
        Oncology. 2018; 95: 344-352
        • Catalano V.
        • Graziano F.
        • Santini D.
        • et al.
        Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?.
        Br J Cancer. 2008; 99: 1402-1407
        • Wilke H.
        • Muro K.
        • Van Cutsem E.
        • et al.
        • RAINBOW Study Group
        Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
        Lancet Oncol. 2014; 15: 1224-1235
        • Rogers J.E.
        • Xiao L.
        • Amlashi F.G.
        • et al.
        Ramucirumab and paclitaxel administered every 2 weeks (mRAINBOW Regimen) in advanced gastroesophageal adenocarcinoma.
        Oncology. 2019; 96: 252-258
        • Conroy T.
        • Hammel P.
        • Hebbar M.
        • et al.
        • Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group
        FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer.
        N Engl J Med. 2018; 379: 2395-2406
        • Conroy T.
        • Desseigne F.
        • Ychou M.
        • et al.
        • Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825
        • Von Hoff D.D.
        • Ervin T.
        • Arena F.P.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703
        • Pusceddu S.
        • Ghidini M.
        • Torchio M.
        • et al.
        Comparative effectiveness of gemcitabine plus nab-paclitaxel and FOLFIRINOX in the first-line setting of metastatic pancreatic cancer: a systematic review and meta-analysis.
        Cancers (Basel). 2019; 11: 484
        • Kokkali S.
        • Drizou M.
        • Tripodaki E.
        • et al.
        Updated results of biweekly gemcitabine/nab-paclitaxel as first-line treatment for advanced pancreatic cancer.
        Ann Oncol. 2018; 29: v39
        • Rogers J.E.
        • Mizrahi J.D.
        • Shroff R.T.
        • et al.
        Dose-modified gemcitabine plus nab-paclitaxel front-line in advanced pancreatic ductal adenocarcinoma with baseline hyperbilirubinemia.
        J Gastrointest Oncol. 2020; 11: 55-60
        • Tong H.
        • Fan Z.
        • Liu B.
        • Lu T.
        The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis.
        Sci Rep. 2018; 8: 8666
        • Pelzer U.
        • Schwaner I.
        • Stieler J.
        • et al.
        Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.
        Eur J Cancer. 2011; 47: 1676-1681
        • Wang-Gillam A.
        • Li C.P.
        • Bodoky G.
        • et al.
        • NAPOLI-1 Study Group
        Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.
        Lancet. 2016; 387: 545-557
        • Gill S.
        • Ko Y.J.
        • Cripps C.
        • et al.
        PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy.
        J Clin Oncol. 2016; 34: 3914-3920
        • Primrose J.N.
        • Fox R.P.
        • Palmer D.H.
        • et al.
        • BILCAP study group
        Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
        Lancet Oncol. 2019; 20: 663-673
        • Valle J.
        • Wasan H.
        • Palmer D.H.
        • et al.
        • ABC-02 Trial Investigators
        Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
        N Engl J Med. 2010; 362: 1273-1281
        • Li J.
        • Merl M.
        • Lee M.X.
        • Kaley K.
        • Saif M.W.
        Safety and efficacy of single-day GemOx regimen in patients with pancreatobiliary cancer: a single institution experience.
        Expert Opin Drug Saf. 2010; 9: 207-213
        • Kim S.T.
        • Kang J.H.
        • Lee J.
        • et al.
        Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.
        Ann Oncol. 2019; 30: 788-795
        • Hyder O.
        • Marsh J.W.
        • Salem R.
        • et al.
        Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis.
        Ann Surg Oncol. 2013; 20: 3779-3786
        • Lamarca A.
        • Hubner R.A.
        • David Ryder W.
        • Valle J.W.
        Second-line chemotherapy in advanced biliary cancer: a systematic review.
        Ann Oncol. 2014; 25: 2328-2338
        • Lowery M.A.
        • Burris 3rd, H.A.
        • Janku F.
        • et al.
        Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study.
        Lancet Gastroenterol Hepatol. 2019; 4: 711-720
        • Mazzaferro V.
        • El-Rayes B.F.
        • Droz Dit Busset M.
        • et al.
        Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
        Br J Cancer. 2019; 120: 165-171
        • Kudo M.
        • Finn R.S.
        • Qin S.
        • et al.
        Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
        Lancet. 2018; 391: 1163-1173
        • Abou-Alfa G.K.
        • Meyer T.
        • Cheng A.L.
        • et al.
        Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
        N Engl J Med. 2018; 379: 54-63
        • Bruix J.
        • Qin S.
        • Merle P.
        • et al.
        • RESORCE Investigators
        Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 389: 56-66
        • Grothey A.
        • Sobrero A.F.
        • Shields A.F.
        • et al.
        Duration of adjuvant chemotherapy for stage III colon cancer.
        N Engl J Med. 2018; 378: 1177-1188
        • Cremolini C.
        • Antoniotti C.
        • Lonardi S.
        • et al.
        Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial.
        JAMA Oncol. 2018; 4: 529-536
        • Cremolini C.
        • Antoniotti C.
        • Rossini D.
        • et al.
        • GONO Foundation Investigators
        Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.
        Lancet Oncol. 2020; 21: 497-507
        • Marmorino F.
        • Rossini D.
        • Lonardi S.
        • et al.
        Impact of age and gender on the safety and efficacy of chemotherapy plus bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies.
        Ann Oncol. 2019; 30: 1969-1977
        • Simkens L.H.
        • van Tinteren H.
        • May A.
        • et al.
        Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.
        Lancet. 2015; 385: 1843-1852
        • Stein A.
        • Schwenke C.
        • Folprecht G.
        • Arnold D.
        Effect of application and intensity of bevacizumab-based maintenance after induction chemotherapy with bevacizumab for metastatic colorectal cancer: a meta-analysis.
        Clin Colorectal Cancer. 2016; 15: e29-e39
        • Aparicio T.
        • Ghiringhelli F.
        • Boige V.
        • et al.
        • PRODIGE 9 Investigators
        Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9).
        J Clin Oncol. 2018; 36: 674-681
        • Pietrantonio F.
        • Morano F.
        • Corallo S.
        • et al.
        Maintenance therapy with panitumumab alone vs panitumumab plus fluorouracil-leucovorin in patients with RAS wild-type metastatic colorectal cancer: a phase 2 randomized clinical trial.
        JAMA Oncol. 2019; 5: 1268-1275
        • Van Cutsem E.
        • Tabernero J.
        • Lakomy R.
        • et al.
        Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.
        J Clin Oncol. 2012; 30: 3499-3506
        • Tabernero J.
        • Yoshino T.
        • Cohn A.L.
        • et al.
        • RAISE Study Investigators
        Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
        Lancet Oncol. 2015; 16: 499-508
        • Kopetz S.
        • Grothey A.
        • Yaeger R.
        • et al.
        Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer.
        N Engl J Med. 2019; 381: 1632-1643
        • Pietrantonio F.
        • Miceli R.
        • Rimassa L.
        • et al.
        Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the colon life nomogram.
        Ann Oncol. 2017; 28: 555-561
        • Bekaii-Saab T.S.
        • Ou F.S.
        • Ahn D.H.
        • et al.
        Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.
        Lancet Oncol. 2019; 20: 1070-1082
        • Bartelink H.
        • Roelofsen F.
        • Eschwege F.
        • et al.
        Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
        J Clin Oncol. 1997; 15: 2040-2049
        • Oliveira S.C.
        • Moniz C.M.
        • Riechelmann R.
        • et al.
        Phase II study of capecitabine in substitution of 5-FU in the chemoradiotherapy regimen for patients with localized squamous cell carcinoma of the anal canal.
        J Gastrointest Cancer. 2016; 47: 75-81
        • Oehler-Janne C.
        • Huguet F.
        • Provencher S.
        • et al.
        HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy.
        J Clin Oncol. 2008; 26: 2550-2557
        • Ajani J.A.
        • Carrasco C.H.
        • Jackson D.E.
        • Wallace S.
        Combination of cisplatin plus fluoropyrimidine chemotherapy effective against liver metastases from carcinoma of the anal canal.
        Am J Med. 1989; 87: 221-224
        • Rao S.
        • Scafani F.
        • Eng C.
        • et al.
        InterAACT: a multicentre open label randomised phase II advanced anal cancer trial of cisplatin (CDDP) plus 5-fluorouracil (5-FU) vs carboplatin (C) plus weekly paclitaxel (P) in patients (pts) with inoperable locally recurrent (ILR) or metastatic treatment naïve disease - An International Rare Cancers Initiative (IRCI) trial.
        Ann Oncol. 2018; 29: 715-716
        • Garcia-Carbonero R.
        • Sorbye H.
        • Baudin E.
        • et al.
        Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas.
        Neuroendocrinology. 2016; 103: 186-194
        • Strosberg J.
        • El-Haddad G.
        • Wolin E.
        • et al.
        • NETTER-1 Trial Investigators
        Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors.
        N Engl J Med. 2017; 376: 125-135
        • Yao J.C.
        • Shah M.H.
        • Ito T.
        • et al.
        • RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group
        Everolimus for advanced pancreatic neuroendocrine tumors.
        N Engl J Med. 2011; 364: 514-523
        • Raymond E.
        • Dahan L.
        • Raoul J.L.
        • et al.
        Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
        N Engl J Med. 2011; 364: 501-513
        • Sorbye H.
        • Welin S.
        • Langer S.W.
        • et al.
        Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.
        Ann Oncol. 2013; 24: 152-160
        • Welin S.
        • Sorbye H.
        • Sebjornsen S.
        • et al.
        Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy.
        Cancer. 2011; 117: 4617-4622
        • Hadoux J.
        • Malka D.
        • Planchard D.
        • et al.
        Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma.
        Endocr Relat Cancer. 2015; 22: 289-298
        • Hentic O.
        • Hammel P.
        • Couvelard A.
        • et al.
        FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3.
        Endocr Relat Cancer. 2012; 19: 751-757
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Lala M.
        • Li M.
        • Sinha V.
        • et al.
        A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.
        J Clin Oncol. 2018; 36: 3062
        • Falvella F.S.
        • Cheli S.
        • Martinetti A.
        • et al.
        DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
        Br J Clin Pharmacol. 2015; 80: 581-588
        • Diaz J.A.
        • Rai S.N.
        • Wu X.
        • Chao J.H.
        • Dias A.J.
        • Kloecker G.H.
        Phase II trial on extending the maintenance flushing interval of implanted ports.
        J Oncol Pract. 2017; 13: e22-e28
        • Solinas G.
        • Platini F.
        • Trivellato M.
        • Rigo C.
        • Alabiso O.
        • Galetto A.S.
        Port in oncology practice: 3-monthly locking with normal saline for catheter maintenance, a preliminary report.
        J Vasc Access. 2017; 18: 325-327
        • Guo T.
        • Fan Y.
        • Chen M.
        • et al.
        Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020 Mar 27;e201017.
        (Online ahead of print)
        • Ay C.
        • Pabinger I.
        • Cohen A.T.
        Cancer-associated venous thromboembolism: burden, mechanisms, and management.
        Thromb Haemost. 2017; 117: 219-230
        • Kraaijpoel N.
        • Di Nisio M.
        • Mulder F.I.
        • et al.
        Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE cancer study.
        Thromb Haemost. 2018; 118: 1439-1449