key: cord-1042839-fa75uczx
authors: Pietrantonio, F.; Morano, F.; Niger, M.; Corallo, S.; Antista, M.; Raimondi, A.; Prisciandaro, M.; Pagani, F.; Prinzi, N.; Nichetti, F.; Randon, G.; Torchio, M.; Corti, F.; Ambrosini, M.; Palermo, F.; Palazzo, M.; Biamonte, L.; Platania, M.; Sposito, C.; Cosimelli, M.; Mazzaferro, V.; Pusceddu, S.; Cremolini, C.; de Braud, F.; Di Bartolomeo, M.
title: Systemic treatment of patients with gastrointestinal cancers during the COVID-19 outbreak: COVID-19-adapted recommendations of the National Cancer Institute of Milan
date: 2020-05-23
journal: Clin Colorectal Cancer
DOI: 10.1016/j.clcc.2020.05.004
sha: b01d8cb595096365d708e521b70353a7d3ddcbba
doc_id: 1042839
cord_uid: fa75uczx

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak poses a major challenge in the treatment decision making of cancer patients, who may be at higher risk of developing a severe and deadly SARS-CoV-2 infection compared to the general population. The healthcare emergency is forcing to reshape 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 epicentre 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.

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 of coronavirus disease 2019 (COVID- 19) and 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 th , Italian authorities reported 124632 SARS-CoV2 confirmed cases and 15362 deaths, thus representing the highest number of COVID-19-related deaths in the world.

[1]

A Chinese single-Institution cohort study showed that cancer patients may be at higher risk of SARS-CoV-2 infection compared to the general population [2] 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. [3] Additionally, since nosocomial transmission was identified in up to 41.3% of hospitalized patients, [4] hospital admissions or repeated clinic visits clearly represent a crucial source of contagion. On top of their disease, cancer patients face several treads related to their frequent hospital accesses, presence of cancer-and treatment-related immune-suppression and co-existing comorbidities.

The risk of hospital transmission of SARS-CoV-2 may be reduced thanks to screening of patients and staff and by minimising face-to-face interactions.

[5] Furthermore, Hanna et al. provided a general framework to prioritise 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. [6] 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 centre located in Lombardy region, which accounts by itself more than half of COVID-19-related deaths in Italy so far. In February 2020, INT faced the challenge of profoundly re-organizing its daily routine and procedures at an unprecedented pace to maintain its cancer patients 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 COVID-19 outbreak, with the aim of providing useful recommendations for physicians that are facing the same challenges worldwide.

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 minimise the potential bias related to physician's stress condition and burnout.

Treatment decisions were discussed on individual basis and, whenever necessary, multidisciplinary meetings were held as routinely via video or call conference. Phone screening surveying patient's conditions, symptoms, latest radiological evaluation and contact with potential infected subjects was carried out on a daily basis. 

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 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. [7] Based on multidisciplinary team assessment, preoperative chemotherapy was recommended only for patients with age <70 years old and resectable high-risk disease. Oxaliplatin-based doublets were the treatment of choice for patients with node-positive disease assessed by both FDG-PET/TC scan and endoscopic ultrasonography, and for selected patients with cT3N0 tumours with adverse prognostic features (i.e. diffuse histotype) or technical risks of incomplete resection (i.e. gastroesophageal junction cancers). FLOT triplet chemotherapy, which is associated with increased survival at the cost of a higher risk of toxicity, [8] Several studies demonstrated the non-inferiority of oxaliplatin compared to cisplatin as part 6 of combination regimens. [11, 12] Therefore, the choice of CAPOX regimen was preferred over FOLFOX thanks to its three-weekly schedule and the oral administration of fluoropyrimidine, with no need for infusion pumps and central venous catheters. [11] [12] [13] 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-randomised 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. [14] [15] [16] 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-VEGFR-2 monoclonal antibody ramucirumab represent evidence-based second-line treatment options, [17] [18] [19] the absolute survival benefit is quite limited and should be carefully evaluated based on the relevant toxicity risk and individual patients' life expectancy. [20] The optimal candidates for second-line therapy may be identified based on ECOG PS, tumour response to first-line treatment and a first-line treatment-free interval of at least 3 months [21] . Noteworthy, the combination of weekly paclitaxel and ramucirumab achieved an unprecedented median overall survival (OS) [22] 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/sqm plus ramucirumab 8 mg/Kg every 2 weeks) as our standard according to the MD Anderson study. [23] Whenever ramucirumab was contraindicated or not available, second-line chemotherapy consisted of three-weekly courses of docetaxel or irinotecan (provided pharmacogenomic testing results were available).

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 post-operative treatments, given the survival advantage of adjuvant mFOLFIRINOX [24] , this triplet regimen was recommended only for patients with ECOG PS 0 and age <70 years -a more selected patients' population compared to 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 PAD is concerned, the two standard first-line regimens are standard-dose FOLFIRINOX [25] and nab-paclitaxel plus gemcitabine. [26] Even in absence of randomised comparison between the two options, the toxicity profile of the triplet regimen is clearly worst [27] and may represents 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. [28, 29] When the triplet was deemed necessary (i.e. 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/sqm and omission of the 5fluorouracil bolus), due to better tolerability. [30] 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 [31] [32] [33] . 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 performance status and chemosensitive disease.

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. [34] However, this study was criticised 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 a) delay treatment start as much as possible, giving the patient time to fully recover from surgery and b) discuss each case according to the riskbenefit profile with regard to performance status, age, comorbidities and patients' preferences.

As far as metastatic or unresectable disease is concerned, the standard initial treatment for patients with a good performance status is the combination of cisplatin and gemcitabine, that achieved superior OS compared to gemcitabine alone. [35] However, the schedule of the The gemcitabine-based GEMOX regimen is considered a reasonable alternative and safer option, also when considering single-day courses given every two weeks. [36] Furthermore, CAPOX was non-inferior to GEMOX in terms of 6-months PFS rate in a recent phase III trial, with a better toxicity profile and less frequent hospital visits. [37] Therefore, CAPOX was recommended as the first-line treatment of choice for ECOG PS 0-1 patients with metastatic or unresectable BTC. For patients with liver-limited unresectable disease, we discussed in a multidisciplinary setting the chance for locoregional therapy (e.g. yttrium-90 radioembolization), when feasible. [38] 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. [39] For IDH1 mutated or FGFR2 translocated intrahepatic cholangiocarcinoma, patients' access to orally administered selective inhibitors was recommended, whenever feasible. [40, 41] For patients with advanced and unresectable hepatocellular carcinoma (HCC), oral treatments were prescribed via web-based telemedicine and continued until symptomatic deterioration or radiological progression, whichever occurred first. The tyrosine kinase inhibitors sorafenib or lenvatinib [42] 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 [43] or regorafenib [44] was recommended only in highly selected patients with good prognostic features. Enrollment in clinical trials with immunotherapy agents was discouraged.

For patients undergoing adjuvant treatment for colon cancer, three-weekly capecitabinebased 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 tumours), the limitation of treatment duration to 3 months was highly recommended in stage III low-risk (pT3 and pN1) tumours. [45] 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 tumours 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-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 tumours), it was combined with a 5-fluorouracil-based doublet. In the case of cetuximab, we used the biweekly schedule, now widely adopted in clinical trials and in the daily practice since its equivalent efficacy and safety compared to the weekly schedule. [46] With regard to the choice of the upfront chemotherapy, in fit patients the triplet FOLFOXIRI provides survival benefit as compared with both oxaliplatin-and irinotecan-based doublets at the price of increased gastrointestinal and haematological toxicities. [47] 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 tumour/KRAS mutation and high tumour burden, or whenever conversion to liver surgery was foreseen in borderline resectable liver metastases. Since in patients aged 70-75 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. [48] In order to minimise the risk of neutropenia the use of 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/sqm instead of 3200 mg/sqm) and irinotecan (150 mg/sqm instead of 165 mg/sqm). [46] If an oxaliplatin-based doublet plus bevacizumab was chosen as upfront option, the use of capecitabine instead of 5-fluorouracil was preferred to reduce the frequency of in-hospital infusional procedures. [49] The duration of the induction therapy was limited to 4-6 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, since the actual benefit of maintenance with fluoropyrimidine and bevacizumab as compared to treatment holiday is modest, [50] while bevacizumab alone does not provide any advantage, [51] we suggested treatment breaks as a reasonable clinical option. With regard to anti-EGFRs, while continuing 5-fluorouracil with panitumumab improves PFS when compared with panitumumab alone, [52] 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 tumour 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, minimising 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 chosed over aflibercept and ramucirumab due to the increased incidence of gastrointestinal and haematological chemotherapy-related adverse events observed with aflibercept [53] and the higher occurrence of neutropenia with ramucirumab. [54] In patients bearing BRAF V600E mutated tumours, the combination of cetuximab and encorafenib was considered a valid option with manageable toxicity profile in 2nd-and 3rd-line, based on results of the phase III BEACON trial. [55] Though in the absence of data in this specific setting, the bi-weekly schedule of cetuximab appears safe and therefore preferable.

Finally, in the chemorefractory, we carefully evaluated the option of best supportive care based on the assessment of individual patients' life expectancy [56] and comorbidities. Two guideline-recommended third-line oral therapies are available: the multikinase inhibitor regorafenib is associated with fatigue, hand&foot skin reaction, skin rash, hypertension, and AST/ALT elevation as most frequent adverse events, while 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 therefore its use is more frequently favoured, in the frame of the COVID-19 outbreak, avoiding neutropenia and its consequences was regarded of paramount importance, thus leading to widen the potential indications for the use of regorafenib. The registrative schedule (160 mg 3 weeks on /1 week off) was not recommended while other schedules of dose escalation, developed to reduce the toxicity burden, were implemented. [57] Out of the frame of clinical trials, therapies supported by low levels of evidence (i.e. anti-EGFR rechallenge or chemotherapy reintroduction, anti-HER2 strategies, alkylating agents in MGMT methylated tumours) were not administered.

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 randomised 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. [58] 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. [59] Finally, HIV-associated ASCC patients are at higher risk of developing toxicities from chemoradiotherapy [60] 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 patients' category, whereas patients not able to receive effective 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. [61] 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 favour of the experimental arm. [62] Based on these data, the combination carboplatin/paclitaxel has entered the clinical practice and was recommended at our hospital.

We recommended the use of somatostatin analogues (SSA) as one of the mainstay treatments of well differentiated gastoenteropancreatic neuroendocrine tumors (NETs). [63] Both octreotide and lanreotide have very low toxicity and may be administered at patients' home.

Notably, since 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 SSA were used after progression to 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 68 Ga-DOTATATE-PET-TC uptake, high tumor burden or presence 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. [64] 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. [65, 66] 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%) [63, 67] and potential symptoms 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 short-infusion of carboplatin plus 3-days of oral etoposide with granulocyte-stimulating factors support for up to 4-6 cycles. Second-line chemotherapy after platinum-containing regimens has not been established nor compared to best supportive care. Even if oxaliplatin-and irinotecan-based doublets showed some activity, temozolomide-based regimens showed promising response rate. [68] [69] [70] Therefore, we chose capecitabine plus temozolomide (CAPTEM) as our reference second-line regimen to be adopted for fit patients with chemosensitive disease, thanks to its four-weekly schedule and fully oral administration.

"Universal" MSI testing was performed for all patients with advanced gastrointestinal adenocarcinomas and, after failure of at least one prior treatment line, those with MSI-high cancers were treated as early as possible with off-label use of immune checkpoint inhibitors.

[71] Our treatment of choice was the 6-weekly schedule of pembrolizumab at the flat dose of 400 mg, which was recently approved by the FDA for several indications. [72] 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 haematological and gastrointestinal toxicities. [73] 

Routine maintenance of central venous catheters (CVCs), as well as the potential complication of such devices, are amongst 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 of the risk of complications in two studies. [74, 75] Based on these data, despite the absence of randomised trials, the delayed schedule of CVCs maintenance was recommended at our Hospital.

COVID-19 has been associated with a hypercoagulable state due to cytokines release syndrome, [76] 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 (1mg/kg b.i.d.), 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 cancer patients are at major risk of thromboembolic events. [77] 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, [78] LMWH should be considered as the preferred agent over direct oral anticoagulants in this phase.

The current COVID-19 pandemic represents an unprecedented challenge to our health care systems. As the Gastrointestinal Oncology Unit of a referral comprehensive cancer centre, 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 two needs: (1) to minimise the number of hospital visits and hospitalizations, and (2) 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. 

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Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

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Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy

Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma

FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

Phase II Trial on Extending the Maintenance Flushing Interval of Implanted Ports

Port in oncology practice: 3-monthly locking with normal saline for catheter maintenance, a preliminary report

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Cancer-associated venous thromboembolism: Burden, mechanisms, and management

Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study