Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016

Practice Guideline


Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016


D. Bossé, MD*a, T. Ng, MD*a, C. Ahmad, MD, A. Alfakeeh, MD, I. Alruzug, MD, J. Biagi, MD*, J. Brierley, MB*, P. Chaudhury, MD, S. Cleary, MD*, B. Colwell, MD§, C. Cripps, MD*, L.A. Dawson, MD*, M. Dorreen, MD§, E. Ferland, MD, P. Galiatsatos, MD, S. Girard, MD, S. Gray, MD, F. Halwani, MD*, N. Kopek, MD, A. Mahmud, MD*, G. Martel, MD*, L. Robillard, MD*, B. Samson, MD, M. Seal, MD, J. Siddiqui, MD, L. Sideris, MD, S. Snow, MD§, M. Thirwell, MD, M. Vickers, MD*, R. Goodwin, MD*, R. Goel, MD*, T. Hsu, MD*, E. Tsvetkova, MD*, B. Ward, MD, T. Asmis, MD*


doi: http://dx.doi.org/10.3747/co.23.3394


ABSTRACT

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5–7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics:

  • ■ Follow-up and survivorship of patients with resected colorectal cancer

  • ■ Indications for liver metastasectomy

  • ■ Treatment of oligometastases by stereotactic body radiation therapy

  • ■ Treatment of borderline resectable and unresectable pancreatic cancer

  • ■ Transarterial chemoembolization in hepatocellular carcinoma

  • ■ Infectious complications of antineoplastic agents

KEYWORDS: Guidelines, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, biliary tract carcinoma, stereotactic body radiation therapy, transarterial chemoembolization, oligometastasis, biologic agents, hepatitis B

INTRODUCTION

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5–7 February. The purpose of the conference was to develop consensus statements on emerging and evolving concepts. Participants were Canadian medical oncologists, radiation oncologists, and surgical oncologist from across Ontario, Quebec, and the Atlantic Provinces, plus an invited speaker from Western Canada.

The recommendations proposed here represent the consensus opinions of health care professionals involved in the care of patients with gastrointestinal and hepatopancreatobiliary malignancies.

Basis of Recommendations

The existing scientific evidence was presented and discussed at the meeting. Recommendations were formulated within the group and categorized by level of evidence1 as follows:

  • ■ Level i: Evidence from randomized controlled trials

  • ■ Level ii-1: Evidence from controlled trials without randomization

  • ■ Level ii-2: Evidence from analytic cohorts or case–control studies, preferably from more than one centre or research group

  • ■ Level ii-3: Evidence from comparisons between times or places with and without the intervention (dramatic results in uncontrolled experiments could be included here)

  • ■ Level iii: Opinion of respected authorities, based on clinical experience; descriptive

COLORECTAL CANCER

Question 1

Is there a clinical benefit to follow-up of colorectal cancer patients who have undergone curative surgical resection?

  • ■ There is general consensus and evidence that some form of surveillance will provide a survival benefit to patients who are eligible for curative therapy at the time of recurrence. (Level i)

  • ■ Current evidence suggests that surveillance is cost-effective. (Level ii-2)

  • ■ Survivorship care can be provided by any one or a combination of medical oncologists, radiation oncologists, surgeons, general practitioners, and nurse practitioners. (Level iii)

  • ■ One study demonstrated that there is no difference in outcome between patients followed by oncologists and those followed by general practitioners. (Level ii-2)

  • ■ Emerging literature suggests that alternative follow-up strategies could be appropriate. (Level iii)

Summary of Evidence

A large meta-analysis that included eleven studies and 4055 patients demonstrated a significant improvement in overall survival (os) [hazard ratio (hr): 0.75; 95% confidence interval (ci): 0.66 to 0.86] with intense post-treatment follow-up of patients with stage ii or iii colorectal cancer2. Recurrences were detected 5.23 months earlier on average (95% ci: −9.58 months to −0.88 months) and were more likely to be asymptomatic [relative risk (rr): 2.59; 95% ci: 1.51 to 4.06]; curative surgery was also more likely to be attempted (rr: 1.98; 95% ci: 1.66 to 4.06). Post-recurrence survival favoured intensive monitoring over other strategies (rr: 2.13; 95% ci: 1.24 to 3.69).

A recent randomized controlled trial (rct) suggested that a less-intensive follow-up strategy alternating carcinoembryonic antigen testing and computed tomography could be appropriate3. The large number of protocol deviations in that trial will likely mandate more studies before the strategy is implemented in practice.

Cost-effectiveness of intensive post-treatment follow-up was demonstrated in a cost analysis study from the United Kingdom in 20044. Average cost per patient was £2479 and within the range of cost acceptability in most jurisdictions. Emerging evidence suggests that general practitioner–led post-treatment follow-up programs are equivalent to specialist-led programs5,6.

Question 2

What is the recommended surveillance for stage ii and iii colorectal cancer patients who have completed treatment?

  • ■ We endorse surveillance based on local jurisdiction guidelines such as those from Cancer Care Ontario and the American Society of Clinical Oncology.

  • ■ Individual scenarios about elements of the surveillance program have to be discussed between the patient and the physician. (Level iii)

  • ■ Combined positron-emission tomography and computed tomography (pet-ct) is not recommended for routine surveillance. (Level iii)

Summary of Evidence

Post-treatment surveillance of patients with stage ii or iii colorectal cancer should be performed in accordance with local jurisdiction guidelines such as those from the American Society of Clinical Oncology and Cancer Care Ontario7,8. Most surveillance guidelines recommend a 5-year evaluation calendar, including history, physical examination and carcinoembryonic antigen testing; imaging of abdomen, pelvis, and chest; and colonoscopy. Imaging by pet-ct leads to false-negative and false-positive results and should not be routinely used for surveillance9. Imaging by pet-ct can be considered in the context of rising serum carcinoembryonic antigen and negative ct imaging.

Question 3

What are the key elements of a cancer survivorship program?

  • ■ Ideally, all patients should be offered a comprehensive survivorship program that includes

    • ■ management of late treatment-related side effects;

    • ■ management of psychosocial side effects; and

    • ■ detection and management of late disease recurrence (Level iii).

  • ■ We endorse continued development and evaluation of survivorship programs. (Level iii)

Summary of Evidence

In the absence of high-level evidence, recommendations about survivorship are based on expert opinion and local jurisdiction guidelines (American Society of Clinical Oncology and Cancer Care Ontario, for instance)7,8. Transition to follow-up by a general practitioner or nurse practitioner can be facilitated using a survivorship care plan, which should include a treatment summary and guidance on a surveillance schedule. Patients should be offered education about secondary cancer prevention, as well as screening and management of psychological and physical long-term and late adverse effects from surgery, chemotherapy, and radiation therapy.

LIVER METASTASES

Question 1

What are the criteria for liver metastasectomy for metastatic colorectal cancer?

  • ■ All cases should be discussed at multidisciplinary rounds, which should include medical and radiation oncologists, hepatopancreatobiliary surgeons, and colorectal surgeons. (Level iii)

  • ■ Noncurative-intent treatment for extrahepatic disease remains a contraindication to liver metastasectomy. (Level iii)

  • ■ All liver metastases should be resected, and adequate future liver remnant function should be preserved regardless of the number of lesions. (Level iii)

  • ■ R0 resection should be considered to be achievable in 1 or more operations. (Level iii)

  • ■ Ablation in addition to resection could be used as an adjunct therapy in selected patients in whom resection of all lesions cannot be achieved. (Level iii)

  • ■ The definition of resectable liver metastases continues to evolve. (Level iii)

Summary of Evidence

Resection of liver metastases from colorectal cancer can lead to a 5-year survival rate of up to 50% in selected patients10,11. No level i or ii evidence is available to guide the selection of patients who should be offered liver metastasectomy. Hence, multidisciplinary team evaluation is pivotal in selecting appropriate patients and coordinating the various treatment modalities and management of the primary tumour in patients who present with synchronous metastasis12. Patients considered for liver resection should be those who are candidates for R0 resection and who have adequate future liver remnant function; residual non-pulmonary extrahepatic disease remains a relative contraindication to metastasectomy13. The size and number of metastatic lesions (included in older resectability criteria) should no longer be used in making the determination; the opinion of a hepatobiliary surgeon is warranted for unclear cases.

The feasibility of resection of liver metastases can be improved by decreasing the size of the metastases and increasing the size of the liver remnant. Multimodality therapy, including preoperative chemotherapy and resection combined with radiofrequency ablation, can reduce the extent of liver resection1417; the size of the future liver remnant can be optimized with portal vein embolization and staged liver resections18,19.

Question 2

What is the optimal sequence and timing of interventions?

  • ■ The timing and sequence of chemotherapy, radiation, and surgery remain to be defined and should be determined in multidisciplinary rounds before initiation of treatment. (Level iii)

Summary of Evidence

Given the lack of high-quality data, the ideal timing and sequencing of chemotherapy, radiation therapy, and surgery should be decided by a multidisciplinary team. For patients who present with synchronous liver metastases, the optimal sequence of treatment can vary based on the initial resectability of the liver metastases, the location of the primary tumour (rectum vs. colon), and complications of the primary tumour. Examples of approaches for an asymptomatic primary with resectable liver metastasis would be to treat with chemotherapy first, followed by sequential liver metastasectomy and resection of the primary. For a rectal primary, the timing and sequence of radiation therapy and liver metastasectomy should carefully planned upfront by a multidisciplinary team.

Management of metachronous liver metastases can vary depending on upfront resectability and the time between treatment of the primary and of the metastases. Perioperative chemotherapy for synchronous and metachronous liver metastases did not significantly increase 5-year os in a European Organisation for Research and Treatment of Cancer trial (51% vs. 48%; hr: 0.88; 95% ci: 0.68 to 1.14), but increased the rate of progression-free survival at 3 years in patients undergoing resection (hr: 0.73; 95% ci: 0.55 to 0.97; p = 0.025)10. Hence, upfront liver metastasectomy is often favoured for resectable metachronous metastases, followed by discussion of adjuvant chemotherapy. More studies are needed before recommendations can be made.

OLIGOMETASTASIS

Question 1

What is the role of stereotactic body radiation therapy (sbrt) in the treatment of oligometastases?

  • sbrt refers to high-dose, high-precision external-beam radiotherapy.

  • sbrt is an effective and well-tolerated form of ablation that is continuing to evolve as a local treatment modality in the management of oligometastatic disease. (Level ii-3)

Summary of Evidence

The American Society of Radiation Oncology and American College of Radiology define sbrt as “an external beam radiation therapy method used to precisely deliver a high dose of radiation to an extracranial target, using either a single dose or a small number of fractions”20. Oligometastasis refers to the presence of advanced cancer with limited—for example, 5 or fewer—regional or distant metastases suitable for local targeted intervention, with possible improvement of local control or os21. No randomized trial has assessed the efficacy of sbrt for the treatment of extracranial oligometastases. Case series have reported local control rates in the realm of 80%, with minimal toxicity22,23. Experts agree that sbrt can be used to achieve local control of growing oligometastases or to delay either initiation or modification of systemic treatment (or both) in selected patients. More studies are needed to clarify whether treatment of oligometastatic disease with sbrt translates into a better os.

PANCREATIC CANCER

Question 1

What is the optimal approach to borderline-resectable pancreatic cancer?

  • ■ A multidisciplinary team is crucial to improve outcomes. (Level iii)

  • ■ Patients should be treated in a clinical trial setting where possible. (Level iii)

  • ■ Surgery provides meaningful survival extension and should be provided at a high-volume centre. (Level ii-2)

  • ■ Where possible, disease should be classified and managed according to prospectively established criteria. (Level iii)

  • A priori classification of resectable, borderline-resectable, and locally advanced unresectable pancreatic cancer should be determined by a multidisciplinary team.

Summary of Evidence

Most patients with pancreatic cancer have a poor prognosis regardless of stage and performance status. Based on data from a population-based study that used Ontario cancer registry data from 2004 to 2011, the overall population of patients with pancreatic cancer had a 1-year survival of 23.5% and a 5-year survival of 7.2%24. An older study using data from the U.S. National Cancer Database (1992–1998) showed that survival was poor regardless of stage at diagnosis25.

Multiple retrospective case series and population-based studies have shown that compared with non-resected patients, those with an R0 resection experience significantly better os2628. A small proportion of them are free of disease at 10 years27.

A systematic review of twelve observational studies showed an inverse relation between hospital volume of pancreatic resections and 30-day mortality. In that review, hospitals that performed fewer than 5 pancreatic resections per year had mortality rates between 13.8% and 16.5%; hospitals that performed more than 24 pancreatic resections per year had mortality rates between 0% and 3.5%29. Furthermore, a population-based study using 3 U.S. state databases to identify patients undergoing complex hepatobiliary surgery found that only volume of the procedure of interest was predictive of mortality30.

The U.S. National Cancer Institute clinical trials planning meeting on pancreatic cancer published a consensus statement on the design of pancreatic cancer clinical trials31. Among other things, the statement recommended studying patients with localized unresectable disease separately from those with metastatic disease. In clinical practice, careful multidisciplinary patient selection is required to decide which patients are resectable, borderline-resectable, and locally advanced or unresectable before a treatment decision is taken.

Question 2

What is the role of chemotherapy or chemoradiation in patients with unresectable locally advanced pancreatic cancer (lapc)?

  • ■ Unresectable lapc is treated with palliative intent. (Level iii)

  • ■ Chemotherapy is the only modality of treatment that provides evidence of improved os. (Level i)

  • ■ Use of chemoradiation after initial chemotherapy for locoregional control could be considered. (Level i and ii-2)

  • ■ Best supportive care is a reasonable option for this population, in patients with poor performance status, through shared decision-making between the patient and the physician. (Level iii)

Summary of Evidence

Patients with unresectable lapc generally have a poor prognosis and are treated with palliative intent.

Based on results of multiple rcts, chemotherapy is the only treatment modality seen to improve survival in metastatic pancreatic cancer. For more than a decade, gemcitabine was considered the standard-of-care systemic treatment32,33. In a phase iiirct, folfirinox (fluorouracil–leucovorin–irinotecan–oxaliplatin), compared with gemcitabine, was associated with improved median os in the metastatic setting (11.1 months vs. 6.8 months; hr: 0.57; 95% ci: 0.45 to 0.73; p < 0.001), making it a standard option in patients with good performance status and no contraindications34. Another phase iiirct also demonstrated an improvement in median os using a combination of gemcitabine and nabpaclitaxel compared with gemcitabine alone (8.5 months vs. 6.7 months respectively; hr: 0.72; 95% ci: 0.62 to 0.83; p < 0.001)35.

There is a paucity of evidence on the best approach in the treatment of unresectable lapc. Some experts advocate for treatment with concurrent chemotherapy and radiation therapy because of the local control benefit that radiation therapy might provide. A retrospective analysis of phase ii and iii trials from the Groupe Coopérateur Multidisciplinaire en Oncologie suggested that, compared with maintenance chemotherapy alone, combined-modality chemoradiation in patients who have not progressed after initial induction chemotherapy might improve os36. In patients with lapc who achieved disease control after induction with gemcitabine, a prospective phase iiirct looked at whether, compared with maintenance gemcitabine, chemoradiation (54 Gy and capecitabine 1600 mg/m2 daily) after induction chemotherapy would improve survival37. Overall survival was 16.5 months (95% ci: 15.5 months to 18.5 months) in the chemoradiation arm and 15.3 months (95% ci: 13.9 months to 17.3 months) in the chemotherapy-only arm (hr: 1.03; p = 0.83). Hence, chemotherapy remains the standard of care for the treatment of lapc. Chemoradiation could potentially be considered an option in patients who have stable disease after induction chemotherapy. Randomized trials of modern radiation therapy, such as sbrt, which have shown promise in single-institution series, have been planned and are starting to recruit patients.

Best supportive care alone is a reasonable option in patients who have a poor Eastern Cooperative Oncology Group performance status (3 or 4) or contraindications to chemotherapy, or in patients who decline chemotherapy.

HEPATOBILIARY CANCERS

Question 1

What is the role of sbrt in the treatment of hepatocellular carcinoma (hcc) and biliary tract cancers?

  • ■ Based on studies and case series, there appears to be a role for sbrt in treating Child–Pugh A and selected B7 hcc patients who are not candidates for resection, transplantation, or other locoregional and curative options. (Levels ii-1 and ii-2)

  • ■ In patients who are not suitable for transarterial embolization, chemoembolization, or radiofrequency ablation, sbrt might be considered a bridging therapy to liver transplantation. (Level ii-2)

  • ■ Because of the potential for increased toxicity, radiation concurrent with systemic therapy is not recommended; it is still considered experimental. (Level ii-1)

  • ■ The role of sbrt for biliary tract cancers is still considered experimental.

  • ■ To better define the role of sbrt in hcc and biliary tract cancers, patient enrolment in clinical trials is encouraged. (Level ii-1 and ii-2)

  • ■ In patients who have untreated hepatitis B (hbv), referral for suppressive therapy of hbv before radiation should be strongly considered. (Level ii-2).

Summary of Evidence

Even in early-stage hcc, patients are often ineligible for surgical resection, transplantation, or local ablation because of advanced cirrhosis, donor shortage, or difficult anatomy. There is mounting evidence that sbrt is a safe and effective alternative for such patients. Three retrospective case series (n = 185, n = 93, n = 42) from Japan and Korea using varying dose–fractionation schedules and eligibility criteria reported 3-year local recurrence–free survival rates ranging from 67.5% to 91% and 3-year os rates ranging from 54% to 70%3840. The rates of reported grade 3 or worse toxicities were low (<10%). A larger retrospective study of 224 patients with inoperable nonmetastatic hcc analyzed outcomes after patients received radiofrequency ablation (n = 161) or image-guided sbrt (n = 63)41. At 1 and 2 years, freedom from local progression for tumours treated with radiofrequency ablation was, respectively, 83.6% and 80.2% compared with 97.4% and 83.8% with sbrt. Acute grade 3 and 4 adverse events were reported in 11% and 5% of patients treated with radiofrequency ablation and sbrt respectively (p = 0.31). At 1 and 2 years, os was, respectively, 70% and 53% compared with 74% and 46%.

One prospective study of 102 patients ineligible for transplantation, resection, radiofrequency ablation, or transarterial chemoembolization (tace) who received sbrt (median 36 Gy in 6 fractions given every 2 days) showed a 1-year local control rate of 87%42. A dose–response relationship was observed; the Child–Pugh score declined by 2 or more points at 3 months in 30% of patients; and deaths in 5 of the 102 patients were possibly related to sbrt. This study provided a strong rationale for conducting a rct to better define the role of sbrt in hcc.

Use of local therapies such as tace and radiofrequency ablation to halt the progression of hcc in patients on waiting lists for liver transplantation might allow for more patients to remain eligible for transplantation. Emerging data from multiple case series suggest that sbrt is a feasible alternative method of bridging patients until liver transplantation. Of the six case series summarized by Klein and Dawson43, 24%–100% of patients treated with sbrt received an orthotopic liver graft, with no local progression or morbidity at the time of transplantation. Explanted livers had 50%–100% necrosis after sbrt4449. In an abstract presented at the International Liver Transplantation Society Annual International Congress 2015, 70.2% of 443 patients waiting for liver transplantation received some bridge treatment, of whom 34% received either tace (77.5%) or sbrt (21.5%)50. The tace and sbrt groups had comparable Model for End-Stage Liver Disease mortality risks of 9.4% and 11.3% respectively. The dropout rate from the waiting list was 21% for tace and 17% for sbrt. The rates of 5-year disease-free survival and os were, respectively, 66% and 68% for tace and 75% and 78% for sbrt.

Based on promising preclinical data, early-phase trials have also attempted to combine systemic targeted treatments with radiotherapy51. Targeted agents that have been tested with radiotherapy include sunitinib and sorafenib. Thus far, combining those agents with radiotherapy has led to increased toxicity, especially gastrointestinal toxicity, which in some cases has been fatal5254. Concurrent use of those systemic agents with radiotherapy off-study is therefore not currently recommended.

The role of sbrt in the management of biliary tract cancers has yet to be defined; initial phase iii trials are ongoing (NRG-GI0001). However, two retrospective analyses of case series and a phase i trial looking at the role of sbrt in the treatment of intrahepatic cholangiocarcinoma suggest that sbrt is relatively effective5557. A multicentre phase ii study of high-dose hypofractionated proton-beam therapy in patients with localized unresectable intrahepatic cholangiocarcinoma demonstrated a 2-year local control rate of 94% and a 2-year os of 46%58. A single-centre retrospective study of 79 patients with unresectable intrahepatic cholangiocarcinoma strongly suggested that, compared with patients receiving a lower biologic equivalent dose, those who receive a biologic equivalent dose of more than 80.5 Gy experience a significant improvement in 3-year os (73% vs. 38%, p = 0.17) and in 3-year local control (78% vs. 45%, p = 0.04)56.

Randomized trials to define the role of sbrt in unresectable hcc (RTOG1112) and intrahepatic cholangiocarcinoma (NRG-GI001) are ongoing. Active accrual of patients to such trials is strongly encouraged.

In two retrospective case series (n = 69 and n = 32), the rate of hbv reactivation associated with radiotherapy for hcc was approximately 20%59,60. Patients receiving conformal radiation for hcc who also received lamivudine before and during conformal radiation were compared with those who did not. The rate of hbv reactivation was significantly greater in the group that was not treated with lamivudine [7 of 32 (21.8%) vs. 0 of 16 (0%), p < 0.05]. The rate of spontaneous hbv reactivation in the control group with hcc who received neither radiotherapy nor suppressive therapy for chronic hbv was 2.3%59. These studies suggest that radiation therapy for hcc increases the risk of hbv reactivation and that hbv suppressive therapy such as lamivudine reduces that risk.

Question 2

What is the role of transarterial chemoembolization in unresectable and non-transplantable Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma?

  • tace is the standard of care for Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma in patients deemed eligible at multidisciplinary rounds. (Level I)

  • ■ Bland embolization might be an alternative to tace in patients who are not candidates for conventional tace. (Level i)

  • tace with drug-eluting beads offers equivalent oncologic outcomes and might be better tolerated. (Level i)

  • ■ Other transarterial therapies such as transarterial radioembolization (tare) and transarterial ethanol ablation (tea) require further study. (Levels ii-1 and ii-2)

Summary of Evidence

For large multinodular hcc confined to the liver, where definitive ablation, resection, or transplantation is not an option, tace is considered the standard of care. That understanding is based primarily on two phase iiircts showing that, compared with conservative treatment only, tace significantly improved 2-year os (63% vs. 27%; hr: 0.47; 95% ci: 0.25 to 0.91; p = 0.025; and 31% vs. 11%; hr: 0.49; 95% ci: 0.29 to 0.81; p = 0.006) in this patient population61,62. A meta-analysis of those two landmark trials and four other smaller trials confirmed an overall benefit favouring tace (odds ratio: 0.53; 95% ci: 0.32 to 0.89; p = 0.017)63. Contradicting those results, a Cochrane systematic review published in 2011 came to the conclusion that there is not firm enough evidence to support or refute tace for patients with unresectable hcc64. The review was criticized for including an older study that involved a heterogeneous group of patients and that used gel foam powder, which is associated with biliary damage; another utilized radio-frequency ablation with ethanol ablation instead of tace; and another enrolled patients with more-advanced disease who had a poorer prognosis6567.

No phase iiirct has shown that, compared with best supportive care, bland embolization or transarterial embolization improves survival. The phase iii study by Llovet in 2002 showed a trend in survival benefit favouring tea, but the study was not designed to detect a survival difference61. An older rct looking at tea compared with best supportive care alone showed that tea had a marked antitumoural effect, but did not improve survival68. There were no differences in the complication rate between tea and best supportive care. If a patient is not eligible for tace, tea might therefore be an alternative.

Four rcts have compared drug-eluting bead tace with conventional tace. None of those trials demonstrated a difference in survival, but patients treated with drug-eluting bead tace consistently experienced fewer adverse events6972.

Few trials have investigated other novel types of transarterial therapies, including tare and tea. In one rct comparing tea with tace (n = 98), patients in the tea arm experienced a longer time to progression and longer progression-free survival73. However, tea was associated with higher rates of fever and pain. Studies of tare are limited to retrospective, observational designs74. Overall, tare and tea are intriguing technologies with some suggestion that they could improve outcomes; randomized trials are warranted.

INFECTION RISK WITH ANTINEOPLASTIC AGENTS

Question 1

What is the best way, in terms of infectious complications, to prepare patients with gastrointestinal malignancies for anticancer treatment?

  • ■ Systemic therapy given to patients with gastrointestinal malignancies can lead to immunosuppression and can increase their risk of infections; thus, a thorough infections and vaccination history should be obtained. (Level ii)

  • ■ Updated vaccinations and appropriate referral to infectious disease specialists might be required. Specific vaccines and their timing and sequence can be complex during cancer chemotherapy. (Level iii)

  • ■ Patients starting antineoplastic therapy who are part of an at-risk population should be screened for hbv and hepatitis C (hcv). (Level ii-2)

  • ■ In patients with hbv, suppressive therapy should be considered when immunosuppressive therapy is used. (Level iii)

  • ■ In patients at risk of tuberculosis (tb), testing should be considered. (Level iii)

Summary of Evidence

Infections commonly seen in colorectal cancer patients receiving myelosuppressive chemotherapy include Clostridium septicum sepsis, gram-negative sepsis, procedure–related wound infections, and nosocomial infections. With the advent of biologics such as cetuximab and bevacizumab, the profile of routine and opportunistic infections is evolving. In a meta-analysis of rcts looking at cetuximab and panitumumab (two monoclonal antibodies against the epidermal growth factor receptor), increased risks of moderate-to-severe infection (rr: 1.49; 95% ci: 1.33 to 1.66; p < 0.001) and febrile neutropenia (rr: 1.27; 95% ci: 1.09 to 1.48; p = 0.002) were observed75. The rates of grades 3–5 infections and febrile neutropenia were 9.3% and 5.3% respectively. One large population-based study showed that patients with nonmetastatic solid tumours who received myelosuppressive chemotherapy commonly received antimicrobial prophylaxis and generally had a low risk of infection (0%–2.5%)76.

Because of a potential increase in the risk of disease reactivation, screening is recommended in patients with risk factors for hbv or hcv who are being considered for systemic antineoplastic treatments. An immunosuppressed state enables the proliferation of hbvdna, and clinical reactivation of hbv occurs as a result of immune reconstitution after myelosuppressive antineoplastic therapy is discontinued77. One retrospective study of 156 patients positive for the hbv surface antigen (including 16 with hematologic malignancies and 140 with solid tumours) and receiving chemotherapy showed a 4% risk of severe acute exacerbations of chronic hbv infection78. Rates of severe acute exacerbations of hbv were much higher in patients with hematologic malignancies (25%) and in those treated with rituximab (40%). Expert review of the literature suggests that the risk of reactivation was greatest in patients positive for the hbv surface antigen, although there is still a small risk of reactivation in patients with serologic evidence of resolved hbv (that is, they are anti-hbc–positive)79,80. The risk of reactivation increases in patients with hbv e-antigen or hbvdna before chemotherapy81, combined with any or all of myelosuppressive biologic therapy, concomitant methotrexate, or steroid use82. On the other hand, there is no evidence to support the use of suppressive therapy for patients with chronic hcv who are receiving chemotherapy for colorectal cancer. A retrospective analysis of hcv-seropositive colorectal cancer patients receiving chemotherapy found no changes in the hcv load or rate of febrile neutropenia83.

One systematic review looked at whether lamivudine reduced hbv reactivation among cancer patients who are hbv surface antigen–positive receiving chemotherapy84. Compared with no use of lamivudine, suppressive therapy with lamivudine reduced hbv reactivation, hbv-related hepatitis, and hbv-related hepatic failure. The authors concluded that preventive therapy with lamivudine in this population might reduce the risk of hbv reactivation and hbv-associated morbidity and mortality. However, those studies, including the two rcts, were heterogeneous and small (n = 17–92; n = 258 in one study).

Approximately one third of the world’s population is positive for latent tb. Lifetime risk of tb reactivation is 7%–10%. A large retrospective analysis of 186,843 cancer patients treated at Memorial Sloan Kettering Cancer Center from 1998 to 2004 showed that, compared with U.S.-born patients without cancer, those with solid tumours did not have an increased risk of tb (census data)85. Paradoxically, a retrospective cohort study (n = 3618) showed that patients with solid-organ malignancies experience a higher incidence of active tb than do control patients without cancer86. In the Memorial Sloan Kettering Cancer Center study, head-and-neck cancer patients experienced a higher incidence of tb (135 per 100,000 vs. 30–52 per 100,000). Foreign-born patients with underlying hematologic malignancy had a tb incidence rate 50 to 100 times that in U.S.-born patients. Reports of reactivation of tb after systemic therapy, especially biologics, have been limited to case studies8789. Based on those data, testing for latent tb should be considered in this population85.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: MT has received honoraria from Celgene and Ispen. MV has received fees as an advisory board member for Eli Lilly, Celgene, Ispen, and Novartis. BC has received honoraria from Celgene, Eli Lilly, Amgen, Genomic Health, and Easai, and has received fees as an advisory board member for Celgene. GM has received a speaker’s honorarium from Sanofi. BS has received speaker’s honoraria and fees as an advisory board member for Bristol–Myers Squibb and AstraZeneca. MS received a research grant from Roche. SS has received speaker’s honoraria from Celgene, Bristol–Myers Squibb, Novartis, Merck, Amgen, Eli Lilly, AstraZeneca and Boehringer Ingelheim, and has received fees as an advisory board member for Bristol–Myers Squibb, Merck, Amgen, AstraZeneca, and Boehringer Ingelheim. LAD has received a speaker’s honorarium and fees as an advisory board member for Sirtex. EF holds investments in Bristol–Myers Squibb. RG has received fees as an advisory board member for Celgene, Ispen, Pfizer, Amgen, and Novartis. TH has received fees as an advisory board member for Celgene and Pfizer. TA has received fees as an advisory board member for Roche, Pfizer, Sanofi, Shire, Amgen, Ipsen, Celgene, and Novartis, and grants or research funding from Novartis, Roche, Eli Lilly, Amgen, and Sanofi. PC has received a research grant from Novartis and fees as an advisory board member for Ispen and Novartis; his institution receives funding from the Canadian Institutes of Health Research, Nordion Quark, and Astellas for a trial in which he is co-investigator. SC has received a honorarium from Olympus.

ACKNOWLEDGMENTS

We thank Dr. Sharlene Gill for her contribution to the 2016 annual Eastern Canadian Gastrointestinal Cancer Consensus Conference.

AUTHOR AFFILIATIONS

*Ontario: The Ottawa Hospital Cancer Centre, Ottawa (Asmis, Bossé, Cripps, Goel, Goodwin, Halwani, Hsu, Martel, Ng, Robillard, Vickers); Queen’s University and Cancer Centre of Southeastern Ontario, Kingston (Biagi); Princess Margaret Cancer Centre, Toronto (Brierley, Cleary, Dawson); Juravinski Cancer Centre, Hamilton (Tsvetkova); Cancer Centre of Southeastern Ontario, Kingston (Mahmud);,
Quebec: Hôpital Charles-LeMoyne Cancer Centre, Greenfield Park (Samson); McGill University Health Centre, Montreal (Alfakeeh, Alruzug, Chaudhury, Kopek, Thirlwell, Ward); Sir Mortimer B. Davis Jewish General Hospital (Galiatsatos); Centre Hospitalier Pierre-Boucher (Ferland); Centre Hospitalier Universitaire de Montréal (Girard, Sideris);,
New Brunswick: Saint John Regional Hospital, Saint John (Gray);,
§Nova Scotia: QEII Health Sciences Centre, Halifax (Colwell, Dorreen, Snow);,
Newfoundland and Labrador: Dr. H. Bliss Murphy Cancer Centre, St. John’s (Ahmad, Seal, Siddiqui)..

REFERENCES

1. Definitions of levels of evidence and grades of recommendations of the Canadian Task Force on Preventive Health Care [e-Appendix1]. In: Palda VA, Guise JM, Wathen CN on behalf of the Canadian Task Force on Preventive Health Care. Interventions to promote breast-feeding: applying the evidence in clinical practice. CMAJ 2004;170:976–8. [Available online at: http://www.cmaj.ca/content/suppl/2004/03/15/170.6.976.DC1/palda_appendix.pdf; cited 16 June 2016]
cross-ref  

2. Pita-Fernandez S, Alhayek-Ai M, Gonzalez-Martin C, Lopez-Calvino B, Seoane-Pillado T, Pertega-Diaz S. Intensive follow-up strategies improve outcomes in nonmetastatic colorectal cancer patients after curative surgery: a systematic review and meta-analysis. Ann Oncol 2015;26:644–56.
cross-ref  

3. Primrose JN, Perera R, Gray A, et al. Effect of 3 to 5 years of scheduled cea and ct follow-up to detect recurrence of colorectal cancer: the facs randomized clinical trial. JAMA 2014;311:263–70.
cross-ref  pubmed  

4. Renehan AG, O’Dwyer ST, Whynes DK. Cost effectiveness analysis of intensive versus conventional follow up after curative resection for colorectal cancer. BMJ 2004;328:81.
cross-ref  pubmed  pmc  

5. Lewis RA, Neal RD, Williams NH, et al. Follow-up of cancer in primary care versus secondary care: systematic review. Br J Gen Pract 2009;59:e234–47.
cross-ref  pubmed  pmc  

6. Wattchow DA, Weller DP, Esterman A, et al. General practice vs surgical-based follow-up for patients with colon cancer: randomised controlled trial. Brit J Cancer 2006;94:1116–21.
cross-ref  pubmed  pmc  

7. Meyerhardt JA, Mangu PB, Flynn PJ, et al. on behalf of the American Society of Clinical Oncology. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2013;31:4465–70.
cross-ref  pubmed  

8. Earle C, Annis R, Sussman J, Haynes AE, Vafaei A. Follow-Up Care, Surveillance Protocol, and Secondary Prevention Measures for Survivors of Colorectal Cancer. Toronto, ON: Cancer Care Ontario; 2012. [Available online at: https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=124839; cited 19 February 2016]

9. Sobhani I, Tiret E, Lebtahi R, et al. Early detection of recurrence by 18fdg-pet in the follow-up of patients with colorectal cancer. Br J Cancer 2008;98:875–80.
cross-ref  pubmed  pmc  

10. Nordlinger B, Sorbye H, Glimelius B, et al. on behalf of the eortc Gastro-Intestinal Tract Cancer Group, Cancer Research UK, the Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie, the Australasian Gastro-Intestinal Trials Group, and the Fédération Francophone de Cancérologie Digestive. Perioperative folfox4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (eortc 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 2013;14:1208–15.
cross-ref  pubmed  

11. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25:4575–80.
cross-ref  pubmed  

12. Adam R, de Gramont A, Figueras J, et al. on behalf of the Expert Group on Oncosurgery Management of Liver Metastases. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus. Cancer Treat Rev 2015;41:729–41.
cross-ref  pubmed  

13. Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13:51–64.
cross-ref  pubmed  

14. Bismuth H, Adam R, Lévi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;224:509–22.
cross-ref  pubmed  pmc  

15. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644–57.
pubmed  pmc  

16. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 2003;10:1059–69.
cross-ref  pubmed  

17. Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8:347–53.
cross-ref  pubmed  

18. Jamal MH, Hassanain M, Chaudhury P, et al. Staged hepatectomy for bilobar colorectal hepatic metastases. HPB (Oxford) 2012;14:782–9.
cross-ref  

19. Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013;15:483–91.
cross-ref  

20. Potters L, Kavanagh B, Galvin JM, et al. American Society for Therapeutic Radiology and Oncology (astro) and American College of Radiology (acr) practice guideline for the performance of stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2010;76:326–32.
cross-ref  pubmed  

21. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10.
pubmed  

22. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013;14:e28–37.
cross-ref  pubmed  

23. Fode MM, Høyer M. Survival and prognostic factors in 321 patients treated with stereotactic body radiotherapy for oligometastases. Radiother Oncol 2015;114:155–60.
cross-ref  pubmed  

24. Raju RS, Coburn N, Liu N, et al. A population-based study of the epidemiology of pancreatic cancer: a brief report. Curr Oncol 2015;22:e478–84.
cross-ref  pubmed  pmc  

25. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition ajcc pancreatic cancer staging system: report from the National Cancer Database. Cancer 2007;110:738–44.
cross-ref  pubmed  

26. Lewis R, Drebin JA, Callery MP, et al. A contemporary analysis of survival for resected pancreatic ductal adenocarcinoma. HPB (Oxford) 2013;15:49–60.
cross-ref  

27. Cleary SP, Gryfe R, Guindi M, et al. Prognostic factors in resected pancreatic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll Surg 2004;198:722–31.
cross-ref  pubmed  

28. Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg Oncol 2009;16:1751–6.
cross-ref  pubmed  

29. van Heek NT, Kuhlmann KF, Scholten RJ, et al. Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands. Ann Surg 2005;242:781–8.
cross-ref  pubmed  pmc  

30. Nathan H, Cameron JL, Choti MA, Schulick RD, Pawlik TM. The volume–outcomes effect in hepato-pancreato-biliary surgery: hospital versus surgeon contributions and specificity of the relationship. J Am Coll Surg 2009;208:528–38.
cross-ref  pubmed  

31. Philip PA, Mooney M, Jaffe D, et al. Consensus report of the National Cancer Institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 2009;27:5660–9.
cross-ref  pubmed  

32. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13.
pubmed  

33. Moore MJ, Goldstein D, Hamm J, et al. on behalf of the National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase iii trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960–6.
cross-ref  pubmed  

34. Conroy T, Desseigne F, Ychou M, et al. on behalf of the Groupe Tumeurs Digestives of Unicancer and the prodige Intergroup. folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–25.
cross-ref  pubmed  

35. Hoff Von DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med 2013;369:1691–703.
cross-ref  

36. Huguet F, André T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in gercor phase ii and iii studies. J Clin Oncol 2007;25:326–31.
cross-ref  pubmed  

37. Hammel P, Huguet F, Van Laethem JL, et al. Comparison of chemoradiotherapy (crt) and chemotherapy (ct) in patients with locally advanced pancreatic cancer (lapc) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international phase iiilap 07 study [abstract 292]. Pancreatology 2013;13(suppl):S89.
cross-ref  

38. Sanuki N, Takeda A, Oku Y, et al. Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients. Acta Oncol 2014;53:399–404.
cross-ref  

39. Yoon SM, Lim YS, Park MJ, et al. Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One 2013;8:e79854.
cross-ref  pubmed  pmc  

40. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer 2010;10:475.
cross-ref  pubmed  pmc  

41. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol 2016;34:452–9.
cross-ref  pmc  

42. Bujold A, Massey CA, Kim JJ, et al. Sequential phase i and ii trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013;31:1631–9.
cross-ref  pubmed  

43. Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities. Int J Radiat Oncol Biol Phys 2013;87:22–32.
cross-ref  

44. O’Connor JK, Trotter J, Davis GL, Dempster J, Klintmalm GB, Goldstein RM. Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl 2012;18:949–54.
cross-ref  

45. Katz AW, Chawla S, Qu Z, Kashyap R, Milano MT, Hezel AF. Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol Biol Phys 2012;83:895–900.
cross-ref  

46. Bush DA, Kayali Z, Grove R, Slater JD. The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. Cancer 2011;117:3053–9.
cross-ref  pubmed  

47. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e447–53.
cross-ref  pubmed  

48. Sandroussi C, Dawson LA, Lee M, et al. Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma. Transpl Int 2010;23:299–306.
cross-ref  

49. Al Hamad AA, Hassanain M, Michel RP, Metrakos P, Roberge D. Stereotactic radiotherapy of the liver: a bridge to transplantation stereotactic radiotherapy of the liver: a bridge to transplantation. Technol Cancer Res Treat 2009;8:401–5.
cross-ref  pubmed  

50. Sapisochin G, Goldaracena N, Doherty M, et al. Is stereotactic body radiotherapy, as a bridge to liver transplantation, as effective as tace? [abstract O-106]. Presented at the 21st Annual International Congress of the International Liver Transplantation Society; Chicago, IL, U.S.A.; 8–11 July 2015. [Available online at: http://prgmobileapps.com/AppUpdates/ilts2015/Abstracts/O-106.pdf; cited 5 October 2016]

51. Plastaras JP, Kim SH, Liu YY, et al. Cell cycle dependent and schedule-dependent antitumour effects of sorafenib combined with radiation. Cancer Res 2007;67:9443–54.
cross-ref  pubmed  

52. Chi KH, Liao CS, Chang CC, et al. Angiogenic blockade and radiotherapy in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2010;78:188–93.
cross-ref  pubmed  

53. Dawson LA, Brade A, Cho C, et al. Phase i study of sorafenib and sbrt for advanced hepatocellular carcinoma [abstract 24]. Int J Radiat Oncol Biol Phys 2012;84(suppl):S10–11.
cross-ref  

54. Chen SW, Lin LC, Kuo YC, Liang JA, Kuo CC, Chiou JF. Phase 2 study of combined sorafenib and radiation therapy in patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2014;88:1041–7.
cross-ref  pubmed  

55. Jung DH, Kim MS, Cho CK, et al. Outcomes of stereotactic body radiotherapy for unresectable primary or recurrent cholangiocarcinoma. Radiat Oncol J 2014;32:163–9.
cross-ref  pubmed  pmc  

56. Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol 2016;34:219–26.
cross-ref  pmc  

57. Tse RV, Hawkins M, Lockwood G. Phase i study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008;26:657–64.
cross-ref  pubmed  

58. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase ii study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2016;34:460–8.
cross-ref  

59. Kim JH, Park JW, Kim TH, Koh DW, Lee WJ, Kim CM. Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus–related hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2007;69:813–19.
cross-ref  pubmed  

60. Huang W, Zhang W, Fan M, et al. Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma. Cancer Sci 2014;105:697–703.
cross-ref  pubmed  pmc  

61. Llovet JM, Real MI, Montaña X, et al. on behalf of the Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet Oncol 2002;359:1734–9.
cross-ref  

62. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–71.
cross-ref  pubmed  

63. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–42.
cross-ref  pubmed  

64. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo) embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011;:CD004787.

65. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe chc. J Hepatol 1998;29:129–34.
cross-ref  pubmed  

66. Akamatsu M, Yoshida H, Obi S, et al. Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004;24:625–9.
cross-ref  pubmed  

67. Doffoël M, Bonnetain F, Bouche O, et al. on behalf of the Fédération Francophone de Cancérologie Digestive. Multicentre randomised phase iii trial comparing tamoxifen alone or with transarterial lipiodol chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402). Eur J Cancer 2008;44:528–38.
cross-ref  

68. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology 1998;27:1578–83.
cross-ref  pubmed  

69. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the precisionv study. Cardiovasc Intervent Radiol 2010;33:41–52.
cross-ref  

70. Golfieri R, Giampalma E, Renzulli M, et al. on behalf of the Precision Italia Study Group. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014;111:255–64.
cross-ref  pubmed  pmc  

71. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22:1545–52.
cross-ref  pubmed  

72. van Malenstein H, Maleux G, Vandecaveye V, et al. A randomized phase ii study of drug-eluting beads versus transarterial chemoembolization for unresectable hepatocellular carcinoma. Onkologie 2011;34:368–76.
cross-ref  

73. Yu SC, Hui JW, Hui EP, et al. Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization. Radiology 2014;270:607–20.
cross-ref  

74. Boily G, Villeneuve JP, Lacoursière L, et al. Transarterial embolization therapies for the treatment of hepatocellular carcinoma: cepo review and clinical recommendations. HPB (Oxford) 2015;17:52–65.
cross-ref  

75. Funakoshi T, Suzuki M, Tamura K. Infectious complications in cancer patients treated with anti-egfr monoclonal antibodies cetuximab and panitumumab: a systematic review and meta-analysis. Cancer Treat Rev 2014;40:1221–9.
cross-ref  pubmed  

76. Weycker D, Chandler D, Barron R, et al. Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin’s lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice. J Oncol Pharm Pract 2015;:[Epub ahead of print].
cross-ref  

77. Nard FD, Todoerti M, Grosso V, et al. Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: extending perspective from old to newer drugs. World J Hepatol 2015;7:344–61.
cross-ref  pubmed  pmc  

78. Shih CA, Chen WC, Yu HC, et al. Risk of severe acute exacerbation of chronic hbv infection cancer patients who underwent chemotherapy and did not receive anti-viral prophylaxis. PLoS One 2015;10:e0132426.
cross-ref  

79. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100:182–8.
cross-ref  pubmed  

80. Hoofnagle JH. Reactivation of hepatitis B. Hepatology 2009;49(suppl):S156–65.
cross-ref  pubmed  

81. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with hepatitis B virus (hbv) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90:1306–11.
cross-ref  pubmed  pmc  

82. Cheng AL, Hsiung CA, Su IJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (hbv) reactivation in hbv-carriers with lymphoma. Hepatology 2003;37:1320–8.
cross-ref  pubmed  

83. Tomizawa K, Suyama K, Matoba S, et al. The safety of chemotherapy for colorectal cancer patients with hepatitis C virus infection. Med Oncol 2014;31:212.
cross-ref  pubmed  

84. Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519–28.
cross-ref  pubmed  pmc  

85. Kamboj M, Sepkowitz KA. The risk of tuberculosis in patients with cancer. Clin Infect Dis 2006;42:1592–5.
cross-ref  pubmed  

86. Kim HR, Hwang SS, Ro YK, et al. Solid-organ malignancy as a risk factor for tuberculosis. Respirology 2008;13:413–19.
cross-ref  pubmed  

87. Lin CC, Wang JY, Pu YS. Active tuberculosis during temsirolimus and bevacizumab treatment. J Clin Oncol 2013;31:e18–20.
cross-ref  

88. Teo M, O’Connor TM, O’Reilly SP, Power DG. Sorafenib-induced tuberculosis reactivation. Onkologie 2012; 35:514–16.
cross-ref  pubmed  

89. Coriat R, Mir O, Ropert S, Loulergue P, Billemont B, Goldwasser F. Reactivation of tuberculosis during temsirolimus therapy. Invest New Drugs 2011;29:1494–6.
cross-ref  


aThese authors contributed equally to the present work. ( Return to Text )

Correspondence to: Timothy Asmis, Division of Medical Oncology, The Ottawa Hospital Cancer Centre–General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6. E-mail: tasmis@ottawahospital.on.ca

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Current Oncology, VOLUME 23, NUMBER 6, December 2016








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