Elsevier

The Lancet Oncology

Volume 10, Issue 2, February 2009, Pages 157-163
The Lancet Oncology

Review
Emergency surgery in the era of molecular treatment of solid tumours

https://doi.org/10.1016/S1470-2045(09)70017-8Get rights and content

Summary

In the advancing era of molecular therapy of solid tumours, emergency treatment of complications, such as bowel perforation, haemorrhage, and tumour rupture, is likely to evolve into one of the main challenges of surgical oncology. These complications might be caused by disease progression from resistance to therapy, side-effects of therapy on normal vasculature, and therapeutic induction of excessively responding tumours. This Review outlines the probability and management of emergency operations during molecularly targeted therapy of solid tumours. Special attention is given to advanced gastrointestinal stromal tumours and colorectal cancer, and therapy with imatinib, sunitinib, and bevacizumab.

Introduction

An important progression in cancer biology was the understanding of the many signalling pathways and metabolic processes contributing to oncogenesis. This progress enabled the identification of several potential molecular targets for anti-cancer therapy. Compared with conventional cytotoxic chemotherapy, so-called molecularly targeted therapy, is characterised by better target selectivity, the possibility for chronic, durable therapy, a better toxicity profile, and (in some cases) oral administration.1 Several new compounds have been tested in clinical trials and a few of these drugs have been approved for the treatment of solid tumours. These drugs induce the death of tumour cells by direct or indirect mechanisms (eg, anti-angiogenic effects). A wider introduction of these drugs into clinical practice will bring new and unexpected adverse events, such as hypothyroidism or bowel perforation (figure 1), due to different mechanisms of action or tumour-drug interactions.2 Oncologists will need to have knowledge of, and preparation for, these adverse events during molecularly targeted therapy of solid tumours. The aim of this Review is to discuss the management of patients on molecularly targeted agents who present with surgical emergencies, as a side-effect of therapy or the progression of underlying, advanced disease.

Section snippets

Clinical applications and adverse events

Targeted therapies for solid tumours are generally small-molecule tyrosine-kinase inhibitors (TKI), such as imatinib, sunitinib, sorafenib, gefitinib, erlotinib, and lapatinib, or monoclonal antibodies, such as cetuximab, trastuzumab, bevacizumab, and panitumumab.3, 4 Some of these agents act on tumour vasculature; disrupting vessel growth by directly inhibiting vascular endothelial growth factor receptor (VEGFR), or acting on other downstream kinases. We tried to find reports addressing

Discussion and further dilemmas

Molecularly targeted therapies have improved the treatment of several types of solid tumours, and the substantial prolongation of progression-free survival has transformed some malignancies into chronic disorders. Compared with cytotoxic chemotherapy, these drugs are believed to be safe, with a favourable toxicity profile, conferred by their mechanism of action—the inhibition of specific targets in tumour cells or the tumour microenvironment. However, some of the biological effects of these

Conclusion

Although emergency surgery associated with disease progression or therapy during molecularly targeted therapy of solid tumours is rare, it can be life-threatening and physicians must be aware of the possibility. Ideally, an experienced oncological surgeon should always be part of the therapeutic team. Targeted therapy with bevacizumab is the most common example of treatment associated with the possibility of bowel perforation. The frequency of emergency operations for GIST is thought to be

Search strategy and selection criteria

A search of Medline, Embase, and PubMed, was done by use of the search terms “targeted therapy”, “tyrosine-kinase inhibitors”, “anti-angiogenic”, “imatinib”, “sunitinib”, “panitumumab”, “erlotinib”, “gefitinib”, “sorafenib”, “cetuximab”, “bevacizumab”, “clinical trials”, “adverse event”, “emergency”, “surgery”, “complication”, “bleeding”, “perforation”, “solid tumour”, and “cancer”. We also identified references from relevant articles on emergency surgical interventions and complications

References (69)

  • K Imai et al.

    Comparing antibody and small-molecule therapies for cancer

    Nature

    (2006)
  • GD Demetri et al.

    Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

    N Engl J Med

    (2002)
  • CD Blanke et al.

    Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033

    J Clin Oncol

    (2008)
  • CD Blanke et al.

    Long-term results from a randomized phase II trial of standard versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT

    J Clin Oncol

    (2008)
  • Oosterom van et al.

    Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group

    Eur J Cancer

    (2002)
  • VL Goodman et al.

    Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma

    Clin Cancer Res

    (2007)
  • L Wiebe et al.

    Activity of sorafenib in patients with imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST): a phase II trial of the University of Chicago Phase II Consortium

    J Clin Oncol

    (2008)
  • FA Scappaticci et al.

    Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab

    J Natl Cancer Inst

    (2007)
  • PJ Flynn et al.

    Incidence of serious bleeding events (sBE) in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab (BV) as part of a first-line regimen: results from the BRiTE observational cohort study (OCS)

    J Clin Oncol

    (2008)
  • MW Saif et al.

    Gastrointestinal perforation due to bevacizumab in colorectal cancer

    Ann Surg Oncol

    (2007)
  • H Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • BJ Giantonio et al.

    Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200

    J Clin Oncol

    (2007)
  • JC Yang et al.

    A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer

    N Engl J Med

    (2003)
  • E Hedrick et al.

    Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: updated results from a large observational registry in the US (BRiTE)

    J Clin Oncol

    (2006)
  • FF Kabbinavar et al.

    Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial

    J Clin Oncol

    (2005)
  • M Sugrue et al.

    Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy

    J Clin Oncol

    (2006)
  • MW Saif et al.

    Incidence and management of bevacizumab-related toxicities in colorectal cancer

    Expert Opin Drug Saf

    (2006)
  • AD Thornton et al.

    Angiogenesis inhibition with bevacizumab and the surgical management of colorectal cancer

    Br J Surg

    (2006)
  • HS Hochster et al.

    Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: final analysis of the TREE study

    Proc Am Soc Clin Oncol

    (2006)
  • LB Saltz et al.

    Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecanrefractory colorectal cancer

    Proc Am Soc Clin Oncol Gastrointestinal Symp

    (2005)
  • M Kozloff et al.

    Efficacy of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: updated results from a large observational registry in the US (BRiTE)

    Proc Am Soc Clin Oncol

    (2006)
  • A Kretzschmar et al.

    Incidence of gastrointestinal perforations and bleeding in patients starting bevacizumab treatment in first-line mCRC without primary tumour resection: preliminary results from the First BEATrial

    Proc Am Soc Clin Oncol Gastrointestinal Symp

    (2006)
  • E Van Cutsem et al.

    Preliminary safety of bevacizumab with first-line FOLFOX, CAPOX, FOLFIRI and capecitabine for mCRC: First BEATrial

    Proc Am Soc Clin Oncol Gastrointestinal Symp

    (2006)
  • HI Hurwitz et al.

    Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer

    J Clin Oncol

    (2005)
  • Cited by (43)

    • Targeted therapy and molecular genetics

      2023, DiSaia and Creasman Clinical Gynecologic Oncology
    • Acute Abdomen, Bowel Obstruction, and Fistula

      2019, Abeloff’s Clinical Oncology
    • Targeted therapy and molecular genetics

      2018, Clinical Gynecologic Oncology
    • Gastrointestinal Stromal Tumors: Imaging Features Before and After Treatment

      2017, Current Problems in Diagnostic Radiology
      Citation Excerpt :

      Larger tumors may necessitate open resection, whereas smaller tumors may be removed laparoscopically. Tumor manipulation and rupture should be avoided to minimize the risk of peritoneal seeding.5 Preoperative imatinib therapy may also help to decrease the risk of intraoperative bleeding and spillage of tumor cells.17

    • Surgical emergencies in oncology

      2014, Cancer Treatment Reviews
      Citation Excerpt :

      Perforation may result from complications of medicinal treatment such as steroids, NSAIDs, or from complications of chemotherapy, for example neutropenic enterocolitis and severe dehydration resulting in decreased bowel perfusion [15]. Last, some systemic agents, serving as anti-angiogenesic drugs such as bevacizumab for colorectal cancer, or sunitinib and imatinib for gastrointestinal stromal tumors (GIST), have been associated with intestinal perforation [12,15,101]. The evidence in the literature on the treatment of perforation induced by anti-angiogenic drugs is based on case series and there is no common approach for this emergency [102].

    View all citing articles on Scopus
    View full text