Curr. Oncol., Volume 13, Issue 5 (October 2006) – 7 articles

Question: What is the role of oxaliplatin combined with 5-fluorouracil (5-fu) and folinic acid (FA) in the first- and second-line treatment of advanced (unresectable locally advanced or metastatic) colorectal cancer? Perspectives: Evidence was selected and reviewed by two members of the Gastrointestinal Cancer Disease Site Group (GI DSG) of Cancer Care Ontario’s Program in Evidence- Based Care (PEBC) and by a methodologist. The resulting practice guideline report has been reviewed and approved by the GI DSG, which comprises medical and radiation oncologists, surgeons, a pathologist, and patient representatives. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee. Outcomes: Outcomes of interest were 1-year survival, response rates, and quality of life. Methodology: The MEDLINE, CANCERLIT, EMBASE, Guidelines International Network, and Cochrane Library databases were systematically searched for relevant studies. Recommendations were formed based on the evidence reviewed. Through a survey, these recommendations were appraised by Ontario clinicians; the recommendations were then revised by the GI DSG. The systematic review and modified recommendations were approved by a review body within PEBC. Results: The literature review found twenty-one randomized controlled trials and two meta-analyses. Evidence on first-line treatment found infusional 5-FU/FA/oxaliplatin (FOLFOX) to be superior to bolus 5-FU/FA/irinotecan (IFL) for rates of median survival and tumour response, with lower incidences of most adverse effects except peripheral neuropathy. For second-line treatment after fluoropyrimidine monotherapy, FOLFOX is a reasonable alternative for patients with contraindications to second- line irinotecan. After progression on infusional 5-FU/FA/irinotecan (FOLFIRI), FOLFIRI is the preferred therapy. Evidence from a single randomized trial suggests that additional benefits can be expected with the addition of bevacizumab to the FOLFOX regimen in second- line treatment. Practice Guideline: These recommendations apply to adult patients with advanced colorectal cancer who have high performance status (Eastern Cooperative Oncology Group score 0–2). Refer to Appendix A for available treatment options and to Appendix B for recommended dosages and schedules. The FOLFOX regimen is an important component of therapy for advanced colorectal cancer. First-line Therapy In one trial, FOLFOX was shown to be superior to IFL. The FOLFOX regimen has superior rates of median survival and tumour response. Compared with IFL, FOLFOX has lower incidences of severe nausea, vomiting, diarrhea, and febrile neutropenia, but a higher incidence of peripheral neuropathy. Short-term infusional 5-FU/FA in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are both acceptable alternatives for fit patients when combination therapy is the preferred treatment. Choice of first-line therapy may rely on patient factors and preferences—for example, less neuropathy with irinotecan versus less alopecia with oxaliplatin. Second-line Therapy After progression on first-line anti-thymidylate synthase monotherapy (for example, 5-FU/FA, capecitabine), irinotecan is standard secondline therapy. The FOLFOX regimen is a reasonable alternative for patients with contraindications to the use of second-line irinotecan. After progression on both irinotecan and an antithymidylate synthase agent, FOLFOX is the preferred therapy. Recent trials suggest that, as compared with FOLFOX alone, FOLFOX combined with bevacizumab provides additional survival benefits. Qualifying Statements: The role of radiation therapy, either alone or in combination with chemotherapy, for locally advanced unresectable colorectal cancer is not addressed in this guideline. Use of chronomodulated regimens is a topic that intersects with the use of oxaliplatin/5-FU combinations, particularly chronomodulation of 5-FU in these combinations. Chronomodulation of oxaliplatin has not been extensively studied, and the topic of chronomodulation is beyond the scope of this guideline and is not addressed. Although data exist to support the use of bevacizumab in combination with FOLFOX in second-line treatment, no first-line treatment data are available on which to make a recommendation. Full article

Questions: (1) In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate? (2) What is the toxicity associated with the use of bortezomib? (3) Which patients are more or less likely to benefit from treatment with bortezomib? Perspectives: Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidencebased Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback. Outcomes: Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events. Methodology: A systematic search was conducted of the MEDLINE, EMBASE, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc. Results: The literature review found one randomized controlled trial (rct)—the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma. The rct found bortezomib to be superior to highdose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation. Practice Guideline: This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status. Recommendations: Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations: (1) For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option. (2) Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline. (3) For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent–based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent–based chemotherapy is recommended. (4) Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials. Qualifying Statements: Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg. For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes. Dosage: Bortezomib 1.3 mg/m² is given as a rapid intravenous bolus over 3–5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed. Response to Treatment: Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone. The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent–based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.

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