Curr. Oncol., Volume 14, Issue 1 (February 2007) – 8 articles

Questions: What is the role of single-agent temozolomide in the treatment of patients with metastatic melanoma? In comparison with single-agent temozolomide, does the addition of interferon-α to temozolomide improve disease-free survival, overall survival, or response rates? In comparison with single-agent temozolomide, does the addition of thalidomide to temozolomide improve disease-free survival, overall survival, or response rates? Perspectives: Because of its oral route of administration and its ability to cross the blood–brain barrier, temozolomide is a potentially attractive chemotherapy agent for adult patients with unresectable metastatic malignant melanoma. To provide treatment recommendations for this new agent, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) decided to review the available literature on single-agent temozolomide and on temozolomide in combination with interferon-α or thalidomide. Outcomes: Outcomes of interest included response rates, disease-free survival, overall survival, quality of life, and adverse effects. Methodology: Evidence was selected and reviewed by two members of the Melanoma dsg and by methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review was obtained through a mailed survey of Ontario practitioners, the results of which were reflected in revisions to the practice guideline. Final approval of the guideline report was obtained from the Report Approval Panel of the pbec. Practice Guideline: These recommendations apply to adult patients with unresectable metastatic malignant melanoma. It is reasonable to use temozolomide at a dose of 200 mg/m² orally for 5 days every 4 weeks as initial systemic treatment for patients with unresectable metastatic malignant melanoma. The addition of moderate-dose interferon-α 2b has produced a significantly higher response rate than has single-agent temozolomide in a large randomized phase iii study. However, overall survival was not altered, and grades 3 and 4 hematologic toxicities were higher with the combined treatment. At the present time, the addition of interferon-α to temozolomide is not recommended. One randomized phase ii study and six other phase ii studies showed encouraging response rates when thalidomide was combined with temozolomide. However, the doses and schedules of temozolomide in those studies differed from the conventionally prescribed doses and schedules. It is not clear whether the improved response rates were attributable to the small number of patients in the studies, the different temozolomide doses and schedules, or the addition of thalidomide. Further phase iii studies are required to confirm whether a benefit is associated with the combination of temozolomide and thalidomide. Therefore, at this time, it is not recommended that thalidomide be combined with temozolomide. Qualifying Statements: Dacarbazine is the only chemotherapy drug currently approved for the treatment of metastatic malignant melanoma. In large randomized trials, response rates with dacarbazine ranged from 6% to 15%. Almost all responses were partial, with a median response duration of only 7–8 months. Given these disappointing overall results, the consensus among most physicians who are treating patients with metastatic malignant melanoma is that recommending more convenient treatment or experimental treatment to these patients is appropriate. Because of oral dosing, temozolomide is a reasonable choice, particularly for patients who would have difficulty traveling to cancer centres for intravenous chemotherapy. Temozolomide has demonstrated efficacy equal to that of dacarbazine in a randomized phase iii trial. However, unlike dacarbazine, temozolomide is a convenient oral treatment that penetrates the blood–brain barrier and that has shown activity against brain metastases. Although surgery is the preferred treatment modality for patients with solitary brain metastases from melanoma, temozolomide is the preferred chemotherapy for patients with brain metastases who require systemic treatment. Full article

Questions: What is the role of single-agent interleukin-2 (il-2) in the treatment of adults with metastatic melanoma? If there is a role for single-agent il-2, what patient population can appropriately be considered for treatment? If there is a role for single-agent il-2, what dose and schedule are appropriate? What are the toxicities associated with il-2? Perspectives: Many agents have been investigated for antitumour activity in melanoma, but few have shown promising response rates. Early detection, appropriate surgery, and adjuvant therapy have all improved outcomes, but approximately one third of patients with early-stage disease will nevertheless develop metastases. Single-agent il-2 has attracted much attention over the past several years. A number of randomized trials and many phase ii trials investigating single-agent il-2 suggest that this systemic treatment produces durable responses in melanoma patients. Given the dismal survival of patients with metastatic melanoma and the limited availability of effective treatments, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) felt that the durable responses seen with il-2 treatment warranted closer examination. Outcomes: Primary outcomes of interest included objective response rate, complete response rate, duration of response, toxicity, and quality of life. Secondary outcomes of interest included progression-free survival and overall survival. Methodology: A systematic review was developed, and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the pebc’s Report Approval Panel. Results: The present practice guideline reflects the integration of the draft recommendations based on a systematic review of the available evidence with the feedback obtained from external review by practitioners and the Report Approval Panel. Practice Guideline: No studies have compared il-2 to the current standard of care—dacarbazine (dtic)—or to placebo in the treatment of metastatic melanoma. After reviewing and weighing the evidence that does exist, the opinion of the Melanoma dsg is that high-dose il-2 is a reasonable treatment option for a select group of patients with metastatic melanoma: (1) Patients should have a good performance status (Eastern Cooperative Oncology Group 0–1) and a normal lactate dehydrogenase level. (2) Patients should have fewer than three organs involved or have cutaneous and/or subcutaneous metastases only, and no evidence of central nervous system metastases should be present. In this select group of patients, il-2 treatment can produce durable complete remissions. High-dose il-2 is recommended to be given at 600,000 IU/kg per dose, delivered intravenously over 15 minutes, every 8 hours, for a maximum of 14 doses. High-dose il-2 delivery is recommended to be done in a tertiary-care facility by staff trained in the provision of this treatment and with appropriate monitoring. To facilitate treatment and to develop expertise in this therapeutic modality, the dsg recommends that high-dose il-2 programs be established in one or two centres in Ontario. Qualifying Statements: High-dose il-2 has response rates that are similar to those seen with standard chemotherapy. However, unlike chemotherapy, il-2 demonstrates low but durable complete response rates that may lead to years of benefit for patients with metastatic melanoma. Based on the available data assessing prognostic factors and patient selection, patients with non-visceral metastases and fewer metastatic sites have a much higher response rate. In these select patients, high dose il-2 may be considered for first-line therapy. The lack of large randomized trials comparing il-2 to dtic or other chemotherapy means that recommendations for this guideline are based largely on phase ii data and limited phase iii data. Further randomized data will not soon become available, because no randomized trials are currently ongoing or planned. Interleukin-2 is currently widely used in the United States, and it is an approved therapy in both Canada and the United States. Full article

Chemotherapy-induced diarrhea (cid) is a common side effect of cancer treatment and can cause significant morbidity and mortality. Diarrhea is frequently severe enough to require a dose reduction of, a delay in, or a discontinuation of chemotherapy. Diarrhea-associated mortality has been reported to be as high as 3.5% in clinical trials of irinotecan and bolus 5-fluorouracil in colorectal cancer. The frequency of cid and its impact on patient management are frequently under-recognized in clinical practice. A Canadian working group, consisting of medical oncologists and an oncology pharmacist, was formed in 2001 to review the optimal approach to managing cid and to identify and implement new areas of research. The recommendations that follow are the result of the group’s work. Acute medical management of cid includes loperamide or diphenoxylate as first-line agents. Subcutaneous octreotide is recommended for intractable grade 2 diarrhea and may be considered for grade 1 cid that does not resolve with high-dose loperamide. Hospitalization is recommended for patients with grades 3 and 4 cid; in-hospital care includes rehydration, antibiotic therapy, and octreotide. A chemotherapy dose reduction is generally advised for patients who have experienced grade 3 or 4 diarrhea in a previous chemotherapy cycle. If a dose reduction is not desired, prophylaxis with intramuscular long-acting release octreotide may be considered. The foregoing recommendations are based on expert opinion and require validation in prospective clinical trials. Full article

Prostate cancer is the most common non-skin malignancy in men. Almost all men who die from prostate cancer have hormone-refractory prostate cancer with metastasis to bone. Emerging supportive treatments—including chemotherapy, bisphosphonates, and surgery—require integration that is optimized in a multidisciplinary setting. A multidisciplinary clinic for bone metastases has been in place at Toronto–Sunnybrook Regional Cancer Centre since 1999, combining orthopedic surgery, radiation oncology, interventional radiology, and palliative medicine for all patients with bone metastases. The addition of a prostate-focused multidisciplinary clinic integrates these services for patients with advanced prostate cancer. Full article

Minimally invasive procedures such as percutaneous cementoplasty can provide immediate pain relief and can restore mechanical stability for patients with bone metastases who are not candidates for surgery or who show resistance to radiotherapy or analgesic treatment. Here, we examine a case of percutaneous cementoplasty to treat a lytic lesion of the acetabulum from breast cancer. Good filling was observed, and no complications occurred. A research assistant recorded the patient’s scores on the Karnofsky Performance Scale, Townsend Functional Assessment Scale, and Brief Pain Inventory before surgery and at days 1, 2, and 4 and weeks 1, 2, and 4 post-procedure. Improvement in pain and walking ability was demonstrated within the first 48 hours of treatment, and that improvement remained constant throughout follow-up. These findings echo the literature, in that percutaneous cementoplasty provides immediate and long-term pain relief with few complications. We recommend that percutaneous cementoplasty be used as an additional tool for palliative treatment of patients with bone metastases. Full article

The day my friend called me to say that she was discontinuing chemotherapy, I was angry and disillusioned. My first comment was “You can’t! The longer they can keep you alive, the better chance you have of surviving. There are new drugs every day.” [...] Full article