Braun S, Pantel K, Muller P, Wolfgang J, Hepp F, Kentenich C, et al. The New England J of Med 2000; 342(8):525-533.

Prepared by: : Dr. Robin Fainsinger

Received during: Journal Rounds on the Tertiary Palliative Care Unit, Grey Nuns Hospital

Abstract:

Background: Cytokeratins are specific markers of epithelial cancer cells in bone marrow. We assessed the influence of cytokeratin-positive micrometastases in the bone marrow on the prognosis of women with breast cancer.
Methods: We obtained bone marrow aspirates from both upper iliac crests of 552 patients with stage I, II, or III breast cancer who underwent complete resection of the tumor and 191 patients with nonmalignant disease. The specimens were stained with the monoclonal antibody A45-B/B3, which binds to an antigen on cytokeratins. The median follow-up was 38 months (range, 10 to 70). The primary end point was survival.
Results: Cytokeratin-positive cells were detected in the bone marrow specimens of 2 of the 191 control patients with nonmalignant conditions (1 percent) and 199 of the 552 patients with breast cancer (36 percent). The presence of occult metastatic cells in bone marrow was unrelated to the presence or absence of lymph-node metastasis (P = 0.13). After four years of follow-up, the presence of micrometastases in bone marrow was associated with the occurrence of clinically overt distant metastasis and death from cancer-related causes (P < 0.001), but not with locoregional relapse (P = 0.77). Of 199 patients with occult metastatic cells, 49 died of cancer, whereas of 353 patients without such cells, 22 died of cancer-related causes (P < 0.001). Among the 301 women without lymph-node metastases, 14 of the 100 with bone marrow micrometastases died of cancer-related causes, as did 2 of the 201 without bone marrow micrometastases (P < 0.001). The presence of occult metastatic cells in bone marrow, as compared with their absence, was an independent prognostic indicator of the risk of death from cancer (relative risk, 4.17; 95 percent confidence interval, 2.51 to 6.94; P < 0.001), after adjustment for the use of systemic adjuvant chemotherapy.
Conclusion: The presence of occult cytokeratin-positive metastatic cells in bone marrow increases the risk of relapse in patients with stage I, II, or III breast cancer.

Comments:

Strengths/uniqueness: This report presents a large cohort of patients comprehensively studied and followed for four years.

Weakness: There is no discussion of whether the follow-up may have been influenced by knowledge of presence or absence of micrometastases. We are not told whether patients were informed of their micrometastases status, and the ethics of withholding this information.

Relevance to Palliative Care: The confirmation of early micrometastases (often already present in Stage I) is important information for palliative care practitioners, who frequently have to counsel distressed patients and family over issues of guilt (e.g. "I should have done self-examination/mammography") and anger (perception of failure of the health care system).

Phase III evaluation of fluoxetine for treatment of hot flashes. Downloadable PDF File

Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, Halyard MY, Pruthi S, Novotny PJ, Rummans TA. Journal of Clinical Oncology Vol 20 (6) 1578-1583

Prepared by: Dr. Sharon Watanabe

Received during: Journal Club, Tertiary Palliative Care Unit, Grey Nuns Community Hospital

Abstract:

Purpose: Hot flashes can be a prominent problem in women with a history of breast cancer. Given concerns regarding the use of hormonal therapies in such patients, other nonhormonal means for treating hot flashes are required. Based on anecdotal information regarding the efficacy of fluoxetine and other newer antidepressants for treating hot flashes, the present trial was developed.
Patients and Methods: This trial used a double-blinded, randomized, two-period (4 weeks per period), cross-over methodology to study the efficacy of fluoxetine (20 mg/d) for treating hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk). Eligible patients had to have reported that they averaged at least 14 hot flashes per week; they could have received tamoxifen or raloxifene as long as they were on a stable dose. The major outcome measure was a bivariate construct representing hot flash frequency and hot flash score, analyzed by a classic sums and differences cross-over analysis.
Results: Eighty-one randomized women began protocol therapy. By the end of the first treatment period, hot flash scores (frequency x average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significant greater marked hot flash score improvement with fluoxetine than placebo (P= .02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. The fluoxetine was well tolerated.
Conclusion: This dose of fluoxetine resulted in a modest improvement in hot flashes.

Comments:

Strengths/uniqueness:
This paper comes from a group that has an established track record in conducting clinical trials of treatments for hot flashes. The study appears to be methodologically sound.

Weaknesses:
The magnitude of fluoxetine's effect in relieving hot flashes is relatively small, especially considering the significant improvement of this symptom with placebo. As the study was conducted in patients who were cancer-free, the tolerability data are not generalizable to advanced cancer patients.

Relevance to Palliative Care:
Hot flashes do not appear to be a prominent symptom in the terminal phase of cancer, although they may be more bothersome earlier in the course of disease. For patients who are troubled by this symptom, there is a growing body of evidence supporting the role of antidepressants as a therapeutic option, particularly when hormones are contraindicated. However, the modest symptomatic benefit must be weighed against potential side effects, which tend to be more pronounced in patients with advanced illness.