Robert Buckman

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Breaking bad news: the S-P-I-K-E-S strategy

Breaking bad news to patients is one of the most difficult and demanding tasks that oncologists face—and one for which they are often poorly trained and emotionally ill equipped. The S-P-I-K-E-S protocol described in this article provides a simple, easily learned strategy for communicating bad news and suggests ways to assess the situation as it evolves and respond constructively to patients. Showing empathy, exploring the patient’s understanding and acceptance of what he or she has just learned, and validating that patient’s feelings can provide muchneeded support to the patient, an essential psychological intervention for managing distress and helping the patient face the treatment decisions ahead. Although breaking bad news will never be easy, having a plan of action and knowing that you can support your patient through a difficult period should help considerably. Psychosocial Oncology

Communication skills in palliative care: A practical guide

Communication skills are frequently regarded as innate and intuitive. Many studies, however, now show that most components of communication techniques can be taught and that these learned skills have an impact on the physicians ability to communicate. This article sets out two fundamental protocols that act as templates or strategies for communication. One, (the C-L-A-S-S strategy) highlights the five central factors in all clinician-patient interviews. The second (the S-P-I-K-E-S protocol) is a variant for the specific task of breaking bad news.

Phase I/II Trial of Metronomic Chemotherapy With Daily Dalteparin and Cyclophosphamide, Twice-Weekly Methotrexate, and Daily Prednisone As Therapy for Metastatic Breast Cancer Using Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor Levels As Markers of Response

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer. PATIENTS AND METHODS The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence. RESULTS Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive. CONCLUSION Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.

Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer

The life and work of Judah Folkman make a fascinating story. There is an old saying to the effect that truth is like daylight shining behind a curtain which has many pinholes—how much you see doesn’t depend on which hole you decide to look through, but on how close to the curtain you get your eye. Judah Folkman, in a research career spanning the last three decades, has clearly got very close to the curtain indeed. Extraordinarily, he arrived in cancer research after starting in a totally different area. The research that eventually moved towards angiogenesis actually began as a project investigating the damage sustained by erythrocytes as they circulated through a prototype heart-lung machine. This was perhaps a rather unpromising pinhole to start peering through, but this book meticulously chronicles and clearly explains every step from that project, to his current research which has far-reaching implications for the way cancers are treated. Folkman wanted to find out why natural blood vessels caused less damage than metal tubes, and to do that he needed a way of looking at blood vessels. That got him interested in what makes blood vessels grow and what stops them from growing, and by that time—from what we learn of his personality—his attention was fully engaged. At times the story reads almost like science fiction, being somewhat reminiscent of Kurt Vonnegut’s creation Felix Hoenikker: the physicist who invents “ice9” (a form of ice that is solid at room temperature) because he wants to help soldiers walk through mud, and freezing the mud seems a good solution. Folkman was clearly capable of that type of thinking and he showed, even early in his career, a rare ability to back up his thoughts and ideas with the dogged persistence to put in the hours, months and years to get a reliable answer. Folkman’s research into the mechanisms involved in tumor-induced angiogenesis has changed many fundamental aspects of the way we think about tumor growth, and ways in which that growth might be controlled. Perhaps it was inevitable that his ideas, running counter to orthodox thinking, should at first have been dismissed. But history has changed prevailing attitudes. Folkman’s work has in many respects now filled the breach created by the failure of high-dose chemotherapy (with autologous marrow or stem-cell support) to cure most common solid tumors. During the 1980s and most of the 1990s when eradication of every last tumor stem-cell seemed the only way to prolong patient survival, it was not surprising that so few people were genuinely interested in tumor vasculature. Now that ‘more-is-better’ is no longer inviolable dogma, the world is turning its attention to Folkman’s suggestion that tumor vasculature might be a far more suitable target for therapy, which might need to be administered virtually continuously rather than as periodic and sometimes highly toxic doses. What makes this book even more interesting for researchers and clinicians alike is the degree of detail, including the naming of names. Robert Cooke, a well-known science journalist, gives the reader a blow-by-blow account of the research projects themselves and of the accompanying difficulties in grant funding, publication and partnerships with pharmaceutical and biological manufacturers. Two things will impress any researcher who reads this. First, even a major figure like Folkman had years of rejection—when his grants were turned down and some of his colleagues treated him as a pariah. Second, partnerships between academia and industry are fraught with traps, ambushes and reverses. I found myself astounded at how Folkman was able to survive and function despite so many projects that didn’t turn out as hoped, rejections from funding agencies for some that had, and tussles with the various hierarchies of academic institutions and major companies. On top of all that, there is the small matter of public relations. The world at large first heard of Judah Folkman’s work in 1998 when the New York Times ran a frontpage headline that was only a hairsbreadth away from the ‘major breakthrough’ cliché. It was based on a conversation with Nobel laureate James D. Watson who had said, informally, that Folkman would cure cancer in two years. Folkman has always had a reputation—completely justified in the view of all those who have heard him lecture—for enthusiasm and clarity. But, unlike a few cancer researchers, he has always resisted far-fetched speculations and any ‘all-we-need-to-do-is’ proclamations, and he has been careful and thoughtful in describing the implications of his work. To someone who always put so much care and thought into his statements, the New York Times headline must have been like a bomb. The whole story of that episode, clearly and neatly explained in this book, is a valuable manual for any scientist trying to handle the media—and it shows that things can get out of hand even when you stick to all the rules yourself. Regarding the future and the import of Folkman’s work, it is only rarely that one can agree with blurbs on the back jacket— especially if they are headed ‘advance praise’. But when MIT’s Robert Weinberg says that Folkman’s ideas will “one day dramatically change cancer therapy,” my guess is that he is right.

Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methothrexate, and daily prednisone (DalCMP) as therapy for metastatic breast cancer (MBC).

1152 Background: We recently published data on 41 patients (pts) treated with DalCMP (JCO 2009). We have now accrued additional pts to further compare responses in pts treated or not with prior anthracycline (A) and taxane (T) based regimens. Methods: Pts with measurable MBC received daily sc dalteparin (5,000UI), po cyclophosphamide (50mg), twice weekly po methothrexate (2.5mg BID) and daily po prednisone (5mg). Primary study endpoint was clinical benefit rate (CBR) (i.e., complete response [CR] + partial response [PR] + prolonged stable disease for ≥ 24 weeks [pSD]). Secondary endpoints included time to progression (TTP), duration of response (DOR), and overall survival (OS). Pts were in group 1 (no prior chemotherapy for metastatic disease) or group 2 (prior A and T for metastatic disease, or prior adjuvant A and T if relapse < 1 year, or prior adjuvant A and prior T for metastatic disease). Adverse events were assessed by common toxicity criteria version 2 (CTCAE). Kaplan-Meier methods and log rank te...