David Coniglio

Prognostic and Predictive Factors for Patients With Metastatic Breast Cancer Undergoing Aggressive Induction Therapy Followed by High-Dose Chemotherapy With Autologous Stem-Cell Support

PURPOSE We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci (</= 2 v > 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases (</= 2 v > 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

The duke afm program intensive induction chemotherapy for metastatic breast cancer

Forty‐five patients have completed treatment with AFM, an intensive induction chemotherapy regimen composed of Adriamycin (doxorubicin, Adria Laboratories, Columbus, Ohio), 5‐fluorouracil, and methotrexate with folinic acid rescue. This regimen was designed to produce rapid and extensive tumor shrinkage prior to high‐dose alkylating agent chemotherapy with autologous marrow support. The overall response rate was 91%, and 38% of patients achieved complete clinical responses after a mean of 70 days on treatment. Hematologic and mucosal toxicity were extensive, but no toxic deaths were noted. AFM is a potent remission induction regimen for metastatic breast cancer, but its considerable toxicity suggests caution in its use for routine breast cancer treatment.

A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy

The prognosis for patients with metastatic breast cancer remains poor. Metastatic breast cancer confined to the bones may have a better prognosis, especially hormone receptor-positive disease. We performed a prospective, randomized clinical trial to compare immediate consolidation with high-dose chemotherapy and hematopoietic support versus observation with high-dose consolidation at the time of disease progression in women with metastatic breast cancer and only bone metastases. The patients received chemotherapy with doxorubicin, 5-fluorouracil and methotrexate before randomization. In all, 85 patients were enrolled and 69 were randomized. The median follow-up is 8.1 years from randomization. The median event-free survival (EFS) for the immediate transplant arm is 12 months and for the observation arm is 4.3 months (P<0.0001). The median overall survival for the immediate transplant arm is 2.97 years and for the observation arm 1.81 years, a difference that is not statistically significant. Immediate high-dose chemotherapy and radiation therapy as consolidation offers a clinically and statistically significant improvement in EFS compared with radiation therapy alone following induction chemotherapy for women with metastatic breast cancer confined to the bones.

A phase I trial of recombinant human interleukin-1β (OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation

We studied the effects of escalating doses of recombinant human IL-1β in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1β, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1β. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to >0.5 × 109/l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte–macrophage (CFU-GM) per 105 mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1β and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1β was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1β may accelerate hematologic recovery.

High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity

SummaryIntensive doses of carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support were given to four patients with advanced melanoma. Three developed clinically diagnosed, severe venoocclusive liver disease, which was fatal in two cases. The dose of carboplatin (450 mg/m2) was comparable with that used in ambulatory regimens. At the doses and schedule employed, this three-drug combination produced excessive hepatic toxicity. Caution is suggested when giving carboplatin in combination with intensive doses of other chemotherapeutic agents with known hepatotoxic potential.

Effects of granulocyte‐macrophage colony stimulating factor produced in Chinese hamster ovary cells (regramostim), Escherichia coli (molgramostim) and yeast (sargramostim) on priming peripheral blood progenitor cells for use with autologous bone marrow after high‐dose chemotherapy

Abstract: Peripheral blood progenitor cells (PBPCs) were collected without prior association with chemotherapy but after the administration of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) produced in Chinese hamster ovary cells (CHO‐GM, regramostim), Escherichia coli (E. coli‐GM, molgramostim), or yeast (Yeast‐GM, sargramostim) and used in conjunction with autologous bone marrow after high‐dose chemotherapy in 69 patients with breast cancer or melanoma. The mean peripheral white blood cell (WBC) counts increased by 2.2 to 2.7‐fold after regramostim, 4.5 to 7.3‐fold after molgramostim and 4.3‐fold after sargramostim. All patients underwent three leukaphereses. The mean (& standard error) total nucleated pheresed cells per kg × 108 were 4.15 & 0.56, 15.10 & 1.77 and 7.24 & 1.00 for patients receiving regramostim, molgramostim or sargramostim respectively. The mean (& standard error) granulocyte‐macrophage colony‐forming units per kg × 104 mobilized into the PB were 8.75 & 3.63, 71.03 & 17.85, and 65.11 & 18.74 for patients receiving regramostim, molgramostim, or sargramostim respectively. The total mean (& standard error) CD34+ cells per kg × 107 collected by three leukaphereses were 3.28 & 1.62, 1.34 & 0.51 and 2.57 & 1.93, for patients receiving regramostim, molgramostim or sargramostim respectively. The use of either molgramostim‐ or sargramostim‐primed PBPCs led to complete elimination of absolute leukopenia with a WBC count under 100/mm3 in 64% and 77% of patients treated, respectively. Patients receiving molgramostim‐primed PBPCs required fewer red blood cells transfusions than patients receiving regramostim‐primed PBPCs (p = 0.0062). Our data indicate that PBPCs collected without prior association with chemotherapy but after either molgramostim or sargramostim with autologous bone marrow support and GM‐CSF shorten the hematopoietic recovery after myeloablative chemotherapy in patients with breast cancer or melanoma.

Use of a Shared Mental Model by a Team Composed of Oncology, Palliative Care, and Supportive Care Clinicians to Facilitate Shared Decision Making in a Patient With Advanced Cancer

Our case describes the efforts of team members drawn from oncology, palliative care, supportive care, and primary care to assist a woman with advanced cancer in accepting care for her psychosocial distress, integrating prognostic information so that she could share in decisions about treatment planning, involving family in her care, and ultimately transitioning to hospice. Team members in our setting included a medical oncologist, oncology nurse practitioner, palliative care nurse practitioner, oncology social worker, and primary care physician. The core members were the patient and her sister. Our team grew organically as a result of patient need and, in doing so, operationalized an explicitly shared understanding of care priorities. We refer to this shared understanding as a shared mental model for care delivery, which enabled our team to jointly set priorities for care through a series of warm handoffs enabled by the teams close proximity within the same clinic. When care providers outside our integrated team became involved in the case, significant communication gaps exposed the difficulty in extending our shared mental model outside the integrated team framework, leading to inefficiencies in care. Integration of this shared understanding for care and close proximity of team members proved to be key components in facilitating treatment of our patients burdensome cancer-related distress so that she could more effectively participate in treatment decision making that reflected her goals of care.

Commentary: Physician Assistant Perspective on the Results of the ASCO Study of Collaborative Practice Arrangements

In this issue of Journal of Oncology Practice, Towle et al1 present the findings of a study exploring collaborative practice models between oncologists and nonphysician practitioners (NPPs). The study design did not differentiate between physician assistants (PAs) and advanced practice nurses. In this commentary, we offer a brief review of these new data in the context of what we know about NPP practice, summarize salient facts about the role of PAs, and provide recommendations for future consideration from our perspective as PAs.

The Pharmacologic Effects of Recombinant, Human Colony-Stimulating Factors and Their Modulation by Theophylline

Study Objectives. To investigate the effect of colony‐stimulating factors (CSFs) on drug metabolism using theophylline as a substrate (phase I), and to evaluate the influence of theophylline on endogenous serum cytokine concentrations (phase II).

Nonphysician Providers in Oncology

To the Editor: The May 2007 issue of Journal of Oncology Practice (JOP) contains two brief references to the use of nonphysician providers in oncology. Both deserve additional comment. Dr James Cohen, in his Letter to the Editor regarding the findings of the workforce study published in JOP in March, writes that the use of physician-extenders will be detrimental to the role of the physician-patient relationship.1 The growing body of data regarding the use of physician-extenders in the workforce suggests, in fact, that physician-extenders improve patient satisfaction, and professional satisfaction without adversely impacting the professional relationship between the patient and the physician.2 Dr Peter Paul Yu, writing for the ASCO Clinical Practice Committee discusses the potential role the nurse practitioner (NP) may play in the oncology workforce by examining what is currently understood about the background and training of the NP in oncology.3 Absent from the discussion is a similar consideration of requirements for physician assistant (PA) education. PA education is structured in the medical model. There are more than 130 accredited PA training programs. PAs must pass a national certifying examination in order to use the title Physician Assistant-Certified. Certified PAs must take a recertification examination every 6 years, in addition to earning 100 hours of continuing medical education credits every 2 years. Specialty certification is not required of PAs wishing to practice in subspecialties. There is currently one postgraduate residency program for PAs interested in additional oncology training. PAs work in the complete spectrum of oncology care, including medical oncology, surgical oncology, and radiation oncology, in the treatment of both pediatric and adult patients. To represent completely the spectrum of nonphysician providers in oncology care, PAs should be included in the ASCO Clinical Practice Committee discussion regarding nonphysician provider education and training.