G. T. Budd

SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer

PURPOSE To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. PATIENTS AND METHODS A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. RESULTS Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). CONCLUSION Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.

Phase II Trial of Liposomal Doxorubicin (Doxil®) in Advanced Soft Tissue Sarcomas

AbstractPurpose: To assess the objective response rate, toxicityexperienced, progression-free survival, and overall survival ofpatients with previously untreated advanced soft tissue sarcomastreated with a liposomal doxorubicin formulation (Doxil). Methods: Patients with metastatic or recurrent soft tissuesarcoma who had received no prior chemotherapy for advanceddisease were treated with liposomal doxorubicin (Doxil) accordingto a two stage accrual design. Doxil was administered at 50mg/m2 every 4 weeks. A total of 15 patients were treated andare evaluable for response and toxicity. Results: The male/female ratio was 7/8, the median age was60 years (34–75) and the ECOG performance status was 0-1 in>90% of patients. Leiomyosarcoma (7/15) and malignant fibroushistiocytoma (2/15) were the most common histologic diagnoses.No objective responses were observed in the 15 evaluablepatients. No lethal toxicity occurred. Grade 3–4 leukopenia orneutropenia were reported in 3/15 (20%) patients. Grade 3mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15(7%) patients respectively and seemed more severe in olderpatients. The median time to progression was 1.9 months (range0.9–6.2). Twelve patients have now died. The Kaplan-Meierestimate of median overall survival is 12.3 months. As called forin the study design, accrual was terminated because no responseswere obtained in the first 15 patients. Conclusion: Though well-tolerated, Doxil given accordingto this dose and schedule to patients with advanced soft tissuesarcoma had no significant therapeutic activity. A correlationbetween older age and skin/mucosal toxicity of Doxil is suggestedin this study but needs confirmation. Future investigations ofDoxil in soft tissue sarcomas should use a different schedule anddose.

Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.

PURPOSE Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated. PATIENTS AND METHODS rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy. RESULTS The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy. CONCLUSION rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.

5-Fluorouracil and Folinic Acid: a Phase I–II trial in gastrointestinal malignancy

SummaryFifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I–II clinical trial. Two different schedules were used: (a) bolus infusion — 5FU 7 –12 mg/kg/d I.V. d1–5, FA 1.6 mg/kg/d I.V. d1–5; (b) continuous infusion — 5FU 600–1200 mg/m2/d I.V. d1–4, FA 60 mg/m2/d I.V. d1–4. Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg/d I.V. d1–5 and 1000 mg/m2/d I.V. d1–4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), including responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equivalent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The possibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.

Phase I study of WR-2721 and carboplatin

Because WR-2721 reduces the toxicity of cisplatin and carboplatin in preclinical systems, we have treated 35 patients in a phase I study of WR-2721 and carboplatin. As the plasma half-life of WR-2721 is short relative to that of carboplatin, WR-2721 was administered in two divided doses. This schedule produced acceptable toxicity in 24 patients treated with carboplatin 400 mg/m2 and escalating doses of WR-2721. In the subsequent 11 patients, WR-2721 was fixed at 740 mg/m2/dose and the dose of carboplatin was escalated. With WR-2721, grade 3-4 thrombopenia (platelets < 50 x 10(9)/l) was produced in 4/5 patients treated with carboplatin 625 mg/m2 and in 1/6 patients treated with carboplatin 500 mg/m2. Carboplatin pharmacokinetic parameters in 4 patients were similar to those reported for carboplatin alone. These results suggest that WR-2721 might increase the maximum tolerated dose of carboplatin from 400 to 500 mg/m2.

Intimal pulmonary artery sarcoma presenting as dyspnea: case report.

BackgroundWe report a case of pulmonary sarcoma which is a rare cause of the common symptom of dyspnea.Case presentationA fifty-one year old previously healthy male presented to the emergency room with complaints of dyspnea on exertion. A cardiac workup including an exercise stress test was negative but an echocardiography showed pulmonary stenosis. Cardiac MRI showed a large mass extending from the pulmonic valve to both the right and left pulmonary arteries suggestive of sarcoma. A complete resection and repair of the pulmonary artery was done and adjuvant chemotherapy with doxorubicin and ifosfamide was recommended. The patient is currently disease free after eighteen months.ConclusionPulmonary artery sarcomas are a difficult diagnosis. The diagnosis may remain elusive for some time until the proper imaging techniques are utilized to make a diagnosis. Earlier and accurate diagnosis may lead to earlier interventions and improve survival.

Phase I and II trials of subcutaneously administered rIL-2, interferon alfa-2a, and fluorouracil in patients with metastatic renal carcinoma

Purpose: A phase I followed by a phase II trial utilizing rIL-2, IFNα, and 5-FU were conducted in patients with unresectable and/or metastatic renal cell carcinoma. Methods: Treatment consisted of: rIL-2 at 5.0 × 106 IU/m2 SQ on days 1–5 for 4 weeks, rHuIFNα-2a at 5.0 × 106 U/m2 SQ on days 1, 3, and 5 for 4 weeks, and 5-FU by IV bolus on days 1–5 during week 1. In the phase I study, patients were treated at varying doses of 5-FU: I-none, II-250 mg/m2, III-300, and IV 375. A phase II trial was then conducted utilizing the same schedule and maximum tolerated dose (MTD) for 5-FU. Results: Twenty patients were entered into the phase I trial. Dose-limiting toxicity included grade III nausea and vomiting, and one sudden cardiac death. The MTD for 5-FU was determined to be 300 mg/m2. In the phase II trial, a median of two cycles of therapy was administered to 25 evaluable patients. Toxicity was moderate and consisted primarily of fevers, chills, fatigue, nausea/vomiting, and anorexia. Grade IV thrombocytopenia, consistent with ITP, developed in one patient each on the phase I and phase II trial. Seven partial responses were seen among 25 patients treated in the phase II trial for a 28% (CI 12–49%) response rate. Conclusions: The addition of 5-FU to rIL-2 and rHuIFNα-2a appears to increase the toxicity of this therapy. Randomized trials will be required to determine if efficacy is enhanced.

Amifostine: potential for clinically useful cytoprotection

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radio-protectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclophosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on non-hematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.

A Phase I Trial of Weekly Gemcitabine and Subcutaneous Interferon Alpha in Patients with Refractory Renal Cell Carcinoma

AbstractIntroduction: Recombinant humaninterferon-α2b (rHuIFN-α2b)and Interleukin-2 have limitedeffectiveness in the treatment ofmetastatic renal cell carcinoma (MRCC).Gemcitabine (Gemzar®) is also reported tohave activity against MRCC, and recent invitro, in nude mice xenografts, and humandata suggests increased activity ofgemcitabine (Gemzar®) when combined withIFN-α2b. Purpose: A phase I clinical trialutilizing gemcitabine (Gemzar®) andrHuIFN-α2b was conducted in patientswith metastatic renal cell carcinoma. Methods: Treatment consisted of:gemcitabine (Gemzar®) 600 mg/m2 I.V.weekly and rHuIFN-α2b 1.0 MU/m2(dose level A) or 3.0MU/m2 S.C. (doselevel B) three times a week for 6 weekswith a 2 weeks rest period. Results: Thirteen patients wereentered into the trial and were evaluated.Dose limiting toxicity was predominantlyhematologic, and was seen at dose level B.This included grade 3 anemia (1 patient),neutropenia (1 patient), and nausea (1patient) and grade 4 neutropenia (1patient). The maximal tolerateddose was gemcitabine (Gemzar®)600 mg/m2 I.V. weekly andrHuIFN-α2b 1.0 MU/m2 threetimes a week. Conclusion: This combination ofgemcitabine (Gemzar®) and rHuIFN-α2bhas significant hematologic toxicitydespite low doses of each agent. Furtherinvestigation of this combination usingthis schedule is not recommended.

Phase II trial of doxorubicin and trifluoperazine in metastatic breast cancer

SummaryPre-clinical and clinical studies have shown that trifluoperazine (TFP) can modulate multidrug resistance. We have performed a Phase II trial of TFP and doxorubicin in doxorubicin-naive patients with metastatic breast cancer. We hypothesized that TFP would inhibit the development of doxorubicin resistance, resulting in an increased rate of complete response or a prolongation in response duration. Twenty patients with metastatic breast cancer were treated every 3 weeks with TFP 5 mg by mouth every 6 hours on days 0–5 and doxorubicin 60 mg/m2/96 hr on days 1–4 by continuous intravenous infusion. The first 5 patients were treated with TFP 15 mg by mouth every 6 hours, but the dose was reduced to 5 mg every 6 hours when grade 3–4 extrapyramidal toxicity was noted in 3 of the first 5 patients. Thereafter, neurologic toxicity was grade 0–2. No complete and 9 partial responses were produced in 20 patients (45%). The median response duration was 17 weeks (range 7–112). The combination of trifluoperazine and doxorubicin did not seem to produce a response rate or duration markedly different than that expected for doxorubicin alone in patients with metastatic breast cancer. Alternative trial designs may be necessary in future clinical trials investigating the inhibition of acquisition of drug resistance.