Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma.

BACKGROUND: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. METHODS: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. RESULTS: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. CONCLUSIONS: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Critical factors for patient management.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Economic analysis of cancer treatment costs: another tool for oncology managers.

Oncology managers increasingly need more information about how much and why treatment costs vary across cancer patients. In response to this need, our Center is building an analytic capacity for investigating economic aspects of cancer treatment. Economic analysis is characterized by a simultaneous consideration of treatment costs and outcomes; it focuses on how treatment cost/outcome ratios vary across patient populations with similar diseases. In this paper, we present an overview of our work, with special emphasis on the measurement of outcomes and the inputs or costs of treatment, the variability of cost/outcome ratios, and the analysis of the factors that predict or explain this observed variation. We illustrate how the analysis is conducted, set out selected results relating to lung and breast cancer patients, and assess some of the advantages and disadvantages of the approach. Among other things, we conclude that economic analysis of cancer treatment costs is feasible and that it can provide useful data for managerial decision making.

Unconventional style reaps rewards for Ruckdeschel. Physician executive's career carries cancer center to the forefront. Interview by Patty Ryan.

He didn't like math. Loved biology. So he ditched his plans to become an engineer and ended up pursuing a career in medicine and hospital administration. He led a sleepy cancer center to new heights of cutting-edge research and progressive types of treatment. And he did it all on his own terms--a mix of practicality and instinct that serves up some interesting perspectives for fellow physician executives to consider. Meet John Ruckdeschel, MD.

Impact of clinical trials on the cost of cancer care.

BACKGROUND: Empirical evidence on the economic impact of cancer clinical trials is in short supply, but it is widely assumed that clinical trials add at least 10% to overall costs. OBJECTIVES: To estimate how much, if at all, trial enrollment increases the use of scarce resources in treating breast, lung, lymphoma, and ovarian cancer patients. RESEARCH DESIGN: A profile of the cumulative charges for all inpatient and outpatient hospital care received by a sample of patients over an observation period beginning at diagnosis and continuing for upwards of 44 months postdiagnosis. Patients are classified by whether they were enrolled on an IRB-sanctioned research protocol and, if so, by the type of protocol. Both univariate and multivariate statistical tests are conducted to appraise whether cumulative charges differ between patients who were enrolled on key types of protocols and those who were not. SUBJECTS: Approximately 1,900 breast, lung, lymphoma, and ovarian cancer patients treated at a single center. MEASURES: Clinical endpoints and demographic, disease, and therapy characteristics of patients that drive treatment costs. RESULTS: Controlling for demographic and disease characteristics, initial therapy, and key endpoints, the net effect of trial participation on cumulative charges for hospital inpatient and outpatient care is never significantly positive at conventional confidence limits. This result is found for each of the four patient groups and three types of protocols encompassed by this analysis. CONCLUSIONS: Support for clinical trials by health care payers does not necessarily risk adding significantly to the cost of cancer care.

Small-cell lung cancer.

The management of small-cell lung cancer (SCLC) evolved rapidly through the 1980s, but has stalled since then. The relative roles of surgery and radiotherapy in this former systemic disease have been worked out well. The chemotherapy of SCLC has progressed less rapidly. This article discusses the latest developments in each modality of treatment of SCLC and summarizes current treatment strategies.

Evaluating the financial impact of clinical trials in oncology: results from a pilot study from the Association of American Cancer Institutes/Northwestern University clinical trials costs and charges project.

PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials. METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer. RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P =.4) CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.

Pilot study with weekly chemotherapy for patients with extensive small cell lung cancer: an Eastern Cooperative Oncology Group Study (PA586).

PURPOSE: Six of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach. PATIENTS AND METHODS: Thirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation. RESULTS: Twenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months. DISCUSSION: This 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.

Strategic physician communication and oncology clinical trials.

PURPOSE: Clinical trials are the primary means for determining new, effective treatments for cancer patients, yet the number of patients that accrue is relatively limited. The purpose of this study was to explore the relationship between physician behavior and patient accrual to a clinical trial by videotaping the interaction. PATIENTS AND METHODS: Forty-eight patient-physician interactions involving 12 different oncologists were videotaped in several clinics at the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL). The purpose of each interaction was to present the possibility of a clinical trial to the patient. A coding system, the Moffitt Accrual Analysis System, was developed by the authors to code behaviors that represented both the legal-informational and social influence models of communication behavior. Thirty-two patients agreed to participate in the clinical trial. RESULTS: Videotaping was found to be a viable, valid, and reliable method for studying the interaction. Physicians who were observed to use both models of influence were found to enroll more patients. Thus, patients were more likely to accrue to the trial when their physician verbally presented items normally included in an informed consent document and when they behaved in a reflective, patient-centered, supportive, and responsive manner. Discussion of benefits, side effects, patient concerns and resources to manage the concerns were all associated with accrual. CONCLUSION: This research has implications for modifying physician behavior and, thus, increasing the numbers of patients accruing to oncology clinical trials.

Oral combination chemotherapy in the management of AIDS-related lymphoproliferative malignancies.

An oral combination chemotherapy regimen initially developed for AIDS-related non-Hodgkin's lymphoma includes lomustine (CCNU), etoposide, cyclophosphamide, and procarbazine. This regimen takes advantage of oral administration, the in vitro synergy of these drugs and their first-line efficacy in lymphoma, and the ability of lomustine and procarbazine to cross the blood-brain barrier. This regimen was used to treat 38 patients with AIDS-related non-Hodgkin's lymphoma. The overall objective response rate was 66% (34% complete response rate) with a 5% CNS relapse rate, and a median survival duration of 7.0 months. One-third of the patients survived for 1 year, 11% for 2 years, and half of the patients survived free from progression of their lymphoma. On the basis of these results, this oral regimen was modified and administered to 5 patients with AIDS-related primary CNS lymphoma as part of a sequential combined-modality chemotherapy and radiation regimen. Rapid progression of CNS disease was observed in this group of patients, with a median survival duration of 1.0 month. The identical regimen was administered to 7 patients with AIDS-related Hodgkin's disease: we observed a 71% partial remission rate and a median survival duration of 7.0 months. Myelosuppression remains the most significant clinical toxicity. Our results with this oral regimen appear comparable to those of standard intravenous combination chemotherapy regimens in patients with AIDS-related non-Hodgkin's lymphoma.

Future directions in non-small-cell lung cancer: a continuing perspective.

Non-small-cell lung cancer (NSCLC) will increasingly come under better control as the current approaches to therapy are more broadly employed and as new therapies are deployed against recently elucidated molecular pathways. In the United States, real progress is finally being made in decreasing tobacco consumption and in lung cancer incidence. The traditional chemotherapeutic compounds that became available earlier this decade (paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine], irinotecan [Camptosar], topotecan [Hycamtin], and edatrexate) have all been tested as single agents and as doublets with cisplatin (Platinol) and carboplatin (Paraplatin). Paclitaxel with cisplatin or carboplatin and vinorelbine, docetaxel, or gemcitabine with cisplatin have all demonstrated significant activity that now appears clearly better than the prior standard therapy of etoposide (VePesid)/cisplatin. Phase III studies sorting out their benefit relative to each other should be completed in the next 1 to 2 years. To date, no triplet therapy appears better than the corresponding doublet. Non-platinum-containing doublets are just completing their first round of assessments. Aside from new drugs and applications, the use of "small" molecules to inhibit either signal transduction pathways or gene activation is likely to accelerate. Most of the newer chemotherapeutic agents can be interdigitated with radiation and surgery, although evaluations into sequence and dose issues continue. The superior outcomes seen with the newer regimens should translate to the adjuvant and preoperative or preradiotherapy settings relatively quickly. It is now clear that NSCLC is as responsive to therapy as small-cell lung cancer (SCLC) and that outcomes are superior for NSCLC. The enthusiasm for treating SCLC displayed by nononcologists and nonthoracic medical oncologists should be shared for NSCLC.

Combined modality therapy of non-small cell lung cancer.

Combined modality therapy of locally advanced non-small cell lung cancer has become a widely used means of treatment with several reports of benefit found in randomized phase III trials. Progress in this area may, however, be less substantive than it appears. Phase III trials routinely take the better part of a decade to initiate, complete, and analyze, and the flood of phase II trials are largely unable to be compared because of a widespread failure to systematically use readily available staging techniques.

Induction paclitaxel/carboplatin in early stage non-small cell lung cancer. Bimodality Lung Oncology Team.

In this feasibility study, a 3-hour infusion of 225 mg/m2 paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was combined with carboplatin dosed to an area under the concentration-time curve of 6 to treat patients with stage T2N0, T1-2N1, or T3N0-1 (excluding superior sulcus tumors) non-small cell lung cancer. Nineteen of a planned 80 patients have been enrolled. To assure that patients meet the study's criteria for inclusion, rigorous physical and laboratory investigations are performed before, during, and after the preoperative chemotherapy and again before the postsurgical chemotherapy. Treatment includes two cycles of preoperative chemotherapy, followed within 3 to 6 weeks with thoracotomy. Up to three cycles of postoperative chemotherapy are planned, commencing 3 to 8 weeks after surgery, as tolerated. To date, 14 patients have completed induction chemotherapy, nine of whom have undergone surgical resection. Three patients have completed postoperative chemotherapy. The study treatment has been well tolerated with no unexpected toxicities. Very preliminary results suggest that perioperative paclitaxel/carboplatin appears to be a feasible and tolerable regimen in patients with early stage non-small cell lung cancer and warrants further investigation. More mature results may provide the basis for an intergroup randomized trial comparing this regimen with surgery alone for patients with early stage disease.

The crisis of cancer: psychological impact on family caregivers.

Cancer causes changes in the family's identity, roles, and daily functioning. Studies document that spouses are as distressed as cancer patients and that spousal and patient distress are correlated. Three major areas of caregiver concern are: fear of cancer and its spread, helping patients deal with the emotional ramifications of the disease, and managing the disruptions caused by cancer. From 20% to 30% of partners suffer from psychological impairment and mood disturbance as a result of the spouse's cancer. Factors that may predict high levels of spousal distress include: disease stage; emotional adjustment of the patient; gender, age, and other characteristics of the spouse; marital adjustment; and family functioning. Studies show that interventions do not reduce spousal distress. Future studies should explore the role of mediating factors, such as coping style, marital adjustment, and family functioning, on the relationship between illness demands or prognosis and distress. Interventions could then be targeted to high-risk individuals.

An allelic variant at the ATM locus is implicated in breast cancer susceptibility.

We have tested a simple procedure, disease association by locus stratification, for identifying breast cancer patients with pathogenetic allelic variants at several candidate loci. The strategy was based on the assumption of epistatic interactions of the candidates. We analyzed 66 independent cases from sib pairs affected with breast cancer that had previously been collected during an investigation of pathogenetic-allele-sharing at the HRAS1 mini-satellite locus. An exon 24 polymorphism of ATM, substituting arginine for proline was associated with breast cancer in these cases with an overall odds ratio of 4.5 (95% confidence interval, 1.2-20.5, nominal p = 0.02, 2-tail Fisher exact test). In the presence of a rare HRAS1 allele, the odds ratio increased to 6.9 (95% CI, 1.2-38.3, p = 0.03). Thus, our procedure identified at least one allelic variant of ATM associated with breast cancer, and indicated that the ATM locus may interact with HRAS1.

Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression.

The United States lung cancer epidemic has not yet been controlled by present prevention and treatment strategies. Overexpression of a Mr 31,000 protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, had shown promise as a marker of lung cancer. In a pilot study of archived preneoplastic sputum specimens, hnRNP A2/B1 overexpression more accurately detected preclinical lung cancer than standard cytomorphology. In separate, ongoing prospective studies, sputum is collected annually from stage I resected non-small cell lung cancer patients at high risk of developing a second primary lung cancer and Yunnan tin miners at high risk of primary lung cancer. After the first year of follow-up, preclinical detection of lung cancer by routine cytology was compared with hnRNP A2/B1 overexpression as measured by quantitative densitometry of immunostained slides. Up-regulation of hnRNP A2/B1 in sputum specimens accurately predicted the outcome in 32 of 40 primary lung cancer and control patients within 12 months, whereas cytological change suggestive of lung cancer was found in only 1 patient. In the primary lung cancer study, overexpressed hnRNP A2/B1 accurately predicted the outcome in 69 of 94 primary lung cancer and control miners, whereas only 10 with primary lung cancer were diagnosed cytologically. These two prospective studies accurately predicted that 67 and 69% of those with hnRNP A2/B1 up-regulation in their sputum would develop lung cancer in the first year of follow-up, compared with background lung cancer risks of 2.2 and 0.9% (35- and 76-fold increase, respectively). Using sputum cells to monitor hnRNP A2/B1 expression may greatly improve the accuracy of preclinical lung cancer detection.