Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with measurable, advanced NSCLC who had not received previous chemotherapy for advanced disease were considered for this study. Eligible patients who gave written informed consent initially received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3 weeks. After three patients received treatment at this dose, the dose was reduced to 500 mg/m(2) IV at the same infusion time and frequency because of toxicity seen in this study and another Canadian MTA trial in colorectal cancer. Patients received up to four cycles after complete or partial remission or six cycles after stable disease was documented. RESULTS: Thirty-three patients were accrued onto the study. All were assessable for toxicity, and 30 patients were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance status score of 0 or 1, 18 patients (55%) had adenocarcinoma, and nine patients (27%) had squamous cell carcinoma. Twenty-five patients (76%) had stage IV disease, and the remainder had stage IIIB disease at trial entry. Seven patients experienced a confirmed partial response and no complete responses were seen; thus, the overall response rate was 23.3% (95% confidence interval, 9.9% to 42.3%). The median duration of response was 3.1 months (range, 2. 3 to 13.5 months) after a median follow-up period of 7.9 months. Four (67%) of six patients with stage IIIB disease and three (12.5%) of 24 with stage IV disease responded to treatment. Four patients (13.3%) experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4 neutropenia, whereas only one patient (3%) developed grade 4 thrombocytopenia. Nonhematologic toxicity was generally mild or moderate, but 39% of patients developed a grade 3 skin rash. Most other toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and anorexia. Ten patients stopped protocol therapy because of toxicity. CONCLUSION: MTA seems to have clinically meaningful activity as a single agent against advanced NSCLC. Toxicity is generally mild and tolerable. Further study of this agent in combination with cisplatin and other active drugs is warranted in this disease.

Lung cancer practice guidelines: lessons learned and issues addressed by the Ontario Lung Cancer Disease Site Group.

PURPOSE: The primary objective was to identify the lessons learned and issues addressed by the Disease Site Group (DSG) developing guidelines on lung cancer for practitioners in the province of Ontario. METHODS: The minutes of the Ontario Lung Cancer Disease Site Group (LCDSG) and the meeting notes of a medical sociologist who attended all LCDSG meetings were reviewed to identify the disease-specific and generic issues addressed by the LCDSG during guideline development. RESULTS AND CONCLUSION: The Ontario LCDSG has completed three practice guidelines and has five evidence-based recommendations (EBRs) in production. Topics for guideline development were selected on the basis of known practice variability (eg, advanced-stage non-small-cell lung cancer [NSCLC]); the size of the patient population that could potentially be affected by the guideline; results of phase II trials of new and potentially expensive agents (vinorelbine, paclitaxel, and docetaxel); and randomized controlled clinical trials that support new practice standards (combined modality therapy for unresectable stage III NSCLC). The wording of each EBR reflects the strength and quality of the evidence in support of the treatment option, the primary outcome(s), and the individual physician and discipline values concerning treatment outcomes in the absence of known patient values.

Combination chemotherapy with bleomycin, etoposide, and cisplatin in metastatic non-small-cell lung cancer.

Fifty-three patients with recurrent and advanced stage (III and IV) non-small-cell lung cancer (NSCLC) were treated with a combination of bleomycin, etoposide (VP-16-213), and cis-diamminedichloroplatinum (BEP). Forty-eight patients were appraisable for response. The response rates were 44% for the entire group, 57% in 30 patients with combined squamous-cell and large-cell carcinoma, and 22% in 18 patients with adenocarcinoma (40%, 50%, and 19%, respectively, if patients not appraisable for response are included as nonresponders). The median survival time of patients with squamous-cell and large-cell carcinoma was slightly longer than that of patients with adenocarcinoma (23 weeks v 19 weeks). Patients with responsive disease survived significantly longer (median, 34 weeks) than did patients with unresponsive disease (median, 16 weeks) (P = .001). In the entire group, the median survival time of patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 was better (23 weeks) than of those with a status of 2 or 3 (15 weeks), but this difference was not seen in the subgroup with squamous-cell and large-cell carcinoma (24 weeks v 23 weeks, respectively). Thus, the performance status was not of prognostic value in the histologic subgroups experiencing the best response rate. There were two treatment-related deaths, but otherwise the toxicity of BEP was acceptable. Only four of the 119 treatment cycles were followed by fever even though there was significant neutropenia (0.5 X 10(9)/L) after 20 of 97 treatment cycles. The majority of patients receiving BEP experienced relief of cough, hemoptysis, pain, and fatigue associated with their disease. There was a good correlation between objective responses and palliation of symptoms. Thus, BEP offers good palliation, particularly for patients with squamous-cell and large-cell lung cancer.

Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma.

Varicella-zoster infection in adult cancer patients. A population study.

In a retrospective review of varicella-zoster (V-Z) Infections in adult cancer patients, 766 episodes of V-Z Infection were studied among 740 patients seen at a large comprehensive cancer center from 1972 to 1980. The highest risk of infection was present among patients with lymphoma and leukemia. The risk of dissemination of V-Z Infection was significantly associated with the presence of active tumor at the time of Infection. The site of the primary tumor correlated with the site of subsequent zoster Infection among patients with breast cancer, cancer of the respiratory tract, and gynecologic cancer. Pain attributable to V-Z Infection was present in a large majority of episodes. The median time from the completion of therapy to the onset of Infection was seven months for patients receiving radiotherapy and less than one month for those receiving chemotherapy. Various attributes of this study group were compared with those of previously studied cancer and noncancer populations.

The use of hydroxyurea to study the proliferative state of T-cell precursors (CFUT) in murine bone marrow.

The cycle specific drug, hydroxyurea (HU), has previously been used to study the proliferative kinetics of various hemopoietic precursor cells such as granulocyte-macrophage precursors (CFUc) and multipotential stem cells (CFUs). We have investigated the kinetics of another hemopoietic precursor, a T-cell colony (CFUT). When mice are exposed to two doses of HU, separated by 7 h, CFUT are reduced to approximately 30% of the control value. Surviving cells in the bone marrow quickly replenish the population and return it to normal values 2 days after HU treatment. When fresh bone marrow cells or bone marrow cells harvested from mice exposed 24 h earlier to HU are treated in vitro with HU, CFUT activity is reduced by approximately 70%. These data indicate that CFUT is a rapidly proliferating population with a large proportion of the cells always in cell cycle.

The evidence for tamoxifen and chemotherapy as treatment for metastatic melanoma.

Tamoxifen, an oestrogen antagonist routinely used in the treatment of breast cancer, has been used in clinical trials for patients with melanoma since the late 1970s. Following initial promise as a single agent for the treatment of metastatic melanoma, tamoxifen was first combined with chemotherapy in this setting in 1984. Since then, numerous phase II studies have combined tamoxifen with different chemotherapeutic agents, with some suggesting that tamoxifen significantly improves the efficacy of cisplatin-containing regimens. Overall response rates range from 8 to 60%. Several randomised trials also have been completed, with response rates of 12-30%. One such study showed statistically significant improvements in response rate and survival when tamoxifen was added to dacarbazine; however, other studies have not observed these benefits with the addition of tamoxifen to cisplatin-containing regimens. At present, the author's opinion is that the strength of evidence does not support the use of tamoxifen in combination with cisplatin-containing chemotherapy for the treatment of metastatic melanoma. Controversy remains as to whether the strength of evidence from the randomised trials outweighs the combined evidence from numerous nonrandomised trials. Resolution of this controversy may depend on the results of the North Central Cancer Therapy Group and/or a common agreement as to relative strength of evidence from clinical trials of different designs.

Combined chemotherapy and radiation therapy for non-small-cell lung cancer.

In a previous study of patients with recurrent or disseminated non-small-cell lung cancer (NSCLC), the combination of bleomycin, etoposide, and cisplatin (BEP) produced objective responses in ten of 17 (59%) patients with large-cell anaplastic carcinoma and in 14 of 35 (40%) with squamous-cell carcinoma. These results prompted a pilot study of combined modality therapy in which two cycles of BEP were administered prior to split-course radiation therapy. Thirty patients with surgically unresectable stage II or III squamous- or large-cell cancer, were entered into the study, of whom 25 were evaluable for response to chemotherapy. One patient (4%) had a complete response (CR), ten (40%) with measureable disease had a partial response (PR), and four (16%) with evaluable disease had significant disease regression prior to radiotherapy (overall response rate, 60%). After radiotherapy, six of 22 (27%) evaluable patients achieved a CR, and six (27%) a PR, for an overall response rate of 55%. Symptom control was achieved with chemotherapy in the majority of patients. The median survival time after the initiation of BEP had not been reached at 52 weeks. The results of this pilot study suggest that a phase III study comparing BEP plus radiation therapy with radiation therapy alone should be undertaken in this subgroup of patients with NSCLC.

Clinical isolation and characterization of aminoglycoside-resistant small colony variants of Enterobacter aerogenes.

Small colony variants of Enterobacter aerogenes, as well as the parental large colony type, grew in blood drawn for cultures on three separate days from a patient who had received suboptimal gentamicin therapy. Minimum inhibitory concentrations of four aminoglycoside antibiotics were eight to more than 16 times higher for small colony variants than for the normal large colony type. Small colony variants had defective catalase activity, which may have interfered with oxidative metabolism and aminoglycoside uptake. Small colony variants reverted readily to the parental type in vitro in the absence of aminoglycosides. Clinically isolated small colony variants appeared similar to those selected in the presence of gentamicin in vitro, with respect to colony morphology, aminoglycoside resistance and catalase deficiency. The isolation of small colony variants during gentamicin therapy in vivo suggests that such variants may be a cause of treatment failure in patients receiving aminoglycosides.

Volume regulation of natural killer cells under hypotonic stress: comparison with T and B cell subpopulations.

In response to hypotonic stress, human T and B cells vary in the ability to adjust their volume. Whereas T cells exhibit a regulatory volume decrease (RVD) under these conditions, B cells do not. We studied the ability of peripheral blood-derived natural killer (NK) cells to regulate their volume in this way. Percoll density gradient purified NK subpopulation showed variable RVD which suggested the presence of mixtures of regulatory and non-regulatory cells within these subgroups. Further purification by flow cytometry into Leu 7+ and Leu 11+ cells showed that these NK cells displayed RVD similar to thymocytes but distinct from B cells and more mature T cells. These data support the hypothesis that NK cells may be derived from T cell precursors which, upon differentiation to NK cells, retain the RVD characteristic of pre-T cells. This finding may also be useful in further characterizing neoplastic clones which display NK-like activity but phenotypic heterogeneity.

Biological response modifiers and infectious diseases: actual and potential therapeutic agents.

Biological response modifiers (BRMs) are agents which can modify the immune response to cancer or invasion of the organism by infectious agents. An explosive appearance of new BRMs has resulted from the development of recombinant gene technology and the availability of monoclonal antibodies. Colony-stimulating factors first became available for the prevention of neutropenia but may also have a role in the treatment of infections. Interleukin-1 is being tested as a modular of hematopoiesis and may be useful as a helper factor for T- and B-cell function. Immunoglobulins are being used against viral and bacterial infections while interferons can prevent viral upper respiratory infections and suppress or irradicate some viral hepatitides. Other BRMs which show promise include chemical agents and traditional herbal medicines.

Consensus on the use of neutrophil-stimulating hematopoietic growth factors in clinical practice: an international viewpoint.

Hematopoietic growth factors (CSFs) are now available for use in patients with myelosuppression due to congenital, acquired and therapy-induced conditions. Variations in the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in different countries are due to differences in approved indications by national regulatory agencies, varying opinions on the importance of certain treatment outcomes, differences in the selection of published and unpublished evidence of efficacy and the impact of the cost of these agents in different health care systems. Through Medline searches and personal files, we have reviewed the published literature on the efficacy and cost of GM-CSF and G-CSF in patients with severe chronic neutropenia and those receiving standard dose chemotherapy or high-dose chemotherapy requiring bone marrow reconstitution. Guidelines were established with regard to (1) the relative merits of different types of clinical studies and (2) the relative importance of different clinical outcomes as reported in these studies. The cost implications of these agents as they apply to the different clinical settings are also reviewed. Recommendations for the use of G-CSF and/or GM-CSF include: (1) the prevention of recurrent, debilitating infections in patients with severe chronic neutropenia; and (2) the maintaining of dose-intensity of potentially curative, standard-dose chemotherapy. While G-CSF and/or GM-CSF have been shown to improve secondary outcomes in higher-than-standard dose-intensive therapy, further studies are needed to test whether such improvements also lead to significant improvements in survival and/or quality of life. These recommendations are based on the collective interpretation of the presented evidence by an international group of investigators in this area.

Systemic infection by Rhodotorula spp. in the immunocompromised host.

Invasive fungal disease continues to be a significant problem among immunocompromised patients. We report a case of systemic Rhodotorula infection in a patient with acute myelogenous leukaemia. Rhodotorula was isolated from bone marrow on two separate occasions despite initial treatment with amphotericin B. Liver computerised tomographic scan suggested liver abscesses, and yeasts were seen on biopsy. The patient survived after aggressive antifungal and antileukaemia treatment. Rhodotorula fungaemia has been occasionally associated with shock. As our case illustrates, Rhodoturola may be a cause of invasive fungal disease in the immunocompromised host but can be eradicated if treated aggressively.

Small-cell carcinoma of the vagina. A clinicopathologic study.

We report a case of small-cell carcinoma of the vagina in a women whose entire uterus, cervix, both fallopian tubes, and both ovaries had been removed 22 years previously. She presented with diffuse submucosal disease of the distal vagina with a possible soft-tissue component extending beyond the end of the vaginal vault. Extensive microscopic and immunohistochemical assessment established the diagnosis; treatment was initiated with chemotherapy, followed by local radiotherapy. To our knowledge, this is the first fully characterized case of its kind. We discuss the aggressive local behavior and the characteristics of gynecologic small-cell tumors in general.

Current approaches to the treatment of advanced-stage Hodgkin's disease.

Combination chemotherapy (CT) has been the mainstay of treatment of advanced-stage Hodgkin's disease since the late 1960s. Although treatment with MOPP (nitrogen mustard, vincristine sulfate [Oncovin], procarbazine and prednisone) has resulted in long-term disease-free survival rates exceeding 50%, newer approaches have been studied to improve on this success rate and to reduce the toxic effects associated with MOPP. Prognostic factors have now been defined that identify patients who may require more aggressive treatment; they include age greater than 40 years, presence of B symptoms and more advanced (especially extranodal) disease. A small number of patients with pathological stage III disease may still be successfully treated with extensive radiotherapy (RT) alone. Among patients with advanced-stage disease, significantly better therapeutic results are being obtained with newer treatment approaches than with MOPP, particularly in patients with factors that predict a poor outcome. These newer approaches include combination CT plus RT, alternating cycles of two non-cross-resistant CT regimens and hybrid regimens, which combine agents from two different CT regimens in one cycle. The prognosis of patients who suffer relapse after combination CT remains poor, even with newer drug regimens. The newer treatment approaches may well lead to better cure rates and fewer short-term and long-term toxic effects.

Are quality of life, patient preferences, and costs realistic outcomes for clinical trials?

Health-related quality of life (HRQL) is a relatively new outcome, which is being considered for incorporation into randomized, controlled clinical trials. Instruments that detect different aspects of HRQL include health profiles and utility measurements. While the results of the former are highly responsive to change over time but not easily comparable between studies, utility measurements are not as responsive to change, but as single numerical values are more comparable between studies. With the growing number of multidimensional instruments available for measurement of the quality of life, investigators must be careful to select instruments that are reliable and have been validated for incorporation into clinical trials. Similarly, investigators must choose an instrument or instruments which are best suited to detection of the primary HRQL outcomes of interest for a specific population. A relatively new method for describing the quality of life during different health states is Q-TWiST analysis. An example is provided, demonstrating how the different short-term health states of patients with small cell lung cancer can be presented and quantified. While economic evaluation has often included quality of life within the concept of the quality-adjusted life year ( QALY ), determination of utilities within this concept has been highly variable and the validity of the QALY as a concept has been questioned. The healthy years equivalent ( HYE ) has been proposed as a more appropriate alternative. At the health policy decision-making level, controversy persists over how much society should pay for expansive new interventions and what boundaries for allocation should be established. Much work is still needed to improve comparability of HRQL results and to incorporate these results into clinical decision making involving individual patients and health policy makers.

Current approaches to the treatment of advanced-stage non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas (NHLs) are a diverse group of malignant diseases whose clinical behaviour and treatment are distinct from those of Hodgkin's disease. In advanced-stage NHL certain histologic subtypes grow relatively slowly, initially produce few symptoms and, even when untreated, are associated with survival that is usually measured in years. Other, less favourable subtypes grow more rapidly, produce symptoms earlier and result in rapid clinical deterioration and death if aggressive treatment is not begun at the time of diagnosis. Many patients with advanced-stage higher-grade NHL can now expect cure, whereas those with lower-grade NHL cannot. Among the higher-grade lymphomas, factors associated with a poorer prognosis include B symptoms, age greater than 50 years, bulky disease (particularly in the abdomen) and extranodal disease with bone marrow or gastrointestinal involvement. These factors have less effect on prognosis in lower-grade lymphomas. Combination chemotherapy (CT) has been the mainstay of treatment for advanced-stage higher-grade NHL. Newer regimens contain more agents given earlier in the treatment plan. Radiotherapy is a useful supplement to CT in some patients with bulky disease. Most CT regimens have been developed through retrospective uncontrolled studies. Prospective randomized clinical trials must be designed to compare the efficacy of newer, more toxic but seemingly more effective regimens and earlier, less toxic regimens. Such trials should determine which patients may achieve optimal survival results with the least toxic therapy.