Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer.

Fifteen patients with Stage IIIB or IV non-small cell lung cancer gave informed consent to receive three or more 96-hour infusions of ATP at a dose of 50 mcg/kg/min or higher to determine whether ATP has antineoplastic activity against this tumor type and to better define the spectrum of toxicity for ATP given as a single agent. There were no objective complete or partial responses observed. The median survival of the overall group was 187 days and the median time to tumor progression was 113 days. The major toxic side effects were chest pain and dyspnea, leading to the cessation of treatment in 5 patients. We conclude that ATP at this dose and schedule of administration is an inactive agent in patients with advanced non-small cell lung cancer.

Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer.

Adenosine 5'-triphosphate (ATP) has antineoplastic activity in vitro and in murine tumor systems, but there are no data in humans defining its potential use as an antineoplastic agent. We conducted a phase I study to determine the spectrum of toxicity, maximum safely tolerated dose (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with advanced cancer received 96-hour infusions of ATP once monthly in doses ranging from 50 to 100 micrograms/kg/minute. Toxicity was assessed by standard National Cancer Institute (NCI) criteria, cardiac function was monitored serially by two-dimensional echocardiography, and whole blood ATP was measured serially in a subset of patients. ATP was generally well tolerated and no significant hematologic toxicity was noted. The dose-limiting toxicity was a cardiopulmonary reaction characterized by chest tightness and dyspnea that resolved within seconds of discontinuing ATP. Dose-limiting cardiopulmonary toxicity occurred in 3 of 3 patients at 100 micrograms/kg/minute, in 3 of 6 patients at 75 micrograms/kg/minute, and 4 of 11 patients at 50 micrograms/kg/minute. Whole blood ATP levels significantly increased with treatment, reaching a steady state by 24 hours and returning to or near baseline by 1 week after treatment. Plateau levels were 63%, 67%, and 116% above base-line at 50, 75, and 100 micrograms/kg/min, respectively. We conclude that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 micrograms/kg/minute is both the MTD and the most appropriate dose rate for subsequent Phase II testing of 96-hour infusions of ATP in patients with advanced cancer.

Clinical use of tumor markers in oncology.

The perfect tumor marker would be one that was produced solely by a tumor and secreted in measurable amounts into body fluids, it should be present only in the presence of cancer, it should identify cancer before it has spread beyond a localized site (i.e., be useful in screening), its quantitative amount in bodily fluids should reflect the bulk of tumor, and the level of the marker should reflect responses to treatment and progressive disease. Unfortunately, no such marker currently exists, although a number of useful but imperfect markers are available. The predominant contemporary markers are discussed here by chemical class, as follows: glycoprotein markers, including carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and prostate specific antigen (PSA); mucinous glycoproteins, including CA 15-3, CA 19-9, mucinous-like cancer antigen and associated antigens, and CA 125; enzymes, including prostatic acid phosphatase (PAP), neuron specific enolase (NSE), lactic acid dehydrogenase (LDH), and placental alkaline phosphatase (PLAP); hormones and related endocrine molecules, including calcitonin, thyroglobulin, and catecholamines; and, molecules of the immune system, including immunoglobulins and beta-2-microglobulin. The biologic properties of each group of tumor markers are discussed, along with our assessment of their role in clinical medicine today.

Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference?

Current chemotherapy treatment of metastatic non-small cell lung cancer has demonstrated some objective responses, but is still largely palliative. This report reviews the results of a randomized trial in patients with advanced metastatic non-small cell lung cancer which compared treatment with supportive care (treatment with palliative radiation, psychosocial support, analgesics, nutritional support) to supportive care plus combination chemotherapy with cisplatin and vinblastine. Although the patients receiving combination chemotherapy had a slightly longer median survival (20.43 weeks versus 13.57 weeks), it was not statistically significant (P = 0.09). In addition, the patients receiving chemotherapy experienced serious toxicity, and showed no significant benefit in terms of quality of life as measured by Karnofsky performance status score. The authors conclude that contemporary combination chemotherapy provides only modest survival benefit to patients with advanced metastatic non-small cell lung cancer and should not be considered standard therapy. Future investigations of chemotherapy in patients with unresectable non-small cell lung cancer should continue to utilize control arms which provide high-quality supportive care.

Estimating the quality of life in a clinical trial of patients with metastatic lung cancer using the Karnofsky performance status and the Functional Living Index--Cancer.

Serial assessments of Karnofsky performance status (KPS) and of the Functional Living Index--Cancer (FLIC) have been used to estimate the quality of life (QOL) of patients in a prospective, randomized trial of supportive care versus supportive care given with combination chemotherapy to patients with metastatic non-small cell lung cancer. There was a good correlation between KPS and FLIC scores at study entry, thus confirming results originally reported using the FLIC. However, a number of unexpected problems were encountered in data collection and quality control with this QOL assessment instrument. This made it impossible to look for differences in treatment effect on QOL in this clinical trial. It is believed that QOL assessment should be an integral part of cancer clinical trials; however, investigators must acknowledge the difficulties in collecting this type of data. The development of new instruments and the refinement of old ones will facilitate the collection of data for this important aspect of clinical trials research.

Non-small cell lung cancer.

Lung cancer stands as the most important malignant neoplasm in the United States because of its high prevalence, increasing incidence, high rate of mortality, and great potential for prevention through the control of cigarette smoking. The World Health Organization (WHO) classification of lung cancer identifies four major types: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma. These tumors are commonly divided into two groups based on differences in their biology and treatment: small cell (SCLC) and non-small cell carcinomas (NSCLC). This review analyzes NSCLC with a strong emphasis on the practical aspects of treatment. We give recommendations about smoking cessation and early diagnosis through screening of high-risk individuals. We review contemporary diagnostic and staging techniques in the context of the new international TNM system of staging. Subsequent discussions of treatment are based on this new staging system. We stress the pivotal role of surgery for the management of local disease, and in addition present the potential contributions of newer radiation therapy techniques. We examine chemotherapy in detail, including a review of the comparative activity of the available cytotoxic agents against NSCLC, the relative contribution of combination chemotherapy, and the role of surgical adjuvant treatment with either chemotherapy or immunotherapy. We advise that patients with NSCLC be treated under the aegis of modern clinical trials of new therapy whenever possible. When this is not possible, we recommend an individualized approach based on such factors as the patient's age, general state of health, cardiopulmonary status, psychosocial status, and personal system of values.

Metastasis of unknown origin.

Metastasis of unknown origin (MUO) constitutes between 5% and 10% of all noncutaneous cancers. An MUO is defined as a metastatic tumor for which the site of origin is not suggested by thorough history, physical examination, chest x-ray studies, routine blood and urine studies, and histologic evaluation. Two major groups of MUO can be defined: MUO to lymph nodes only (N1-3), and MUO to visceral sites. The prognosis may be quite good for patients with MUO limited to lymph nodes in the mid to high cervical, axillary, and groin areas. However, MUO in other lymph node areas is far more serious, with the possible exception of that in patients with a new syndrome, i.e., "advanced poorly differentiated carcinoma of unknown primary origin." There is some suggestion that these patients may respond to cisplatin-based combination chemotherapy. Patients with MUO to visceral sites have a poor prognosis. However, metastases from some primary tumors are sensitive to chemotherapy and a limited search for these tumors should be undertaken. These tumors include leukemia-lymphoma, germ cell tumors, small cell carcinoma of the lung, adenocarcinomas of the breast, ovary, endometrium, thyroid, or prostate, and possibly adrenal carcinoma. We start by reviewing the biochemical events of metastasis that may be targets for therapy. The importance of a correct tissue diagnosis is then considered, including the role of standard histochemistry, electron microscopy, enzyme histochemistry, and immunohistochemistry. The relatively limited value of radiologic tests in localizing the primary site of origin of the tumor is emphasized, as well as the limited role of currently available biomarkers. We conclude by discussing the treatment of each of the subtypes of MUO.

Non-small cell lung cancer.

Lung cancer stands as the most important malignant neoplasm in the United States because of its high prevalence, increasing incidence, high rate of mortality, and great potential for prevention through the control of cigarette smoking. The World Health Organization (WHO) classification of lung cancer identifies four major types: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma. These tumors are commonly divided into two groups based on differences in their biology and treatment: small cell (SCLC) and non-small cell carcinomas (NSCLC). This review analyzes NSCLC with a strong emphasis on the practical aspects of treatment. We give recommendations about smoking cessation and early diagnosis through screening of high-risk individuals. We review contemporary diagnostic and staging techniques in the context of the new international TNM system of staging. Subsequent discussions of treatment are based on this new staging system. We stress the pivotal role of surgery for the management of local disease, and in addition present the potential contributions of newer radiation therapy techniques. We examine chemotherapy in detail, including a review of the comparative activity of the available cytotoxic agents against NSCLC, the relative contribution of combination chemotherapy, and the role of surgical adjuvant treatment with either chemotherapy or immunotherapy. We advise that patients with NSCLC be treated under the aegis of modern clinical trials of new therapy whenever possible. When this is not possible, we recommend an individualized approach based on such factors as the patient's age, general state of health, cardiopulmonary status, psychosocial status, and personal system of values.

Pharmacologic aspects of lung cancer chemotherapy.

A relatively small group of chemotherapeutic agents have gained widespread acceptance in the treatment of lung cancer. The pharmacologic properties of these agents are reviewed.

Carcinoembryonic antigen in breast cancer. Clinical review.

Carcinoembryonic antigen is widely used as a tumor marker for gastrointestinal neoplasms. Its role in the management of other tumors is poorly defined. This review considers the place of carcinoembryonic antigen measurement in the management of breast cancer and concludes that sufficient data exist to support its use in clinical practice. Of the many potential uses, the major role for carcinoembryonic antigen measurement in breast cancer is in following patients with advanced disease, especially patients with bone metastases.

Clinical thermochemotherapy. A controlled trial in advanced cancer patients.

In vitro and in vivo animal studies and some clinical trials have shown apparent benefit from thermochemotherapy; however, this treatment modality has not been adequately tested in humans. This investigation evaluated response to and toxicity of secondary thermochemotherapy, using each patient as his own control. Patients with advanced cancer who had documented disease progression while receiving chemotherapy alone were subsequently treated with the same drug, by the same dose and route, combined with localized hyperthermia. Thirty-four patients whose diseases included metastatic colon carcinoma, melanoma, sarcoma and hepatoma in viscera (29) or surface tissues (5) were treated with combination thermochemotherapy for 1 hour daily for 5 days/month. Effective heating from 41 to 45 degrees C minimum tumor temperature was possible in 17/19 (89%) tumors in which temperatures could be measured safely. The authors observed 5 (15%) tumor regressions for 1 to 5 months (median, 2 months), and 19 (56%) tumor stabilizations (growth arrest of previously progressive disease) for 1 to 9 months (median, 4 months). Subjective improvement in activity and/or pain control occurred in 6 (18%) patients and 20 (59%) had no progression of symptoms during treatment. Moreover, there was no detectable morbidity from localized hyperthermia, and no evidence of increased chemotherapy toxicity. While the mechanism(s) of response is poorly understood, the documented disease regressions and stabilizations of previously progressive disease in 24 (71%) patients during secondary combination thermochemotherapy indicates that the addition of hyperthermia may have useful anticancer activity. Expanded trials are warranted.

Monoclonal antibodies to carcinoembryonic antigen: ionic strength as a factor in the selection of antibodies for immunoscintigraphy.

As part of an ongoing effort to improve the technique of immunoscintigraphy for the detection of human carcinomas with radiolabeled monoclonal antibodies (MABs) to carcinoembryonic antigen (CEA), we have developed a series of MABs to CEA and have studied the effects of low- and physiological molarity buffers on their CEA binding and affinity, as well as their cross-reactivity with granulocyte glycoprotein(s). These in vitro results in different buffer systems were then correlated with the use of these MABs to CEA in the detection of human colon carcinoma grafts in nude mice. Our results show that the binding of CEA by some MABs is influenced by ionic strength and that this may be an important factor in their successful use for the immunolocalization of carcinomas in vivo.

Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice.

Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross-reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their F(ab')2 and Fab fragments was compared in nude mice bearing grafts of a serially transplanted, CEA-producing, human colon carcinoma. The distribution of radiolabeled MAb and their fragments after intravenous injection was analyzed by direct measurement of radioactivity in tumor and normal organs, as well as by whole-body scanning and by autoradiography of tumor sections. Paired labeling experiments, in which 131I-labeled antibody or fragments and 125I-labeled control IgG are injected simultaneously, were undertaken to determine the relative tumor uptakes of each labeled protein. The tumor antibody uptake divided by that of control IgG defines the specificity index of localization. Tumor antibody uptakes (as compared with the whole mouse), ranging between 7 and 15, and specificity indices ranging between 3.4 and 6.8, were obtained with the four intact MAb at day 4-5 after injection. With F(ab')2 fragments of the four MAb, at day 3, the tumor antibody uptakes ranged between 12 and 24 and the specificity indices between 5.3 and 8.2. With the Fab fragments prepared from the two most promising MAb, the antibody uptakes reached values of 34 and 82 at day 2-3 and the specificity indices were as high as 12 and 19. The scanning results paralleled those obtained by direct measurement of radioactivity. With intact MAb, tumor grafts of 0.5-1 g gave very contrasted positive scans 3 d after injection. Using MAb fragments, tumors of smaller size were detectable earlier. The best results were obtained with Fab fragments of MAb 35, which gave clear detections of tumors weighing only 0.1 g as early as 48 h after injection. Autoradiographs of tumor sections from mice injected with 125I-labeled MAb demonstrated that the radioactivity was localized in the tumor tissues and not in the stromal connective tissue of mouse origin. The highest radioactivity concentration was localized in areas known to contain CEA such as the pseudolumen of glands and the apical side of carcinoma cells. The penetration of radioactivity in the central part of tumor nodules and the pseudolumen appeared to be increased with the use of MAb fragments.

Difference in effect of single immunosuppressive agents (cyclophosphamide, CCNU, 5-FU) on peripheral blood immune cell parameters and central nervous system immunoglobulin synthesis rate in patients with multiple sclerosis.

Cyclophosphamide (CY), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-fluorouracil (5-FU) were given in single course schedules to chronic progressive multiple sclerosis (MS) patients clinically stable for 6 months. The following peripheral immune cellular parameters were measured before, during and after each drug administration: white blood count (WBC), polymorphonuclear count (PMN), lymphocyte count, percentage of T cells, T cell response to phytohaemagglutinin (PHA), percentage of B cells, percentage of cells bearing receptors for the Fc portion of immunoglobulin (% FcR cells), killer (K) cell activity defined by antibody-dependent cellular cytotoxicity (ADCC), and natural killer (NK) cell activity. Central nervous system (CNS) immunoglobulin G (IgG) synthesis was also measured. The patients were followed carefully by both quantitative and qualitative methods for any change in their neurologic condition. Selective reduction in NK activity was observed with CY and 5-FU while no significant alteration was seen in %FcR cells and K activity. CY differed from 5-FU in reducing lymphocyte count and B cell percentage while 5-FU decreased the percentage of T cells. CCNU, but not the other drugs, reduced T cell proliferative response to PHA. In addition, CCNU, which is known to penetrate well into the nervous system, caused a modest reduction in CNS IgG synthesis, while 5-FU had an uncertain effect. Clinically the patients were unchanged or continued to progress in their disability. The results suggest an independence of the CNS immune from the systemic immune system in MS in response to many immunosuppressive drugs.

Clinical radiofrequency hyperthermia: a review.

Localized radiofrequency (RF) hyperthermia is being investigated for potential use in cancer therapy, both as a single agent and in combination with radiation therapy and chemotherapy. Standard capacitive and inductive heating techniques and new technology, including magnetrode magnetic-loop induction, are being compared for safety and efficacy. Clinical trials suggest that effective localized RF hyperthermia may be administered safely to both superficial and deep visceral tumors with proper equipment. Temperatures of 42 degrees C or greater appear to be tumoricidal, though higher temperatures and longer and multiple treatments seem most beneficial. Effective heating of tumors has been independent of histology but could be related to size and blood flow. Combined with radiation therapy and chemotherapy, hyperthermia appears to have a synergistic or additive effect. These trials indicate that localized RF hyperthermia may soon provide a significant contribution to our armamentarium against cancer.