Patrick S. Gentile

The production of myeloid blood cells and their regulation during health and disease

The regulation of myelopoiesis in vivo most likely entails a complex set of interactions between cell-derived biomolecules and their target cells: hematopoietic stem and progenitor cells and accessory cells. Stimulating and suppressing factors have been characterized through in vitro studies, and their mechanisms of action in vitro and in vivo have begun to be elucidated. Among those factors being studied are the hematopoietic colony-stimulating factors (CSF): interleukin-3 (multi-CSF), granulocyte-macrophage-CSF, granulocyte-CSF, and macrophage-CSF; other molecules include erythropoietin, B-cell-stimulating factor-1, interleukin-1, interleukin-2, prostaglandin E, leukotrienes, acidic ferritins, lactoferrin, transferrin, the interferons-gamma, -alpha, and -beta, and the tumor necrosis factors-alpha and -beta (lymphotoxin). These factors interact to modulate blood cell production in vitro and in vivo. The proposed review characterizes these biomolecules biochemically and functionally, including receptor-ligand interactions and the secondary messengers within the cell which mediate their functional activity. The production and action of the molecules are described under conditions of hematopoietic disorders, as well as under normal conditions. Studies in vitro are correlated with studies in vivo using animal models to give an overall view of what is known about these molecules and their relevance physiologically and pathologically.

High‐dose cisplatin in patients with advanced malignancies

A study was conducted to determine if cisplatin (CDDP) can be given at higher doses than usual, utilizing aggressive supportive measures. Twelve patients were entered into three dose levels of CDDP: level I, 180 mg/m2 given as a short infusion; level II, 220 mg/m2 also given as a short infusion; level III, 200 mg/m2 divided in five daily doses, each infused over 6 hours. In all cases, CDDP was dissolved and given in 250 ml of a 5% saline solution. For levels I and II, intravenous hydration with 200 to 250 ml/hour D51/2NS with potassium and magnesium supplements, was started 24 hours before therapy and continued for 3 to 4 days after, longer if nausea persisted. Mannitol was given before (25% solution, 50 ml bolus) and after (20% solution, 500 ml over 3 hours) CDDP. At level III hydration with the same intravenous (IV) fluids was begun the day before therapy and continued without interruption at 200 to 250 ml/hour for a minimum of 24 hours after the completion of the 5 days of chemotherapy. Each daily dose of CDDP was preceded by injection of mannitol (25% solution, 50 ml bolus) and accompanied by a 6‐hour infusion of 1000 ml 20% mannitol. Three patients received five CDDP courses at level I; 4 patients, seven courses at level II; and 5 patients, seven courses at level III. Ototoxicity was dose‐limiting in three patients at level II. Transient elevation of serum creatinine was seen following two courses at level I and two courses at level II. The renal impairment was asymptomatic in all cases; dialysis was not needed. At level II, leukocyte nadir counts between 1.0 and 2.0 × 103/mm3 were seen following two courses and between 2.0 and 3.0 × 103/mm3 following three courses. Platelet nadir counts below 50 × 103/mm3 were recorded after four courses and between 50 and 100 × 103/mm3 after one course. Nausea and vomiting occurred frequently, but were tolerable. At level III, myelosuppression was dose‐limiting. Nadir leukocyte counts between 1.0 and 2.0 × 103/mm3 followed four courses and between 2.0 and 3.0 followed one course. Nadir platelet counts below 50 × 103/mm3 were seen after three courses; two patients required prophylactic platelet transfusions. Nadirs between 50 and 100 × 103 platelets/mm3 followed three further courses. Ototoxicity and nephrotoxicity did not occur at level III. Responses were seen in all three dose levels in patients with prostate carcinoma, non‐small cell lung cancer, adenocarcinoma of the esophagus, and malignant fibrous histiocytoma. It was concluded that CDDP at a dose of 200 mg/m2, divided in five daily fractions, is tolerable and can be introduced into Phase II trials.

Disseminated prostatic carcinoma simulating primary lung cancer. Indications for immunodiagnostic studies

Recognition of disseminated adenocarcinomas potentially responsive to current treatment programs is an important objective in the management of cancer patients. Metastatic adenocarcinoma of the prostate gland is a malignant entity which often can be palliated effectively by hormonally based therapeutic strategies. In cases of metastatic prostate cancer presenting with typical clinical features, the correct diagnosis can be readily achieved, but in patients with less obvious presentations the diagnosis of prostatic carcinoma may be overlooked. In the current report, a group of elderly men presenting with a clinical syndrome resembling either metastatic primary adenocarcinoma of the lung or primary adenocarcinoma of the lung coexisting with prostate cancer were found in fact to have metastatic prostatic carcinoma as their sole disease process. In each case, cytologic characterization of clinically involved tissue specimens by the prostate specific antigen and prostatic acid phosphatase immunohistochemical markers enabled clinical investigators to arrive at the correct diagnosis. Other clinical features, such as a positive bone scan and an enlarged prostate gland on physical exam and/or radiographic studies were noted to be present in these patients. All the patients in the current series responded to hormonal treatment regimens once the diagnosis of metastatic prostate cancer had been established. In elderly male patients presenting with what appears to be primary adenocarcinoma of the lung, the diagnosis of metastatic prostate cancer should be considered and when necessary evaluated by the use of appropriate clinical and immunohistochemical studies.

Combination chemotherapy with cis-diamminedichloroplatinum and vinblastine in advanced non-small cell lung cancer.

Twenty-seven patients (25 males and 2 females) with histologically confirmed, unresectable, or metastatic non-small cell lung cancer were entered on a combination chemotherapy protocol including cisplatinum and vinblastine sulfate (DDP)(VLB). Patients had to have measurable disease as defined by the presence of two clearly measurable perpendicular diameters, be untreated with either chemotherapy or radiation therapy, and give informed consent to be eligible for study entry. The median age was 57 yr and the median performance status was 70 (Karnofsky scale); 10 patients had epidermoid carcinoma, 9 adenocarcinoma, 4 large cell carcinoma, and 4 undifferentiated carcinoma. All patients had intrathoracic disease, 12 also had extrathoracic lymph node involvement, 8 bone involvement, 2 liver metastasis, and 2 central nervous system metastasis prior to beginning chemotherapy; 9 patients had involvement of one site, 12 of two sites, 5 of three sites, and 1 of four sites. Cisplatinum was given as a short intravenous infusion of 120 mg/m2 on days 1 and 28, and then every 6 wk. Vinblastine was administered as an intravenous injection of 8 mg/m2 on days 1, 14, and 28, and then every 3 wk. Patients were evaluated prior to each course of cisplatinum. If progression occurred, therapy was discontinued. If stabilization or response was noted, then therapy was continued until intolerable toxicity or progression supervened. Every patient entered is considered evaluable for toxicity and response. There were no complete remissions; 14 patients achieved a partial response, 3 had a minimal response, 5 had stabilization of their disease, 1 had disease progression, and 4 are considered to have had drug deaths. Responses were seen after the first cisplatinum course in 13 patients and after the second in 1. Toxicities seen were universal nausea and vomiting; elevation of creatinine occurred in 6 patients, ranging from 2.1 to 14.6 mg/dl, and was clinically significant in 2 patients. Myelosuppression, with a leukocyte nadir of less than 3.0 X 10(9)l in 10 cases and platelet nadir of less than 100.0 X 10(9)l was seen in 5 cases and partial hearing deficit occurred in 2 patients. Median survival was 22 wk for the whole group (24 wk for the whole group if the 4 early drug deaths are excluded). Median survival was 26 wk for responding patients and 13 wk for nonresponding patients (remains the same if the early deaths are excluded from the latter group).(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial

Background. Hydroxyurea is an S‐phase specific drug. Constant exposure of tumor cells with a low S‐phase fraction to the agent may result in improved cell kill. Because of its short half‐life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses.

A Phase I Trial of Chlorambucil Administered in Short Pulses in Patients with Advanced Malignancies

We carried out a phase I trial with chlorambucil. Thirty patients with advanced cancer were entered in six dose levels: 36, 48, 60, 84, 108, and 144 mg/m2. The drug was given in six divided oral doses every 6 hours and the regimen was repeated every 3 weeks. The median age was 62 years (31-84), median Karnofsky performance status (KPS) 60 (40-90). All patients but one had received prior radiation therapy, chemotherapy, or both. Central nervous system toxicity was dose limiting, occurring in 5 of 6 patients at 144 mg/m2. It was characterized by transient seizures, hallucinations, lethargy, stupor, and coma. Metoclopramide was successful in controlling nausea and vomiting, which was severe if the antiemetic was not used. Leukopenia (3 patients) and thrombocytopenia (2 patients) were mild. One patient with colorectal carcinoma had a minor response, and two patients with non-small cell lung cancer had stable disease. A safe dose for phase II trials is 108 mg/m2 in six 6-hourly oral doses.

High-dose cisplatin and vinblastine infusion with or without radiation therapy in patients with advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) patients with locally advanced or metastatic measurable disease were given a combination of cisplatin, 200 mg/m2 divided in five daily doses, and simultaneously, vinblastine, 7.5 mg/m2 as a continuous intravenous (IV) infusion over five days. Five courses of chemotherapy were planned. Afterwards or on progression, patients were randomized to receive maximally tolerated radiation to all sites of disease v observation only. Forty males and seven females were entered. Median age was 60 years (range, 37 to 74), median Karnofsky performance status was 70 (range, 30 to 90). Five patients had previous brain radiation therapy for metastatic disease, all others were previously untreated. Side effects in the 87 courses of chemotherapy administered included leukopenia (WBC less than 1,000/microL following nine courses) and thrombocytopenia (platelets less than 20,000/microL following four courses). Ten patients became septic, nine of them while leukopenic. Elevations of serum creatinine followed eight courses; in all cases the level was less than 3.0 mg/dL. Nausea and vomiting were mild to moderate. Five patients experienced mild hypoacusis and six had sensory polyneuropathy. The deaths of three patients were considered drug-related. The response rate was 28%. The median survival for the group was 22 weeks, 63.2 weeks for responders and 17.9 weeks for nonresponders. Twenty-six patients received radiation therapy, 16 randomized to this arm as planned, ten to palliate symptoms. Median survival of all irradiated patients was 24.8 weeks. Seven responders to chemotherapy were randomized to receive radiotherapy; their median survival was 25 weeks. In six responders randomized not to receive radiation, the median survival was 77.8 weeks (P greater than .3). Among nonresponding patients, the median survival of those radiated was 22.2 weeks, while that of nonradiated patients was 11 weeks. This regimen is cumbersome and toxic. It has offered no major survival benefits, or improvement in response rates, therefore, we do not recommend it for the standard treatment of NSCLC.

Approaches to ablating the myelotoxicity of chemotherapy

Myelotoxicity remains a significant dose-limiting side effect of chemotherapy contributing to the morbidity and mortality of patients undergoing treatment for cancer. A number of different experimental approaches are being studied, both in the clinic and in the laboratory, in an attempt to prevent this iatrogenic complication. The present review provides a synopsis of the various myeloprotective strategies now being employed in experimental trials. Emphasis is placed on the use of putative physiologic bioregulatory molecules (lactoferrin, prostaglandin E, interferon) to prevent or lessen chemotherapy-induced myelotoxicity, with consideration also given to other promising treatment modalities (i.e., adenosine, lithium, diethyldithiocarbanate).

A phase II trial of vinblastine, bleomycin, and cisplatin induction followed by dacarbazine and dibromodulcitol maintenance in the treatment of metastatic melanoma. A follow-up study of twenty-two patients.

Twenty-two patients with metastatic melanoma were treated with a chemotherapy regimen consisting of two cycles of induction therapy with vinblastine, bleomycin, and cisplatin, followed by maintenance therapy with dacarbazine and dibromodulcitol. A 17% response rate was noted in this patient group, with a median survival of 40 weeks. Objective responses were limited to cutaneous, nodal, pulmonary, and one adrenal site of metastatic disease. Toxicity was acceptable and was limited to myelosuppression and nausea with emesis. Further study appears warranted to define the optimal treatment plan for metastatic melanoma.

A phase I trial of dactinomycin intravenous infusion in patients with advanced malignancies

Eighteen patients with advanced malignancies refractory to other forms of treatment were given dactinomycin (Act D) as continuous intravenous infusions. Their median age was 51 years (range, 36–67); their median performance status was 50 (range, 40–90) on the Karnofsky scale. Act D was administered continuously for 5 days, utilizing a central venous line and a perfusion pump. The starting dose was 0.1 mg/m2/24 hours 5 days (total dose, 0.5 mg/m2) and was escalated according to a modified Fibonacci scale to 0.2, 0.33, and 0.5 mg/m2/24 hours × 5 days, respectively. Three, three, four, and eight patients were entered, respectively, in each dose level. Toxicities observed were: leukopenia in four patients (nadir leukocyte count <1000 cells/mm3 in one patient and 2000–3000 cells/mm3 in 3 patients); thrombocytopenia, with nadir platelet counts between 50,000 and 100,000 platelets/mm3 in 2 patients; stomatitis in four patients; and nausea in three patients. Vomiting was not observed during the infusions. Two patients may have had a radiation recall phenomenon. Blood count depression, lausea, and mucositis were transient, resolving after a few days. One patient at level IV died of sepsis, which was diagnosed on the fourth day of the infusion, before leukopenia intervened. No objective responses were seen. It was concluded that a higher dose of Act D can be given by continuous infusion than by a bolus injection; the authors recommended 0.5 mg/m2/day × 5 days (total dose 2.5 mg/m2) for further studies.