Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies.

A phase I trial of piritrexim was conducted by use of a prolonged, low-dose oral schedule. A number of different regimens were tested, including daily dosing for 21 days followed by 7 days of no drug therapy; continuous dosing; and daily dosing for 5 of 7 days for 3 consecutive weeks followed by a week of rest. Dose escalation was accomplished by increasing the dosing frequency from once a day to twice a day and then to three times a day and by increasing the number of days of administration. Fifty-one patients with advanced cancer were entered in the study. One hundred twenty-four (96%) of 129 courses were considered assessable. Myelosuppression proved to be the dose-limiting toxic effect. Other toxic effects included stomatitis, nausea and vomiting, anorexia, diarrhea, skin rash, fatigue, and elevation of liver transaminase levels. Antitumor activity was observed in patients with melanoma and bladder cancer, and disease stabilization occurred in those with sarcoma and pheochromocytoma. The recommended dosing schedule for phase II clinical trials is 25 mg three times a day for 5 days for 3 consecutive weeks followed by 1 week of no drug therapy.

Effects of physiological oxygen concentration on human tumor colony growth in soft agar.

Cloning efficiencies of 67 fresh human tumor specimens, consisting of 29 ovarian, 10 lung, and 7 each of colon, breast, mesenchymal, and miscellaneous tumors, from 58 patients were studied using the technique of Hamburger and Salmon to evaluate the effect of incubation in a 5% rather than 20% oxygen environment. Under the low-oxygen tension, carcinomas exhibited an average of 170% increase in cloning efficiency (p less than 0.01). The number of carcinomas forming at least 30 colonies/dish increased from 22 to 27. Mesenchymal tumors, however, exhibited a 20% decrease in cloning efficiency (not significant). A mixture of 5% oxygen, 5% carbon dioxide, and 90% nitrogen gives a higher cloning efficiency than 20% oxygen, 5% carbon dioxide, and 75% nitrogen for certain human carcinomas in semisolid agar.

A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial. PATIENTS AND METHODS: Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks. RESULTS: The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm. CONCLUSION: Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.

Synergistic effect of prochlorperazine and dipyridamole on the cellular retention and cytotoxicity of doxorubicin.

Incubation of drug-resistant human tumor cells with a combination of prochlorperazine and dipyridamole has additive/synergistic effect on the cellular retention and cytotoxicity of doxorubicin. In patients administered a fixed dose of doxorubicin and prochlorperazine with escalating doses of dipyridamole, mean plasma levels of dipyridamole and prochlorperazine achieved were as high as 3.01 +/- 0.41 microm and 0.94 +/- 0.09 microm, respectively. Plasma samples from patients were analyzed in an in vitro assay to monitor the effect on the cellular retention of tritium-labeled daunorubicin in MDR1-transfected P388 cells. In 22 of 49 of the plasma samples analyzed, the daunorubicin in efflux blocking activity was one-half or greater than that of cells incubated with 12.5 microM verapamil, a well-known efflux blocker. These observations suggest that a combination of prochlorperazine and dipyridamole may enhance cellular doxorubicin retention by blocking efflux while reducing normal tissue toxicity and unwanted side effects in vivo.

Somatostatin receptor expression in Hürthle cell cancer of the thyroid.

Somatostatin receptor expression, which was not a previously described marker for Hürthle cell cancer of the thyroid, was demonstrated by in vivo imaging with (111)In-pentetreotide in three patients. This phenomenon not only adds another imaging technique to the nuclear medicine armamentarium for detecting recurrent and metastatic cancer in patients with Hürthle cell cancer but also opens up an alternative therapeutic avenue with somatostatin analogs or their radiolabeled compounds.

Present and past smoking history and other predisposing factors in 100 lung cancer patients.

This study assessed the accuracy of obtaining smoking history, relationships between smoking and the histologic subtypes of lung cancer, past and present smoking history, and co-carcinogen history in 100 patients seen between 1982 and 1989. A standard questionnaire filled out by the patients, a data base filled out by the physician, and medical records were abstracted, and detailed information on smoking and co-carcinogen history was obtained. Eleven percent of the patients were nonsmokers and another 41 percent were former smokers who had quit smoking more than one year prior to the diagnosis of lung cancer. Mean ages at onset and cessation of smoking and diagnosis were 17, 59, and 62 years, respectively. The histologic subtypes were as follows: adenocarcinoma, 34; squamous, 18; small cell, 24; adenosquamous, nine; large cell, nine; and bronchioloalveolar carcinoma, six. Mean pack-years of cigarette smoking for the subtypes were as follows: squamous, 82; small cell, 78; large cell, 72; adenocarcinoma, 65; adenosquamous, 48; and bronchioloalveolar carcinoma, 41. The patient and physician questionnaires had comparable data on smoking status in continued smokers and never smokers. Many former smokers filled out the patient questionnaire as a nonsmoker, but on query by the physician admitted to smoking in the past. The physician data set was more accurate in former smokers than questionnaires completed by the patients. Patients with squamous and small cell carcinomas were heavier smokers than patients with adenosquamous and bronchioloalveolar carcinomas. About 50 percent were active smokers until the diagnosis of lung cancer, but only 18 percent of patients continued to smoke after the diagnosis. About 10 percent were never smokers and about 40 percent were former smokers. Most former smokers quit smoking less than five years antecedent to the diagnosis of lung cancer.

Lung cancer in patients with human immunodeficiency virus infection compared with historic control subjects.

Lung cancer infrequently may be associated with human immunodeficiency virus (HIV) infection. This retrospective case-control study was undertaken to determine if there were differences in age, sex, and stage distribution and in survival between HIV-positive and HIV-indeterminate lung cancer patients. We compared 19 patients with both pathologically verified lung cancer and HIV infection proved by serologic study with lung cancer patients with an indeterminate HIV status. All 19 HIV-positive lung cancer patients were men. This was significantly (p = 0.004) different from the 69 percent male preponderance in 1,335 HIV-indeterminate lung cancer patients. Median ages of HIV-positive and HIV-indeterminate patients were 48 and 61 years, respectively. HIV-positive patients were significantly (p = 0.0139) younger. Stage distribution was similar in both groups. Histologic features and smoking were not significantly different between the two groups. Survival data that were available in 16 HIV-positive patients were compared with 32 HIV-indeterminate control subjects matched for stage, age, sex, and race. The median survival was three months in the HIV-positive group and ten months in the HIV-indeterminate cohort. The survival was significantly different (p = 0.002). There were no one-year survivors in HIV-positive lung cancer patients.

Digital clubbing and lung cancer.

OBJECTIVES: To determine the relative frequency of clubbing in small cell lung carcinoma (SCLC) versus non-small cell lung carcinoma (NSCLC). DESIGN: Examine patients with lung cancer for digital clubbing and relate the findings to the histopathologic subtype of lung cancer. SETTING: Cancer center at a tertiary teaching hospital. PATIENTS OR PARTICIPANTS: One hundred and eleven consecutive patients with a pathological diagnosis of lung cancer examined by one physician (KSS). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Clubbing was present in 32 (29%) of the 111 patients with lung cancer. Clubbing was more common in women (40%) than in men (19%; chi2 test p = 0.011), and was more common in patients with NSCLC (35%) than those with SCLC (4%; chi2 test p = 0.0036). CONCLUSION: In a prospective study, digital clubbing was less frequently observed in men than women and in patients with SCLC than NSCLC. These clinical observations may assist in the initial evaluation of patients for planning workup and therapy.

MDR-1 gene expression, anthracycline retention and cytotoxicity in human lung-tumor cells from refractory patients.

Lung-tumor cells from pleural effusion of four refractory patients and in cell lines established from them were analyzed for anthracycline retention, cytotoxicity, and MDR-1 gene and P-glycoprotein expression. Murine leukemic P388 and doxorubicin-resistant P388/R84 lines were used as controls. The 50% growth-inhibitory concentration (IC50) for doxorubicin among lung-tumor lines varied from 0.16 to 0.31 microM in soft agar. Heterogeneity in doxorubicin or daunorubicin retention and response to the efflux-blocking action of 25 microM prochlorperazine was noted in pleural effusion of FCCL-1, -4, and -8. Among the cell lines established, an efflux-blocking effect in a subpopulation was noticed only in FCCL-1 and -4. Although the MDR-1 gene was present in all cell lines, including P388, its expression was pronounced only in P388/R84 and FCCL-1. In situ hybridization of antisense RNA probe to tumor cells showed high heterogeneity for MDR-1 message in the human lung-tumor cells as compared with the murine cells. Northern and slot blot hybridization confirmed in situ hybridization in lines with high levels of MDR-1 expression. The synthesis of MDR-1 mRNA and P-glycoprotein in tumor lines was correlated. The results suggest that because of extensive tumor-cell heterogeneity in human tumors, monitoring of MDR expression by in situ hybridization, quantitation of P-glycoprotein content by laser flow cytometry (and/or immunohistochemical methods), and drug efflux (by laser flow cytometry) may be the best ways to monitor multidrug resistance in human tumors.

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker.

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m2. The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m2 DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m2 PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m2. Large interpatient variation in peak PCZ plasma levels (91-3215 ng/ml) was seen, with the plasma half-life (t1/2 alpha) being approximately 57 min in patients given 135-180 mg/m2 PCZ. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) were 350.1 +/- 183.8 1/m2, 260.7 +/- 142.7 l m2 h-1 and 1539 +/- 922 ng ml h-1, respectively, in patients given 180 mg/m2 PCZ and the respective values for patients receiving 135 mg/m2 were 48.9 +/- 23.76 l/m2, 33.2 +/- 2.62 l m2 h-1, and 4117 +/- 302 ng ml h-1. High PCZ plasma levels (> 600 ng/ml) were sustained in all patients treated with 135 mg/m2 PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m2 PCZ, and a > 10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m2 with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.

Randomized double-blind comparison of three dose levels of intravenous ondansetron in the prevention of cisplatin-induced emesis.

The selective 5-hydroxytryptamine3 (5HT3) antagonist ondansetron has been shown to be an effective antiemetic in patients receiving cisplatin chemotherapy. This double-blind study compared the efficacy and safety of three doses of intravenous ondansetron in the prevention of nausea and vomiting associated with high-dose (> or = 100 mg/m2) cisplatin chemotherapy. A total of 125 patients were randomized (1:1:1) to receive 0.015, 0.15, or 0.30 mg/kg every 4 h for a total of 3 doses. All patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 h following cisplatin administration. The 0.15-mg/kg dose was superior to the 0.015-mg/kg dose with respect to the median number of emetic episodes (P = 0.033) and complete response (no emetic episodes, P = 0.005). No statistically significant difference was found between the 0.15 and the 0.30-mg/kg groups. The most common adverse event was headache. Three 0.15-mg/kg doses of intravenous ondansetron are safe, effective, and adequate for the control of cisplatin-induced emesis.

Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies.

Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i.v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were: t1/2 alpha (+/- SE), 20.9 +/- 5.3 min; t1/2 beta, 1.8 +/- 0.3 h; and t1/2 gamma, 21.9 +/- 5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254 +/- 886 l/m2, 60.2 +/- 13.5 l m-2 h-1, and 1624 +/- 686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i.v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.

Hypercalcemia in head and neck squamous-cell carcinoma.

Hypercalcemia was previously considered a terminal phenomenon in advanced head and neck squamous-cell carcinoma. We report on six patients with head and neck carcinoma and hypercalcemia refractory to conventional measures. Three patients had stage IV tumor not amenable to surgery or radiation therapy and three others had carcinoma recurrent after surgery and/or radiation therapy. Five of the six patients had paraneoplastic hypercalcemia and one had extensive bone metastases. One refused chemotherapy and died in 2 months. Five treated with cisplatin 100 mg/m2 i.v. and 5-fluorouracil (5-FU) 960 mg/m2/day x 5, on days 2-7 as a continuous infusion, had prolonged control of hypercalcemia and required no other therapy to maintain eucalcemia. All three patients with no prior therapy, and one of the two patients with recurrent cancer, had a partial response after chemotherapy. The survivals of the patients with recurrent cancer were 1 and 3 months. The survivals in the patients with no prior antitumor therapy were 10, 11+, and 23 months, respectively. In conclusion, hypercalcemia in head and neck carcinoma can be well controlled by cisplatin and 5-FU chemotherapy for a prolonged period. The impact of chemotherapy on survival was minimal in patients with recurrent cancer. In contrast, patients with hypercalcemia at initial presentation of an advanced head and neck cancer have a high likelihood of tumor control and prolongation of survival by chemotherapy.

Spontaneous pneumomediastinum in esophageal carcinoma.

Although fistulae and hypercalcemia are rare at the time of diagnosis of esophageal carcinoma, they are not uncommon terminal events. Most fistulae communicate with the respiratory tract. Uncommon sites of fistulae due to esophageal carcinoma include extension to the aorta, pleura, pericardium, and mediastinum. We report a patient with a spontaneous pneumomediastinum discovered during radiologic staging of esophageal carcinoma. The symptoms were dysphagia, weight loss, and pneumonia. The patient had hypercalcemia refractory to conventional measures, another adverse prognostic factor. Cisplatin 100 mg/m2 was tolerated without acute toxicity and lowered the serum calcium to normal. However, the patient died due to respiratory failure 2 days after cisplatin therapy. To our knowledge, this is the first report of a spontaneous pneumomediastinum at presentation of an esophageal carcinoma. The course of our patient and a review of the literature suggest that fistulae and/or hypercalcemia are medical emergencies and are often fatal in esophageal carcinoma.

Detection of early anthracycline cardiotoxicity by monitoring the peak filling rate.

Three patients developed clinical congestive heart failure after cumulative doxorubicin doses of 264, 440, and 450 mg/m2, respectively, despite serial monitoring of systolic cardiac function by resting gated radionuclide scanning. All three patients had depressed diastolic function, as shown by a decreased peak filling rate preceding a change in systolic function, which was assessed by left ventricular ejection fraction prior to the development of clinical congestive heart failure. We recommend serial monitoring of the peak filling rate, in addition to left ventricular ejection fraction. If broader experience confirms our impression that the peak filling rate is more sensitive than the current standard assessment of left ventricular ejection fraction, new guidelines may need to be drawn to monitor cardiotoxicity of anthracyclines and anthraquinones.

Prognostic factors in lung cancer based on multivariate analysis.

Multivariate analysis was performed on 1,336 patients with lung cancer to determine the prognostic significance of stage, race, gender, age, and treatment in each histologic subtype. The study was designed to establish a subgroup of patients whose survival outcome might be better, based on these factors. On univariate analysis, stage and surgery were significant factors in each histologic subtype. The presence of liver metastases, was an important prognostic factor in all subtypes except large cell carcinoma. However, 131 of 140 patients with large cell carcinoma had liver metastases, and this factor may account for the observation that liver metastases was not a significant prognostic factor. In the multivariate analysis, good prognosis was associated with early stage disease and surgical treatment in all cell types. For a given stage, the improvements in relative risk due to surgery represent both the effect of treatment and the effects of other unmeasured patient characteristics, such as performance status and physiological status, that make the patient a suitable candidate for surgery.

The increasing recognition of adenosquamous lung carcinoma (1977-1986).

A retrospective analysis of the data in the tumor registry on all 103 patients with adenosquamous lung carcinoma diagnosed and treated at our center between 1977 and 1986 was performed. The history of tobacco use was available for 100 patients (72 men and 28 women). Ninety-four percent of the patients (100% of men and 79% of women) were smokers, suggesting that adenosquamous carcinoma may be a Kreyberg I type of lung carcinoma. The gender, race, and age distributions in adenosquamous carcinoma were similar to other histologic subtypes of lung carcinoma. Patients less than 45 years old constituted 10%; 45-54 years old, 24%; 55-64 years old, 34%; 65-74 years old, 25%; and greater than 75 years, 7%. In the 95 patients whose stage at the time of diagnosis was known, 11% had local stage; 28%, regional; and 61%, distant stage. The 1-, 2- and 5-year survival of the 103 patients were 27%, 18%, and 8%, respectively. Survival was related to stage. Local stage had the best survival, and greater than 50% of patients were alive at 4 years. Regional stage had an intermediate median survival of 10 months but no survivors at 5 years. Distant stage had the worst median survival (5 months), and one patient (2%) was alive at 3 years. There was a significant increase (two- to three-fold) in the frequency of adenosquamous carcinoma over the 10-year study period, 1977-1986.

Brain metastases in malignant pleural mesothelioma. Case report and review of the literature.

Recent advances in pleural malignant mesothelioma include the sequential use of palliative surgery, perioperative radiation therapy, and systemic chemotherapy. Radical treatments may not only palliate but also improve survival in some patients. The latter may be associated with the appearance of metastases in unusual sites including the central nervous system. In malignant mesothelioma, brain metastases were previously reported in 19 patients at autopsy and in only 1 patient antemortem. We detail the clinical presentation in the second patient with pleural malignant mesothelioma thus far reported to develop brain metastases. The difficulties in diagnosis, the role of immunoperoxidase stains in malignant mesothelioma, excellent tolerance of different modalities of treatment, and a review of the literature of brain metastases in mesothelioma are discussed. Based on our report, the possibility of brain metastases should be investigated by careful clinical examination prior to a radical treatment in patients with progressive refractory mesothelioma.

Combination chemotherapy and radiotherapy for small-cell carcinoma of the esophagus. A case report of long-term survival and review of the literature.

Small-cell carcinoma of the esophagus is a rare tumor and has received little attention until recent years. It should be differentiated from the far more common poorly differentiated squamous-cell carcinoma of the esophagus, because treatment by surgical resection alone or by radiation therapy results in limited survival of a few months. It is now recognized that esophageal small-cell carcinoma presents with early widespread dissemination and is chemosensitive, similar to primary small-cell carcinoma of the lung. We report on a patient with small-cell carcinoma of the esophagus treated with combination chemotherapy consisting of cyclophosphamide, vincristine, and VP-16 followed by local radiation therapy. Pathologic complete remission was achieved. The patient is currently in remission 22 months after diagnosis, the longest survival reported thus far.

Sensorimotor myeloradiculoneuropathy in thymoma.

This is the first report describing the clinical, electrophysiological, and neuropathological findings in a patient with thymoma and sensorimotor myeloradiculoneuropathy. Degeneration of the Clarke's nucleus and posterior horns were noted in addition to segmental demyelination and variable axonal loss of the anterior and posterior roots. The segmental demyelination was more severe in the anterior roots of the lower thoracic and lumbosacral regions. A possible rare association between paraneoplastic myeloradiculoneuropathy and thymoma is suggested.