Randomized clinical trial of mitomycin-C with or without pretreatment with WR-2721 in patients with advanced colorectal cancer.

The use of mitomycin for metastatic colorectal cancer has been limited by mitomycin's myelosuppressive potential. The objective of this randomized study was to determine whether WR-2721 would decrease the hematologic toxicity of mitomycin in patients with colorectal cancer resistant to fluorouracil-based therapy. Ninety-seven patients with refractory colorectal cancer were randomized to receive either mitomycin 20 mg/m2 only or the same dose of mitomycin after pretreatment with WR-2721, 910 mg/m2. The principal toxicity in both groups was thrombocytopenia. The platelet nadirs were lower in patients receiving single-agent mitomycin (P = 0.026). Surprisingly, no clinical complete or partial responses were noted in either group, and survival was not different between the two groups. Thus, while WR-2721 decreased the thrombocytopenia associated with mitomycin therapy, mitomycin was ineffective in the treatment of refractory colorectal carcinoma.

Dichloromethotrexate, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small cell lung cancer. A MAOP study.

The combination of dichloromethotrexate, cisplatin, and infusional 5-fluorouracil was evaluated as treatment for non-small-cell lung cancer in a phase II trial using 43 evaluable patients. Grade III or IV toxicity included thrombocytopenia (21%), leukopenia (14%), nausea/vomiting (14%), mucositis (9%), infection (5%), and other (16%). There were six responders (14%), with a 95% confidence interval of [5%, 28%]. Two additional patients achieved a 50% reduction in cross-sectional tumor size that was not documented twice. Median survival time was 6.5 months. This combination is not considered sufficiently active for further evaluation in this disease.

A prospective randomized comparison of protracted infusional 5-fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A Mid-Atlantic Oncology Program study.

One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.

Protracted infusion of 5-FU with weekly low-dose cisplatin as second-line therapy in patients with metastatic colorectal cancer who have failed 5-FU monotherapy.

Forty four patients who had documented progression of metastatic colorectal cancer while receiving 5-fluorouracil (5-FU) monotherapy were treated with continuous infusion 5-FU, 300 mg/mg2/day, plus weekly low-dose cisplatin, 20 mg/m2. Treatment was given in 12-week cycles, consisting of 8 weeks of chemotherapy followed by a 4-week rest period, and was well tolerated. Three of 23 patients (13%) who had failed bolus 5-FU but not been exposed previously to infusional 5-FU responded. Of 21 patients who had failed infusional 55-FU monotherapy, only one (5%) responded. Time to progression (5.7 vs. 1.8 months) and survival (12 vs. 5.5 months) were significantly longer for patients who had not previously received infusional 5-FU but who had failed bolus schedules, compared with patients who had previously failed infusional 5-FU (p less than .001).

Homograft valve durability: host or donor influence?

Antibiotic sterilized valves have been shown to function longer than those chemically sterilized; however, the reason remains obscure. Current hypotheses cite either retention of donor fibroblasts capable of repairing the grafted valve, or host fibroblast ingrowth into and onto the leaflet ground substance. A cryopreserved aortic homograft from a male donor was explanted from a female recipient after 10 months, and subjected to immunocytochemistry, tissue culture, and karyotyping. The leaflet bases exhibited normal morphology with an intact endothelium. The distal one-third of the leaflets was devoid of fibroblasts from the leaflet bases showed them to be of host origin. This homograft seems to have been implanted with an intact ground substance which allowed for host cell repopulation of the inner one-third of the leaflets. Perhaps donor cell viability in itself is not as important to durability as is preservation of the leaflet ground substance, but rather the presence of viable cells may be an index of the structural integrity of the collagen and elastic matrix.

The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer.

Small-cell lung cancer (SCLC), a chemotherapy-responsive disease, is characterized by neuroendocrine properties. In contrast, non-small-cell lung cancer (NSCLC) is at best moderately responsive to chemotherapy, and only 10% to 20% of cases demonstrate neuroendocrine properties. The present study is a retrospective analysis of the use of immunoperoxidase markers for neuron-specific enolase (NSE), Leu-7, and chromogranin A in NSCLC patients treated with chemotherapy. It was designed to determine if the presence of neuroendocrine markers predict for response to chemotherapy. The diagnostic slides and blocks were obtained on 52 NSCLC patients who were treated with chemotherapy (26 responders and 26 nonresponders). Immunoperoxidase studies were performed, and slides were scored without knowledge of the patient's response. Markers were positive in responders and nonresponders, respectively, as follows: NSE, 14 of 26 (54%) versus seven of 26 (27%), P = .04; Leu-7, 11 of 25 (44%) versus five of 26 (19%), P = .08; and chromogranin A, three of 26 (12%) versus 0 of 26 (0%), P = .71. Two markers were positive in 10 of 26 responders (38%) and 0 of 26 nonresponders (0%), P less than .01. Responders with two or more positive markers showed superior survival (median, 79 weeks) compared with responders with fewer than two positive markers (median, 51 weeks) and nonresponders (median, 27 weeks). These data suggest that the presence of neuroendocrine markers in NSCLC is associated with an increased likelihood of response to chemotherapy and may add to the standard parameters (performance status, weight loss) used to select patients for chemotherapy.

Phase II study of iproplatin (CHIP) in previously treated small-cell lung cancer.

Eighteen patients with previously treated extensive small-cell carcinoma of the lung were entered into a Phase II study employing iproplatin (CHIP), a cis-platin analog. Patients had received a mean of two prior chemotherapeutic regimens. Fifty-five percent had received prior cis-platinum and 33% had received prior radiation therapy. CHIP (225 mg/m2) was administered by intermittent intravenous infusion over 30 min for 5 days of a 28-day cycle without prehydration. Sixteen patients with Zubrod performance scores of less than or equal to 3 received 27 courses of therapy (mean 1.7, range 1-6). One partial response of 167 days duration was observed, with complete regression of involved lymph nodes and stabilization of nonevaluable disease in the chest. Six patients had stable disease following one cycle of CHIP, but all progressed following a second cycle of drug. The main toxicity was myelosuppression with prominent thrombocytopenia. Median survival was 75 days from initiation of therapy. In this group of heavily pretreated patients with advanced disease, iproplatin has only minimal activity as a single agent and does not show non-cross-resistance with cis-platinum.

A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study.

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.

Phase I trial of recombinant interleukin-2 and recombinant beta-interferon in refractory neoplastic diseases.

Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are cytokines with profound immunobiological effects on T-cell and natural killer (NK) cell activity; IL-2 also induces lymphokine-activated killer (LAK) cell cytotoxicity in humans. Both lymphokines induce antineoplastic activity against several refractory tumors. This Phase I study of 50 patients assessed the toxicities, maximally tolerated dose (MTD), effects on certain immune effector cells, pharmacokinetics of IL-2, and development of antibodies to the combination of subcutaneously administered IL-2 and intravenously administered beta-IFN. Fever was common. Indomethacin reduced the incidence and severity of fever and was necessary to prevent it from becoming dose-limiting. Hypotension occurred but never required pressors or produced complications. Constitutional symptoms, local skin toxicity at the site of IL-2 injection, generalized desquamation, eosinophilia, nausea, and vomiting were also observed. One patient had reversible renal dysfunction. Two patients experienced drug-related dyspnea without evidence of capillary leak syndrome; neither required intubation. Fluid retention and cardiotoxicity were not observed. The MTD was 5 x 10(6) U/m2 s.c. of IL-2 and 2 x 10(6) U/m2 i.v. of beta-IFN when given in combination. Enhancement of in vivo NK cell cytotoxicity and proliferation of T4+, T8+, and NK cells occurred. In vivo induction of LAK cell cytotoxicity was observed in three patients. Four patients developed nonneutralizing anti-IL-2 IgG antibodies, but none developed antibodies to beta-IFN. Peak IL-2 serum levels typically occurred 4 h following drug administration. Serum levels were within a factor of 3 of the peak level in the period studied, 1-6 h postinjection. No complete responses occurred. One patient with rectal cancer and one with transitional cell carcinoma each had a partial response, and 13 other patients (5 with renal cell, 4 with colorectal, and 4 other cancers) had stable disease. Induction of NK cell cytotoxicity was seen more commonly in patients with stable disease than in those with progressive disease. Combined administration of these agents is feasible with acceptable toxicity, and Phase II trials are warranted.

Adverse prognostic effect of N2 disease in treated small cell carcinoma of the lung.

We reviewed survival of patients with clinically localized small cell carcinoma of the lung treated by surgical resection, combination chemotherapy, and prophylactic cranial irradiation. Long-term survival was defined as continuing complete remission 30 months after the start of treatment. Initial TNM staging determined the course of treatment. Ten patients with disease in Stages I and II were treated over 30 months ago by initial resection followed by the full course of chemotherapy. Only one has had a relapse, whereas 80% remained disease-free at 30 months. Five of these patients have passed 5 years. Four patients with T3 N1 disease were treated by two cycles of chemotherapy, surgical resection, and cranial irradiation plus resumption of chemotherapy thereafter; two remained in remission at 30 months. Sixteen patients initially with N2 disease were treated according to the same schedule; 10 of the 16 underwent successful resection. All 16 patients have had a relapse, but the relapse occurred very late in three--at 27, 30, and 37 months. The reasons for the apparently poor prognosis of N2 disease are not clear. Considerations of tumor response kinetics and somatic mutation suggest that these biologic factors are fundamentally responsible. Other studies may find disease control achieved in a very few patients with N2 disease.

Histologic alterations in small cell carcinoma of the lung after two cycles of intensive chemotherapy.

In patients treated nonsurgically for "limited" small cell carcinoma of the lung, the most frequent site of relapse is within the chest. We have treated patients with clinical Stage III M0 disease (T3 and/or N2, M0) by two cycles of chemotherapy, surgical resection of the primary site and mediastinal nodes, and continued chemotherapy thereafter. Since May, 1979, the regimen has consisted of cyclophosphamide, doxorubicin, vincristine, and etoposide on a 3 week cycle. The first 12 patients so treated had partial or complete remission after two cycles. Resection was technically not possible in two. Residual small cell carcinoma was not identifiable in the specimens from two of the 10 patients undergoing resection. Microscopic tumor extended to a resection line in two of the eight with residual tumor. Malignant tissue appearing to have the structure of papillary adenocarcinoma was found in hilar and paratracheal nodes in one patient, but nowhere in the resected lung; some residual small cell carcinoma remained in the lung. Nuclear ballooning and eosinophilic inclusions were noted in cells still identifiable as small cell carcinoma in one case. Marked fibrotic scarring was noted in eight cases, acute and organizing bronchopneumonia in three, and multiple small parenchymal abscesses in one case. Long disease-free survival occurred in one patient, in whom residual tumor could not be found in the specimen; in at least one more in whom residual tumor was present; and even in one patient in whom tumor was present at the bronchial resection line.

The prospect of disease control by surgery combined with chemotherapy in stage I and stage II small cell carcinoma of the lung.

Ten patients with localized small cell carcinoma of the lung (clinical stages I and II) were treated by surgical resection more than 2 years ago; operation was followed by a course of intensive combination chemotherapy. Relapse of the disease has occurred in the central nervous system in 1 patient. One patient died of a surgical complication, and another died more than 4 years later of an unrelated malignancy. All others remain well, and 3 patients have survived longer than 5 years following resection.

Phase II studies of methyl glyoxal bis-guanylhydrazone (NSC 32946) in carcinoma of the colon and lung.

We have tested methyl glyoxal bis-guanyl hydrazone (NSC 32946) for antitumor activity in patients with colorectal carcinoma and non-small cell bronchogenic carcinoma. The drug dose was 500 mg/m2 administered by single weekly injection, and with a provision dose escalation. No responses were seen in 38 evaluable patients with colorectal cancer, including 17 who had received no prior chemotherapy. Three responses were seen among 42 patients with bronchogenic carcinoma. These included one each with epidermoid carcinoma, adenocarcinoma and large cell anaplastic carcinoma. None of these responders had received prior chemotherapy. Toxicity of the drug was predominantly gastrointestinal, namely nausea, vomiting and diarrhea, and tended to increase with repeated drug doses. Neurologic symptoms of various sorts were also prominent. We conclude that methyl-G is of marginal benefit in this dose and schedule to patients with bronchogenic carcinoma.

Phase II trial of extended indications for resection is small cell carcinoma of the lung.

Surgical resection offers distinct theoretical advantages as the "local" modality in treatment of Stage I and II small cell carcinoma of the lung. We have treated 10 such patients by initial resection since 1975; all survivors but one received adjuvant chemotherapy for the full course thereafter. One patient died of a pulmonary embolus; the other nine remain without evidence of disease from 7 to 69 months after resection. A trial was undertaken of extended indications for resection in selected patients with Stage III-M0 disease. Criteria for patient selection have been developed gradually; these exclude patients for reasons of refusal, physiological inadequacy, disease unsuited to gross total eradication, or lack of adequate initial response to chemotherapy. Of six patients who survived the exclusion criteria and underwent resection, one has had a relapse at 26 months. All others remain without evidence of disease, 5 to 25 months after the start of treatment. We believe that systematic patient selection on the basis of defined criteria will identify a subset of patients having markedly improved chances for disease control. This group may represent as many as half of the patients first presenting with localized or MO disease. Patients excluded as candidates for resection have continued to receive standard nonsurgical combined-modality therapy.

Synthesis and anti-inflammatory evaluation of 3-methylthio-1,2,4-triazines, 3-alkoxy-1,2,4-triazines, and 3-aryloxy-1,2,4-triazines.

To develop nonacidic, nonsteroidal anti-inflammatory agents without GI complications, a series of asymmetric triazines was synthesized and evaluated for anti-inflammatory efficacy in the carrageenan-induced pedal edema assay. Toxicity was estimated by determination of approximate LD50 values in mice. Twenty-five compounds possessed activity comparable to the standard, indomethacin. Thirteen of the 25 compounds were selected for dose-response evaluation in the carrageenan assay based on their relative toxicity and anti-inflammatory activity. Neurotoxicity of the 13 triazines was estimated by determination of NTD50 values in mice. Five of the 13 compounds tested in the dose-response assay were active in terms of anti-inflammatory efficacy (ED50 values) and lack of overt neurotoxicity (NTD50 values) when compared to indomethacin. To determine the effect of these five developmental triazines on chronic inflammation, they were evaluated in the adjuvant-induced polyarthritis assay. One was comparable to indomethacin in reducing adjuvant-induced inflammation in this assay.

Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion.

The pharmacokinetics of cis-dichlorodiam-minoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7-22.5 min) and a prolonged second phase (30.5-106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3-65.6 liters and it was 26.6-50% excreted in the urine in 48 h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4-25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and gamma-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.

Synthesis and antihypertensive activity of novel 3-hydrazino-5-phenyl-1,2,4-triazines.

In an effort to develop antihypertensive agents with peripheral vasodilator activity, a series of 40 novel 3-hydrazino-5-phenyl-1,2,4-triazines (II) were synthesized and evaluated in the spontaneously hypertensive rat assay (SHR assay). Based on the performance of the structurally related standard, hydralazine (I), 15 triazines were active. Thirteen of these hypotensive triazines possessed LD50 values in the mouse greater than I (LD50 = 100 mg/kg); only one active triazine had an LD50 value greater than 300 mg/kg (11d). Four asymmetric triazines had moderate antihypertensive activity and LD50 values greater than 300 mg/kg (6b, 7c, 8f, and 9g). Based on the relationship between toxicity and antihypertensive activity, three triazines (8f, 9g, and 11d) were chosen for dose-responses studies in the SHR assay. None were as efficacious as I, but all three were less toxic, resulting in similar therapeutic indices relative to I.