Effects of brain irradiation and chemotherapy on myelosuppression in small-cell lung cancer.

The effect of brain irradiation on myelosuppression was studied in patients with untreated small-cell lung cancer (SCLC) by comparing 24 patients who received brain irradiation for brain metastasis at presentation (irradiated patients) with 24 control patients who were selected by matching ages and non-CNS metastatic sites with those of irradiated patients. All patients were evaluated during the first three courses of chemotherapy. More irradiated patients than control patients had chemotherapy dose reductions from the starting dose level for the second (nine of 22 v two of 24; P = .03) and the third (nine of 18 v three of 20; P = .05) courses of chemotherapy. Overall, more irradiated patients had chemotherapy dose reductions than did control patients (11 of 22 v three of 24; P = .01). The difference was highly significant even after other variables were considered in a multivariate analysis (P less than .001). Myelosuppression was more severe in irradiated patients for WBCs (P = .01) and for platelets (P = .05). When the second course of chemotherapy was administered at the same dose levels as in the first course, irradiated patients had greater decreases in nadir counts after the second course compared with the first course than did control patients. Irradiated patients had a higher incidence of infectious complications than did control patients (14 of 24 v six of 24; P = .02), particularly after the second course of chemotherapy (seven of 22 v one of 24; P = .04). There were four treatment-related deaths due to sepsis in irradiated patients. Following brain irradiation given concurrently with intensive chemotherapy, close monitoring of myelosuppression and adjustments of chemotherapy doses are advised.

High-dose intensification therapy with autologous bone marrow support for limited small-cell bronchogenic carcinoma.

The efficacy and toxicity of high-dose chemotherapy with autologous bone marrow transplantation (ABMT) was studied in 32 patients with untreated limited small-cell bronchogenic carcinoma (SCBC). Ten patients received three courses of induction therapy consisting of vincristine (VCR) (1.5 mg X 2), ifosfamide (5 g/m2), and Adriamycin (Ad; Adria Laboratories, Columbus, Ohio) (60 mg/m2). Patients then received two courses of intensification therapy with cyclophosphamide (CYT) (4.5 g/m2), 4' demethyl-epipodophyllotoxin-d-D-ethylidene glucoside (VP-16-213) (600 mg/m2) and VCR (2 mg) with ABMT. Another 22 patients received induction therapy with VCR, CYT (600 mg/m2), Ad (50 mg/m2), and VP-16-213 (180 mg/m2). All 22 patients also received intensification therapy of the same dose of CYT (4.5 g/m2) and VP-16-213 (600 mg/m2). Nine patients also received high-dose methotrexate (MTX), four patients received Ad (40 to 60 mg/m2), and two patients received both Ad and MTX. After intensification, patients received elective prophylactic brain irradiation (3,000 rad) and chest irradiation (5,000 rad). After induction therapy, there were 13 (41%) complete remissions (CR) and 17 (53%) partial remissions (PR). After intensification therapy, there were 22 CRs (69%) and 10 PRs (31%). Median survival for all patients was 14 months (range, 5 to 59+). Of the 13 patients who received intensification therapy in CR, five remain disease free (DF), four for 4 years or longer. Of the nine patients to achieve CR with intensification, only one is DF. No patient died during intensification. In conclusion, intensification with high-dose chemotherapy can increase the CR rate, and this approach is most likely to show long-term benefits in patients with minimal disease (CR) at the beginning of intensification therapy.

Small cell bronchogenic carcinoma: factors associated with pneumonia during chemotherapy.

Sixty-five patients with small cell bronchogenic carcinoma were treated with intensive induction chemotherapy and supportive treatment. The clinical course of 43 patients who had pretreatment spirometry and arterial blood gases was studied. Thirteen patients developed pneumonia. Moderate hypoxemia, advanced age, and a low forced expiratory flow 25%-75% were associated with the development of pneumonia. Endobronchial obstruction and neutropenia, other factors associated with infection in cancer patients, appeared to be less important in this patient population.

Randomized trial of three combinations of cisplatin with vindesine and/or VP-16-213 in the treatment of advanced non-small-cell lung cancer.

One hundred sixty-seven evaluable patients with non-small-cell lung cancer were randomized to receive high-dose cisplatin and vindesine (PVD), or cisplatin and VP-16-213 (etoposide epipodophyllotoxin) (PVP), or cisplatin with VP-16-213 and vindesine (PVPVD). The patient distribution and characteristics were similar in all the treatment arms. The response rate differences (35% in PVD arm, 30% in PVP arm, and 22% in PVPVD arm) were not statistically significant (P = .33). Response durations were 43 weeks in the PVD arm, 20 weeks in the PVP arm, and 27 weeks in the PVPVD arm. Median survival was 29 weeks in the PVD and PVP arms and 28 weeks in the PVPVD arm. Median survival time of responding patients was 76 weeks in the PVD arm and 65 weeks in the PVP arm; 78% of patients were alive at 22+ to 87+ weeks follow-up in the PVPVD arm. Myelosuppression was similar in all three treatment arms. Significantly more azotemia occurred in the PVD arm than in the PVP and PVPVD arms (P = .002), and significantly more neuropathy in the PVD and PVPVD arms than in the PVP arm (P = .003 and .005). All the treatment arms have similar antitumor activity in non-small-cell lung cancer, but the PVP combination is slightly less toxic than the PVD and PVPVD treatment arms.

The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.

Clinical kinetics of 1, 4-dihydroxy-5,8-bis [(2-[(2-hydroxyethyl) amino] ethyl] amino ]-9, 10-anthracenedione.

The clinical kinetics of 1, 4-dihydroxy-5,8-bis[[ 2-[(2-hydroxyethyl) amino] ethyl] amino]-9,10-anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half-life (t 1/2) of 13.7 min and a terminal t 1/2 of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 +/- 2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

Combined chemoradiotherapy in limited-disease, inoperable non-small cell lung cancer.

Forty-three patients with limited-disease, inoperable non-small cell lung cancer received two intravenous courses of cyclophosphamide, Adriamycin, and cisplatin (CAP) chemotherapy over a 6-week period. This was followed by 5 weeks of combined chemoradiotherapy (CCRT) consisting of low weekly doses of CAP for 5 weeks plus 50 Gy continuous X ray therapy (XRT) to the primary tumor site. Chemotherapy was continued until disease progression occurred or until the total dose of Adriamycin reached 450 mg/m2, whichever came first. CCRT improved the response rate [complete response (CR) plus partial responses (PR)] from 25% after two courses of CAP alone to 65% after CCRT. Previous response to two courses of CAP influences response subsequent to CAP plus XRT. A pretherapy weight loss of 6% or greater had a significant adverse effect on both response and survival time. The median survival time for all patients was 50 weeks; patients whose disease responded to treatment survived significantly longer than patients with nonresponding disease. The median time until disease progression was 37 weeks. Twenty-seven patients relapsed. The first sites of relapse were local in 30% of the patients, distant in 56% of them, and both local and distant in 15%. Severe esophagitis occurred in 30% of the patients and was dose-limiting. The administration of CCRT resulted in an improved response rate compared with the rates reported in previous studies of chemotherapy or radiotherapy alone. Further improvement of the CCRT program is needed to increase long-term survival time and to decrease esophageal toxicity.

Neurotoxicity in long-term survivors of small cell lung cancer.

Chronic central nervous system neurotoxicity was studied in 38 long-term survivors (greater than or equal to 3 years) of small cell lung cancer who were treated at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1971 and 1980. All but one patient received combination chemotherapy with or without chest irradiation. Twenty-four patients received whole brain irradiation (Group I), 22 for "elective" and two for therapeutic purposes, while 14 did not (Group II). Abnormalities in computed tomographic (CT) scans of the brain were more frequently observed in Group I than in Group II (70% vs. 0%, p less than 0.01). Clinical central nervous system neurotoxicity developed in three patients in Group I, while none developed in patients in Group II (p less than 0.05). Patients who received methotrexate and procarbazine after whole brain irradiation were at a higher risk for clinical central nervous system neurotoxicity (p less than 0.05), and for development of periventricular white matter changes in CT brain scans (p less than 0.05) than were patients in Group II. Impaired methylation of the myelin sheath is proposed as a possible underlying pathogenic mechanism.

Timing of elective brain irradiation: a critical factor for brain metastasis-free survival in small cell lung cancer.

Risk factors for brain metastasis in small cell lung cancer were studied in 260 patients without brain metastasis at presentation who were treated on 5 protocols. The first three protocols offered elective brain irradiation (EBI) to all available patients after 2 or 3 courses of chemotherapy (early EBI), whereas the other two offered it after 5 or 6 courses of chemotherapy (late EBI). The overall incidence of brain metastasis was higher in the late EBI group than in the early EBI group (23.6% vs. 14.3%, p = 0.08), primarily due to higher incidence of brain metastasis developing before EBI in the former. There was a higher incidence of brain metastasis in patients without than in patients with bone marrow metastasis (21.4% vs. 6.8%, p = 0.04), in patients less than 60 years old than in patients 60 years or older (23.4% vs. 13.4%, p = 0.06), and in patients with than in patients without bone metastasis (30.2% vs. 16.8%, p = 0.07). Major risk factors for short brain metastasis-free survival were bone metastasis (p = 0.008), late EBI (p = 0.03), and failure to achieve complete remission after induction chemotherapy (p = 0.001) or as a best response (p = 0.0001). The early EBI group had a longer brain metastasis-free survival than the late EBI group, even among patients with bone metastasis (p = 0.02) or bone marrow metastasis (p = 0.05) and those who achieved complete remission after induction chemotherapy (p = 0.06) or as a best response (p = 0.05). These results indicate that timing of EBI is a critical factor in brain metastasis in patients with small cell lung cancer. There was no difference in overall survival between the two groups, however, even among patients who achieved complete remission as a best response.

Esophageal complications from combined chemoradiotherapy (cyclophosphamide + Adriamycin + cisplatin + XRT) in the treatment of non-small cell lung cancer.

Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2 (p less than 0.025). Weekly low-dose chemotherapy administered concomitantly with chest irradiation (R) at the onset of treatment significantly increases esophageal complications. A review of the literature suggests that CCRT may be used safely with split courses of R. The duration between onset of chemotherapy either before or after R should be greater than one week.

Pharmacokinetics of homoharringtonine in dogs.

We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.

Clinical pharmacokinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone]dihydrochloride.

We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120-250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6 +/- 0.3 h and a terminal t1/2 of 24.7 +/- 6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1 +/- 5.9 l/kg, and the total clearance was 1045.5 +/- 51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4% +/- 1.1% of dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Phase II study of idarubicin in extensive-disease non-small-cell lung cancer.

Fourteen patients with extensive-disease non-small-cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (idarubicin, 4DMDR) at a dosage of 10 mg/m2/day x 5 days every 3 weeks. The median cumulative dose was 110 mg/m2 (range: 50-1,100). Two patients had stable disease for 12 and 56 weeks, respectively, one patient had failed to respond to a doxorubicin hydrochloride (Adriamycin)-containing regimen, and one had had no prior therapy. Twelve of the 14 patients had prior radiotherapy, chemotherapy, or both. Median survival for this heavily treated group was 16 weeks. Myelosuppression was minimal. Nausea and vomiting occurred in 44% of all courses. No cardiac toxicity and no decrease in cardiac ejection fraction was observed. We conclude that 4DMDR is ineffective in heavily treated E-NSCLC patients. However, the drug's activity in untreated patients is unknown. Further study of 4DMDR is indicated in patients who have had no prior chemotherapy or radiotherapy, with routine administration of antiemetic drugs along with pharmacokinetic studies.

Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer.

A pilot study was conducted using a combination of cisplatin (70 mg/m2 i.v., day 1), etoposide (60 mg/m2 i.v., days 1 through 5), continuous-infusion 5-fluorouracil (800 mg/m2 i.v., days 1 through 5), and allopurinol (600 mg p.o., days 1 through 7). Treatment was repeated every 3-4 weeks. Ten patients with metastatic non-small cell lung cancer were treated. Significant toxicities were observed, including electrocardiographic changes simulating acute myocardial infarction in three patients. There was no objective response, therefore the study was closed early according to its design.

Phase II clinical evaluation of dihydroxyanthracenedione in patients with advanced lung cancer.

A phase II clinical study of dihydroxyanthracenedione ( DHAD ) was conducted in 50 patients with advanced lung cancers. DHAD was administered intravenously on a 5-day schedule repeated every 4 weeks. Most patients had adenocarcinoma (46%), and had received previous chemotherapy (66%) and radiation therapy (50%). Among 41 evaluable patients, there were four partial remissions, eight disease stabilizations and 29 disease progressions. Remissions were more common among previously untreated patients (20% vs. 4%), particularly in patients with adenocarcinoma and large cell carcinomas of whom 3/10 (30%) responded. Responses lasted 9+, 9, 7, and 3 months, respectively. Cardiac toxicity was not observed. Other toxicities were tolerable. DHAD is a potentially useful agent for the therapy of adenocarcinoma and large cell lung cancers.

Ifosfamide with mesna uroprotection in the management of lung cancer.

Fourteen patients with extensive disease small cell bronchogenic carcinoma (SCBC) received ifosfamide at 2,000 mg/m2/day for 5 consecutive days with simultaneous mesna and vincristine while 26 patients with extensive disease non-small-cell bronchogenic carcinoma (N-SCBC) received the same regimen without vincristine. Eight partial responses (57%) were observed with a 40-week median survival in the case of SCBC and four partial remissions (15%) with a 31-week median survival in N-SCBC. Granulocytopenia was the dose-limiting toxicity, whereas urotoxicity was well controlled with mesna. Neuropsychiatric toxicity consisted of anxiety, agitation, confusion, and hallucination. Neurobehavioral testing detected worsened performance during ifosfamide treatment. Ifosfamide is one of the few active agents in N-SCBC.