Primary chemotherapy of brain metastasis in small-cell lung cancer.

Fourteen patients with brain metastases from previously untreated small-cell lung cancer (SCLC) were treated with three courses of systemic chemotherapy as an initial mode of treatment. Whole brain irradiation was given concurrently with the fourth course of chemotherapy. The chemotherapy consisted of cyclophosphamide, 600 mg/m2 intravenously (IV) on day 1; doxorubicin, 50 mg/m2 IV on day 1; vincristine, 1.5 mg IV days 1 and 5; and etoposide, 60 mg/m2 IV days 3 through 5; all repeated every 3 weeks with dosage adjustments. There were ten men and four women, with a median age of 59 years (range, 47 to 75). Six patients had multiple brain lesions, and the brain was the sole site of distant metastasis in four patients. Three patients were inevaluable for response in the brain, as two died early and the third dropped out of the trial too soon. Brain lesions responded to chemotherapy in nine (one complete remission [CR], eight partial remissions [PR]) of 11 (82%) evaluable patients, and objective responses in the extracranial lesions were documented in nine (one CR, eight PR) of 12 (75%) evaluable patients. Median survival was 34 weeks (range, 1 to 93), and two patients are still alive. Toxicity was significant, with severe granulocytopenia (less than 500/microL) and thrombocytopenia (less than 50,000/microL) observed in 85% and 15% of patients, respectively. Six patients had major infectious complications, which resulted in septic deaths in two. However, there was no deterioration of neurologic status during the initial phase of treatment with chemotherapy. We conclude that systemic chemotherapy alone can induce objective regression of metastatic brain lesions in patients with previously untreated SCLC.

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.

Relationship between myelosuppression and chemotherapeutic response in small cell bronchogenic carcinoma.

Most cancerocidal agents have myelosuppression as their major toxicity. In some clinical studies it has been possible to show a relationship between the amount of administered drug and the therapeutic efficacy. Within any defined protocol, however, there may be much variability in the severity of myelosuppression. We attempted to determine whether the tumor response might be related to this toxicity. We evaluated a total of 177 patients with small cell bronchogenic carcinoma, treated by five successive regimens of combination chemotherapy, consisting of either cyclophosphamide and vincristine alone or with doxorubicin or doxorubicin plus bacillus Calmette-Guerin (BCG) or doxorubicin plus methotrexate, for a number of prognostic factors (age, sex, extent of disease, performance status, sites and number of metastases, serum LDH and alkaline phosphatase, weight loss, leukopenia, and thrombopenia). Leukopenia (mean 415 +/- 478/mm3, range 0-2000/mm3) had a weak influence on the incidence of complete remission, which was highest with the least severe nadir (P = 0.027). Thrombopenia was a nonsignificant factor (P = 0.738). Both leukopenia and thrombocytopenia had no influence on the overall survival. Because these drug combinations were based on cyclophosphamide, which requires metabolic activation, we evaluated the relationship of myelosuppression and the incidence of response in a second group of patients with small cell bronchogenic carcinoma treated with a VP16, cyclophosphamide, doxorubicin, vincristine sulfate protocol. In this analysis, no relationship could be detected between remission and myelosuppression. Granulocytopenia or thrombocytopenia also-showed no significant influence on the achievement of long-term survival beyond 36 months.

The role of consolidation irradiation in combined modality therapy of small cell carcinoma of the lung.

Forty-four patients with small cell carcinoma of the lung (SCCL) were treated with a program of combined chemotherapy and radiation therapy. Prophylactic cranial irradiation was given concurrent with the first of six planned cycles of chemotherapy consisting of Cyclophosphamide, Adriamycin, Vincristine and high dose Methotrexate (CAV-M). All patients judged as complete responders (CR) received consolidative thoracic irradiation (CTI) to the locoregional primary lung involvement. The CR rate to chemotherapy alone was 84% for patients with limited disease (LD) and 44% for extensive disease. In comparison to a prior trial, which used similar chemotherapy, but with irradiation withheld until primary site relapse, the actuarial primary site relapse rate at 2 years was reduced by CTI from 92% to 18% (P less than .01). The median primary site remission duration has not yet been reached in the CTI group and was 34 weeks without CTI (P less than .01). CTI increased the 2 year actuarial survival from 6% to 66% (P less than .01) in the chemotherapy CR patients. Median survival has not yet been reached in the CTI group, but was 48 weeks without CTI (P less than .01). Leptomeningeal spinal cord relapse in patients with no prior central nervous system (CNS) involvement occurred in 16% of patients relapsing.

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung.

Two chemotherapy trials using cyclophosphamide, doxorubicin hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first trial without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfate is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.

The role of thoracic and cranial irradiation for small cell carcinoma of the lung.

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.

Low-dose continuous infusion cisplatin combined with external beam irradiation for advanced colorectal adenocarcinoma and unresectable non-small cell lung carcinoma.

In a dose escalation study, CIS-diamminedichloroplatinum II (cisplatin) was combined with a standard dose of external beam irradiation in 15 patients with localized non-small cell lung cancer (NSCLC) and 16 patients with fixed or recurrent localized adenocarcinoma of the rectum. Cisplatin was given 5 days a week during irradiation using an outpatient portable infusion pump system, at doses of 3.2 mg/m2/24 hr in 15 patients, 4.0 mg/m2/24 hr in 13 patients, and 5.0 mg/m2 24 hr in 3 patients. Twelve of 15 patients with NSCLC received 66 Gy in 33 fractions in 6 1/2 weeks; one received 46 Gy followed by a surgical resection; for the other two patients treatment was discontinued after 50 Gy and 64 Gy, respectively, because they developed distant metastases. The 16 patients with rectal carcinoma received a preoperative dose to the pelvis of 45 Gy in 25 fractions in 5 weeks. Of 12 patients who underwent laparotomy, 10 had a surgical resection, 2 with close or positive surgical margins. Four patients who had resections received an intraoperative electron boost. Of the two patients who did not undergo resection at laparotomy, one received an intraoperative electron boost, the other a boost with interstitial iridium-192. Among the four patients with rectal adenocarcinoma who were not candidates for surgery because of advanced local disease, two had further external beam therapy up to 59.4 Gy, and two had no further therapy. Major toxicity was site-specific, with esophagitis predominating in the patients with NSCLC, diarrhea in the patients with rectal carcinoma, and nausea experienced by both. Cisplatin dose and toxicity seemed to be related. The maximum tolerated dose for low-dose continuous infusion cisplatin given 5 days/week in these patients was 3.2 mg/m2/24 hr combined with 66 Gy in patients with NSCLC and 4.0 mg/m2/24 hr combined with 45 Gy in patients with rectal carcinoma.

A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract.

A prospective, randomized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract (UAD) was conducted between July 1979 and September 1982. Eighty-three patients with locally advanced Stage III-IV tumors received standard treatment (STD RX; defined as preoperative irradiation and radical excision or irradiation alone), or induction chemotherapy (CTX) followed by STD RX. Chemotherapy consisted of two cycles of bleomycin (30 units/day by continuous infusions Days 1-4), cyclophosphamide (200 mg/m2 IV Days 1-5), methotrexate (30 mg/m2 Days 1 + 5), and 5-fluorouracil (400 mg/m2 IV Days 1-5). Response to CTX was complete in 2 and partial (greater than 50% reduction) in 27; the overall response rate was 68%. Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and/or surgery and in 24/43 CTX patients (17/29 responders, 7/14 non-responders). Freedom from local-regional disease was noted at 2 years in 53% STD RX and 35% CTX patients (p less than .06). CTX patients had a higher proportion of local-regional persistence and recurrence. The difference was apparent only in the subset of patients treated with primary irradiation; local-regional control following irradiation and surgery was equal in STD RX and CTX groups. Survival at 2 years was 43% STD RX and 31% CTX. Disease-free survival in those with clearance was 64% STD RX and 59% CTX. Induction chemotherapy did not improve tumor clearance or survival in this series. Caution regarding local-regional control with CTX and primary irradiation is noted.

Neurocardiogenic syncope and Prinzmetal's angina associated with bronchogenic carcinoma.

A clinical case is presented illustrating a previously unreported association of (1) neurocardiogenic syncope of new onset in a 57-year-old man, (2) Prinzmetal's angina, and (3) bronchogenic carcinoma of the lung. Initiation of aggressive chemotherapy resulted in immediate suppression of both cardiac manifestations. This newly described paraneoplastic syndrome is discussed.

Cyclophosphamide, vincristine and sequential split-course radiotherapy in the treatment of small cell lung cancer.

Thirty-nine patients with small cell lung cancer were treated with large dose intravenous cyclophosphamide combined with vincristine. Sequential split-course radiotherapy was added when the gross disease was limited to one hemithorax and draining scalene nodes. Fifteen of 16 patients in the limited disease category showed objective response, eight of which were complete. Fourteen of 23 patients in the extensive disease category yielded an objective response, six of which were complete. The median survival for complete responders was 48 weeks, 38 weeks for partial responders and 14 weeks for non-responders. The difference between responders and non-responders was statistically significant. The major toxicity was myelosuppression with a median leukocyte nadir of 500/mm-3 noted on treatment day no. 15. Prompt recovery was the rule. Toxicity appeared to be cumulative for patients receiving radiotherapy. These results are superior to those evolving from treatment with cyclophosphamide as a solitary agent.

The pharmacokinetics of bleomycin in man.

A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.

Intrapleural etoposide for malignant effusion.

The pharmacology, toxicity, and therapeutic effectiveness of etoposide (VP-16) given by the intrapleural route were examined in a phase I trial. Ten patients with malignant pleural effusion received 100, 150, or 225 mg/m2 VP-16 infused over 2 h into the pleural space after drainage of pleural fluid. The administration of VP-16 was tolerated well, with no local pain, increase in cough, dyspnea, or infection. Myelosuppression was mild at doses of 150 mg/m2 or less but severe at 225 mg/m2. Drug levels were followed in both plasma and pleural fluid for up to 12 h. Clearance of VP-16 from the pleural cavity was low at 2 ml/min m2. Peak pleural-fluid drug levels in patients receiving 225 mg/m2 exceeded 300 micrograms/ml, whereas peak drug concentrations in corresponding plasma samples obtained at the same time amounted to less than 10 micrograms/ml. Serial chest X-rays showed no disappearance of pleural effusion in nine evaluable patients. However, follow-up investigation of pleural fluid characteristics [carcinoembryonic antigen (CEA), lactic dehydrogenase (LDH), and cytologic examination] suggested some evidence of local therapeutic benefit.

Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting.

Didemnin B (NSC 325,319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m2 was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m2. Neuromuscular toxicity was dose-limiting. Nausea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m2, following the premedication of patients with antiemetics.

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.

Changes in the relative risk and sites of central nervous system metastasis with effective combined chemotherapy and radiation therapy for small cell carcinoma of the lung.

Prolongation of survival of patients with small cell carcinoma of the lung with current effective systemic therapy has been accompanied by a marked increase in the frequency of relapse in the central nervous system (CNS). Prophylactic cranial irradiation (PCI) was shown to reduce the frequency of brain metastasis, but there was no increased short-term survival. Therefore, the necessity for PCI early in the course of treatment has been questioned, especially for patients with extensive disease. From January 1974 through March 1982, 205 patients with small cell carcinoma of the lung were treated at the Medical College of Wisconsin Affiliated Hospitals. None had clinical, radioisotopic, or computed tomographic evidence of brain metastasis. Eighty-two patients received radiotherapy and chemotherapy, but no PCI; 123 patients received combination chemotherapy and radiation therapy with PCI. The cumulative probability of brain metastasis without PCI was 36% at 12 months and 47% at 24 months; the probabilities were 6 and 10%, respectively with PCI. The 24-month probability of brain metastasis in patients with limited disease and no PCI was 45%; for those with extensive disease, it was 47%. No patient presented with extracranial central nervous system (ECNS) metastasis and no one without PCI developed it. Twelve patients who received PCI developed ECNS metastasis; the cumulative probabilities rose to 14% at 12 months and 22% at 24 months. The increased frequency of ECNS involvement has led to a phase I trial of PCI followed by six cycles of combination chemotherapy, without maintenance chemotherapy, followed by irradiation of the chest and spinal cord for patients with complete response.

Multiagent chemotherapy, prophylactic neuraxis irradiation, and consolidative irradiation for small cell carcinoma of the lung.

Between 6/81 and 6/83, 73 patients with small cell carcinoma of the lung were treated according to a prospective protocol in which cyclophosphamide, doxorubicin, and vincristine (CAV) were given concurrently with prophylactic craniocervical irradiation to the level of C5. Both limited and extensive disease patients with normal computed tomography of the brain received 25 Gy in 10 fractions in 2 weeks. Complete responders to CAV received consolidative thoracic irradiation (CTI) to the local-regional primary (37.5 Gy in 15 fractions in 3 weeks), the first 25 Gy in 10 fractions serving as prophylaxis of the C6 to T12 spinal cord. The neuraxis from L1 to S2 then received 25 Gy in 10 fractions in 2 weeks. Consolidative irradiation of localizable metastatic sites was given in extensive disease patients. Partial and nonresponders to CAV received 50-60 Gy in 5-6 weeks to local-regional disease. With a median followup of 29 months, survival was significantly better (p less than .01) in patients receiving CTI to the chest after complete response to CAV (both limited disease and extensive disease) than without CTI. Of 41 patients completing the protocol and without central nervous system (CNS) involvement at presentation, four (9%) failed initially in the CNS (two brain, two spinal axis); CNS failure was the cause of death in all four patients with no other sites of metastases at death in two of these. Failure to complete protocol treatment was due to disease progression during chemotherapy in 25/73 (34%) and chemotherapy related complications (three sepsis, one gastrointestinal bleed) in four of 73 (5.5%) patients. CTI and prophylactic neuraxis irradiation did not increase morbidity or result in mortality in the sequence utilized; prophylactic neuraxis irradiation appears to reduce the CNS relapse rate, and CTI benefits survival.

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.

The prognostic significance of histologic subtyping in small cell carcinoma of the lung.

Previously untreated patients with small cell carcinoma of the lung (SCCL), who were treated at the Medical College of Wisconsin with combined chemotherapy and radiation therapy, were retrospectively subtyped according to the 1981 World Health Organization Lung Cancer Classification. Of 54 evaluated patients, 27 (50%) had "oat cell" subtype, 22 (41%) "intermediate cell" variety, and five (9%) were classified as "combined" type. There was no significant difference in response to therapy or median survival between the subtypes. In addition to the absence of prognostic significance among the subtypes, there were many technical factors affecting accuracy of subtyping, including tissue-crushing artifacts, size of biopsy materials, fixation of tissue samples, and variation of subtypes within the same biopsy. We conclude that subtyping of SCCL should not be construed as a prognostic tool or guideline to therapy. However, the recognition that SCCL may manifest in a variety of histologic patterns, some of which may be misinterpreted as a histology other than SCCL, is probably more important for choice of therapy and prognosis than the individual subtypes.

What is the lowest effective biologic dose for prophylactic cranial irradiation?

Between January 1974 and September 1984, 327 consecutive patients with small cell carcinoma of the lung (SCCL) free of clinical and brain scan (radionuclide or computed tomography) evidence of brain metastasis were treated at the Medical College of Wisconsin Affiliated Hospitals. All patients received single agent chemotherapy, consisting of cyclophosphamide or methotrexate (1974-1975), or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine with or without methotrexate and leukovorin (1976-1984). Between January 1974 and December 1974, 82 patients were treated with chemotherapy without prophylactic cranial irradiation (PCI). Between 1978 and 1984, all patients received PCI during the first week after diagnosis, simultaneous with their first cycle of chemotherapy. Chest irradiation was given to the complete responders to the chemotherapy. During the first 31/3 years of the study with PCI (January 1978-May 1981), 51 patients received 30 Gray (Gy) in 10 fractions in 2 weeks and five of them (10%) developed brain metastasis. Thereafter, 25 Gy in 10 fractions was consistently administered for PCI. Six of 194 patients (3%) developed brain metastasis. The cumulative (time corrected) probability of brain metastasis was approximately 10% at 1 year and was similar for patients who received 25 Gy and those who received 30 Gy. Although detailed neuropsychological testing has not been performed, clinically apparent late sequelae that might be attributed to PCI have not been seen. Nonetheless, the dose fractionation regimen of 25 Gy in 10 fractions with combination chemotherapy, cyclophosphamide, doxorubicin (or methotrexate), and vincristine is as effective in eliminating subclinical metastasis to the brain. It can be recommended for future trials until more data become available about late sequelae of treatment of SCCL and the patient characteristics and treatment factors that may contribute.

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.