Baseline tumour measurements predict survival in advanced non-small cell lung cancer.

BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.

Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC). METHODS: Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics. RESULTS: Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907,ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS(HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P<0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.03), and patients with body weight loss ≤5% versus >5% (P=0.04). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension,haemorrhagic events, neutropenia, and febrile neutropenia [corrected]. CONCLUSIONS: Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

BACKGROUND: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. PATIENTS AND METHODS: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort. RESULTS: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men. CONCLUSIONS: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma .

BACKGROUND: Eastern Cooperative Oncology Group (ECOG) Study E1594 compared paclitaxel and cisplatin with three newer chemotherapy doublets in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). The accrual of patients with an ECOG performance status (PS) of 2 was discontinued due to a perceived rate of unacceptable toxicity. METHODS: Patients were stratified by PS and randomized to one of the following treatments: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the curve, 6). All tests of statistical significance were two-sided. RESULTS: Sixty-eight patients with an ECOG PS of 2 were enrolled, and 64 patients were evaluable for toxicity and response. Fifty-six percent of 64 evaluable patients were male, and 81% had Stage IV disease. Grade 3-4 hematologic toxicities occurred in > 50% of the patients in each treatment group. Nonhematologic Grade 3-4 toxicities occurred significantly less often in the paclitaxel and carboplatin arm (P = 0.0032). The overall rate of toxicity did not differ significantly from the rate of toxicity in the PS-0 or PS-1 cohorts. There were 5 deaths (7.35%) among 68 patients with a PS of 2 during therapy; however, only 2 of those deaths were attributed to therapy. The overall response rate for the 64 evaluable patients was 14%. The overall median survival of all 68 patients with a PS of 2, as determined by an intent-to-treat analysis, was 4.1 months. CONCLUSIONS: Patients with advanced NSCLC and a PS of 2 experienced a large number of adverse reactions and overall poor survival. A comparison with patients with a PS of 0-1 suggests that these events and the shorter survival were related to disease process rather than treatment. Alternative strategies need to be explored with therapy specifically tailored for this group of patients.

The epidemiology of lung cancer.

Lung cancer continues to be the leader in cancer deaths in the United States. The incidence of lung cancer in men has slowly decreased since the late 1980s, but has just now begun to plateau in women at the end of this decade. Despite modest advances in chemotherapy for treating lung cancer, it remains a deadly disease with overall 5-yr survival rates having not increased significantly over the last 25 years, remaining at approximately 14%. Tobacco smoking causes approximately 85-90% of bronchogenic carcinoma. Environmental tobacco exposure or a second-hand smoke also may cause lung cancer in life-long non-smokers. Certain occupational agents such as arsenic, asbestos, chromium, nickel and vinyl chloride increase the relative risk for lung cancer. Smoking has an additive or multiplicative effect with some of these agents. Familial predisposition for lung cancer is an area with advancing research. Developments in molecular biology have led to growing interest in investigation of biological markers, which may increase predisposition to smoking-related carcinogenesis. Hopefully, in the future we will be able to screen for lung cancer by using specific biomarkers. Finally, dietary factors have also been proposed as potential risk modulators, with vitamins A, C and E proposed as having a protective effect. Despite the slow decline of smoking in the United States, lung cancer will likely continue its devastation for years to come.

Irinotecan in small-cell lung cancer: the US experience.

There will be approximately 40,000 new cases of small-cell lung cancer this year. Prior to 1990, there were several agents with single-agent response rates of 30% to nearly 90% in the untreated small-cell lung cancer population and approximately 10% to 20% in relapsed patients. During the 1990s, several new chemotherapy agents have displayed activity in small-cell lung cancer (paclitaxel [Taxol], gemcitabine [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan [Camptosar, CPT-11]). The majority of studies with irinotecan have been conducted in Japan. The US experience is limited to a single multi-institution trial that was conducted in patients with previously treated small-cell lung cancer. A total of 44 patients were entered in the study. Patients were stratified by response to prior therapy. Responses occurred in 7 of 44 patients for an overall response rate of 14%. The overall median survival was 4.8 months.

Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2). RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.

Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial.

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.

Phase II trial of gemcitabine in patients with previously untreated metastatic cancer of the esophagus or gastroesophageal junction.

BACKGROUND: There were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,-difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer. PATIENTS AND METHODS: A total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30-60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles. RESULTS: Gemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3-4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients. CONCLUSIONS: At the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.

Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.

A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study.

The purpose of this study was to evaluate the toxicity and determine the response rate, duration of remission, and survival using gemcitabine plus carboplatin in non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky Performance Status of at least 80. Gemcitabine was administered intravenously at 1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was administered immediately after gemcitabine at an area under the curve (AUC) of 5 given intravenously on day 1 of an every-4-week cycle. Seven patients were entered in the study and five were evaluable for toxicity. The median age of patients was 68 years (range, 52-72). The protocol was prematurely terminated because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia was observed in four of the first five patients. These toxicities were all observed with the first course of chemotherapy. There were no objective responses seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a logical combination. However, because of the severe thrombocytopenia associated with this regimen, we do not recommend this two-drug combination in the dose and schedule used in this study.

Treatment of advanced (stages III and IV) non-small-cell lung cancer.

Lung cancer is the leading cause of cancer deaths, and approximately 85% of patients in whom this neoplasm is diagnosed will die of this disease as a result of micrometastatic disease from tumors that appeared surgically resectable or of surgically unresectable disease that is either locally advanced or metastatic. It will affect approximately 171,000 people in the United States in 1998 and about 75% of these cases will be non-small-cell lung cancer (NSCLC). In only 25% of cases can complete surgical resection and cure be considered. Despite this grim outlook, advances have recently been made that beckon in an era of cautious optimism. In this review, a discussion of the latest developments in the management of locally advanced and metastatic NSCLC will be presented in detail. One of the significant developments has been the modifications to the staging system after the natural history of various stages was better characterized by reviewing the outcome of more than 5000 patients. Advances have also been seen in the diagnostic field. Specifically, positron emission tomography and endoscopic ultrasonography and biopsy are being evaluated to determine their role in diagnosing and staging lung cancer. At the present, however, history and physical examination, serum evaluation, computed tomography, and conventional approaches for obtaining a histologic diagnosis are standard practice. The role of adjuvant therapy, both postoperatively and in the neoadjuvant setting, has been studied. There are no data to support the use of radiotherapy or chemotherapy, with or without radiotherapy, in the postoperative setting. In the neoadjuvant setting, some intriguing results in favor of adjuvant chemotherapy have been observed. As discussed in detail these results provide preliminary data and need to be evaluated on a larger scale. Before the 1990s radiotherapy was the principal treatment modality used in the treatment of patients with locally advanced NSCLC. However, the results of several studies have shown the superiority of chemotherapy and radiotherapy in combination for patients with unresectable stage III NSCLC. Many questions regarding the optimal modes of chemotherapy and radiotherapy and the timing of these two modalities have yet to be answered. Concurrent with these advances has been the development of new chemotherapeutic agents that have been extensively evaluated in phase I and II trials. These agents include gemcitabine, paclitaxel, docetaxel, vinorelbine, and irinotecan. These agents have shown significant activity and acceptable toxicity when used in combination with cisplatin or carboplatin, but the results from the large cooperative trials that are ongoing are eagerly awaited to help define the optimal regimen. Further studies are either planned or ongoing to further define the role of these newer agents in the treatment of metastatic disease, in combination with radiotherapy for unresectable disease, and in the surgical adjuvant setting.

A phase II trial of paclitaxel in refractory germ cell tumors.

BACKGROUND: A significant percentage of patients with refractory germ cell tumors will not respond to standard salvage regimens. Thus there is a need for new active agents. Paclitaxel has demonstrated activity against a variety of solid tumors in both laboratory and clinical studies. METHODS: Eighteen patients with refractory germ cell tumors who failed initial cisplatin-based chemotherapy and a maximum of 2 salvage regimens were enrolled into a Phase II trial of paclitaxel at a dose of 170 mg/m2 by intravenous infusion over 24 hours every 21 days without growth factor support. The median age of the patients was 32.5 years (range, 18-49 years). The testis was the primary site of tumor for 13 patients (72%) and the tumor was extragonadal in 5 patients (28%). Six patients (33%) were late recurrences. Twelve patients (67%) had > or = 2 metastatic sites. The median number of previous chemotherapy cycles was six (range, four to nine). Three patients (17%) previously had undergone autologous bone marrow transplantation. RESULTS: Two patients (11%) responded to paclitaxel. Major toxicities were Grade 3-4 neutropenia (55% of patients) and Grade 3-4 neurotoxicity (2 patients). Neutropenic fever occurred in 3 patients (17%). CONCLUSIONS: Paclitaxel demonstrated minimal activity in heavily pretreated patients with multiple, poor risk clinical features. These results in part may be due to the unfavorable characteristics of the patients in the current study, specifically the high percentage of patients with late recurrences and extragonadal primary tumors, both of which are known to respond poorly to salvage therapy. Other trials with different patient populations and doses of paclitaxel reported response rates ranging from 13.3%-26%. The role of paclitaxel in the treatment of patients with refractory germ cell tumors remains to be defined in future studies.

Etoposide plus ifosfamide plus cisplatin in the treatment of small cell lung cancer.

Approximately 25% of all lung cancer cases diagnosed in 1993 were due to small cell lung cancer (SCLC). Approximately one third of all SCLC patients present with limited disease. Efforts to improve treatment results for patients with limited-stage SCLC include two recent meta-analyses of combined-modality treatment involving chemotherapy with thoracic radiotherapy versus chemotherapy alone. Both of these studies showed improvements in survival with the combined-modality approach. In addition, preliminary results of a Hoosier Oncology Group phase II study of cisplatin/ifosfamide/etoposide (VIP) in combination with thoracic radiotherapy in patients with limited disease indicate that VIP has an acceptable toxicity profile and should be studied further. For patients presenting with extensive-stage SCLC, several combination regimens have been shown to be effective in inducing responses of approximately 60%, although none has established superiority. Results of several studies evaluating the standard cyclophosphamide/doxorubicin/vincristine (CAV) regimen versus cisplatin-containing combination regimens have shown no obvious survival advantage of the cisplatin regimens over CAV. On the other hand, results of a Hoosier Oncology Group study of VIP versus cisplatin/etoposide in extensive-disease SCLC showed that overall survival favored (P = .044) the VIP arm (9.1 months v 7.3 months), although these results need to be confirmed in another trial.

Current management of small cell lung cancer.

There will be approximately 45,000 new cases of small cell lung cancer (SCLC) this year. Despite the initial sensitivity to chemotherapy, only 10% of all SCLC patients will have significant long-term survival. Studies have yet to show significant survival advantage for maintenance chemotherapy, and it appears that four to six cycles of chemotherapy is as effective as longer durations of chemotherapy. There is as yet no defined role for dose increase in the treatment of SCLC. In extensive disease no one chemotherapy combination has shown a definitive survival advantage, although it appears that single-agent oral etoposide may be inferior to combination intravenous chemotherapy. In limited disease, however, cisplatin plus etoposide alone or in alternation with cyclophosphamide, doxorubicin, and vincristine is superior to other approaches. Also, in limited disease, chemotherapy plus radiotherapy is superior to chemotherapy alone and it appears that early concurrent radiotherapy may be the ideal approach. Myeloid growth factors should not be given concurrently with thoracic radiotherapy. There are several new agents with significant activity in SCLC awaiting further study.

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Sp1 is critical for basal and E2-transactivated transcription from the bovine papillomavirus type 1 P89 promoter.

The bovine papillomavirus type 1 (BPV-1) long control region (LCR) contains at least three consensus binding sites for the transcription factor Sp1 at nucleotides (nt) 7800, 7833 and 7854. A high basal-level P89 expression vector consisting of an origin-deleted LCR fused to the chloramphenicol acetyltransferase (CAT) gene was utilized to determine the role of these Sp1 sites in the regulation of transcription from the BPV-1 P89 promoter. The three Sp1 sites were capable of binding Sp1 in vitro. Mutation of these sites in the background of the origin-deleted LCR-CAT or a wild-type LCR-CAT construct resulted in decreased basal expression from P89. In addition, mutation of the Sp1 sites in the wild-type background caused a reduction in E2-transactivation potential. These data illustrate the importance of these Sp1 sites in regulating both basal and E2-transactivated P89 expression.

A phase I pilot study of BCNU plus thymidine in patients with refractory cancer.

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m2/day to 105.5 g/m2/day for 48 hr, along with 100 mg/m2/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m2/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m2/day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.

Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: a Hoosier Oncology Group Trial.

PURPOSE: The study was undertaken to determine the activity and toxicity of oral etoposide (VP-16), ifosfamide, and cisplatin combination chemotherapy for previously treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS: In this phase II trial, 46 patients were enrolled to receive oral VP-16, 37.5 mg/m2/d for 21 days, ifosfamide 1.2 g/m2/d for 4 days, and cisplatin 20 mg/m2/d for 4 days, with courses repeated every 28 days. Response, survival, and toxicity data were then noted. RESULTS: Forty-two of 46 patients were assessable for response, survival, and toxicity. Thirty-six of 42 patients had received prior cisplatin plus VP-16. The first 22 patients received oral VP-16 for 21 days, but the subsequent 20 patients received oral VP-16 for 14 days after an interim analysis showed marked myelosuppression. Twenty-three of 42 patients (55%) had an objective response, with six complete responses (CRs; 14%), and 17 partial responses (PRs; 40%). The median progression-free survival time was 20 weeks (range, 2 to 66) and the overall median survival duration was 29 weeks (range, 1 to 76). Myelosuppression was significant, with six treatment-related deaths, four as a result of sepsis. CONCLUSION: The combination of oral VP-16, ifosfamide, and cisplatin is an active regimen in the treatment of recurrent SCLC. However, hematologic toxicity was severe in this pretreated patient population.