Randomized Controlled Trial of a Cohesive Eight-Week Evolution Unit That Incorporates Molecular Genetics and Principles of the Next Generation Science Standards.

In response to calls for curricular materials that integrate molecular genetics and evolution and adhere to the K-12 Next Generation Science Standards (NGSS), the Genetic Science Learning Center (GSLC) at the University of Utah has developed and tested the "Evolution: DNA and the Unity of Life" curricular unit for high school biology. The free, 8-week unit illuminates the underlying role of molecular genetics in evolution while providing scaffolded opportunities to engage in making arguments from evidence and analyzing and interpreting data.  We used a randomized controlled trial design to compare student learning when using the new unit with a condition in which teachers used their typical (NGSS-friendly) units with no molecular genetics. Results from nationwide testing with 38 teachers (19 per condition) and their 2269 students revealed that students who used the GSLC curriculum had significantly greater pre/post gain scores in their understanding of evolution than students in the comparison condition; the effect size was moderate. Further, teacher implementation data suggest that students in the treatment condition had more opportunities to engage in argumentation from evidence and have in-class discussions than students in the comparison classes. We consider study implications for the secondary and postsecondary science education community.

A phase I/II study to evaluate the toxicity and efficacy of accelerated fractionation radiotherapy for the palliation of dysphagia from carcinoma of the oesophagus.

AIMS: We hypothesised that accelerated fractionated radiotherapy may provide a good palliative approach for dysphagia relief in patients with incurable oesophageal cancer, significantly reducing the overall duration of treatment, while providing symptom response with an acceptable toxicity profile. A phase I/II accelerated fractionation study was conducted to evaluate the efficacy and toxicity of this approach. MATERIALS AND METHODS: Patients with incurable oesophageal cancer, symptomatic with dysphagia, Eastern Cooperative Oncology Group performance statusor=6 h apart), 5 days a week, over 2 weeks. RESULTS: Of the 39 evaluable patients, the dysphagia response rate was 69% (27/39) with a median response duration of 5.5 months. The median time to response was 4 weeks. Twenty-eight per cent (11/39) of patients had transient worsening in their dysphagia scores. Acute toxicity (weeks 1-8) occurred in 41% (16/39) of patients. An improvement in global quality of life by week 8 was seen in 42% of patients. There were no late neurological sequelae. The median overall survival was 8 (range 1.7-58+) months. CONCLUSION: The ideal palliative regimen should be relatively short, with minimal toxicity, while offering a favourable response profile. Accelerated fractionation fulfils these criteria and is a suitable treatment alternative for the palliation of dysphagia, especially if the goal is to deliver a higher total biological dose within a shorter (2 week) period of time.

P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy.

BACKGROUND: Fewer than 20% of patients with bone cancer who are treated with surgery alone are cured. Even with the best current treatment, surgery combined with chemotherapy, only 60%-80% of patients with nonmetastatic bone cancer and 10% of patients with metastatic bone cancer are cured. Thus far, the reason for treatment failure in the nonresponding subset has not been identified. It has been hypothesized that P-glycoprotein, which confers multidrug resistance, might be the cause. We sought to determine whether the expression of P-glycoprotein is associated with poor treatment outcome in osteosarcoma. METHODS: In a retrospective study, we correlated P-glycoprotein expression with the outcome of conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed as having osteosarcoma between 1980 and 1989. RESULTS: P-glycoprotein was overexpressed in 27 patients but not in another 34 patients, and expression was ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the 34 patients whose tumors did not express P-glycoprotein had significantly better relapse-free rates than the 27 subjects whose tumors expressed the protein (87% versus 0%; P<.00001) and had improved survival rates (94% versus 35%; P<.00001). Among the 46 patients who received chemotherapy before surgery, the 23 whose tumors were negative for P-glycoprotein showed significantly better long-term outcomes (P<.00002), although differences in tumor necrosis in response to therapy were only of borderline significance (P = .057). CONCLUSIONS: P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.

Modulatory activity of chemotherapeutic agents on phagocytosis and intracellular bactericidal activity of human polymorphonuclear and mononuclear phagocytes.

Thirteen chemotherapeutic agents were tested for modulatory activity on phagocytosis by human granulocytes and monocytes. Phagocytosis, phagocytic index, and intracellular bactericidal activity were assessed using Staphylococcus aureus, smooth strain of Escherichia coli, and latex particles. Modulation of phagocytic activity depended on the type of particle used and the presence of serum in the medium. Testing granulocytes, only 1,3-bis(2-chloroethyl)-1-nitrosourea suppressed phagocytosis of all three types of particles used for ingestion. Other drugs suppressed either phagocytosis of E. coli and S. aureus or of one of the bacteria and latex particles. Three drugs enhanced ingestion of latex particles. The most pronounced modulation of phagocytosis was observed in conditions similar to those in vivo, namely, when serum was added to the medium and when the cells were exposed for longer time to the drugs. In the absence of serum, very little modulation of phagocytosis was observed, and only 1,3-bis(2-chloroethyl)-1-nitrosourea retained strong suppressive activity. Intracellular bactericidal activity was markedly suppressed by 7 of 13 drugs tested. Monocytes were less influenced by chemotherapeutic agents, their phagocytic activity being either suppressed or enhanced. The influence of chemotherapeutic agents on phagocytosis must be taken into consideration when assessing defense mechanisms and susceptibility to infection in patients with malignant diseases.

Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras.

Levels of p27 have been found to have independent prognostic significance in a variety of tumors including breast, colon, prostate, ovary, and gastric carcinomas. We investigated p27 levels and determined ras mutational status in 136 non-small cell lung cancers. We found reduced levels of p27 in 86% of cases and showed a statistically significant inverse correlation between p27 levels and tumor grade. ras mutations were found exclusively in adenocarcinomas and showed no relationship to p27 levels. Clinical data on a subset of the patients studied indicated that all 16 patients who died of disease and 21 of 22 patients who relapsed had low p27 levels, whereas all patients with high p27 levels were alive at last follow up. These findings suggest that alteration in p27 levels plays an important role in lung tumor progression and that p27 levels may have independent prognostic significance in non-small cell lung cancer.

Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma.

p27Kip1 is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation by mediating cell cycle arrest in G1. This study was undertaken to assess the prognostic value of p27Kip1 in localized human prostate cancer. Archival material from 113 radical prostatectomy specimens obtained between 1985 and 1993 was stained immunohistochemically for p27Kip1 protein using a commercially available antibody. Patient charts were reviewed for preoperative serum prostate-specific antigen, clinical and pathological staging, Gleason tumor grade, time to biochemical and clinical recurrence, and survival. Strong p27Kip1 staining was uniformly seen in benign prostatic epithelial components in all tumor sections. p27Kip1 staining was reduced in most prostate cancers and was variable in prostatic intraepithelial neoplasia. Decreased p27Kip1 staining (<25% of nuclei stained positive for p27Kip1) correlated with seminal vesicle involvement (P = 0.0032) and with higher Gleason grade (P = 0.0114). On univariate analysis, low p27Kip1 predicted an increased risk of treatment failure in the node-negative cohort (P = 0.0037) and in the subset who did not receive neoadjuvant hormonal therapy (P = 0.049). Low p27Kip1 expression was an independent predictor of treatment failure on multivariate analysis of lymph node negative prostate cancers following radical retropubic prostatectomy (n = 102; P = 0.047). Seminal vesicle involvement (P = 0.034) and positive surgical margins (P = 0.047) were also independent prognostic factors for disease recurrence. In patients who received preoperative neoadjuvant hormonal therapy, low p27Kip1 in the pathological specimen was an even stronger predictor of outcome than it was in the entire group (n = 23, P = 0.015).

Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer.

Seventy-eight patients with evaluable small-cell lung cancer (SCLC) were treated with etoposide (VP-16) and cisplatin after their disease failed to respond to, or relapsed after, induction combination chemotherapy, consisting primarily of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV). Twenty-four patients had limited disease (LD) and 54 had extensive disease (ED). In six (8%) patients, a complete response (CR) was achieved and in 37 (47%), there was a partial response (PR). The median duration of response for responding patients was 22 weeks (range, 4 to 50 weeks) for patients with LD and 18 weeks (range, 4 to 49 weeks) for those with ED. Twelve percent of patients demonstrated stable disease, and 33% of patients had progressive disease on treatment. The median survival times of LD patients achieving a CR or PR were 59 and 34 weeks, respectively, whereas the comparable figures for ED patients were 45 and 23 weeks, respectively. Gastrointestinal toxicity was mild, but myelosuppression, predominantly leukopenia and thrombocytopenia, was common. Mild to moderate nephrotoxicity occurred in 11 patients, but was reversible in all cases. Two febrile episodes occurred during periods of drug-induced neutropenia, but no other significant toxicities were identified. These results provide further evidence that VP-16 and cisplatin is an effective and tolerable combination chemotherapy regimen for SCLC resistant to CAV.

VP-16 and cisplatin as first-line therapy for small-cell lung cancer.

Thirty-one patients with small-cell lung cancer (SCLC) were treated with VP-16 and cisplatin as first-line therapy. In the majority of cases an Adriamycin (Adria Laboratories, Columbus, Ohio) containing regimen was contraindicated because of severe cardiac or hepatic disease. Eight patients who presented with cerebral metastases were also included in the series. Eleven patients had limited disease (LD), and 20 had extensive disease (ED). Of the 28 evaluable patients, 12 (43%) achieved a complete response (CR) and 12 (43%) had a partial response (PR). Four patients (14%) either had no response or progressed on treatment. The median duration of response for patients with LD was 39 weeks and for those with ED, 26 weeks. The median survival time (MST) for the whole group of responding (CR and PR) LD patients was 70 weeks (range, 28 to 181 + weeks), and for responding ED patients, it was 43 weeks (range, 17 to 68 weeks). Gastrointestinal toxicity was mild, but leukopenia and thrombocytopenia were common. There were four febrile episodes during periods of drug-induced neutropenia and this led to one treatment-related death. Nephrotoxicity occurred in 15 patients and required discontinuation of cisplatin in two. These results compare favorably with reports of standard induction chemotherapy regimens and provide further evidence of the activity of the VP-16 and cisplatin regimen in patients with SCLC.

Carcinoembryonic antigen: a useful prognostic marker in small-cell lung cancer.

Plasma carcinoembryonic antigen (CEA) was determined in 180 patients with small-cell lung cancer (SCLC) before treatment. An abnormal level (greater than or equal to 6 ng/mL) was found in 34% of patients tested. Patients with extensive disease (39/83) had a significantly higher frequency of abnormal CEA (P = .001) than those with limited disease (22/97). There was a strong correlation between obtaining an objective response--particularly a complete response (P = .00003)--and the absence of an elevated CEA. Patients with an abnormal CEA also had a shorter survival time (P = .0007) and the difference remained statistically significant after logrank adjustment for extent of disease and ECOG (Eastern Cooperative Oncology Group) performance status. There was also a negative correlation between survival time and the quantitative level of CEA. In this series, only the group of patients with normal initial CEA levels included all survivors beyond 2.5 years. We conclude that CEA is a useful prognostic factor in SCLC.

Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.

One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.

A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer.

Pretreatment serum lactate dehydrogenase (LDH) levels were assayed in 288 patients presenting with small-cell lung cancer (SCLC) between 1976 and 1985. Patients were routinely staged by physical examination, chest x-ray, bone, brain, and liver scans, and bone marrow evaluation. Clinical response and survival were assessed following treatment with combination chemotherapy as part of four clinical trials. Patients with extensive disease (ED) presented with a higher incidence (108 of 147, 73%) of abnormally elevated LDH (greater than 193 IU/L) than those (65 of 141, 46%) with limited disease (LD) (P = 2 x 10(-6)). Forty percent of patients had an initial normal LDH level and a higher response rate (89 of 108, 82%; complete response [CR], 47%) than those with elevated values of LDH (119 of 156, 76%; CR, 29%). The CR rate varied inversely with the level of LDH in patients with LD (P = .026) but not in those with ED (P = .300). The median survival time and 1-year and 2-year survival rates for patients with elevated LDH were 39 weeks and 33% and 6%, respectively, whereas for those with a normal LDH level these were 53 weeks and 54% and 16%, respectively. Patients with LD and elevated levels of LDH manifested a higher relative death rate (1.63:1) when compared with patients with LD and LDH in the normal range (P = .0083). The survival of patients with ED did not differ between those with normal and elevated levels of LDH (P = .273). A significant survival advantage persisted for patients with LDH in the normal range following adjustments for extent of disease, performance status (PS), and treatment protocol (P = .044, log-rank analysis). In conclusion, serum LDH appears to be a significant independent pretreatment prognostic factor in patients with SCLC that correlates with stage of disease, response to treatment, and survival.

Importance of clinical staging in limited small-cell lung cancer: a valuable system to separate prognostic subgroups. The University of Toronto Lung Oncology Group.

PURPOSE: In an attempt to assess the response to treatment and survival of a group of patients treated with standard chemotherapy and radiotherapy, we undertook a retrospective review of small-cell lung cancer (SCLC) patients treated by the University of Toronto Lung Oncology Group. PATIENTS AND METHODS: We reviewed the records of 264 patients with limited SCLC who were treated from 1976 to 1985. Based on radiologic review and physical examination, patients were assigned to three prognostic groups: group 1 (very limited SCLC), negative mediastinoscopy and/or no evidence of mediastinal nodes on radiologic review; group 2, x-ray evidence of mediastinal node involvement or a positive mediastinoscopy; group 3, supraclavicular adenopathy or x-ray evidence of pneumonic consolidation, pleural effusion, or atelectasis. All patients received combination chemotherapy, radiotherapy to the primary site, and prophylactic cranial irradiation. RESULTS: Complete response was seen in 52% of patients and partial response in 29%. Response rates did not differ among the three prognostic subgroups. The median survival time for patients in group 1 was 15.7 months, compared with 12 months for group 2 and 11 months for group 3 (P = .0175). Projected 5-year survival for group 1 was 18%, compared with only 6% and 2% for groups 2 and 3, respectively. There was no difference among the prognostic subgroups with respect to either local or distant recurrence rates. CONCLUSION: Using simple clinical staging techniques, we were able to identify a subgroup of patients with very limited SCLC who had a significantly better prognosis. We recommend that randomized clinical trials stratify patients according to the presence or absence of clinically detectable mediastinal lymphadenopathy.

Second primary malignancies following diagnosis of small-cell lung cancer.

PURPOSE AND METHODS: The records of 800 patients with small-cell carcinoma of the lung (SCLC) treated between 1971 and 1985 at University of Toronto-affiliated hospitals were reviewed for the occurrence and relative risk of second primary malignancies (SPMs). Almost all patients who developed a SPM were treated previously with chemotherapy and radiation therapy. RESULTS: Nineteen metachronous SPMs (MSPMs) and 11 synchronous SPMs (SSPMs) were identified. SSPMs were detected between 1 and 12 months after the diagnosis of SCLC. The MSPMs were identified between 1 and 10 years after the diagnosis of SCLC. MSPMs included non-small-cell lung cancer (NSCLC) (four patients), hematologic malignancies (HM) (three patients), and 12 with other solid tumors (OST). The median survival times after the diagnosis of MSPM was 33 months, 10 months, and 1 month, respectively, for those with NSCLC, OST, and HM. Expected cancer incidence rates were used to compute a relative risk rate for developing a MSPM in a subset of 392 patients on whom accurate follow-up information was available. The calculated relative risk for all tumors was 3.73. The relative risk for the development of secondary NSCLC was 6.83. CONCLUSION: We suggest that increased predisposition to SPM may relate to secondary effects of multimodality treatment and biologic considerations.

MYCN protein expression as a predictor of neuroblastoma prognosis.

About half of nonlocalized neuroblastomas have MYCN gene amplification and usually progress rapidly, but the half without such amplification also do poorly, albeit progressing more slowly. We hypothesize that overexpression of MYCN protein can occur without gene amplification and that this expression reliably predicts the prognosis of neuroblastoma. To determine whether MYCN expression correlated with outcome, we assayed MYCN protein immunohistochemically in 180 archival pretreatment and posttreatment samples and stratified the 57 conventionally treated stage IVS, III, and IV patients by these conventional prognostic factors: stage, age, serum ferritin, Shimada histology, urinary catecholamine ratio, and MYCN gene status. At a median follow-up of >/=6.8 years, we found in patients with known MYCN gene status that the 23 of 37 without gene amplification fared no better than the 14 of 37 with gene amplification (P = 0.35 and 0.21, comparing relapse-free and survival rates). Conversely, in patients without MYCN gene amplification, 9 of 23 were found to overexpress MYCN protein pretreatment, and they did worse than the 14 of 23 without detectable MYCN protein (P = 0.0016 and 0.022, comparing relapse-free and survival rates). Furthermore, MYCN protein expression was prognostic without (P = 0.00001) and with (P = 0.0007) stratifying all 57 patients by MYCN gene status, each conventional prognostic factor (P ranging from 0.00001-0.013), or simultaneously by the two most important factors, stage and age (P = 0.00076). We conclude that overexpression of MYCN protein without gene amplification correlated significantly with the clinical behavior of neuroblastoma and predicted outcome independently of other prognostic factors. This strongly supports the hypothesis that expression of the MYCN oncogene is critical for progression of neuroblastoma.

Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.

Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.

Empiric therapy for infections in patients with granulocytopenia. Continuous v interrupted infusion of tobramycin plus cefamandole.

A combination of tobramycin sulfate and cefamandole nafate was used as initial empiric therapy for the treatment of 71 evaluable febrile (temperature greater than 38.5 degrees C) episodes in 64 (neutrophils, less than 1,000/microL) adult patients with cancer and granulocytopenia. Carbenicillin sodium or ticarcillin disodium was substituted for cefamandole in patients with Pseudomonas infections and in patients in whom the initial regimen was unsuccessful. Twenty-nine episodes were randomized to receive tobramycin by continuous infusion, while 42 were randomized to receive tobramycin by interrupted infusion. Twenty-seven (79%) of the 34 documented infections responded to the initial empiric antibiotic combination, ten (83%) of 12 being given continuous infusion and 17 (77%) of 22 being given interrupted infusion of tobramycin. Nephrotoxic reaction occurred in 7% of patients treated with continuous infusion and 15% treated with interrupted infusion, mostly patients older than 60 years. Tobramycin, by either continuous or interrupted infusion, plus cefamandole is safe and efficacious empiric therapy for infections in patients with cancer and granulocytopenia.

Combined modality treatment of small cell carcinoma of the lung.

Ninety patients with extensive and 61 with limited small cell carcinoma of the lung were treated with three courses of intravenous chemotherapy (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) followed by radiotherapy to intrathoracic disease, and a second three-drug oral combination consisting of lomustine, procarbazine, and methotrexate for one year. Among the 147 patients who were evaluated, 55 of 66 (83%) with limited disease and 53 of 81 (65%) with extensive disease showed response after three courses of chemotherapy. The complete response rate in patients with limited disease prior to radiotherapy was 24%, but increased to 58% when evaluated following radiotherapy. The median survival was 47 weeks for patients with limited disease and 36 weeks for those with extensive disease. A 24% two-year survival is projected for complete responders. Important prognostic factors for survival are performance status, extent of disease, and sex, with female subjects doing somewhat better than male subjects. Among patients with limited disease, 45% failed within the CNS despite the use of chemotherapeutic agents that cross the blood-brain barrier. The initial induction regimen and radiotherapy were well tolerated; the oral three-drug combination was more toxic and did not prevent CNS metastases.

First-line therapy with VP-16 and cisplatin for small-cell lung cancer.

VP-16 and cisplatin were used as first-line therapy in 31 patients with small-cell lung cancer (SCLC) in whom chemotherapy regimens that contained doxorubicin (Adriamycin [Adria Laboratories, Columbus, Ohio]) were contraindicated because of severe cardiac or hepatic disease. Eight patients who had cerebral metastases at presentation were also included in the study. There were 11 patients with limited disease (LD) and 20 with extensive disease (ED). Of the 28 evaluable patients, 12 (43%) had a complete response (CR) and 12 (43%) had a partial response (PR). Four patients (14%) failed to respond. The median duration of response (MDR) for LD patients was 39 weeks and for ED patients was 26 weeks. Patients with LD who responded (CR and PR) had a median survival time (MST) of 70 weeks (range, 28 to 232+ weeks), whereas ED patients who responded had an MST of 43 weeks (range, 17 to 68 weeks). Gastrointestinal toxicity was mild, but leukopenia and thrombocytopenia were common. Mild degrees of reversible nephrotoxicity occurred in 15 patients, but required discontinuation of cisplatin in only two. The results of this study are compared with several other recently published reports of VP-16 and cisplatin used as first-line therapy in SCLC.

Herpes zoster in patients with carcinoma of the lung.

Herpes zoster was observed in only four of 250 (1.6 percent) patients with small cell carcinoma of the lung, who were treated in a prospective, combined modality therapy trial. Induction chemotherapy in this study consisted of six courses of cyclophosphamide, doxorubicin, and vincristine (CAV), followed by intrathoracic and cranial irradiation. Those with extensive disease also received single doses of upper half-body irradiation. Patients did not receive maintenance chemotherapy (CAV2 protocol). This contrasted with our previous study (CAV1 protocol), which consisted of three courses of the same induction chemotherapy, the same intrathoracic irradiation, but with one year of oral maintenance chemotherapy. During the CAV1 regimen, we observed that herpes zoster developed in 13 of 161 (8.1 percent) patients in association with their therapy. A retrospective analysis of 6,576 patients with lung cancer revealed that herpes zoster developed in 58 (0.9 percent). This complication developed in 10 of 622 (1.6 percent) patients with small cell carcinoma of the lung, as compared to 48 of 5,954 (0.8 percent) patients with non-small cell carcinoma of the lung. The risk of development of herpes zoster in the CAV1 group was significantly greater than the historical group (p = 0.007) and was also greater than the CAV2 group (p = 0.031). However, there was no significant difference between the historical group and the CAV2 group. Attempts to explain the differences in the rate of herpes zoster in our three studies and those in the literature suggest that the duration of therapy, the type of chemotherapy used, and the improving survival rate may be important contributing factors to this complication in patients aggressively treated for small cell carcinoma of the lung. The literature and our own studies suggest that procarbazine is the most likely chemotherapeutic agent predisposing to this complication.