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Traffic crashes cost society billions of dollars each year as a result of property damage, injuries, and fatalities. Additionally, traffic crashes have a negative impact on mobility, as they are a primary cause of non-recurring delay. With the Interstate 10 corridor between the ports of Los Angeles and Houston being one of the most vital links for goods movement across the United States, safety and mobility along this freeway, particularly for freight traffic, are of significant concern. This study, which utilized six years of crash data from the state of Arizona, explores factors affecting the frequency and severity of crashes along the Arizona portion of the I-10 corridor, with a particular focus on freight-related crashes. The safety performance along the I-10 is analyzed through the development of crash frequency and severity prediction models using integrated crash, roadway, traffic, and environmental data. Negative binomial and ordered logit models, with the incorporation of random parameters, were estimated to provide a detailed understanding of factors associated with freight-involved crashes and how they compare to non-freight crashes in terms of frequency and severity. The results showed that several roadway- crash-, vehicle-, and person-related variables were associated with the frequency and/or severity of crashes along the study corridor. These findings provide important insights which can be used to develop or plan countermeasures aimed at improving the safety and efficiency of freight travel, which may include new ITS technologies, and targeted educational and enforcement campaigns.

Purpose. Cancer patients who are deficient in literacy skills are particularly vulnerable to experiencing different outcomes due to disparities in care or barriers to care. Outcomes measurement in low literacy patients may provide new insight into problems previously undetected due to the challenges of completing paper-and-pencil forms. Description of study. A multimedia program was developed to provide a quality of life assessment platform that would be acceptable to patients with varying literacy skills and computer experience. One item at a time is presented on the computer touchscreen, accompanied by a recorded reading of the question. Various colors, fonts and graphic images are used to enhance visibility, and a small picture icon appears near each text element allowing patients to replay the sound as many times as they wish. Evaluation questions are presented to assess patient burden and preferences. Results. An ethnically diverse group of 126 cancer patients with a range of literacy skills and computer experience reported that the ‘talking touchscreen’ (TT) was easy to use, and commented on the usefulness of the multimedia approach. Clinical implications. The TT is a practical, user-friendly data acquisition method that provides greater opportunities to measure self-reported outcomes in patients with a range of literacy skills. Copyright © 2003 John Wiley & Sons, Ltd.

BACKGROUND A number of single agents have been tested in patients with carcinoma of the head and neck receiving palliative treatment. In general, 15-30% of patients achieve a partial response lasting 3-4 months. Treatment has not been shown to alter survival rates. It is clear that new drugs with potentially greater activity need to be identified. For this purpose, the Eastern Cooperative Oncology Group conducted a Phase II evaluation of paclitaxel. METHODS Patients with recurrent, metastatic, or locally advanced, incurable squamous cell carcinoma of the head and neck were eligible. The dose and schedule tested was the maximum tolerable dose of 250 mg/m2 determined from Phase I trials using a 24-hour infusion schedule and granulocyte-colony stimulating factor support. Courses were given at 3-week intervals until progression of disease was documented. Dose modifications were specified for hematologic toxicity and for neurotoxicity. RESULTS Thirty-four patients were registered on study and 30 were eligible. Severe or life-threatening granulocytopenia was the most frequent toxicity observed, occurring in 91% of patients. Prior to response evaluation, one patient died of sepsis and one died of a myocardial infarct. Response was observed in 40% of eligible patients (4 complete and 8 partial responses). The median duration of response was 4.5 months (range, 2-20 months), with a median survival of 9.2 months and a 1-year survival rate of 33%. CONCLUSIONS These results indicate that paclitaxel is an active agent for the treatment of squamous cell carcinoma of the head and neck. Studies evaluating alternative infusion schedules and combination regimens currently are underway. Cancer 1998;82:2270-2274. © 1998 American Cancer Society.

Background The purpose of this study was to analyze long-term follow-up of a single institution's experience with a regimen of concomitant cisplatin/fluorouracil (5-FU) infusion and radiation given every other week. This analysis was stimulated by results of a randomized trial showing superiority for this regimen over induction cisplatin/5-FU chemotherapy followed by radiotherapy, especially in regional disease control. Methods All patients with stage III/IV disease who were referred by surgeons for nonoperative therapy and had a follow-up of at least 2 years were included. Concomitant chemoradiotherapy was administered days 1–5 of a 2-week treatment cycle, for a total of 7 cycles, with cisplatin 60 mg/m2 day 1, 5-FU 800 mg/m2 given over 24 hours days 1–5, and radiation 2 Gy days 1–5. Results Seventy-eight patients with stage III (n = 16) or IV (n = 62) were treated and followed for a median of 8 years. Six patients died during treatment, of aspiration pneumonia, sudden death, gastrointestinal bleeding, and stroke. When assessed 6 weeks after the end of treatment, 45 patients (63%) had no clinical evidence of disease, whereas 27 (37%) still had some persistent abnormality. However, 17 of these “partial responders” have not recurred. In all, 24 patients (31%) have recurred or progressed, 13 at the primary site, 5 after 3 years. None of 16 stage III and 24 (39%) of 62 stage IV patients ever progressed. Tongue and glottic larynx did best, with only 1 of 22 patients ever failing (none locally). Supraglottic and oral cavity cancers other than tongue had the worst failure rates. Nineteen patients (24%) died of other causes (DOC), tumor-free. Patients who DOC correlated strongly with T stage (p < .002) but not with N stage or with AJC stage. The 5-year progression-free survival was 60% (confidence interval [CI] = 49% to 72%), and overall survival was 43% (CI = 33% to 56%). Conclusions Disease control for this advanced head and neck cancer population was excellent. This regimen was especially effective in advanced tongue and glottic cancers and all stage III disease sites. Advanced supraglottic and hypopharynx cancers are problematic. These, and especially T4 lesions, are associated with high DOC rates, possibly in part related to swallowing malfunction. Nevertheless, the long-term survival without surgical intervention was high with this regimen. © 1997 John Wiley & Sons, Inc. Head Neck19: 684–691, 1997.

PURPOSE: To analyze disease failure patterns by pretreatment characteristics and treatment groups in a prospective randomized trial. METHODS AND MATERIALS: Patients with medically inoperable Stage II, unresectable IIIA and IIIB nonsmall cell lung cancer with KPS > or =70 and weight loss < or =5% were randomized to one of three treatment groups: standard radiation therapy with 60 Gy at 2.0 Gy per day (STD RT), induction chemotherapy with cisplatin 100 mg/m2 days 1 and 29 with vinblastine 5 mg/m2 weekly for 5 weeks followed by 60 Gy at 2.0 Gy per day (CT + RT), or hyperfractionated radiation therapy with 69.6 Gy at 1.2 Gy b.i.d. (HFX RT). Of 490 patients enrolled, 458 were evaluable. Minimum and median periods of observation for this analysis were 4 years and 6 years, respectively. RESULTS: Pretreatment characteristics were equally distributed. Toxicities were previously reported. Median survival rates were 11.4, 13.6, and 12.3 months for STD RT, CT + RT, and HFX RT, respectively (log rank p = 0.05, Wilcoxon p = 0.04). Survivals were 20, 31, and 24% at 2 years, and 4, 11, and 9% at 4 years in the STD RT, CT + RT, and HFX RT groups, respectively. There were no differences in local tumor control rates among the treatments. Patterns of first failure showed less distant metastasis (DM) (other than brain) for CT + RT compared to the RT alone arms (p = 0.04). Within squamous cell carcinoma (SCC), DM (other than brain) rates were 43%, 16%, and 38% in SCC for STD RT, CT + RT, and HFX RT, respectively (p = 0.0015). Patients with peripheral/chest wall lesions were significantly more likely to fail first in the thorax when treated on STD RT compared to CT + RT and HFX RT (p = 0.009). Survival rates were similar among the treatment arms for patients with squamous cell carcinoma. Among patients with nonsquamous cell carcinoma, failure patterns did not differ by treatment group, but survival was significantly better in those who were treated by induction chemotherapy (p = 0.04). CONCLUSION: Patients with squamous cell carcinoma treated on the CT + RT arm had a significant reduction of first DM other than brain, but there was difference in survival. Survival favored CT + RT in nonsquamous carcinoma despite similar failure patterns. Reasons for improved survival with CT + RT in NSCLC are not yet available.

The physician-patient relationship has critical importance in the quality of medical care, especially in the oncology setting. Of particular interest over the past two decades has been the communication between physicians and their patients. It is understood that communication is related to patient and physician satisfaction as well as other medical outcomes. However, despite this interest and attention, investigators have only recently begun to assess the communication between physicians and patients from the patient's point of view. Additionally, previous investigations have primarily relied upon retrospective reports of the interaction from patients or physicians. The current investigation assessed physician–patient communication in an oncology setting, both as it was occurring and following the interaction. The units of analysis included participant ratings as well as those of trained observers. Findings revealed that physicians and patients disagree as to the valence of the messages which transpired. Additionally, results suggest that it is the patients who distort the messages in the positive direction. Research and clinical implications of this disagreement and positivity bias are discussed.

Background Morphologically noninvolved mucosa in patients with head and neck cancer is altered by carcinogens. These alterations may include chromosome alterations, gene mutations, and other molecular abnormalities which may explain very high incidence of second tumors in this group of patients. The purpose of this study was to investigate the in vivo proliferative characteristics in epithelial tissues adjacent to the tumor in a series of patients with head and neck cancer. Methods Twenty-one patients with head and neck tumors received IV infusions of iododeoxyuridine (IdUrd) and/or bromodeoxyuridine (BrdUrd). Surgical specimens containing normal-appearing epithelium adjacent to the tumor were selected and stained with the respective monoclonal antibody. The percentage of S-phase cells (labeling index, LI) was counted in the basal and suprabasal layers of the epithelium. Results In 27 samples of oral epithelium obtained from 14 previously untreated patients, labeled (S-phase) cells were predominantly located in suprabasal layers with LI 31.6 ± 3.1% (range 13.5–73.2%). In contrast, the LI of the basal layer was very low: 1.6 ± 0.2% (range 0.5%–8.8%). There was no statistically significant difference between normal appearing and dysplastic samples (p > 0.05). In 10 samples obtained from 7 patients whose biopsies were studied 2 days to 2 month after concomitant radiation and chemotherapy, the LI of the oral mucosa basal layer was significantly higher (21.0 ± 4.1%, range 6.3–39.2%). The LI of the suprabasal layer in treated patients was 14.3 ± 2.4% (range 5.9–31.1%). The LI of nasal pseudostratified epithelium (4 samples) was 11.2%. The average LI of “basal” cells was 8.3% (range 5.9–11.9%) and that of “suprabasal” cells was 13.8% range (3.2–29.5%). The basal layer of the skin (5 samples) contained 9.3% labeled cells (range 3.3–16.3%); the LI of suprabasal layers of skin was 21.3% (range 7.8–33.2%). Conclusion Both the frequency and the spatial distribution of S-phase cells are disordered in noninvolved epithelia in patients with head and neck tumors. These observations suggest that disordered proliferation may be an early consequence of field cancerization, a consequence that occurs prior to appearance of morphologically apparent hyperplasia or dysplasia. HEAD & NECK 1996;18:522–528 © 1996 John Wiley & Sons, Inc.

The frequency and distribution of labelled cells were studied immunohistochemically in 37 squamous cell carcinomas (SCC) of head and neck after in vivo infusion of IdUrd and BrdUrd. Tumours were classified according to their labelling patterns. Low and moderate grade SCC consisted of tumour islands separated by interstitial tissue. In some tumours labelled cells only appeared near the basal layer while in others proliferative cells were evenly distributed within the neoplastic island. In anaplastic carcinomas labelled cells were distributed either randomly or around blood vessels (cord structures). While the basal layer in adjacent normal epithelium contained very few labelled cells (LI = 1.6 +/- 0.2%), the LI of basal cells in tumour islands were much higher than the average LI of the tumour (47.2 +/- 2.8% and 23.8 +/- 1.6%, respectively). In patients who had received cytotoxic therapy up to two months before the biopsy, the LI in the basal layer of normal epithelium was 19.0 +/- 3.5%. In sequential biopsies obtained 1-2 weeks after the infusion of IdUrd and BrdUrd some labelled tumour cells were found in necrotic foci and in pearl structures. Additionally, in six tumours, we found areas of cells labelled with IdUrd alone, even though the IdUrd infusion had been followed by a BrdUrd infusion 1 h later. This is in agreement with the phenomenon of intermittent tumour blood flow described earlier in experimental tumours.

A phase II study was performed to determine the efficacy and toxicity of the etoposide, doxorubicin, cisplatin (EAP) regimen in the treatment of patients with advanced measurable gastric cancer in a multi-institutional cooperative group setting. Thirty-one evaluable patients with advanced measurable gastric adenocarcinoma were treated with etoposide 120 mg/m 2 on days 3, 4, and 5, doxorubicin 20 mg/m 2 on days 1 and 8, and cisplatin 40 mg/m 2 on days 2 and 9. The treatment was repeated every 28 days. Objective responses were seen in 7 (23%) patients, all achieving partial remissions. Median survival was 9 months for the entire group. Toxicity was mostly hematologic, with grade 3 leukopenia in 26% and grade 4 leukopenia in 55% of the patients. There were 4 treatment-related deaths that were attributable to severe leukopenia and sepsis. Because of the high toxicity and moderate response rate, this regimen is not superior to other less toxic regimens and cannot be recommended for the treatment of advanced gastric cancer outside of an investigational protocol.

Background. From February 1988 to August 1991, 82 patients were treated on a Phase II trial of split-course multimodality treatment for locally advanced, non-small cell lung cancer (NSCLC). Methods. Treatment consisted of twice-daily radiation (150 cGy/fraction) delivered with concomitant infusional cisplatin, etoposide, and fluorouracil for 1 week every third week. Patients were classified before initial treatment as either potentially resectable (eligible for surgery [ES]) or ineligible for surgery (IES). The ES group consisted of 38 Stage IIIA and 7 Stage IIIB patients. The IES group had 5 patients staged as IIIA and 32 staged as IIIB. Most patients were staged clinically. ES patients received three cycles of treatment (39 Gy) before resection

To investigate whether breast cancer cells with unusually high nuclear DNA content are associated with an adverse outcome, Eastern Cooperative Oncology Group investigators selected breast cancer trial patients who suffered an early death (ED) within two years after diagnosis to compare with other trial patients who had a survival of at least 7.5 years. Paraffin blocks of primary breast cancers were obtained from 93 evaluable patients who had been enrolled in two surgical adjuvant trials for lymph node positive (LN +) disease (T1-3N1M0). Single cell monolayer preparations from these blocks were stained with acriflavine-Feulgen and analyzed by image analysis for DNA content with the automated Leiden Television Analysis System (LEYTAS). Standard prognostic variables (estrogen receptor (ER) status, number of lymph nodes with metastases, and size of the cancer) were compared with three DNA content characteristics: DNA ploidy status, number of nuclei with > 5C DNA content, and percent of nuclei with > 5 C. Estimates of the odds ratio in multivariate comparisons showed that ER negativity was associated with ED (p = 0.0005) and an odds ratio estimate using negative/positive of 4.87. The number of positive lymph nodes associated with ED had a p-value of 0.0005 and an odds ratio estimate of 4.63 when comparing the > 3 nodes group to the 1–3 nodes group. In contrast, the strongest association for any of the DNA content characteristics with ED had a p-value of 0.017 and an odds ratio estimate of 2.76. This power of association disappeared when stratified on ER status. Therefore, the presence of breast cancer cells with highly aneuploid (i.e. > 5 C) DNA content does not possess independent prognostic information in LN + breast cancer. An association remains to be tested in lymph node negative breast cancer.

A number of prospective controlled trials currently exist, with consistent results that help define the current role of chemotherapy in patients with advanced-stage head and neck cancer, and they may offer directions for future research. Neoadjuvant combination chemotherapy appears to offer no survival advantage but does appear to select a subgroup of patients who do not require surgical intervention, thereby resulting in organ preservation. Patients who have received neoadjuvant chemotherapy and obtain a prompt complete response are more likely to realize a significant local control advantage following regional therapy. Randomized studies using simultaneous chemotherapy and radiotherapy have resulted in higher clinical local control and overall survival rates. These studies have used only single agents, however. Phase II trials with drug combinations have been even more encouraging as compared with historical data. By comparing different treatment schemes, such as alternating and sequential, to simultaneous schedules, it is hoped that differences in toxicity, the role of dose-intensity, and regional control rates can be further defined. The information now exists for the formulation of well-designed, prospective randomized clinical trials comparing different schemes of concomitant chemotherapy with standard regional treatment regimens.

Multi-modality treatment consisting of cisplatin, VP-16, and 5-fluorouracil chemotherapy given concomitantly with external beam radiation was used to treat 64 patients with locally advanced Stage III non-small cell lung carcinoma. This regimen was used in a preoperative fashion for four cycles in patients considered surgically resectable and with curative intent for six cycles in the remainder of patients. The clinical response rate for the entire group was 84% and the overall local control rate was 74%. The median survival was 13 months with a median follow-up for live patients of 19 months. The actuarial 3-year survival and disease-free survival rates were 30% and 23%, respectively. Histologic complete response was 39% and appeared to predict for survival. The 3-year actuarial survival and disease-free survival rates for 23 resected patients were 69% and 45%, respectively, with the complete histologic responders having a disease-free survival of 78%. The pattern of first recurrence did not appear to differ by histology or presence of lymph nodes in this subset of patients. The actuarial 3-year survival and disease-free survival rates for inoperable patients receiving six cycles of treatment were 18% and 23%, respectively. The local control was 67% with the majority of these patients having Stagemore » IIIB disease. The Mountain International staging system appeared to predict for operability, local recurrence, and survival. This concomitant treatment regimen is feasible, with the major toxicities being leukopenia, nausea, and vomiting.« less

Seventy-four patients from January 1975 through December 1982, with clinical Stage III Mo non-small cell carcinoma of the lung were treated at our Medical Center with a course of pre-operative radiation therapy to be followed by surgical resection. Radiation therapy consisted of delivering a total dose of 40 Gy with 200 cGy per fraction over a period of 4 weeks to the primary tumor in the lung and the regional lymph nodal areas. Surgical resection was attempted 4 weeks later. Fifty-eight percent of the patients had squamous cell carcinoma whereas the remaining had other histologies like adenocarcinoma, large cell carcinoma, or a combination thereof. All the patients except two were followed up to a minimum of 5 years or until death. Sixty-four patients (82%) had T3 tumors whereas mediastinal nodal involvement was found in 41 patients (55%). Fifteen patients (20%) did not have the operation because of tumor progression, patient's refusal or death. All but two surgically treated patients had tumor resection. Of these 19% had histologically negative specimens, 9 patients (16%) had microscopic disease only, and 37 patients had gross residual disease at the time of surgery. The actuarial 5-year survival and recurrence-free survival rates for the entire group were 20% and 24%, respectively. Patients with a pathologic response had an actuarial recurrence-free survival rate of 53% at 5 years whereas only 17% of those with gross residual disease at surgery had remained recurrence-free at 5 years. One-half of the patients with clinically uninvolved nodes were living recurrence-free at 5 years whereas only 20% of the patients with N2 disease did so. The patterns of failure according to the histology and stage of the disease will be presented.

Forty-two patients with local or superficial metastatic or recurrent malignant tumors were treated in a non-randomized Phase I/II study to assess the tumoricidal effects of heat combined with radiation and/or chemotherapy. Radiation doses administered averaged 3130 ± 350 cGy; chemotherapeutic agents employed included bleomycin, mitomycin-C, adriamycin, and cis-platin, heat was induced by radiative or interstitial microwave applicators operating at frequencies ranging from 95 to 900 MHz. Forty-one of the forty-two patients were evaluated for initial therapeutic effects yielding the following response distributions: local hyperthermia with radiation-42% complete response (CR), 44% partial response (PR), and 15% no response (NR); local hyperthermia with chemotherapy-0%o CR, 50% PR and 50% NR. Long-term response duration was evaluated for local hyperthermia with radiation, yielding mean time to recurrence of 9.4 months for CR's and mean time to progression of 3.4 months for PR's. In retrospective analysis, we examined the correlations of previously established response-predictor variables of tumor volume and minimum thermal dose with both initial and long-term response rates. Initial complete response rates were correlated directly with non-site-specific minimum thermal dose, varied inversely with tumor volume and exhibited a positive correlation for a limited histologic type/treatment site combination. Surprisingly, long-term response did not correlate either with tumor volume or thermal dose. The frequency of thermally induced complications, which did not correlate with any measured thermal parameters, was found to be 42%, expressed on a per-patient basis.

Background : Management of neuropathic pain is challenging. Medications that interfere with sodium channel transport, such as lidocaine, mexilitene and flecainide, are promising as analgesics.Objective : In a general population of patients with a working diagnosis of neuropathic pain, whether if flecainide produces enough of an improvement in pain to warrant further clinical study is determined.Design : Phase I/II prospective exploratory clinical trial. Eligible patients were observed for week 1, then 50 mg flecainide was administered twice daily for week 2 and then administered 100 mg twice daily for week 3.Setting/ Subjects : Multi-institutional members of the Eastern Co-operative Oncology Group. Patients had neuropathic pain diagnosed by their oncologists as defined by the International Association for the Study of Pain and a diagnosis of cancer or AIDS.Measurements : The Wisconsin Brief Pain Inventory was used. The primary endpoint was a decrease of 3 points (0—10 numerical scale) or a decrease of 50% in the worst pain rating at either day 15 or day 22 relative to the average of days 1 and 8 ratings.Results : Nineteen patients were registered for the study. Four patients were ineligible. Of the remaining 15, one was unevaluable due to incomplete pain rating. Four out of 14 patients had an average drop of 5 points or 53% in their worst pain ratings on a 0—10 numerical scale of pain. No patients withdrew from study because of toxicity. There were no life-threatening or lethal toxicities. All patients were alive at the time of the analysis.Conclusions : Flecainide produced a 30% response rate. Response in this study was defined to be highly relevant and clinically significant reduction in pain. The drug merits study in a randomized placebo-controlled trial. Palliative Medicine 2007;21 : 667—672

When induction chemotherapy is used in locally advanced squamous cell cancer of the head and neck (SCCHN), patients often receive cisplatin-5-fluorouracil (PF) followed by radical loco-regional therapy. Phase II studies of docetaxel-cisplatin-5-fluorouracil (TPF) induction therapy, with or without leucovorin (L), have achieved high survival rates versus those reported in phase III PF trials. However, the distribution of prognostic factors may vary between phase II and phase III study populations, making the extrapolation of phase II TPF/L results to phase III PF populations difficult. This study used a patient selection standardization method and Cox model to adjust for potential selection bias. Thus, the survival benefit from adding docetaxel into PF induction regimens in SCCHN could be more accurately assessed. The TPF/L dataset comprised 195 patients from six phase II trials. The PF dataset of 585 patients was derived from five large randomized trials included in the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) database. TPF/L and PF datasets differed significantly concerning the distribution of several prognostic factors. Adjusting for these differences, the relative risk of death in the PF versus TPF/L datasets was 1.85 (95% confidence interval 1.37-2.49), corresponding to a 20% 2-year survival benefit (p < 0.0001). Sensitivity analyses confirmed that this improved 2-year survival rate of TPF/L over PF was robust, irrespective of the distribution of studied prognostic factors between treatment datasets. We conclude that this improved survival might be due either to docetaxel's pharmacologic effect or to uncontrolled prognostic factors.

Cancer patients who have limited literacy skills or English language proficiency are particularly vulnerable to receiving sub-optimal care. Outcome measurement in these patients may provide new insight into previously undetected problems. This report describes the development and testing of a Spanish language, multimedia program for quality of life (QOL) assessment. Pilot testing was conducted with 30 Latino cancer patients with a range of education levels and computer experience. Patients found the program easy to use and understand. The "Talking Touchscreen" is a practical, user-friendly method that provides greater opportunities to assess QOL in Spanish-speaking patients with a range of literacy skills.

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

Rapid proliferation of squamous cell carcinomas of the head and neck (SCCHN) during therapy may contribute to treatment failure. We have investigated the presence of p53 abnormalities in patients with SCCHN as a correlate of proliferation rate and other pathologic and clinical variables. p53 Mutation, as determined by polymerase chain reaction and single-strand conformation polymorphism analysis of microdissected frozen sections of tumor biopsies, was significantly associated with a high labeling index, as determined by in vivo infusion of IUdR and BrdU (P = 0.017). p53 Protein expression was detected by immunohistochemistry with two different antibodies, followed by quantitative image analysis. Many cases exhibited strong p53 protein expression in the absence of mutations within the conserved region of the gene, and expression was not related to proliferation. The presence of p53 mutations was related to tumor differentiation in this group of patients.

Attempts to improve the effectiveness of therapy for neoplastic diseases have largely focused on increasing the cytotoxic efficacy of therapy. While this approach is logical, there is another approach, based on the concept of regrowth resistance, which offers an alternate means of improving treatment outcome. The term "regrowth resistance" refers to the reduction in treatment efficacy resulting from the regrowth of neoplastic cells between courses of therapy or even between doses of radiation therapy. Regrowth resistance is likely to play a significant role in determining the outcome of treatment in rapidly proliferating neoplasms. A reduction in the rate of tumor regrowth would increase the net effectiveness of cytotoxic therapy and would also inhibit the development of resistance to cytotoxic therapies.

The present studies were undertaken to determine the incidence of apoptosis in plastic embedded head and neck (HN) tumor biopsies (n=31) using in situ end labeling (ISEL) of fragmented DNA. The extent of spontaneous apoptosis in untreated tumors was correlated with histological grade, percent S-phase cells (Labeling Index, LI) and with the mutational status of p53 gene in these tumors. Additionally, the in vivo effects of chemo- and/or radiotherapy on apoptosis were evaluated in seven patients. In the majority of tumors studied (25/31) spontaneous apoptosis was virtually undetectable or was very low (1-15% positively labeled cells). Only 6 tumors showed intermediate to high apoptosis (>15% positively labeled cells). High apoptosis was more frequent in poorly differentiated tumors (similar to 50%), as compared to well and moderately differentiated tumors. The median LI for 31 tumors studied was 20.2%. The mean LI for moderately differentiated tumors (23.7+/-1.7%) was significantly higher than that in well differentiated (15.1+/-2.1%, p=0.005) and was comparable in poorly differentiated tumors (24.5%). Cytotoxic therapy significantly increased the degree of apoptosis in 5/7 specimens studied (p=0.03). Double labeling of 5 of these tumors before and after the therapy, combining ISEL with detection of IUdR/BrdU, showed compartmentalized apoptosis and proliferation with virtually no double labeled cells in any specimen. Interestingly, tumors with a mutated p53 gene (n=6) showed intermediate to high degree of pretherapy, baseline apoptosis in contrast to low or undetectable levels of apoptosis in tumors bearing wild-type p53 (n=13, p=0.034). It appears that low levels of apoptosis and high proliferation may be characteristic of HN tumors. The spontaneous apoptosis in HN tumors seems unrelated to mutations in the p53 gene. Moreover, our data also show that despite overall increase in apoptosis induced by cytotoxic therapy, some proliferating tumor cells escaped the effects of therapy, which may contribute to the tumor relapse.

Background: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. Purpose: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. Methods: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m 2 ) on days 1 and 29 and 5 mg/m 2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). Results: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy-46%, 11.4 months; chemotherapy plus radiotherapy-60%, 13.8 months; and hyperfractionated radiation therapy-51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P=.03). Conclusions: In «good-risk» patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage

From 1981 to 1989, 21 patients with heavily pretreated head and neck cancers were retreated with combined chemotherapy (CT) and irradiation (RT). All patients had previously received radiation therapy with doses of 50-70 Gy. Metastatic disease to lungs and/or osseous sites occurred in 4 patients. Treatment consisted of simultaneous cisplatin, 5-fluorouracil, and external beam radiation therapy, with planned doses of 20 to 70 Gy. The RT+CT was given over 5 consecutive days every 2 weeks. Four patients did not complete treatment due to toxicity (2 patients) or disease progression (2 patients). All patients developed grade 2-3 mucositis. Because of toxicity, 11 patients required treatment delays of 1 to 3 weeks. Clinically complete responses were noted in 10 patients (48%), with partial responses occurring in 5 patients (24%). Of the 21 patients, 18 have died: 13 had local and/or regional recurrence, 2 died of treatment toxicity and 3 died of intercurrent disease. Median time to progression was 5 months (range: 1-15 months). Three patients remain alive with no evidence of disease at 44, 86, and 88 months after retreatment.

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scaleor = 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m2 every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC1000/microliters 36%), and thrombocytopenia (50,000/microliter 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.

Encouraging results of several clinical trials utilizing combination chemotherapy and irradiation in unresectable non-small-cell lung cancer have been reported. A recent report from a cooperative group study suggested that preirradiation vinblastine and cisplatin improved survival over irradiation alone. In an attempt to enhance the possible effectiveness of combination chemotherapy and irradiation, the Radiation Therapy Oncology Group embarked on a Phase II trial utilizing preirradiation vinblastine (5 mg/m2 weekly x 5) and cisplatin (100 mg/m2) on days 1 and 29 prior to irradiation and on days 50, 71, and 92 during irradiation. The irradiation began on day 50 and consisted of 6300 cGy in 7 weeks. Between May 20, 1988 and May 1, 1989, 30 patients were entered on study. Seventy-two percent of patients had Karnofsky status greater than 90, and 76% had weight loss less than 5%. Forty-eight percent of the patients were younger than 60 years of age. Forty-five percent of the patients had Stage IIIA disease. Eighty-three percent of the patients received at least four courses of vinblastine, and 59% received at least four courses of cisplatin. Seventy-eight percent of the patients received at least 95% of the prescribed irradiation. The major toxicity was hematologic, and there were two fatal complications in the study group. The preliminary survival figures are encouraging. This combination of chemotherapy and irradiation appears to be tolerable and may merit further investigation.

Patients with Stage III non-small cell lung carcinoma continue to pose a therapeutic problem with dismal cure rates. In an effort to improve on these results, 129 patients with biopsy-proven clinical Stage III non-small cell lung carcinoma from November 1982 through November 1987, were entered into two consecutive Phase II studies at Rush-Presbyterian-St. Luke's Medical Center. Treatment in the first study consisted of Cisplatin and 5-Fluorouracil infusion with concomitant split course radiation; in the second Etoposide was added. Radiation and chemotherapy were given simultaneously on days one through five of each cycle in a preoperative fashion for four cycles in patients considered eligible for surgery and in a definitive fashion for six cycles in patients considered ineligible for surgery. Radiation was given in 2 Gy fractions for a planned preoperative dose of 40 Gy and a definitive dose of 60 Gy. Surgical resection was attempted four to five weeks later in patients treated preoperatively. Thus, 83 patients were treated preoperatively and 46 definitively. Eighty-three patients (64%) had IIIA disease and IIIB disease was found in the remainder of the patients. Sixty-two patients (75%) in the eligible for surgery group had a thoracotomy after the combined treatment with a resectability rate of 97% and an operative mortality rate of 5%. There were 17 patients (27%) with no evidence of residual cancer in the resected specimen. Three-year survival for the eligible for surgery group at 40% was significantly better than 19% observed in the ineligible for surgery group (p = 0.003). Seventy-six percent of the patients with no residual cancer in the resected specimen are recurrence-free at three years compared to 34% of the patients with gross residual. A total of 81 patients have failed after their treatment; 49 (59%) in the eligible for surgery group and 32 (70%) in the ineligible for surgery group. Of all the patients who failed, local failure alone and as a component occurred in 21 (26%) and 36 (44%) patients, respectively. Failure in distant sites alone was noted in 56% of the overall failures. Severe toxicity was unusual. There were three treatment related deaths (2%). Radiation esophagitis and pneumonitis were only mild to moderate seen in less than 10% of the patients. Survival rates and patterns of failure according to the stage of the disease, histology, treatment group and pathologic response will be presented in detail.

To assess the ability of simultaneous cisplatin, 5-Fluorouracil, and radiation to substitute for surgery and radiation in advanced head and neck cancer, we have retrospectively selected from our phase II study a subgroup of 29 patients having primary disease requiring either more than a hemiglossec-tomy or a laryngectomy for control. Patients included 22 with stage IV and 7 with stage III disease, 12 tongue, 10 hypopharynx, and 7 larynx primaries. The treatment consisted of concurrent cisplatin, 5-Fluo-rouracil, and split-course radiation every other week for a total of 7 cycles within 13 weeks. With a median follow-up of 5 years, 86% of patients had preservation of speech and/or swallowing function. Median survival was 45 months, with 14 (48%) patients currently alive and disease free, 11 (38%) dead from their cancer, and 4 (14%) dead of other causes. The overall failure rate was 38%. Advanced-stage presence of N3 nodal disease and fewer than 7 cycles of chemotherapy received were significantly associated with increasing failure rates. This program of concomitant cisplatin, 5-Fluorouracil, and radiation produced control rates quite competitive with surgery and radiation and is appropriate for definitive testing in a randomized trial.

Approximately one-third of non-small cell lung cancer (NSCLC) patients present with locally advanced disease. Increasing numbers of clinical trials are being conducted in this group of patients and recently a new international staging system has been introduced, resulting in the sub-division of Stage III into IIIa (potentially operable disease) and IIIb (inoperable disease). Kaplan-Meier survival analyses and Cox regression analyses were used to analyze data from 129 Stage III NSCLC patients who had been treated on two consecutive Phase II trials testing combined modality treatment. The pretreatment characteristics of these patients were: median age--59 years, males/females--87/42, caucasian/non-caucasian--111/18, squamous cell or adenocarcinoma/large cell carcinoma--57/72, previous weight loss less than or equal to 5%/greater than 5%-76/46, previous history of cardiorespiratory disease--no/yes--91/36, performance status (PS) 0-1/2-3--102/27, Stage III, 2 groups--IIIa/IIIb--83/46, Stage III, 3 groups--IIIa T3 N0/IIIa N2/IIIb--41/41/47, surgical eligibility--eligible/ineligible--83/46. Kaplan-Meier statistics revealed significantly longer survival for PS 0-1 versus 2-3 (p = .001), for eligible versus ineligible for surgery (p = .003), for Stage-IIIa versus IIIb (p = .004), and for Stage-IIIa T3N0 versus IIIa N2 versus IIIb (p = .004). The best model developed from Cox regression analyses included stage (IIIa T3 N0 vs IIIa N2 vs IIIb), PS, and sex. These observations appear to have implications for clinical research in Stage III NSCLC.

Cisplatin has been an important addition to the treatment of head and neck cancer. It is the only drug to have been proven to cause a survival benefit when compared with supportive care alone in the palliative management of advanced head and neck cancer (Morton et al. 1985). It has interesting radiation-sensitizing properties in some systems and it is part of the most active drug combination in head and neck cancer when combined with 5-ftuorouracil infusion. In comparison with the newer analogs of carboplatin and iproplatin, cisplatin has the highest tumor cell uptake of the platinates when given parenterally (Hecquet.et al. 1987).

Use of chemotherapy with radiation therapy, rather than giving the two in sequence, has undergone a resurgence of interest over the last 5 years. 1988 witnessed an approximately equal distribution of publications on combining chemotherapy with radiation and on induction chemotherapy reports in contrast to publications over the previous decade in which reports on induction chemotherapy regimens markedly predominated [1]. This new interest has resulted from several controlled, randomized studies over the years that have demonstrated an advantage to combining chemotherapy with radiation, as well as to the failure of similar controlled studies to find any survival advantage to various induction chemotherapy programs. Reluctance to fully endorse the use of combined chemotherapy and radiation remains widespread, however, due primarily to concern over toxicity.

Objectives: To assess how p53 gene mutations and microvessel density (MVD) may be used as prognostic markers for the study and management of head and neck squamous cell carcinomas and to investigate putative associations between p53 gene mutations and MVD and the relationship of these factors to tumor response to radiotherapy and/or chemotherapy at 6 weeks. Patients and Design: Thirty-nine patients with squamous cell carcinoma of the head and neck, stages I to IV, who were examined at Rush-Presbyterian-St Luke's Medical Center, Chicago, 111, and its affiliated hospitals between 1993 and 1995 were monitored. Mutations in the p53 gene were identified by microdissection of tumor cells on frozen sections, followed by single-strand conformation polymorphism analysis of the products of polymerase chain reaction amplification of exons 5 to 9. The microvessels were immunostained with monoclonal antibodies to factor VIII and/or CD31. Microvessel counts were done by 2 investigators blinded to each other's counts and to the p53 gene status. Intratumoral or peritumoral microvascular hot spots were assessed and counts were done with an ocular grid in 3 X 200 fields of hot spots by each investigator. The mean of the highest values was considered. Statistical analysis was done with the Wilcoxon rank sum test, the log-rank test, and proportional hazard models. Results: Of the 39 patients, 13 had mutations in exons 5 to 9. Mutations in the p53 gene were associated with unfavorable overall (P=.003) and disease-free (P=.02) survival. A strong inverse relationship was seen between MVD and p53 mutations (P=.01). No statistically significant relationship was seen between mean MVD and overall and disease-free survival. The response to therapy differed significantly (P=.03) by p53 mutations, whereas there was no statistical significance with MVD counts. Conclusion: In this study a strong inverse relationship was seen between MVD and p53 mutations. p53 Mutations in exons 5 through 9 were associated with unfavorable survival, whereas MVD showed no association with survival.

A retrospective review of the Eastern Cooperative Oncology Group adjuvant chemotherapy studies EST 5177 and EST 6177 was performed in order to ascertain the first indicator of relapse in women with breast cancer and pathologically positive axillary lymph nodes. Of 856 evaluable patients, 208 have relapsed. In 175 patients who relapsed, the first indicator could be clearly identified: symptoms, 36%; patient self-examination, 18.3%; physical examination by the physician, 19.4%; abnormal blood chemistries, 12%; bone scans, 8%; chest x-rays, 5.1%; and mammograms, 1.1%. Although 74% of recurrences are therefore detected clinically, in a sizable proportion (26%), the ancillary tests were the earliest indicators of relapse. The manner of detection was not influenced by nodal, estrogen receptor (ER), or menopausal status. These results suggest that the follow-up schedule currently employed by ECOG appears reasonable.

More than i of all non-small cell lung carcinoma (NSCLC) patients present with locally advanced non-metastatic disease. Despite radiation therapy and surgery the survival of these patients remains poor. In an effort to improve upon these results 33 clinical Stage III M 0 patients from April 1985 through September 1986 were entered into a Phase II study at Rush-Presbyterian-St. Luke's Medical Center. Treatment included 5-FU by continuous infusion, VP-16, cisplatin and concurrent split course radiation therapy followed by surgical resection when possible. The overall clinical response rate is 74%. Fifty-seven percent of the preoperative group of patients went to surgery with a 100% resectability rate. These patients had a 50% pathologic complete response with no tumor found in the resected specimen. All surgical margins were free of disease and there were no operative deaths. This concurrent combined modality therapy is feasible with the major toxicities being leukopenia, nausea, and vomiting. With an overall median follow-up of 15 months, 36% of the patients remain alive. Overall local control is 71%. Actuarial observed 2 yr. survival is 33% and the median survival is 15 months. Histologic complete response appears to be an early indicator of the efficacy of this treatment regime. With 83% of the resected pathologic complete responders alive without evidence of disease, this preoperative combined modality therapy offers an appealing approach.

This review highlights the most important recent advances in the chemotherapeutic management of patients with squamous cell carcinoma of the head and neck. Previous chemotherapy trials must be interpreted with caution in the absence of information concerning important prognostic variables, such as prior treatment, nutritional and performance status, and the heterogeneity of primary sites. In patients who have recurrent or metastatic disease, methotrexate, platinum, and bleomycin are three active drugs when used as single agents. There is no evidence that high dose methotrexate therapy is superior to more conventional weekly intravenous administration of methotrexate in the treatment of recurrent disease. Platinum is a new agent that has demonstrated activity against hematogenous as well as regional disease. In the absence of evidence of a dose-response curve for platinum, the lower dosage schedules that can be used with acceptable toxicity on an outpatient basis should be selected. Combination chemotherapy has resulted in a high proportion of objective responders and approximately 20 per cent complete remissions with any of several platinum containing regimens. However, the median duration of response remains short, and none of the combination drug programs has as yet been established to be superior to single agent chemotherapy in a randomized trial. Both single agent and combination chemotherapy programs have been used prior to initial surgery or radiation in patients with advanced inoperable but nonmetastatic disease. Despite dramatically higher response rates over those obtained with the same drugs used in recurrent disease, there is as yet no evidence that chemotherapy given in this manner has resulted in improved disease free or overall survival compared with local treatment alone. Similarly, the use of adjuvant chemotherapy following tumor clearance to eradicate potential micrometastatic disease is currently under investigation and cannot be recommended in the absence of a controlled trial. This article reviews the clinical trials currently in progress both for patients with recurrent squamous cell carcinoma of the head and neck and those with advanced local or regional disease.

Sixty-four patients with stage III (M 0 ) non–small cell lung cancel were treated with cisplatin fluorouracil infusion chemotherapy and simultaneous radiation therapy for 5 days every other week. A total of 4 cycles (40 Gy) was followed by attempted surgical resection. Clinical response to the preoperative treatment included 5 (8%) complete and 32 (48%) partial responses. Thirty-nine (61%) underwent the planned operation, and in 9 (23%) of these patients the resected specimens were histologically negative. Clinical assessment failed to predict histological response. With 17 months median follow-up (range, 2.4–29 months), estimated 1-year survival was 61% and median survival was 16 months for all patients.

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.

A patient with a late recurrence (13 years) of Wilms tumor is presented. After relapse with conventional chemotherapy, an objective partial remission was obtained with bleomycin, vinblastine, cyclophosphamide, and cis-platinum. Stable disease was noted when bleomycin was withheld. Bleomycin in this combination appeared to effect a good response, and further studies of chemotherapy of Wilms tumor should include bleomycin in combination with other active agents.

Sixty patients with metastatic or primary inoperable breast cancer not suitable for hormone alteration therapy were blindly randomized between weekly 5-fluorouracil, intravenously, and daily physiologic doses of conjugated estrogens by mouth against weekly 5-fluorouracil, intravenously, and placebo. There was no difference in the survival or the effect on the tumor in the two groups. Numerous factors were analyzed as to their effect on the course of the disease. The number of organ sites of tumor involvement, age of the host, and previous treatment for the disseminated disease were not shown to influence the survival or the results of therapy of either group. However, the duration of the clinical cancer-free period from primary treatment to recurrence, the sites of organ involvement, and the performance status of the patients at the time of entry into the study significantly did influence the survival. There is no evidence in this study that physiologic doses of conjugated estrogens deleteriously influenced the course of the disease.

A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral or soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy.

The effectiveness of DTIC in the treatment of Grade III and IV astrocytomas was analyzed in two phases. In the first phase, 14 patients (Group A) with progressive neurologic dysfunction following primary treatment were treated with DTIC alone (8 patients) or in combination with CCNU or methyl CCNU (6 patients) and evaluated for change in neurologic status. Five of the 8 treated with DTIC responded symptomatically for a median duration of 18 weeks, and 3 of 6 treated with the combination of drugs responded for a median duration of 12 weeks. In the second phase, 15 patients (Group B) were treated within 4 weeks of surgical resection with radiation therapy and adjuvant chemotherapy with DTIC and/or MeCCNU. These patients were followed for survival and compared to a historical control group of 15 patients (Group C) treated with surgery and radiation only. The drug-treated group had a median survival of 55 weeks, compared to 35 weeks for the control group. Hematologic toxicity was life threatening in 2 of 14 patients treated with combination drugs, but mild with DTIC alone. DTIC appears to be active against malignant astrocytomas. Survival may be lengthened by combining chemotherapy with surgery and radiation therapy.