TG cell involvement in the leukocyte adherence inhibition phenomenon.

Peripheral blood mononuclear cells (PBMC), T-cells, non-T-cells, TG cells, and TM cells were tested for leukocyte adherence inhibition (LAI) reactivity to purified protein derivative (PPD) in normal human volunteers to determine the reactive cell subfractions. T-cells were separated by sheep red blood cell rosetting and TM and TG cells by rosetting with anti-ox red blood cell (ORBC) IgM- and IgG-treated ORBC. Fresh PBMC, T-cells, and TG cells gave positive LAI reactivity to PPD in PPD-positive donors only. PBMC that had undergone 24-hour incubation or extensive washing, non-T-cells, and TM cells were unreactive. All cell subfractions were negative in PPD-negative donors. Indirect LAI assay was performed on the spent media from overnight incubation of unstimulated PBMC and also following a 1-hour incubation of the various cell subfractions obtained from a PPD-reactive donor with PPD. Positive reactions, indicating the release of an LAI factor (LAIF), were obtained with the spent media and with the T-cell and TG cell subfractions following PPD stimulation, whereas non-T-cell and TM cell subfractions yielded no reactivity. Incubation of sensitized T-cells with PPD in the presence of cycloheximide and preincubation of T-cells for 24 hours with cycloheximide before PPD exposure failed to inhibit LAI reactivity. These data suggest that T-cells, specifically TG cells, can release LAIF upon specific antigen stimulation with PPD, whereas non-T-cell and TM cell subpopulations fail to respond to the same stimulus. LAIF may also be released into the culture media with prolonged (overnight) incubation in artificial media or with extensive washing. Inhibition of protein synthesis during antigen exposure or up to 24 hours before antigen exposure does not appear to inhibit LAI reactivity.

Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance.

Ninety-two patients with advanced breast carcinoma and no prior chemotherapy from 65 to 90 years old were treated with the combination cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (F) (CMF). Because of the primary renal excretion of the first two drugs, their initial doses were calculated using a linear function of creatinine clearance. 5-Fluorouracil was given at 2/3 of the usual dose. These doses resulted in no significant age trends in almost all toxicity, response, time to failure, or cycle by cycle percentages of calculated dose actually received. There was significantly less nausea and vomiting as age increased (P less than .001) and patients greater than 80 years had a significantly shorter survival (P = .01) than patients aged 65 to 79 years. The toxicity results are in marked contrast to the experience of 126 patients aged 24 to 65 years treated with usual doses of CMF on earlier protocols. Among these younger patients there was a significant upward trend with age in diarrhea (P less than .001) and noticeable upward trends with age in hematologic toxicity (P = .06), infection (P = .06), and severe mucositis (P = .09). Patients greater than 65 years had their doses decreased less quickly than did patients less than 65 years; hence by the sixth cycle, the young and elderly patients were receiving almost the same amount of M and F.

A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer.

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.

Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients.

PURPOSE: The Eastern Cooperative Oncology Group (ECOG) entered 766 patients onto two prospectively randomized surgical adjuvant clinical trials for lymph node-positive breast cancer (T1-3N1M0). Ninety-five percent (n = 728) of eligible patients have complete information on the prognostic covariables under study (tumor necrosis [TN], tumor size, number of positive lymph nodes, age) and a median follow-up duration of 10.3 years. METHODS: TN was defined as confluent cell death in invasive areas of primary cancers, visible at 4 x objective lens magnification. Cox proportional hazards models were used to estimate presence versus absence of TN effects on clinical outcomes over full cross-stratification of variables, including delivery of chemotherapy versus observation only. Time-varying effects were modeled using spline functions of time, and by fixing proportional hazards models separately in the time periods 0 to 2 and 2+ years. RESULTS: Presence of TN was an independent predictor for time to recurrence (TTR) (P = .007) and for survival (P = .0003) in the overall 10-year follow-up period. Presence of TN was also an independent predictor for TTR and for survival (each P < .0001) in the period 0 to 2 years after diagnosis. Spline function time-modeling calculations showed different hazard ratios in the TN-present (TN+) versus TN-absent (TN-) groups for both TTR and survival (each P < .0001). This difference is changing over time (P = .0001 for TTR, P = .0005 for survival). Once a patient has been disease-free beyond 2 years after diagnosis, presence or absence of TN is irrelevant to future prognosis. CONCLUSION: Confluent TN of any dimension in invasive areas of lymph node-positive breast cancer is an independent predictor for early recurrence and death from the disease.

A randomized trial of adjuvant chemotherapy in head and neck cancer.

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study.

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.

Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer.

PURPOSE: To compare two published schedules of cisplatin plus fluorouracil (5-FU) infusion and radiation as either sequential or concomitant treatment for toxicity and efficacy in patients with unresectable head and neck cancer. PATIENTS AND METHODS: This was a randomized trial between cisplatin 100 mg/m2 over 15 minutes on day 1 plus 5-FU 1.0 g/m2 by continuous infusion on days 1 to 5, repeated every 3 weeks for three cycles, followed by 70 Gy of radiation in 7 to 8 weeks, versus cisplatin 60 mg/m2 over 15 minutes on day 1 plus 5-FU 800 mg/m2 by continuous infusion on days 1 to 5 plus radiation 2 Gy on days 1 to 5, repeated every other week for seven cycles. Unresectable head and neck squamous cancer patients not previously treated with radiation or chemotherapy and with a performance status of 0 to 2 were stratified by tumor (T) and node (N) groupings and performance status and randomized. RESULTS: Two hundred fifteen patients were entered and 214 analyzed, 107 on each arm. After all treatment, overall response rates were different (P = .003), with similar complete response rates, but more partial responses and fewer patients with no change or progression with concomitant treatment. Cox regression analysis for progression-free survival identified concomitant treatment (P = .003), Radiation Therapy Oncology Group (RTOG) stage III grouping (P < .0001), performance status (P = .0002), concomitant treatment (P = .003), and treating institution (P = .006) as significant. The sequential and concomitant treatments showed similar distant failure patterns (10% and 7%, respectively), but divergent regional failure rates (55% and 39%). Severe and worse toxic events were similar between the treatment programs, but radiation-induced mucositis combined with cisplatin-induced water-losing nephropathy, in the concomitant arm only, demanded more supportive care. Survival duration was similar between the treatment arms, but significantly more patients in the sequential arm died of their cancer (P = .011). CONCLUSION: Concomitant treatment offered improved disease control, predominantly of regional disease, but benefit was dependent on the experience of the treating institution. Translation of this benefit into improved survival is not yet evident, with an excess of deaths from other causes in the concomitant arm.

Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group.

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.

Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.

Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.

Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

Treatment of metastatic breast cancer with a split-course high-dose chemotherapy regimen and autologous bone marrow transplantation.

PURPOSE: We investigated the role of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) as the initial systemic treatment in patients with hormone-unresponsive metastatic breast cancer. We studied a regimen involving a split-course schedule using sequential administration of two pairs of alkylating agents separated by 5 days of rest. The rest period was intended to provide time for recovery from the treatment-immediate adverse effects, thereby allowing further dose escalation. PATIENTS AND METHODS: The treatment consisted of thiotepa 225 to 300 mg/m2/d (days - 11 to -9), cisplatin 50 to 100 mg/m2/d (days - 11 and -3), and cyclophosphamide 60 mg/kg/d (days - 3 and -2). Dose escalation was performed in the initial 15 patients before reaching dose-limiting toxicities. When feasible, responding patients received posttransplant irradiation to sites of residual or prior bulky disease. Patients with bone marrow or CNS involvement, prior pelvic irradiation, or age greater than 55 years were excluded. RESULTS: Thirty-nine patients with measurable or assessable tumor were enrolled: 23 with visceral metastases, 11 with only soft tissue disease, and five with skeletal involvement. Twenty-five patients had received no chemotherapy for metastatic disease before transplantation. The dose-limiting toxicities of this therapy were renal and gastrointestinal. Six patients died from complications: four of a fungal infection and two of hemorrhage. A complete response was achieved in 14 patients (36%), three of whom are free of disease at 79+, 55+, and 40+ months after transplantation. Ten of 25 patients not treated with standard-dose chemotherapy for metastatic disease achieved a complete response (40%). The three patients in continuous remission were in the untreated relapse group. CONCLUSION: This single high-dose treatment achieved a relatively high complete response rate in patients with metastatic breast cancer and may have cured some of them. On the other hand, the split-course dose schedule as tested here did not permit significant dose-intensification.

Phase II evaluation of Taxol in advanced head and neck cancer: an Eastern Cooperative Oncology group trial.

The Eastern Cooperative Oncology Group (ECOG) is conducting a phase II trial of Taxol in patients with histologically confirmed, advanced squamous cell carcinoma of the head and neck. Patients entered in the study to date either had recurrent disease or were newly diagnosed with incurable local-regional disease or distant metastases. Prior chemotherapy was limited to induction or adjuvant chemotherapy at least 12 months prior to entry in the study. All patients had an ECOG performance status of 0 or 1 and measurable disease. The treatment schedule was Taxol 250 mg/m2 by 24-hour continuous intravenous infusion followed by r-met Hu granulocyte-colony stimulating factor 5 micrograms/kg/day subcutaneous injection day 3 to 15 or until the absolute neutrophil count was greater than 1500. Cycles were repeated every 3 weeks. As of September 1, 1992, 27 patients were registered in the study. Of these, three patients were determined to be ineligible, and three were too early to evaluate. There were two early deaths, one definitely and one possibly drug related. Two complete and five partial responses have been observed. Twenty-three patients receiving 83 courses were evaluable for toxicity. Myelosuppression was the primary toxicity observed with 17 (74%) patients experiencing grade 3 or 4 leukopenia and with 20 (87%) patients experiencing grade 3 or 4 neutropenia lasting an average of 2 days (range, 1-4). Peripheral neuropathy occurred in nine patients (grade 1, five patients; grade 2, three patients; grade 3, one patient). Other infrequent toxicities were stomatitis, nausea and vomiting, and myalgias. This trial will continue until 30 eligible patients are accrued.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II trial of etoposide, cisplatin, continuous infusion 5-fluorouracil, and simultaneous split-course radiation therapy in stage III non-small-cell bronchogenic carcinoma.

Survival in patients with locally advanced, non-small-cell lung cancer (NSCLC) is relatively short, despite treatment with surgery or radiation. A phase II study of simultaneous continuous infusion 5-fluorouracil and split-course radiation with or without surgery has shown possible improvement in median survival compared with that observed in trials of radiation alone. Past success with etoposide plus cisplatin in NSCLC has led to the addition of etoposide to the 5-fluorouracil plus cisplatin plus radiation combination. Twenty-four stage III NSCLC patients were treated with this three-drug regimen, and a 74% clinical partial remission rate was observed. Thoracotomy was done in eight of these patients; subsequent histologic examination of the resected specimen revealed no residual tumor in four patients (50%) and only microscopic foci of tumor in two patients (25%). Major toxicities were leukopenia, nausea, and vomiting. Median leukocyte nadir was 2,900/mm3. A leukocyte count less than 1,000/mm3 was observed in two of 24 patients (8%), one of whom expired from progressive pneumonia. All patients experienced nausea and vomiting, which were classified as moderate in three patients (12%) and severe in four (16%). Moderate to severe esophagitis, dermatitis, and pneumonitis were not observed. Median progression-free interval and median survival were not reached after a median follow-up of 163 days.

Retrospective analysis of hyperthermia for use in the palliative treatment of cancer: a multi-modality evaluation.

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% 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.

Pre-treatment prognostic factors in stage III non-small cell lung cancer patients receiving combined modality treatment.

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.

Treatment of advanced head and neck cancer with concomitant radiation and chemotherapy.

Forty-four patients with predominantly inoperable or recurrent head and neck cancers were treated with combined chemotherapy (CT) and radiation therapy (RT) in a Phase I/II study. CT and RT were combined in a concomitant fashion to take advantage of radiosensitizing properties of the chemotherapeutic agents. Each treatment cycle consisted of cisplatin 60 mg/M2 on day 1, 5-FU infusion at a dose of 800 mg/M2 per day continuously for 5 days and RT at 200 cGy per day, days 1 through 5. The treatment cycle was repeated every 2 weeks for 7 cycles in patients treated curatively and for 2 to 6 cycles in patients treated palliatively due to prior radiation therapy or the presence of metastatic disease. Regional control was achieved in 98% of the patients. Regional control has persisted in 87% of the patients treated curatively with a minimum follow-up of 24 months. Distant failure occurred in 23% of this group. Actuarial survival of 2 years for the curative group is 66%. Concomitant combination of radiation with radiation potentiating chemotherapeutic agents shows promise of increase in local control.

Combined modality therapy for stage III non-small cell lung carcinoma: results of treatment and patterns of failure.

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.

Preoperative radiation therapy in regionally localized stage III non-small cell lung carcinoma: long-term results and patterns of failure.

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.

Induction cisplatin/vinblastine and irradiation vs. irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88-08/ECOG 4588. Radiation Therapy Oncology Group. Eastern Cooperative Oncology Group.

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.

Relaxant activity of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans on guinea pig isolated trachealis.

A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.