Biomedical subjects

S Seagren

Publications and source records attributed to S Seagren.

11 recordsLinked to original sources

PubMed1998

Phase I trial of retinoic acid and cis-platinum for advanced squamous cell cancer of the head and neck based on experimental evidence of drug synergism.

OBJECTIVE: Cis-platinum and 13-cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid-cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13-cis-retinoic acid and cis-platinum. METHODS: Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale. RESULTS: In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection. CONCLUSIONS: 13-Cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen.

Administration, Oral↗

PubMed1998

Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy. RESULTS: Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts. CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.

Adult↗

PubMed1996

A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx.

OBJECTIVE: To pilot a targeted chemoradiation protocol for patients with advanced carcinoma of the larynx and pharynx that would circumvent upper aerodigestive tract dysfunction related to major oncologic surgery. DESIGN: Weekly intra-arterial infusions of supradose cisplatin (150 mg/m2 per week x 4) rapidly delivered to the tumor bulk, simultaneous intravenous sodium thiosulfate for systemic drug neutralization, and conventional external-beam irradiation (1.80-2.00 Gy per fraction x 35) were used. Between February 1991 and April 1994, 42 patients were treated who would otherwise have required a major resection of the tongue base, pharyngeal wall, or larynx. MAIN OUTCOME MEASURES: Tumor response, toxic effects, disease control above the clavicle, preservation of the larynx, maintenance of oral nutrition, and overall and disease-related 2-year survival. RESULTS: Three complications were related to the weekly transfemoral superselective intra-arterial procedures performed 160 times. Grade 3 to 4 chemotoxic effects were infrequent, occurring in 9 (5.5%) of 160 cycles, and only 1 patient required a radiotherapy break because of severe mucositis. A complete response in the primary site was obtained in 36 (86%) of 42 patients, 2 of whom had residual disease in the neck. Median follow-up was 13 months (range, 3-46 months). To date, there have been 5 recurrences: 2 regional and 3 distant. The 2-year overall and disease-related survival was 64% and 76%, respectively. The rate of disease control above the clavicle at 2 years was 86%. CONCLUSIONS: We believe this chemoradiation protocol represents an effective management scheme for patients with advanced head and neck cancer while minimizing dysfunction and possibly improving survival.

Adolescent↗

PubMed1994

A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer.

BACKGROUND: Hypothesizing that cisplatin (DDP) drug resistance is dose dependent and the radiosensitizing effect of DDP is clinically beneficial, we conducted a chemoradiation protocol using extremely high doses of DDP delivered intra-arterially (IA) to locally advanced head and neck tumors. PATIENTS AND METHODS: Twenty-nine patients with untreated stage IV disease received 4 weekly infusions of 150 mg/m2, simultaneous systemic DDP neutralization with intravenous (IV) bolus sodium thiosulfate, and concomitant radiotherapy (180 to 200 cGy/day x 35 fractions). RESULTS: The complete response rate of the 24 evaluable patients as determined with repeat biopsies was 23/24 (96%). Of the 29 patients evaluable for toxicity, central nervous system complications related to the infusion technique occurred with 2/110 infusions, both of which were reversible. The rate of grade III to IV chemotoxicity was 13%. The median length of follow-up was 22 months. There have been 6 recurrences: 1 local; 3 regional; and 2 at distant sites. The projected overall and disease-free 3-year survival was 88% and 53%, respectively. CONCLUSION: We conclude that the combination of rapid selective delivery of supradose DDP/IV thiosulfate neutralization and concomitant radiotherapy can be safely and effectively applied to patients with advanced head and neck cancer. Preliminary survival analysis indicates that this approach may improve the prognosis for patients with an otherwise devastating disease.

Adult↗

PubMed1994

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

PURPOSE: To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. PATIENTS AND METHODS: Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. RESULTS: Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. CONCLUSION: This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Adult↗

PubMed1988

MOHS for head and neck mucosal cancer: report on 111 patients.

Microscopically Oriented Histologic Surgery (MOHS) has been applied to primary epidermoid cancers of the mucosal tissues of the head and neck since 1979. In that time we have treated 170 patients and maintained excellent records, losing no patients to follow-up. One hundred three patients have been followed for 2 years. Of this group, only nine patients have developed local recurrences; three were salvaged, six were not. This presentation reviews the concept of MOHS and its application to head and neck mucosal lesions. The results are analyzed, and conclusions are drawn regarding what we have learned about the biologic behavior of head and neck tumors and the role of MOHS in treating these neoplasms.

Carcinoma, Squamous Cell↗

PubMed1987

Microscopically oriented histologic surgery for head and neck mucosal cancer.

Frozen section directed surgery, called MOHS, has been successfully utilized in the resection of primary epidermoid tumors of the head and neck. For the 93 cases reviewed in this study, 70% had microscopically identified tumor 1 cm away from clinically evident disease. Tumor spread was along planes of least resistance, most commonly in the submucosa. Microscopically directed excisions were able to trace and remove these tumor extensions. Local control in 93 patients with 2-year follow-up was 91% and, with salvage of recurrences, was 95%. The authors' observations suggest three important concepts. First, epidermoid cancer of the head and neck grows as a continuous neoplasm. Second, this work casts serious doubt on the concept of "field cancerization" or multiple primaries as a cause of local recurrence. Third, conventional frozen section analysis of surgical margins is highly unlikely to discover microscopic extensions because many tumor extensions are thin, finger-like projections which require examination of the entire surgical margin to detect.

Carcinoma, Squamous Cell↗

PubMed1984

The biology of head and neck cancer. Detection and control by parallel histologic sections.

Microscopic fingers of epidermoid cancer can extend submucosally 1 to 3 cm from grossly discernible borders of upper aerodigestive tract cancers. These fingers are best detected by sectioning all surgical margins parallel to the margins. Microscopic disease was found at the original excisional margins in 75% of 70 cases. Using this principle for frozen-section evaluation, and reexcising further tissue as indicated, local disease was completely controlled in all 24 patients eligible for two-year follow-up.

Carcinoma, Squamous Cell↗

PubMed1982

Extensive disease small cell carcinoma of the lung: trial of non-cross resistant chemotherapy and consolidation radiotherapy.

Twenty-nine patients with extensive disease, small-cell carcinoma of the lung, were treated with two cycles of intensive combination chemotherapy: HexaVAC (hexamethylmelamine, vincristine, Adriamycin, cyclophosphamide). Responders received prophylactic cranial radiation (2000 rad/10 fractions) and non cross resistant chemotherapy via a schedule of alternating cycles of CMV (cyclophosphamide, methotrexate, VP-16-213) and AMV (Adriamycin, methotrexate, VP-16-213). Whenever a complete response was achieved, consolidation radiotherapy was given to the lung primary (4000 rad/20 fractions, split dose) and abdominal metastases (2000 rad/10 fractions) synchronous with CMV therapy. The complete response rate was 14% with HexaVAC, but increased to 38% during CMV/AMV. Total response rate (complete and partial) was 59% and median survival was 42 weeks. Prophylactic brain radiation prevented clinical relapse in the brain in all 14 patients who received it. However, consolidation radiotherapy failed to prevent clinical relapse in the lung and/or liver, and therapeutic brain radiation (3000 rad) failed to prevent relapse in that site. The simultaneous administration of radiotherapy and chemotherapy was well-tolerated although two patients with poor performance status died of infectious complications while leukopenic. In spite of the high response rate, durable remissions with prolonged disease free survival were rare. Further evaluation of induction, consolidation, and maintenance modes of therapy are indicated.

Adult↗

PubMed1980

Infusional 5-fluorouracil and X-ray therapy for non-resectable esophageal cancer.

Six patients with unresectable carcinoma of the esophagus received a combined course of external radiation therapy (1000 rads in four fractions in four days commencing on day 2) combined with constant infusional 5-fluorouracil (20 mg/kg every 24 hours for five days beginning on day 1). This program was repeated every other week to give a total x-ray dose of 6000 rads. This regimen has been well-tolerated by the majority of the patients and resulted in a complete response rate within the x-ray treatment field of 83% (5/6). All patients who showed a demonstrable systemic response to 5-fluorouracil reached complete response. The median survival has not yet been reached at six months with post-treatment survivors alive and without disease (four patients) at one, six, nine, and 22 months. Our previous median survival by x-ray therapy alone was 4 1/2 months. Toxicity consists primarily of hematologic suppression at a subclinical level. Although the length of therapy is substantial (11 weeks), the program appears tolerable and is capable of inducing long-term remissions. The program is currently being studied for dose escalation because neither local nor systemic side effects of a dose-limiting nature have been observed at 20 mg/kg 5-FU.

Bone Marrow↗

PubMedDate not supplied

Rapid superselective high-dose cisplatin infusion for advanced head and neck malignancies.

Advances in vascular radiology techniques for superselective arterial infusions and methods to overcome systemic toxicity from high-dose cisplatin chemotherapy encouraged us to reevaluate the effects of rapid regional cisplatin infusion for patients with head and neck malignancies. Twenty patients (17 carcinomas, three sarcomas) received high-dose cisplatin (100-200 mg/m2) by this method. Fifteen of the 17 patients with upper aerodigestive tract carcinoma are part of an ongoing phase I dose escalation of cisplatin with sodium thiosulfate neutralization. Three additional patients with sarcomas were treated with intra-arterial (IA) cisplatin and systemic Adriamycin. Fifty-three IA infusions were performed without any complications. Only minimal toxicity related to the chemotherapy was observed. The overall response rate for previously untreated patients was nine of 10 (90%) [complete response (CR) 67%; partial response (PR) 33%]. The response rate for patients with recurrent disease was five of eight (63%) (CR 20%, PR 80%). The average length of follow-up is 9.5 months and the actuarial survival rate is 56%. Superselective rapid infusion of high-dose cisplatin for patients with advanced head and neck malignancies is feasible, relatively nontoxic, and may have important applications in multimodality therapy, particularly for patients with bulky primary disease.

Antidotes↗