Matti Mäntylä

Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer.

In a prospective multicenter study, 186 patients with squamous cell esophageal carcinoma, who after evaluation were considered suitable for surgery, were randomized to 4 treatment groups: Group 1, surgery alone; Group 2, pre-operative chemotherapy (cisplatin and bleomycin) and surgery; Group 3, pre-operative irradiation (35 Gy) and surgery; Group 4, pre-operative chemotherapy, radiotherapy, and surgery. Three-year survival was significantly higher in the pooled groups receiving radiotherapy as compared with the pooled groups not receiving radiotherapy. Comparison of the groups having pre-operative chemotherapy with those not having chemotherapy showed no significant difference in survival. Female patients had a significantly better survival than males. The results indicate that pre-operative irradiation had a beneficial effect on intermediate term survival, whereas the chemotherapy regime used did not influence survival.RésuméDans une étude prospective, multicentrique, 186 patients ayant un cancer épidermoïde de loesophage ont été randomisée dans quatre groupes: le groupe 1 a eu la chirurgie seule; le groupe 2, une chimiothérapie préopératoire (cis-platine et bléomycine); le groupe 3, une radiothérapie préopératoire suivie de chirurgie; et le groupe 4, une chimiothérapie et une radiothérapie préopératoires suivies de chirurgie. La survie à trois ans a été supérieure chez lensemble des patients ayant reçu la radiothérapie préopératoire par rapport à ceux qui nen ont pas eu. Aucune différence de survie na pu être mise en évidence dans les groupes ayant eu ou pas de chimiothérapie. La survie des femmes a été significativement supérieure à celle des hommes. Ces résultats indiquent que la radiothérapie préopératoire apporte un plus en ce qui concerne la survie à moyen terme, alors que la chimiothérapie ninfluence pas la survie.ResumenEn un estudio prospectivo multicéntrico sobre 186 pacientes con carcinoma escamocelular del esófago candidatos para cirugía, se constituyeron cuatro grupos para randomización: Grupo 1, cirugía solamente; Grupo 2, quimioterapia preoperatoria (cisplatino y bleomicina) y cirugía; Grupo 3, irradiación preoperatoria (35 Gy) y cirugía; Grupo 4, quimioterapia preoperatoria, radioterapia y cirugía. La comparación entre el grupo que recibió quimioterapia y el que no la recibió no demostró diferencia significativa en cuanto a supervivencia. Las pacientes femeninas exhibieron una mejor supervivencia que los pacientes masculinos. Los resultados indican que la irradiación preoperatoria tuvo un efecto benéfico sobre la sobrevida a término medio, en tanto que la quimioterapia, en el regimen utilizado, no tuvo influencia sobre la supervivencia.

Inoperable non-small cell lung cancer: Radiation with or without chemotherapy

We report a randomized multicentre study of split-course radiotherapy (RT), with or without combination chemotherapy (CT), in 238 patients with inoperable non-small cell lung cancer (NSCLC), previously untreated, confined to one hemithorax and the mediastinal nodes. In both treatment groups RT consisted of 55 Gy in 20 F given over 7 weeks with a 3-week rest interval. CT consisted of the 3-drug regimen CAP: C = cyclophosphamide 400 mg/m2, A = adriamycin 40 mg/m2, P = cisplatin 40 mg/m2; 2 cycles of CAP given before RT, one during the rest interval and six after RT. Seventy per cent in the RT arm and 67% in the RT-CT arm had epidermoid carcinoma. No significant difference was apparent between the RT and the RT-CT arms with respect to objective response rates (CR + PR) (44 and 49%, respectively), median duration of response (278 and 320 days), local failure (31 and 20%), distant progression (23 and 20%) or median survival (311 and 322 days). The survival figures showed an almost significant (P = 0.05) therapeutic advantage of the combined regimen with stage IIIM0 disease. Progressive disease was the cause of death in 92% and 88%. We conclude that chemotherapy did not contribute significantly to either local control or survival as compared to radiotherapy alone.

Bleomycin/cis-platin as neoadjuvant chemotherapy before radical radiotherapy in localized, inoperable carcinoma of the esophagus: A prospective randomized multicentre study: The second Scandinavian trial in esophageal cancer

Survival and swallowing function were studied in a randomized trial of 97 patients with inoperable, localized esophageal carcinoma. Radical radiotherapy was given to 51 patients, while 46 patients had two courses of bleomycin/cisplatin before radiotherapy. The survival was 29% after one year, and 6% after 3 years in the radiotherapy group. The survival in the combined treatment group was 18 and 0%, respectively; p = 0.1895. The number of patients who could swallow any food increased from 6% before treatment to 38% after 3 months in the radiotherapy group, and from 0% to 23% in the combined group. No benefit was found by combining bleomycin/cisplatin with radiotherapy.

Intra-arterial and intravenous use of 4' epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma. A randomized comparison.

Between October, 1986, and March, 1990, 20 consecutive untreated and noncirrhotic patients with measurable and histologically and/or cytologically confirmed unresectable primary liver cancer were randomly assigned to intravenous (10 patients) or intra-arterial (10 patients) therapy. Patients were treated every 4 weeks with a combination chemotherapy regimen containing 4′ epidoxorubicin and 5-fluorouracil. A 3-min bolus injection of 4′ epidoxorubicin was followed by 5-fluorouracil given in a 90-min infusion. The dose of 4′ epidoxorubicin was escalated: the starting dose was 40 mg/m2, the second dose was 50 mg/m2, and thereafter 60 mg/m2 during subsequent cycles. The dose of 5-fluorouracil was always 800 mg/m2. Objective response rates (20%) were similar in both treatments; two patients had partial responses in the intra-arterially treated group and one complete and one partial response were recorded in the intravenously treated group. The median survival time was 15.2 months for the patients treated intra-arterially and 13.8 months for the patients treated intravenously. Toxicity was mainly mild in both groups with less hematopoietic toxicity in the I.A.-treated group. 4′ epidoxorubicin combined with 5-fluorouracil given intra-arterially is not superior to the intravenous therapy, but it may diminish systemic toxicity.

Concomitant chemotherapy and IFN-alpha for small cell lung cancer : a randomized multicenter phase III study

Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.

Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer--a feasibility study.

This randomized phase II multi-center study was designed to determine the time to progression, duration of response and the feasibility of an intensified maintenance regime consisting of a combination of interferon (IFN)-alpha and retinoic acid after high-dose combination chemotherapy and radiotherapy in patients with small cell lung cancer. The patients received four courses of combination chemotherapy consisting of ifosfamide, carboplatin and etoposide, with higher doses of ifosfamide and carboplatin given in the first course, with routine growth factor support. Responding patients were then randomly assigned to one of three maintenance therapy arms. All patients with limited disease (LD) were given thoracic radiotherapy before maintenance therapy and those who had also achieved a complete response (CR) or minimal residual disease (MRD) received prophylactic cranial irradiation. In Arm 1 patients received IFN-alpha-2a, 6 MIU s.c. TIW for 4 weeks, followed by 3 MIU s.c. TIW, and 13-cis-retinoic acid 1 mg/kg/day p.o. BID daily. In Arm 2 patients received trophosphamide 100-150 mg/day p.o. BID. No maintenance treatment was given in Arm 3, the control group. Maintenance therapy was continued for 1 year. Eighty-five patients were treated according to the protocol. Twenty-one patients achieved CR, four achieved MRD and forty-two achieved partial responses to chemotherapy and radiotherapy. Sixty patients (71%) were randomly assigned for maintenance treatment. Median survival was 17.1 months in the IFN-alpha-retinoic acid arm, 12.4 months in the trophosphamide arm and 13.5 months in the control arm. One-year survival rates were 82, 56 and 55%, respectively. Duration of response was 6.5, 5.5 and 4.7 months, respectively. Time to progression was 8.6, 8.0 and 6.8 months, respectively The differences were not statistically significant. The IFN-alpha-retinoic acid maintenance treatment was well tolerated. Patients who received IFN-alpha-retinoid maintenance therapy lived longer after the onset of progressive disease. The treatment regime was effective, feasible and well tolerated.

Biweekly escalated, accelerated hyperfractionated radiotherapy with concomitant single-dose mitomycin C results in a high rate of local control in advanced laryngeal and hypopharyngeal cancer.

Abstract: The purpose of this study is to evaluate the efficacy of a dose-escalated, accelerated, and hyperfractionated radiotherapy schedule with a concomitant single dose of mitomycin C in the treatment of patients with advanced laryngeal or hypopharyngeal cancer. Twenty-one previously untreated patients with advanced squamous cell carcinoma (stage III, n = 6; stage IV, n = 15) were treated with a biweekly dose-escalated, accelerated, and hyperfractionated schedule up to a total dose of 74.4 Gy in 54 fractions over 5 weeks. A single dose of intravenous mitomycin C 10 mg/m2 was given on day 30. The median follow-up after treatment of surviving patients is 48 months (range, 28 to 61 months). All patients showed complete tumor control at the primary site when evaluated 2 months after chemoirradiation by laryngomicroscopy or hypopharyngoscopy and radiologic imaging (CT, MRI). Two laryngectomies were carried out after given therapy: 1 for residual cancer and 1 for suspected residual cancer. After a median follow-up of 43 months (range, 28 to 61 months), a local control rate of 70% and disease-free survival (DFS) rate of 60% were achieved in the laryngeal cancer patients; in patients with hypopharyngeal cancer, the corresponding figures were 64% (82% after salvage surgery) and 36%. The results are promising and warrant comparison with other chemoradiotherapy regimens.

556Altered fractionation of hemithorax irradiation for pleural mesothelioma and failure patterns after treatment

Malignant pleural mesothelioma is a rare malignancy with a bleak prognosis. The role of radiotherapy has not yet been clarified. Our aim was to study the effect of altered fractionation on mesothelioma. We have treated 57 patients, 41 males and 16 females, with hemithorax irradiation with six different fractionation schedules. All the patients have been included in a combined modality program consisting of surgery followed by chemotherapy and finally by hemithorax irradiation. The radiotherapy schedules used were: I. Conventional fractionation of 20 Gy in 10 fractions over 12 days. II. Split-course radiotherapy 55 Gy in 25 fractions of 2.2 Gy over 7 weeks (a two weeks rest halfways) followed by a boost dose of 15 Gy over 8 days to the major tumour area. III. Hyperfractionation of 70 Gy over 7 weeks, 1.25 Gy BID with a 6-h interval and a 10-day rest halfways. IV. Combined hyperfractionation and hypofractionation, 35 Gy hyperfractionation in 28 fractions (1.25 Gy BID with a 6-h interval) over three weeks followed by 36 Gy hypofractionation 9 fractions of 4 Gy given every other day over 3 weeks to the major tumour areas only. V. Hypofractionation of 38.5 Gy over 15 days (9 x 3.5 Gy). VI. Combined conventional radiotherapy and hypofractionation with 20 Gy given conventionally in 10 fractions followed by 10 fractions of 3 Gy over two weeks, overall time 4 weeks. The 2-year survival rate of all patients was 21% and the 5-year survival rate 9%. Two patients are still alive more than 6 and 9 years after radiotherapy. Progression occurred after surgery in four patients, during and after chemotherapy in 22 patients and after completed radiotherapy in 29 patients. The pattern of progression was similar in each treatment group.