Lars R. Holsti

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.

Enhancement of radiation effects by alpha interferon in the treatment of small cell carcinoma of the lung

The effects on lung tissue and tumor of natural human alpha interferon (IFN) and radiotherapy were investigated in a multimodality treatment program for selected patients with small cell carcinoma of the lung (SCLC). Interferon was given first as a single agent, then concomitantly with radiotherapy to 12 previously untreated patients with limited disease. At disease progression outside the chest, interferon was discontinued and combination chemotherapy was initiated. In the first series, 7 patients received a high interferon induction dose (800 X 10(6) IU i.v. over 5 days) followed by low-dose maintenance therapy (6 X 10(6) IU i.m. TIW), median total dose 1380 X 10(6) IU (range 794-2074). At local progression, split-course radiotherapy, 55 Gy/20 F/7 wk, was added to interferon therapy. In the second series, 5 patients received low-dose interferon from the start (6 X 10(6) IU i.m. daily) combined with twice-a-day fractionated radiotherapy 44 Gy/40 F/4 wk. Median total dose of interferon in this series was 698 X 10(6) IU (range 354-828). Tumor response and normal tissue reactions were evaluated by monthly chest X rays, 3-monthly CT scans, restaging bronchoscopies and by serial respiratory function tests. Autopsy specimens from both lungs within and outside the radiation field were systematically evaluated when available. After the completion of radiotherapy, there were 4/7 CR in the high-dose IFN group compared to 3/5 CR in the low-dose IFN group. Rapid shrinkage of huge tumor masses was observed. At 2 months post radiotherapy radiological grade III fibrosis occurred in 4/7 patients in the high-dose and 1/5 patients in the low-dose group. Lung function studies showed a significant decrease in diffusing capacity and in lung volumes. Seven patients died within 12 months from start of interferon treatment, one of them from treatment complication. At autopsy the tumor area was in most cases replaced by severe fibrosis. Outside the radiation field lung fibrosis was mild. Our results suggest enhancement of radiation effect by interferon with a possible dose and/or schedule dependence of interferon and radiotherapy and call for more clinical studies of IFN and radiotherapy in combination.

A randomized study of split-course radiotherapy of lung cancer: Long term results☆

Abstract A randomized clinical trial was performed from 1964 to 1967 to compare the results of split-course treatment with those of continuous daily fractionated treatment. No difference in survival was apparent between the two treatment regimens. Furthermore, no difference was evident in disease free survival between the groups. No significant difference was found for epidermoid carcinoma, small cell carcinoma, anaplastic carcinoma and unclassified carcinoma. In the patients with localized diasease the survival results were somewhat better in the split-course group for 6 months and 1 year, but not later. The continuously treated responders did slightly better than the split-course treated responders. It is evident that end results are achievable with split-course treatment which are similar to those with continuous treatment. Split-course treatment has the advantage of better tolerance and less marked or milder side effects.

Natural alpha-interferon in combination with hyperfractionated radiotherapy in the treatment of non-small cell lung cancer

Our previous study in patients with small-cell lung cancer indicated that natural alpha interferon might be a radiosensitiser. In this study we considered 20 patients with inoperable non-small cell lung cancer, who were randomly assigned to receive either hyperfractionation radiotherapy alone, 1.25 Gy twice a day (6 hr interval), 60 Gy/48F/32d; or the same radiotherapy concurrently with alpha interferon. Patients in the radiotherapy+alpha interferon arm received 3 x 10(6) IU natural alpha interferon intramuscularly and 1.5 x 10(6) IU inhaled via a dosimeter-equipped jet nebulizer 30 min before each radiotherapy session. Tumor response and radiation-induced lung injury were assessed by serial chest radiographs, computerized tomography scans and lung function studies, during a 1 year follow-up period. No patient in either arm achieved complete response. On the other hand, five patients in the radiotherapy arm and six in the radiotherapy+interferon arm experienced partial response, and the corresponding figures for stable disease were three and one. Combined treatment with radiotherapy and inhaled and intramuscular interferon proved feasible but laborious, for both patients and staff. Pneumonitis and/or oesophagitis in the radiotherapy+interferon arm were moderate to severe, and only two patients tolerated the treatment without any modifications. No treatment modifications were necessary in the radiotherapy arm. The early deaths in the radiotherapy+interferon arm may have been treatment-related. The optimal way to combine interferon and radiotherapy to further evaluate its role as a radiosensitiser needs further studies in larger series.

Procollagen-III in serum, plasminogen activation and fibronectin in bronchoalveolar lavage fluid during and following irradiation of human lung

In the search for predictors of late radiation-induced lung injury we studied procollagen type III peptide concentration (P-III-P) in serum as well as fibronectin and plasminogen activation in bronchoalveolar lavage (BAL) fluid during and following irradiation of human lung. The patients received either high-dose hemithorax irradiation for pleural mesothelioma (11 patients) or high-dose irradiation with individually shaped fields for non-small cell lung cancer (12 patients). The severity of radiation fibrosis was assessed clinically from CT scans 6 months and 12 months after treatment. Four scores were used: severe, moderate, mild, or normal. Radiological lung injury varied from severe (9 patients) to near absence of injury-normal (6 patients). Serum levels of P-III-P, when measured weekly during the 5-week period of radiotherapy or at several time-points after treatment, did not show consistent changes, nor did the levels correlate with the score for radiation fibrosis as assessed by CT scanning. Changes in fibronectin levels or in markers of plasminogen activation in BAL fluid did not correlate with the development of late lung injury. The levels of BAL fluid plasmin and plasminogen activator as assessed zymographically, but not the free net enzyme values, showed a tendency to be elevated in patients with severe radiation-induced lung injury, suggesting a possible role for inhibitors of the plasminogen activation cascade in the process of radiation-induced lung injury.

CHROMOSOME ABERRATIONS INDUCED BY X-RAY THERAPY AND MYXOVIRUS INFECTION IN HUMAN PERIPHERAL LEUKOCYTES.

Abstract The dose-response relationships and the distribution of breaks induced by irradiation were studied in phytohemagglutinin-stimulated peripheral lymphocytes from female patients treated with X-rays for cancer of the breast. The yield of dicentrics and rings was expressed by the formula y = 0.0086 + 1.53 (± 0.15) · 10 −5 D , and the yield of fragments by y = 0.022 + 1.68 (± 0.17) · 10 −5 D , where D is the accumulated skin dose in rad. The percentage of damaged cells, however, reached a plateau of 22% at about 6000 rad. In all dose ranges, the distribution of cells with various numbers of breaks deviated significantly from a Poisson distribution, which should have been obtained if all cells in the blood had been exposed to irradiation. It was possible to calculate the number of undamaged cells present in excess and, when these were omitted, a close agreement with a Poisson distribution was obtained. The results suggested that almost 30% of the circulating lymphocytes had been exposed to irradiation with the fractionated partial body procedure utilized. The effect of Newcastle disease, Sendai, measles and mumps virus infection in vitro on peripheral blood lymphocytes from irradiated patients was also studied. Virus treatment caused a decrease in the frequency of chromosome-type damage. No effect, or a slight decrease of chromatid-type damage, was seen as compared with controls treated with normal allantoic fluid.

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.