Interferon maintenance therapy for small cell lung cancer: improvement in long-term survival.

Two hundred thirty-seven patients with small cell lung cancer (SCLC), who had responded to induction chemotherapy and radiotherapy, were randomly assigned to receive low-dose natural interferon-alpha (nIFN alpha) for 6 months; or 6 cycles of maintenance chemotherapy (CAP); or no maintenance therapy (control group). Although there was no difference in median survival between the groups, there was a significant difference (p = 0.04) in the long-term survival of patients with limited disease, in favour of nIFN alpha maintenance therapy. This finding is now confirmed by a further analysis of the most recent data. Ten percent of patients in the IFN group survived for five years or more, but the 5-year-survival rate in the CAP and control groups was only two percent. All long-term survivors had good performance status. The majority had limited disease and had achieved a complete response to the induction therapy. These results suggest that interferon-alpha improves the long-term survival of SCLC patients for whom other prognostic factors are favorable.

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.

Phase II intravenous study of epirubicin with 5-fluorouracil in patients with advanced hepatocellular carcinoma.

Between August 1986 and September 1990, 22 previously untreated non-cirrhotic patients with measurable unresectable primary liver cancer were treated every 4 weeks with a combination of epirubicin and 5-fluorouracil. The dose of epirubicin 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 rate was 14%. Most of the patients experienced only mild haematological toxicity, and no other dose limiting toxicity was observed. Nonetheless, increasing the dose would probably not have increased the response rate.

Oral tegafur in the treatment of metastatic breast cancer: a phase II study.

Between February 1985 and October 1989, 26 patients previously treated for metastatic breast cancer received oral tegafur, at a median daily dose of 1200 mg. Of these, 21 were evaluable for response. The overall response rate was 29%; six (two in lungs, two in skin and two in lymph nodes) of 44 evaluable lesions (14%) responded to therapy. Haematological toxicity was mild, and no other dose-limiting toxicity was seen. The data indicate some activity in heavily pretreated metastatic breast cancer even after previous 5-FU therapy.

Effect of split-course radiotherapy on survival and local control in advanced localized prostatic carcinoma.

PURPOSE: to analyze the effect of overall treatment time of radiotherapy on survival and local control in locally advanced prostatic cancer in a split-course treatment setting. METHODS AND MATERIALS: 168 patients with Stage C prostatic cancer treated during 1979-1989 by the split-course method where the overall treatment time is protracted. Treatment consisted of whole pelvis irradiation of 40 Gy in 4 weeks, followed by a planned 3-week interruption and an additional 26 Gy by the reduced field technique to a total dose of 66 Gy in 9 weeks and 30-33 fractions. The overall treatment time varied from 55 to 100 days. Thirty-eight percent (63) of the patients were treated primarily with radiotherapy, while the rest (105) had received androgen ablative therapy during 2 to 4.5 years before radiotherapy. To examine the effect of treatment time on local control, the patients were divided into three groups ( < or = 63 days, 64-70 days, and > 70 days) by treatment time. RESULTS: the 5-year actuarial survival rates, calculated from the date of diagnosis, were 91% for the hormonally manipulated patients and 69% for the patients treated with radiotherapy alone. The 5-year actuarial local control rates, counted from the start of radiotherapy, were 84% for radiotherapy and 80% for the hormonally manipulated group. Overall, no significant effect of treatment time could be seen, either for radiotherapy alone or for the hormonally manipulated group. The results were similar when the material was further divided by T category and histologic grade. CONCLUSIONS: no significant effect of overall treatment time (55 to 100 days) on survival or local control was found in either group. The survival time from diagnosis was longer in the hormonally pretreated group. Apparently, with adequate doses ( > or = 65 Gy) the overall treatment time becomes less important for local control of advanced prostatic cancer, even in a split-course treatment setting.

Effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus.

PURPOSE: To analyze the effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus. METHODS AND MATERIALS: Three hundred and fifty-three patients with inoperable esophageal cancer (tumor length < or = 10 cm in all cases) treated during 1963-1988 by radical radiotherapy alone either as continuous or split-course therapy. The overall treatment time varied from 35 to 55 days and the total dosage from 50 to 71 Gy in the continuous therapy group (n = 138), and in the split-course group (n = 215) with a planned 3-week rest interval in the middle of the treatment from 56 to 70 days and from 55 to 70 Gy, respectively. The logit method of the linear-quadratic formula for local control at 1 year was used to examine the effect of treatment time on local control. All patients were pooled to obtain a wide range of overall treatment times. RESULTS: The 1-, 2-, and 5-year actuarial survival rates according to the T-stage in the continuous therapy group from the first day of the radiotherapy were: 57%, 32%, and 10% for the T1 tumors and 23%, 8%, and 5% for the T2 tumors. The corresponding figures for the split-course group were: 50%, 19%, and 4% for the T1 tumors and 17%, 6%, and 3% for the T2 tumors. The 1-year local control rate was 56% for the T1 tumors and 15% for the T2 tumors in the continuous therapy group and 48% for the T1 tumors and 10% for the T2 tumors in the split-course group. The results of the logit method did not fit well with the T1 tumors. For the T2 tumors, they showed Dprolif to be about 0.24 Gy/day for local control at 1 year. As a consequence, protraction of overall time by 1 week should be compensated by increasing the total dose by 1.8 Gy for 1 year local control. CONCLUSIONS: More attention should be focused on repopulation. Shortening of overall treatment time might be beneficial for the treatment of squamous cell carcinoma of esophagus.

Biweekly dose escalation in curative accelerated hyperfractionation for advanced head and neck cancer: a feasibility study.

PURPOSE: To study the feasibility of a dose-escalated accelerated hyperfractionation schedule for patients with advanced head and neck cancer. MATERIALS AND METHODS: Twenty-nine previously untreated patients with advanced squamous cell carcinoma were treated with the following biweekly dose-escalated accelerated hyperfraction schedule: during the first 2 weeks 1.2 Gy twice a daily (bid) up to 24 Gy, thereafter during the next following 2 weeks 1.4 Gy bid to 28 Gy in 20 fractions, and thereafter 22.4 Gy in 1.6 Gy bid fractions during 1 1/2 weeks. Thus, the the total dose was 74.4 Gy in 54 fractions given in 5 1/2 weeks. RESULTS: The planned total dose was given within the planned time to 19 (66%) patients. For seven patients the treatment time was prolonged with 1 to 6 days because of department closure for holidays or machine-down days, and in three cases the treatment time was prolonged more than 8 weeks. When the tumor responses were evaluated at 3 months after given radiotherapy, 27 (93%) patients showed complete tumor clearance, 1 patient had a recidual focus, and 1 patient showed progressive disease. The ultimate 1-, 2-, and 3-year local control rates were: 87, 71, and 60%. Four patients had a salvage laryngectomy. The 1-, 2-, and 3-year survival rates for all patients were as follows: 96, 81, and 73%. All patients developed confluent mucositis, 15 patients were hospitalized for nutritional support, and 11 patients had moist desquamation. However, all acute reactions healed completely, and no serious late complications were observed. CONCLUSIONS: This is a safe and effective treatment schedule for patients with advanced head and neck cancer.

Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation.

The characteristic of malignant pleural mesothelioma is a tumor that grows by plate-like extension over the pleura, and invades adjacent tissues and organs. Radical surgical removal of the tumor is generally not possible, and most treatment regimens involve combined chemotherapy and radiotherapy, as well as debulking surgery. We have prospectively evaluated five locally-aggressive multi-modality treatment programs, using different hemithorax irradiation schedules and chemotherapy regimens. One hundred patients with confirmed malignant pleural mesothelioma entered the study between 1977 and 1989. The treatment programs, which can consecutively, were: I, 20 Gy (10 x 2 Gy) to the hemithorax + CYVADIC (cyclophosphamide 500 mg/m2 d 1, vincristine 1 mg/m2 d 1 and 5, adriamycin 40 mg/m2 d 1 and dacarbazine 200 mg/m2 d 1 and 5, several cycles before and after irradiation); II, 55 Gy (25 x 2.2 Gy) to the hemithorax + 15 Gy (6 x 2.5 Gy) to the tumor + CYVADIC (2 cycles before, 1 cycle during, and 2 cycles after irradiation); III, Mitoxantrone (14 mg/m2 q 28 d, < or = 6 cycles) followed by 70 Gy (56 x 1.25 Gy, twice a day); IV, 4-Epirubicin (110-130 mg/m2 q 28 d, < or = 6 cycles) followed by 35 Gy (28 x 1.25 Gy twice a day) to the hemithorax + 36 Gy (9 x 4 Gy every 2 days) to the tumor; V, Etoposide (150 mg/m2 1, 3, 5 q 28 d) followed by 38.5 Gy (11 x 3.5 Gy) to the hemithorax. A new system for evaluating tumor response in pleural mesothelioma was applied. None of the combined treatment programs prevented local invasive growth or the spread of mesothelioma outside the hemithorax. The median survival time was slightly increased from 8 to 12 months for those patients who completed the protocol treatments, but progressive disease was the invariable outcome. Radiation pneumonitis and fibrosis were severe and compatible with results of total loss of lung function on the irradiated side. We conclude that data relating to therapeutic responses and treatment programs in malignant mesothelioma should be better correlated internationally, if the problems associated with the evaluation of treatment and the management of patients with mesothelioma are to be improved.

The use of large fractions in radiotherapy for malignant melanoma.

Eighty-nine cutaneous, subcutaneous or lymph node metastases of malignant melanoma in 15 patients were treated with radiotherapy using electron beams at appropriate energies (6-15 MeV). A total dose of 40 Gy was given in 8 fractions (fraction size 5 Gy) over 23 days. The therapy was given as two weekly fractions on two consecutive days with a 24-h interval. The next two fractions were given after a pause of 6 days. Eighty-six of 89 lesions (97%) responded to treatment, response rate being clearly dependent on tumour size. All the 67 lesions less than 2 cm in diameter responded, 51 of them (78%) completely disappearing, while in tumours over 4 cm among 10 lesions only 2 CR lesions were achieved. In cases where prolonged follow-up (greater than one year) was possible no major late side-effects were observed. The treatment scheme with large fractions appears to be well-tolerated and effective for metastatic malignant melanoma.

Radical surgery and postoperative split-course radiotherapy in squamous cell carcinoma of the mobile tongue: factors influencing local control and the time to recurrence.

During 1981-1988 63 patients with squamous cell carcinoma of the oral tongue (27 females and 36 males) were treated with radical surgery and postoperative split-course radiotherapy. The 3-week rest period was compensated with a 10% increase in the total radiation dose to 66 Gy. The local control rate was 76% in stage I, 71% in stage II, 45% in stage III and 0% in stage IV. Failures were observed in 25 (40%) patients, and 8 patients died of intercurrent diseases. For further analysis the material was stratified in three groups according to the time interval between surgery and postoperative radiotherapy: less than 6 weeks, 6-8 weeks and greater than 8 weeks. The local control rate in the three strata were 75, 57 and 44%, and the 5-year actuarial survival 61, 46 and 30%, respectively. In the logistic regression analysis and the proportional hazard's regression analysis the histologic grade of the primary tumour and the time interval between surgery and the start of radiotherapy were the most important factors influencing respectively local control and time to recurrence. However, it appeared that the lengthening of the time interval was often caused by factors or events which directly can influence the prognosis, such as surgical complications, infections and poor general condition. When cases with such special causes for lengthening of the interval were excluded, the effect of the time interval nearly completely disappeared. It would seem that a final evaluation of the effect of the time interval requires a prospective randomized trial. The same may well hold true for reliable evaluation of the influence of overall treatment time.

Radiation therapy of intracranial malignant melanoma.

Sixty-four consecutive patients with intracranial malignant melanoma were irradiated between January 1980--March 1994. The long-term results of the irradiation were analyzed. Four patients with intended radiation therapy interrupted were excluded from the survival analysis. The remaining sixty were divided into groups using the total dose of 40 Gy and normalized total dose at 3 Gy (NTD3Gy) with 30 Gy as cutpoints. These subgroups did not differ markedly as to sex, age, KPS, single vs. multiple metastases, extracranial disease, surgical intervention on brain, prior chemo and/or immunotherapy. Those with higher total doses to the tumour area had significantly better (P = 0.0006) survival. The median survival of the whole group was 4.1 months and those with NTD3Gy > 30 Gy survived the median time of 9.6 months, whereas those with NTD3Gy < or = 30 Gy had a median survival of 2.1 months. The survival difference existed also after the exclusion of those with previous craniotomy (median survival 11.9 months) and was 1.9 vs. 8.3 months when NTD3Gy > 30 Gy was the cutpoint between the groups. In a multivariate analysis, the NTD3Gy turned out to be the most significant prognostic factor (P < 0.0001). The results reveal that the total dose of radiotherapy in the treatment of cerebral metastases of malignant melanoma might have a greater impact on patients' prognosis than previously considered.

Repopulation during radical radiotherapy for T1 glottic cancer.

BACKGROUND AND PURPOSE: Because opinions on the significance of repopulation during radiotherapy of T1 laryngeal cancer vary, we have estimated the effective rate of tumour cell repopulation during radiotherapy in patients with T1 laryngeal cancer. MATERIALS AND METHODS: One hundred seventeen consecutive patients with T1 laryngeal cancer were treated from 1982 to 1993 by radical radiotherapy alone either as continuous (n = 28) or split-course treatment (n = 89). The logit method of the linear-quadratic formula for local control at 3 years was used to examine the effect of treatment time on local control. The analysis was made for all patients to obtain a wide range of overall treatment times. RESULTS: The 3-year overall survival rate was 76% and the 3-year local control rate was 85% (range 82-88%). The local control rates were 95% (range 94-96%) for the continuous and 81% (range 75-91%) for the split-course therapy groups, respectively. The results showed a mean Dprolif value at the steepest part of the response versus time curve of 0.48 Gy/day for local control at 3 years although this was not statistically significant. The trade-off of dose required to compensate for a 1 week increase in treatment time for local control at the 90% level achieved at 3 years was calculated to be 3.5 Gy. CONCLUSIONS: The present results suggest that repopulation should be taken into account even when treating small T1 laryngeal cancer and that protraction of the overall treatment time should be avoided.

High syndecan-1 expression is associated with favourable outcome in squamous cell lung carcinoma treated with radical surgery.

Expression of syndecan-1 is down-regulated in many cellular transformation models. We studied the clinical significance of syndecan-1 expression in 116 squamous cell lung carcinomas treated with radical surgery. Paraffin-embedded tissue samples were immunostained with two antibodies against human syndecan-1 (B-B4 and 104-9). Syndecan-1 expression was higher in well differentiated cancers than in moderately or poorly differentiated cancers with either antibody (P=0.001 for B-B4, and P<0.0001 for 104-9), but no significant association was found with the primary tumour size (T-stage) or the clinical stage. When the median expression (10% of cancer cells positive in B-B4 staining) was used as the cut-off value, cancers with high expression were associated with more favourable survival than those with low expression (the 2-year survival rate corrected for intercurrent deaths 84% vs 61%, P=0.026). However, syndecan-1 expression was not an independent prognostic factor in a multivariate survival analysis. We conclude that syndecan-1 expression decreases in parallel with histological dedifferentiation in squamous cell carcinoma of the lung, and that low syndecan-1 expression is associated with unfavourable outcome.

Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system. A phase II study.

A combination chemotherapy was used to treat patients with advanced cancer of the extrahepatic biliary system not amenable to surgical resection. Between February 1985 and April 1992, 22 consecutive patients entered into the study; 17 (11 with extrahepatic bile duct cancer and 6 with gallbladder cancer) were evaluable for response and toxicity. The treatment schedule was as follows: epirubicin 20 mg/m2 given as a bolus, followed by methotrexate 150 mg/m2 as a 30-minute infusion, 1 hour later 5-fluorouracil 600 mg/m2 as a 30-minute infusion. Leucovorin rescue (15 mg orally every 6 hours for eight doses) was started 24 hours after methotrexate. This course was administered once a week in 3 successive weeks followed by a 2 to 3 weeks rest period. A total of 174 courses was given. No objective tumor regression was observed. This regimen was well tolerated, the main toxicity being gastrointestinal. The median survival time for the 17 evaluable patients was 9 months.

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.

The clinical effect of medroxyprogesterone (MPA) in elderly patients with lung cancer.

Eighty-nine patients over 70 years old with untreated lung cancer, of various cell type and in various stages, were randomly assigned to chemotherapy (CT) alone or CT combined with medroxyprogesterone acetate (MPA). CT consisted of cisplatin, 60 mg/m2 i.v., along with etoposide (VP-16), 150 mg/m2 i.v., on day 1. The VP-16 was increased to 200 mg/m2, orally, on day 3. The entire regimen was given every 4 weeks for a maximum of six cycles. MPA was administered in daily 500-mg doses, i.m., 5 days a week for 1 month, followed by 1000 mg i.m., once a week, for 5 months. Changes in body weight and appetite were documented. After two cycles of CT, 64 patients were found to be evaluable for response. Forty-five had non-small-cell lung cancer (NSCLC) and 19 had small-cell lung cancer (SCLC). Thirty-seven patients had received CT alone and 27 CT plus MPA. In NSCLC, the objective response to CT alone was 36% versus 37% with CT plus MPA. In SCLC, the corresponding figures were 63% and 22%. The overall objective response rate was 60% in NSCLC and 48% in SCLC. Median survival using CT alone was 10 months for NSCLC patients and 11 months for SCLC patients. Using CT plus MPA, it was 10 months for NSCLC patients and 7 months for SCLC patients. In the control arm, 1-year survival was 42% for NSCLC patients and 48% for SCLC patients; in those who were given MPA, it was 48% for NSCLC patients and 9% for SCLC patients. Improved appetite and weight gain were reported more frequently by MPA patients, and they did not complain of CT's usual side effects. The fact that MPA had no significant effect on CT response or survival in patients also treated with a combination of cisplatin and VP-16, along with the small survival advantage for the control group in SCLC patients, suggests that combining MPA and CT may result in improved quality of life.

Treatment of olfactory neuroblastoma. A report of 11 cases.

Eleven olfactory neuroblastomas treated at Helsinki University Central Hospital between 1970 and 1991 were reviewed retrospectively. The distribution of the patients was according to Morita's staging (modified Kadish's classification) as follows: one stage A, one stage B and nine stage C. Tumor resections were performed in all cases, and five were considered radical. All patients received radiotherapy: total doses ranged from 42 to 70 Gy. At least a short treatment response was achievable in all cases. Chemotherapy was given to two patients: one remission was obtained by methotrexate with leucovorin rescue and doxorubicin for residual disease after radiotherapy. Distant metastases were observed in three cases, two in the lungs and one intraperitoneally. After a median follow-up of 63 (range, 6-140) months, five patients are alive and well, two patients have died with no evidence of disease; two patients who received only 42 and 50 Gy in 5 and 6 weeks have died of local recurrences and two of distant metastases. None of the patients with advanced (stage B or C) disease who received radical radiotherapy ( > or = 60 Gy given in 6 to 9 weeks) developed local recurrence. The increasing incidence of distant metastasis justifies an intensification of initial treatment, especially in state C disease.

Imaging of olfactory neuroblastoma by In-111 bleomycin complex.

No other successful nuclear method, besides bone scanning, has been reported in the literature for in vivo imaging of olfactory neuroblastoma. In this article, excellent uptake is reported by an In-111 labeled bleomycin complex (BLMC) in the ethmoid region of a histologically confirmed olfactory neuroblastoma. The uptake of BLMC was 0.7 x 10(-3)% ID/g at 48 hours after injection, and tumor-to-muscle and tumor-to-fat ratios were 6:1 and 11:1, respectively. The authors conclude that BLMC should be considered as a useful imaging agent, and the BLMC has potential as a radiochemotherapeutic agent against an olfactory neuroblastoma.

Orchiectomy, estrogen therapy and radiotherapy in locally advanced (T3-4 M0) prostatic cancer.

In this randomized trial 151 patients with locally advanced prostatic carcinoma (T3-4 M0) were treated with orchiectomy, estrogens or radiotherapy. In comparison of these therapy modalities attention was paid to the progression free survival and to the complications associated with these therapies. There was no significant difference in the progression free survival during the four-year follow-up period. The frequency of cardiovascular complications was highest in the estrogen group, where 13 of 50 patients had 19 complications. In the radiotherapy group 19 of 45 patients had bowel or bladder complications.