Aila Niiranen

Natural interferon alfa as maintenance therapy for small cell lung cancer

We performed a 3-armed phase III study between 1982 and 1990 to evaluate low dose natural interferon alfa (nIFN-alpha) as a maintenance therapy in small cell lung cancer (SCLC) following induction chemotherapy (CT) and consolidation radiotherapy (RT). All patients received four cycles of CT (cyclophosphamide, vincristine, etoposide), followed by split-course RT (55 Gy in 20 fractions over 7 weeks). 410 patients entered the study. 237 patients who completed induction CT + RT and were classified as responders (complete response + partial response) were randomly assigned to arm 1: low dose nIFN-alpha (91 patients); arm 2: maintenance CT, six cycles of CAP (cyclophosphamide, doxorubicin, cisplatin) (59 patients); or arm 3: control arm (no maintenance treatment) (87 patients). Halfway through the study the CAP arm was discontinued. There was no difference in median survival between the groups (IFN: 11 months, CAP: 11 months, control: 10 months), but a clear difference in long-term survival and in survival in the limited disease group, favouring nIFN-alpha maintenance therapy. Proportional hazards regression analysis also showed a significant effect of IFN treatment on survival. Our results suggest a role for nIFN-alpha in maintaining a clinically disease-free status achieved with other treatment modalities.

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.

Treatment of small cell lung cancer. Two-drug versus four-drug chemotherapy and loco-regional irradiation with or without prophylactic cranial irradiation.

Fifty-five patients with untreated small cell lung cancer were allocated randomly to receive either a standard 2-drug or a 4-drug chemotherapy regimen. The patients were further randomized to receive or not to receive prophylactic cranial irradiation (PCI) 40 Gy/20 fractions/4 weeks. Each patient also received split-course irradiation against the primary tumour (55 Gy/25 fractions/8 weeks), the mediastinum, and the supraclavicular areas. The standard 2-drug regimen consisted of cyclophosphamide 10 mg/kg i.v. days 1-4 and vincristine 1 mg i.v. days 1 + 4; every 4 weeks. The 4-drug regimen comprised cyclophosphamide 10 mg/kg i.v. days 1-3, vincristine 2 mg i.v. day 1 and 1 mg i.v. day 5, methotrexate 30 mg i.v. days 3 and 5, CCNU 80 mg/m2 i.v. day 2; every 7 weeks. The total treatment time for both protocols was 9 to 12 months. Objective response after 2 cycles of chemotherapy was seen in 46% of patients with the 2-drug regimen and in 56% with the 4-drug regimen. Local radiotherapy increased the response rates to 58% and 90% respectively. The median survival time was 12 months with the 2-drug regimen and 14 months with the 4-drug regimen. The 2-year and 3-year survival rates were 11% and 0% in the 2-drug group and 19% and 15% in the 4-drug group respectively. Toxicity was more severe in the 4-drug group with 4 deaths due to myelosuppression. Altogether, 25 patients received PCI. This did not in any subgroup increase median survival significantly but a reduction of relapses in the central nervous system was seen. Median survival was 13 months with versus 10 months without PCI; 2-year survival rates were 15% and 6% respectively. Morbidity due to PCI did not occur. Although no statistically significant survival advantage could be documented, there was obviously a higher rate of complete responses with multidrug therapy, and longer median duration of remission, median survival and maximal survival.

A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy

AN ANTI-EMETIC DRUG, NABILONE, a synthetic cannabinoid, has been compared with prochlorperazine in 24 lung cancer patients receiving cancer chemotherapy. Each of the drugs studied was given orally every 12 hours, starting the night before chemotherapy, during one of two consecutive identical chemotherapy cycles in accordance with a double-blind crossover random order assignment. Single doses were 2 mg of nabilone, or 15 mg of prochlorperazine. The chemotherapeutic regimens given included the following drugs in various combinations: Cis-platinum, vincristine, cyelophosphamide, adriamycin, vinde-sine, and etoposide (VP16). Nabilone was significantly superior to prochlorperazine in the reduction of vomiting episodes. Side effects, mainly vertigo, were evident in nearly half of the patients after nabilone, and three patients were withdrawn from the study due to decreased coordination and hallucinations after nabilone. Side effects from prochlorperazine were limited to mild drowsiness in one patient. Two-thirds of the patients preferred nabilone to prochlorperazine. We conclude that nabilone is a moderately effective anti-emetic drug, but that the unpredictability of its side effects call for careful patient information, especially with elderly outpatients. We recommend that at least after the first dose of nabilone, the patient should be kept under close observation during 4 hours.

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.

Long-term survival in small cell carcinoma of the lung

A series of 1019 patients with small cell carcinoma of the lung, treated at the Department of Radiotherapy and Oncology at the Helsinki University Central Hospital during the period 1963-1982, included 19 patients who survived for 5 years or more after the diagnosis. The clinical data of these patients were retrospectively studied in order to elucidate factors which may have contributed to the more favourable outcome. All of the 5-year survivors were previously untreated, and all had a good performance status at the time of diagnosis. In 95%, the disease was limited to one hemithorax, and 74% had a stage I or II tumour. All treatment modalities, except immunotherapy, were used during the two decades. Surgery alone, or with adjuvant radiotherapy, and/or chemotherapy, was the primary treatment in eight of the long-term survivors (42%). Chemotherapy, either alone or in combination with radiotherapy, was the primary treatment in 10/19 (53%) patients and radiotherapy alone was given to one of the 5-year survivors. The objective response rate to the primary treatment was 100% and complete response was achieved in 95%. There were seven carcinoma related deaths after 5-year disease-free survival. The first site of relapse was the central nervous system in three cases and the liver in three cases. Acute myocardial infarction was the cause of death in five patients. One patient died of the other carcinoma and six are still alive with no evidence of SCCL. In conclusion, a good performance status at diagnosis, no pretreatment weight loss, the extent of disease and good response to the primary treatment appeared to be prognostically important in the present study. Some patients with very limited disease may benefit from primary treatment comprising surgery and adjuvant chemotherapy.

Natural interferon-alpha alone and in combination with conventional therapies in non-small cell lung cancer. A pilot study.

Fourteen previously untreated patients with non-small cell lung cancer (NSCLC) were treated with natural interferon-alpha (IFN) in combination with conventional therapies. The planned dose of IFN was 6 x 10(6) IU/d.i.m. 5 days a week for 12 weeks. After 12 weeks of IFN monotherapy patients with M0 disease underwent twice-daily fractionated radiotherapy (RT), 55 Gy/4F/30 d, while IFN continued. Patients with M1 disease received 3 cycles of chemotherapy (CT) concomittantly with IFN. CT consisted of cisplatinum (P) 90 mg/m2 i.v. on days 1, 28, and 56 and of vindesine (VDS) 3 mg/m2 i.v. once a week 5 times and every other week thereafter for up to 8 courses. Thirteen patients were evaluable for response and toxicity. There were 9 patients with epidermoid, 3 with adeno- and one with large cell carcinoma. In 12 of 13 patients, the disease remained stable for 1 month during IFN monotherapy and one acheived a minimal response, which lasted 4 weeks. Of seven patients who completed the 12-week course of IFN monotherapy, 4 achieved stable disease (SD) and 3 had progressive disease. Three patients received RT and one received CT in combination with IFN as their subsequent treatment. There were 3 partial responses (2/3 after RT + IFN, 1/1 after CT + IFN), and 1 SD. Fatigue and weight loss were the most severe side-effects during IFN monotherapy. The combination of IFNs with conventional therapies might be clinically useful. We recommend further testing in larger studies.

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 eisplatin, 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 I 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 1 1 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 CTs 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.

Vincristine-Cyclophosphamide, the Classical Two-Drug Regimen for Small-Cell Lung Cancer, Evaluated in a Randomized Study with Vindesine

We performed a randomized study from February 1979 to August 1981 in patients with small-cell lung cancer (SCLC) with the aim of defining the potential advantages of replacing vincristine (VCR) with vindesine (VDS), at that time a new semisynthetic vinca alcaloid, in the classical two-drug combination cyclophosphamide (CTX)-VCR. A total of 116 previously untreated patients were admitted to the study. Of 104 patients evaluable for response, 49 had limited disease and 55 extensive disease. Patients received 10 mg/kg CTX i.v. on days 1–4 and either 1 mg VCR i.v. or 2 mg/m2 VDS i.v. on days 1 and 4, and repeatedly every 4 weeks for 12 courses. In addition, the patients with limited disease received split-course radiotherapy (30 Gy/10 F, 3 or 5 weeks rest, 25 Gy/10 F, total treatment time 7 or 9 weeks) to the primary tumor, the mediastinum, and the supraclavicular areas between the second and third cycles of chemotherapy. The response rate to the first two chemotherapy cycles was 47% (4 complete response [CR] and 22 partial response [PR]) to CTX-VCR and 47% (4 CR and 19 PR) to CTX-VDS. Subsequent to radiotherapy the response rate increased to 93% for CTX-VCR and 100% to CTX-VDS, respectively, in the patients with limited disease. Local recurrence and/or progression occurred in 49% of limited disease responders and in 96% of extensive disease responders. In responders with limited disease, the first site of relapse was loco-regional in 25% for the VDS group as opposed to 15% in VCR group. In the patients with extensive disease, the corresponding figures were 62% for the VDS and 50% for the VCR group. Median duration of remission in all patients treated with CTX-VCR was 132 days compared to 203 days in the CTX-VDS group (not significant, NS). Median survival was 338 days for CTX-VCR vs. 342 for CTX-VDS in patients with limited disease, and 214 days for CTX-VCR vs. 312 days for CTX-VDS in extensive disease (NS). One-year survival figures were 47% for CTX-VDS and 35% for CTX-VCR patients. Two-year survivals were 4 and 9%, respectively. Neurotoxicity was the main toxic manifestation in both treatment groups. Severe peripheral neuropathy (grade 4, World Health Organization [WHO]) did not occur with either drug regimen. Treatment was discontinued because of grade 2–3 neuropathy in one patient after 6 cycles of CTX-VCR and in five patients after 1–6 cycles of CTX-VDS. With the dosages utilized, CTX-VDS was at least equally effective against small-cell lung cancer as CTX-VCR. Because our overall results compare favorably to results achieved with modern aggressive chemotherapy, where median survival figures vary between 9 and 14 months, we encourage further studies with different dosages of VDS to possibly increase the therapeutic benefit of vinca alcaloids in the treatment of SCLC.