Mikael Kajanti

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.

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.

Regional intra‐arterial infusion of cisplatin in primary hepatocellular carcinoma. A phase II study

Ten consecutive adults with localized nonresectable hepatocellular carcinomas were selected as a nonrandom sample for an investigation into the effectiveness of cisplatin (DDP) as a single agent when administered regionally via the hepatic artery from 1981 to 1984. The dose of DDP was 50 mg/m2 (normally, 80 mg). Complete remission (CR) was observed in one patient, partial remission (PR) in three patients, and in five patients, there were no significant changes in tumor size; the disease progressed in one patient. The mean period of survival of the group was 19.7 months. All patients suffered from severe nausea and vomiting, ordinarily until the afternoon of the day after treatment. One patient died of uremia, which related to the cytostate. The authors consider cisplatin useful in the intra‐arterial treatment of hepatocellular carcinoma with favorable prognostic factors in patients for whom surgical treatment is not suitable.

Comparison of granulocyte-macrophage colony-stimulating factor and sucralfate mouthwashes in the prevention of radiation-induced mucositis: a double-blind prospective randomized phase III study

PURPOSE To compare granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwashes with sucralfate mouthwashes in the prevention of radiation-induced mucositis. METHODS AND MATERIALS Forty patients with radically operated head-and-neck cancer were randomly allocated to use either GM-CSF (n = 21) or sucralfate (n = 19) mouthwashes during postoperative radiotherapy (RT). All patients received conventionally fractionated RT to a total dose of 50-60 Gy in 2-Gy daily fractions during 5-6 weeks to the primary site and regional lymphatics. A minimum of 50% of the oral cavity and oropharyngeal mucosa was included in the clinical target volume. GM-CSF mouthwashes consisted of 37.5 microg GM-CSF and sucralfate mouthwashes of 1.0 g of sucralfate distilled in water. Both washes were used 4 times daily, beginning after the first week of RT and continued to the end of the RT course. Symptoms related to radiation mucositis and body weight, serum prealbumin level, and blood cell counts were monitored weekly. RESULTS Oral mucositis tended to be less severe in the GM-CSF group (p = 0.072). Complete (n = 1) or partial (n = 4) healing of mucositis occurred during the RT course in 5 patients (24%) in the GM-CSF group and in none of the patients in the sucralfate group (p = 0.049). Patients who received GM-CSF had less mucosal pain (p = 0.058) and were less often prescribed opioids for pain (p = 0.042). Three patients in the sucralfate group needed hospitalization for mucositis during RT compared with none in the GM-CSF group. Four patients (21%) in the sucralfate group and none in the GM-CSF group required an interruption in the RT course (p = 0.042). No significant differences in weight, prealbumin level, or blood cell count were found between the groups, and both mouthwashes were well tolerated. CONCLUSION GM-CSF mouthwashes may be moderately more effective than sucralfate mouthwashes in preventing radiation-induced mucositis and mucositis-related pain, and their use may lead to less frequent RT course interruptions from mucositis. The present findings need to be confirmed before adopting GM-CSF mouthwashes in routine clinical use.

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.

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.

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.

Clinicopathological Characterization and Genomic Aberrations in Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphomas (SPTLs) represent a rare, difficult-to-diagnose, and poorly characterized subtype of cutaneous T-cell lymphomas (CTCLs) affecting younger people more than the other CTCL forms. We performed a thorough clinical, immunohistological, and molecular analysis of nine Finnish SPTL patients. Specifically, we performed single-cell comparative genomic hybridization (CGH) from laser microdissected, morphologically malignant SPTL cells, as well as loss of heterozygosity (LOH) and fluorescence in situ hybridization (FISH) analysis for the NAV3 (neuron navigator 3) gene. CGH revealed large numbers of DNA copy number changes, the most common of which were losses of chromosomes 1pter, 2pter, 10qter, 11qter, 12qter, 16, 19, 20, and 22 and gains of chromosomes 2q and 4q. Some of the DNA copy number aberrations in SPTL, such as loss of 10q, 17p, and chromosome 19, overlap with those characteristic of common forms of CTCL (mycosis fungoides (MF) and Sezary syndrome (SS)), whereas 5q and 13q gains characterize SPTL. Allelic NAV3 aberrations (LOH or deletion by FISH), previously found in MF and SS, were identified in 44% of the SPTL samples. This study demonstrates that SPTL is also moleculocytogenetically a uniform entity of CTCL and supports the current World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification defining SPTL as a subgroup of its own.

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.

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 Moritas staging (modified Kadishs 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.