Timo Muhonen

5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy—A randomised study

166 patients receiving moderately emetogenic chemotherapy were entered into a randomised prospective study in which the efficacy of single dose ondansetron 8 mg, tropisetron 5 mg and granisetron 3 mg in the prophylaxis of acute vomiting was evaluated. 130 patients were evaluable for analysis. During the 24 h following the start of chemotherapy complete control of vomiting was achieved in 80% [95% confidence interval (CI) 73.1; 86.9] of patients receiving granisetron compared with 75% (95% CI 67.1; 82.1) of those on tropisetron and 69% (95% CI 60.5; 76.5) on ondansetron. The patients experienced significantly fewer failures with granisetron (6.2%, 95% CI 2.1; 10.3) than with either ondansetron (14.6%, 95% CI 8.5; 20.6) or tropisetron (13.8%, 95% CI 7.9; 19.7). When asked, 34 (26%) patients out of 130 expressed no preference, 54 (42%) preferred granisetron, 22 (17%) preferred ondansetron and 20 (15%) preferred tropisetron. All the 5-HT3 receptor antagonists were highly effective in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy. The observed differences in the control of emesis, although statistically significant, may not have clinical significance.

An overview of randomised studies comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting

Ten years after it was demonstrated in the ferret that cisplatin-induced emesis could be blocked by the selective 5-HT3 receptor antagonist MDL 72222, 5-HT3 receptor antagonists have become routine anti-emetic agents for chemotherapy-induced emesis. However, although in association with highly emetogenic, mainly cisplatin-containing regimens, the use of these agents is well justified, the net benefit of 5-HT3 receptor antagonists in association with moderately emetogenic regimens has not been that well clarified. Here, we present an overview of 30 randomised studies comparing 5-HT3 antagonists with the conventional anti-emetics in the prophylaxis of acute vomiting induced by cytotoxic chemotherapy. A meta-analysis showed that 5-HT3 antagonists reduce the risk of acute vomiting in comparison to conventional anti-emetics both with cisplatin treatments (15 trials; odds ratio 0.60; 95% confidence interval 0.51-0.70) and with moderately emetogenic treatments (11 trials; odds ratio 0.47; 95% confidence interval 0.39-0.58). The risk of acute vomiting seems to be further reduced when 5-HT3 antagonists are combined with dexamethasone.

SECOND CANCER AMONG LONG-TERM SURVIVORS FROM HODGKIN'S DISEASE

PURPOSE There are limited data on the frequency of second cancer among long-term survivors from Hodgkins disease. The aim of this study was to determine the frequencies of second cancers, and their locations with respect to radiotherapy portals. METHODS AND MATERIALS Medical records of 202 consecutive patients who survived at least for 5 years after treatment for Hodgkins disease, and who were treated with radiotherapy in Helsinki University Central Hospital between 1970 and 1979, were reviewed. Survival data were collected also from the Finnish Cancer Registry and records of other hospitals. The median follow-up time of the patients still alive was 22 years (range, from 13 to 26). All patients received radiotherapy; in addition, 65 patients received MOPP and 3 received MOPP and ABVD. RESULTS During the follow-up consisting of 4020 person-years, 27 patients developed a second cancer. The cumulative risk for a second cancer was 17% (95% CI, from 10.4 to 23.1 %) at 20 years after the diagnosis of Hodgkins disease. Of the 26, 20 (77%) solid second cancers were found within or adjoining the irradiated fields, and the 20-year cumulative risk for a second cancer within the irradiated fields was 12% (6.3-17.5%). The most common second cancers were lung (n = 7) and breast (n = 4) cancer. In a multivariate analysis, predictive factors for a second cancer were: age at diagnosis greater than the median (30 years, relative risk, 3.97, 1.6-12.5), treatment for recurrent lymphoma (RR, 2.75, 1.3-6.7) and primary treatment without splenectomy (RR 4.31, 1.7-11.0). However, portal size and inclusion of chemotherapy as part of the primary treatment were not significantly associated with second cancer in a univariate analysis. CONCLUSION Patients treated with radiotherapy for Hodgkins disease have a considerable risk for a second cancer in long-term follow-up. The majority of second cancers arise within or next to the irradiated portals, and particular attention should be paid to the irradiated sites in posttreatment follow-up.

Effects of granisetron with doxorubicin or epirubicin on ECG intervals.

Commercially available serotonin-type 3 (5-HT3) receptor antagonists (ondansetron, granisetron, and tropisetron) have shown no clinically significant adverse effects on the cardiovascular system. In the dose-ranging evaluation of dolasetron, computer-generated ECGs revealed clinically asymptomatic prolongations of ECG intervals. We performed a clinical trial in which the possible changes in ECG intervals following a single 3-mg i.v. injection of granisetron and an injection of either doxorubicin or epirubicin were registered using computerized ECG analysis in cancer patients. A total of 30 patients who were designated to receive 3 mg granisetron i. v. for the prophylaxis of emesis induced by doxorubicin or epirubicin were entered into the study. Computer-generated ECG tracings were obtained before treatment, following the injection of 3 mg granisetron, and immediately after doxorubicin or epirubicin injection. The mean PR interval duration increased from 160 to 166 ms after granisetron infusion (P = 0.02). Doxorubicin and epirubicin did not potentiate this change. There was no statistically significant change in cardiac rhythm, QRS duration, or QTc intervals. The observed minor changes in the PR time following i. v. injection of granisetron do not seem to be of clinical relevance.

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.

Radiation therapy of intracranial malignant melanoma

Abstract 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 ≤ 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

VASCULARITY AND PROGNOSIS OF METASTATIC MELANOMA

The clinical role of vascularity was examined in metastatic melanoma, analyzing the correlation of the blood vessel density and prognosis. Our study included 51 specimens of metastatic melanoma tissue samples from 31 patients treated with combined chemo‐immunotherapy. PECAM‐1 (CD31) was used for assessing vascularity by immunohistochemical staining. On the basis of blood vessel counts, patients were classified into 2 main groups: low and high vascularity. A higher blood vessel density was found to be associated with shorter survival, estimated from the primary diagnosis of the disease (38 months), compared with patients with low blood vessel counts (68 months). A similar tendency was observed when vascularity was correlated to the survival period after the detection of the first metastases (13 vs. 30 months) and with survival since the initiation of chemo‐immunotherapy (8 vs. 16 months). When vascularity and some common prognostic factors, such as age, sex, DNA ploidy and WHO tumor response, were used for a Cox multivariate analysis, vascularity turned out to be the most significant independent prognostic factor. Our results suggest that counting the blood vessels identified by immunohistochemical staining for the endothelial cell‐specific CD31 is a powerful predictor for prognosis in patients with metastatic melanoma and should be considered when selecting patients for therapy. Int. J. Cancer 74:326‐329, 1997.

Granulocyte colony-stimulating factor (G-CSF) with or without a quinolone in the prevention of infection in cancer patients

59 patients who had earlier developed an infection following antineoplastic chemotherapy were randomised to receive either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF+quinolone as prophylaxis during subsequent identical chemotherapy courses. 30 patients received 48 courses of G+CSF, while 29 patients received 44 courses of G-CSF+ofloxacin or ciprofloxacin. The overall infection rate was 23%. Patients with WHO grade IV leukopenia at the onset of prophylactic treatment developed infection in 61% of cases when on G-CSF, but only in 22% when on G-CSF+quinolone (P = 0.002). Patients with initial leukopenia of grade WHO III-I had only a 11% infection rate showing no significant difference between the treatment groups. The median duration of leukopenia < 1 x 10(9)/l was 4 days for patients receiving G-CSF alone and 3.5 days for those receiving additional quinolone. Patients developing infection had grade IV leukopenia for a median of 5 days. Both prophylactic treatments were well tolerated. We conclude that when prophylactic G-CSF is initiated at WHO grade IV leukopenia, addition of an oral quinolone reduces the risk of infection.

A combination of subcutaneous recombinant interleukin-2 and recombinant interferon-α in the treatment of advanced renal cell carcinoma or melanoma

In this phase II study, we have evaluated the efficacy and toxicity of low-dose subcutaneous (s.c.) recombinant interleukin-2 (IL-2) and recombinant interferon (IFN)-alpha in 16 patients with advanced renal cell carcinoma (RCC) and in 4 patients with advanced melanoma. The complete course on this protocol comprised 6 weeks of s.c. IL-2 plus IFN-alpha followed by a 2-week rest period. The treatment was moderately strenuous for patients, requiring frequent dose reductions; only eight cycles (30%) could be administered to 75-100% of the projected dose. Main side-effects were fever, fatigue, hypotension, liver toxicity, neurotoxicity and skin reactions. Among the evaluable 17 patients, two responses (one partial, one complete) were seen in patients with RCC. This regimen proved to be rather toxic and yielded a modest response rate of 15% in RCC, but initial findings concerning the duration of survival seem promising.

Tumour growth rate and DNA flow cytometry parameters as prognostic factors in metastatic melanoma.

The prognostic value of flow cytometric parameters and tumour growth rate of melanoma metastases under the mouse renal capsule was investigated for tumours from 117 consecutive patients referred to the Helsinki University Central Hospital Melanoma Team. DNA flow cytometry (FCM) was interpretable for the tumours of 114 patients, and growth rate analysis for 82 patients, both results being available from 79 patients. Thirty-six percent of the tumours were DNA diploid and 64% DNA aneuploid. Tumour ploidy and S-phase fraction were shown by multivariate Cox model analysis to be independent prognostic variables and major determinants of survival after first recurrence. Patients with DNA diploid or aneuploid tumours survived a median 16 and 27 months, respectively. A high growth rate of tumour sample in vivo under the mouse renal capsule tended to be a sign of poor prognosis, although not reaching statistical significance. Combining the results of FCM, tumour growth rate and TNM stage, we propose a highly efficient prognostic scoring method. Patients with a score above 0.75 had a median survival of 11 months compared to 30 months among patients scoring under 0.75 (P less than 0.0001). This score was the most significant (P less than 0.0001) prognostic factor in the Cox model when TNM stage, age, ploidy, SPF, and tumour growth rate were analysed as covariates.