Seppo Pyrhönen

Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer

BACKGROUND In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial. METHODS Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300-350 mg/m2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio. FINDINGS 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58.8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0.001). Survival without performance-status deterioration (p=0.0001), without weight loss of more than 5% (p=0.018), and pain-free survival (p=0.003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group. INTERPRETATION Our study shows that despite the side-effects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone.

Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis

Human papillomavirus (HPV) is an agent responsible for squamous cell tumors (verrucae, condylomata and papillomas) at various sites of the body, the oral cavity included. Due to the recently pointed-out association between these HPV lesions and the squamous cell dysplasias and malignancies in the uterine cervix, in the bronchus and in the larynx, the present work was carried out to assess, whether morphological signs (cytopathic effects of HPV) or HPV antigens could be found in lesions of oral squamous cell carcinomas. Biopsies from 40 cases of oral squamous cell carcinomas were surveyed by light microscopy with special emphasis on the presence of the histopathological features suggesting an HPV lesion, i.e. whether flat, inverted or papillomatous condylomas are present concomitantly with the malignancy. All specimens were also subjected to immunoperoxidase staining with anti-HPV serum to disclose the possible HPV antigens in the lesions. Morphological signs of the flat-type HPV lesion were found in 4 cases (10%), those of an inverted type in 3 cases (7.5%), and those of a papillomatous type in 9 cases (22.5%). Epithelial cells (mostly koilocytes) showing HPV-positive nuclei were disclosed in 5 papillomatous lesions, in 2 inverted lesions and in 1 flat lesion. The results suggest that HPV might be the agent involved in the development of at least certain special types of oral squamous cell carcinomas; albeit further confirmatory evidence with other techniques (DNA hybridization) is still needed.

Tumor doubling times in metastatic malignant melanoma of the uvea: Tumor progression before and after treatment

OBJECTIVE To obtain estimates of growth rate of metastatic uveal melanoma to infer appropriate follow-up programs and to assess the impact of current chemoimmunotherapy regimens. DESIGN Retrospective case series. PARTICIPANTS Of 70 consecutive patients diagnosed with metastatic uveal melanoma from 1986 through 1998, 37 patients who attended regular follow-up and had measurable metastases were eligible for this study. METHODS Tumor doubling time (DT) was calculated by the Schwartz formula using three presumed sizes of metastasis at last negative follow-up. DT was compared according to tumor characteristics, and time of micrometastasis was estimated. MAIN OUTCOME MEASURES Doubling time of untreated and treated metastases. RESULTS Doubling time of untreated metastases ranged from 34 to 220 days (median, 63 days). Regardless of the presumed size of metastasis at last screening, two thirds of the metastases had a DT between 30 and 80 days. No significant correlation between DT and the observed disease-free interval was detected. Assuming constant growth rate, most metastases had predictably initiated within 5 years before primary treatment. Mean DT during active treatment of metastases in 18 patients who did not show an objective response ranged from 25 to 2619 days (median, 255 days). CONCLUSIONS Based on the estimated growth rates, a rational follow-up interval to detect metastatic uveal melanoma would be 4 to 6 months. Primary uveal melanomas that develop clinically detectable metastasis after conservative therapy may micrometastasize several years before treatment. These estimates are rough and must be confirmed by prospective studies. Current chemoimmunotherapy regimens slow down the growth rate of metastases even if objective response is not obtained.

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.

Toremifene, a new antiestrogenic compound, for treatment of advanced breast cancer. Phase II study

Forty-six postmenopausal women with estrogen receptor positive advanced breast cancer were treated with the novel antiestrogen toremifene in this phase II study. The patients had no prior or concurrent hormonal or cytostatic treatment. Sixty milligrams of toremifene was given as a single daily dose for a minimum treatment period of 6 weeks. Eight patients (17%) achieved complete response, 17 (37%) partial response and 12 (26%) showed no change. The median durations of responses were 93, 66 and 24 weeks, respectively. Three patients still continue the treatment in complete response, four patients in partial response. No significant differences in response rates could be seen when related to different estrogen receptor concentrations. The treatment was well tolerated, only two patients had remarkable side-effects; one of the patients interrupted the treatment mainly because of tremor. Our conclusion is that toremifene is an effective, safe and in clinical practice easily applied choice of treatment in estrogen receptor positive advanced breast cancer.

Diploid predominance in hereditary nonpolyposis colorectal carcinoma evaluated by flow cytometry

Fifty‐nine colorectal carcinomas of patients with verified cancer family syndrome (CFS) were analyzed for DNA ploidy using flow cytometry. Sixty‐eight percent of the tumors were diploid, and 32% were aneuploid. The aneuploid tumors had a median DNA index of 1.24 (range, 1.12–1.97). In 90% of all tumors the DNA index was less than 1.27. This predominance of diploid/near‐diploid tumors was seen both in primary and in metachronous carcinomas. In 21 cases a cell cycle analysis was possible. Tumors with the S‐phase fraction (SPF) ± 9.8% had a worse prognosis than tumors with the SPF of <9.8%. These findings suggest that the predominance of diploid/near diploid DNA values is one of the characteristics of colorectal carcinomas in CFS. This might signify the existence of two or more pathogenetically different subgroups of colorectal carcinoma and explain the proposed better prognosis of colorectal carcinoma in CFS compared with other colorectal carcinomas.

Immunohistochemical demonstration of Human papilloma virus (HPV) antigens in oral squamous cell lesions

Six oral squamous cell tumours classified as focal epithelial hyperplasia (FEH), Condyloma acuminatum (CA) and squamous cell papilloma (SQP) were subjected to indirect immunoperoxidase staining with anti-human papillomavirus (anti-HPV) antiserum to demonstrate the possible presence of HPV antigens in these lesions. The results are discussed in the light of the observations on HPV-lesions elsewhere in the body (in uterine cervix), and a suggestion is made to adopt the name condyloma for all those tumours where HPV aetiology can be established by ultrastructural or immunohistochemical means.

Survival of breast cancer patients in BRCA1, BRCA2, and non‐BRCA1/2 breast cancer families: A relative survival analysis from Finland

Reports on the prognosis of familial breast cancer patients have been contradictory. True differences in survival, if they exist, would have important implications for genetic counselling and in treatment of hereditary breast cancer. We assessed the survival rates of 359 familial breast cancer patients (32 patients from BRCA1‐positive families, 43 patients from BRCA2‐positive families and 284 patients from BRCA1/2‐negative breast cancer families) and compared them with those of all other breast cancer patients diagnosed in Finland from 1953 to 1995 (n = 59,517). Cumulative relative survival rates (RSR) were calculated by dividing the observed survival rates by the expected ones. The expected survival rates were derived from the sex, age and calendar year specific life‐tables of the general population in Finland. Regression model was used to calculate relative excess risk of death (RR) and to adjust for confounding factors. The overall 5‐year RSR of the patients in the BRCA1 families, BRCA2 families, non‐BRCA1/2 families and among sporadic cases was 67%, 77%, 86% and 78%, respectively. However, we found no significant differences in the RR adjusted for age, stage and year of diagnosis between the different familial patient groups or the general breast cancer population. In the BRCA1 families the RR tended to be higher [RR 1.30, 95% confidence interval (CI) 0.63–2.70] and in the BRCA2 families lower (RR 0.78, 95% CI 0.39–1.57) than among the general breast cancer patient population. The RR among patients in the non‐BRCA1/2 families did not differ from that of the general patient population.

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.

Wart-virus antibodies and the prognosis of wart disease.

Abstract Wart-virus antibodies from 182 patients Summary with warts were studied by the micro-immunodiffusion method. 57% of the patients had measurable antibodies, the titres varying from 1 to 512. The longer the duration of the disease or the larger the number of tumours, the lower the serum antibody levels were. Complement-fixation antibodies were of the IgG type only, and were demonstrable in only 12% of the cases (titres 4-512). If the antibodies were IgG type, there was a good chance of healing.