Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time, and age.

PURPOSE: In the period 1968 through 1988, The Norwegian Radium Hospital (NRH) treated an unselected population of 1,152 patients with Hodgkin's disease (HD) that comprised more older patients (mean age, 43 years) than most other institutions. We considered it important to evaluate these patients for development of second cancers (SCs). PATIENTS AND METHODS: The Norwegian Cancer Registry identified previously untreated patients with HD treated at NRH who had developed a SC more than 1 year after diagnosis of HD. The relative risk ratio (RR) (observed/expected cases) and the cumulative risk were calculated. RESULTS: Sixty-eight patients had developed a SC, including nine acute nonlymphocytic leukemias (ANLLs), eight non-Hodgkin's lymphomas (NHLs), and 51 solid tumors, including 11 lung cancers. The RR of SC and leukemia was 1.86 (95% confidence interval [CI], 1.4 to 2.4) and 24.3 (95% CI, 11.1 to 46.2), respectively. The RR of SC was highest in younger patients (< 41 years, RR = 3.8). No significant association between splenectomy and development of ANLL was found. The influence of treatment and follow-up time on the development of SC agrees with data from other large cancer institutions. CONCLUSION: (1) The low RR of developing a SC in this study is probably due to the number of older patients included, who have a lower RR of developing a SC due to less aggressive treatment, shorter follow-up time, and higher incidence of cancer in the expected background population. (2) The low RR and cumulative risk of developing ANLL may be due to the limited use of extensive chemotherapy (CT) in our hospital in the earlier years.

Neuron-specific enolase as a prognostic factor in metastatic malignant melanoma.

Serum neuron-specific enolase (NSE) was measured in 63 patients with metastatic malignant melanoma. 20 patients (32%) had elevated serum NSE (> 10 micrograms/l) before the start of treatment. Another 13 patients (21%) developed pathological NSE values during the course of the disease. In many patients, elevated NSE was related to a large tumour burden, and a gradual rise in serum NSE indicated disease progression. Patients with elevated pretreatment NSE had a median survival time of 3 months compared with 12 months for those with normal pretreatment NSE values. NSE thus proved to be a useful prognostic factor in metastatic malignant melanoma.

Weekly doxorubicin with or without high-dose medroxyprogesterone acetate in hormone-resistant advanced breast cancer. A randomised study. The Norwegian Breast Cancer Group.

In a randomised study, 218 patients with advanced breast cancer, resistant to hormone therapy, received either doxorubicin 20 mg every week (Awkly) alone or Awkly combined with high doses (1000 mg daily) of oral medroxyprogesterone acetate (HD-MPA). Of the 210 evaluable patients, the response rates were 26% [95% confidence interval (CI) 18-34%] for Awkly and 38% (95% CI 29-47%) for Awkly + HD-MPA (P = 0.08). There was no significant difference with regard to duration of response. Median survival was 11 months in both groups. Considerable toxicity was seen from HD-MPA, particularly weight gain and fluid retention. The present study provides evidence that, in concordance with preclinical studies and a previous randomised study, interaction between chemotherapy and HD-MPA may exist in breast cancer normally resistant to hormone therapy. For further studies, other gestagens and/or a dose reduction could be investigated.

Chemotherapy with or without high-dose medroxyprogesterone acetate in oestrogen-receptor-negative advanced breast cancer. Norwegian Breast Cancer Group.

In a randomised study 142 patients with advanced oestrogen-receptor-negative breast cancer in the tumour tissue received chemotherapy alone or chemotherapy combined with high doses (1000 mg daily) of oral medroxyprogesterone acetate (HD-MPA). Of the 126 fully evaluable for response, the response rates were 46% for chemotherapy alone and 73% for chemotherapy with HD-MPA (P = 0.005). There was no significant difference with regard to duration of response. Of the 138 patients evaluable for survival and toxicity, survival was shorter in the combined treatment group; median survival of 9 versus 13 months (P less than 0.05). Considerable toxicity was seen from HD-MPA, especially weight gain and fluid retention. The present study provides evidence that in concordance with preclinical studies an interaction between chemotherapy and HD-MPA may exist in breast cancer normally resistant to hormone therapy. The side-effects from MPA were substantial, however, and the survival data are of great concern.

Socio-medical situation for long-term survivors of Hodgkin's disease: a survey of 459 patients treated at one institution.

We present the socio-medical situation for 459 adult disease-free long-term survivors of Hodgkin's disease (HD) 3-23 years after first line curative treatment. In 1994, 557 patients were sent a self-report questionnaire relating to their social status and 459 patients (82%) replied. Educational or professional plans were changed due to HD in 142 patients (32%). After 6, 12 and 18 months from start of treatment, 52, 82 and 95% of the patients, respectively, had returned to their job or education. The sum of full-time and part-time employment was in men 78% at diagnosis and 85% at follow-up, and in women 57% at diagnosis and 64% at follow-up. Only 2% of men and 3% of women did not have a job at follow-up in 1994. At diagnosis 2% of the patients were permanently disabled versus 19% at follow-up in 1994. Age > 40 years at diagnosis, increased the total score of psychological distress and fatigue and long-term disablement after first line treatment were predictors for permanent disablement. Transient or permanent sexual problems were reported in 16% and 13%, respectively. MVPP (mustine, vinblastine, procarbazine and prednisone) or LVPP (chlorambucil, vinblastine, procarbazine and prednisone) chemotherapy was responsible for most cases of early menopause in women older than 30 years, and of infertility in both men and women. In summary, most long-term HD survivors had adapted well to their socio-medical situation except a high number of permanently disabled patients. By focusing more on factors predisposing for permanent disablement and early treatment for these, more patients may be helped to return to their job.

Follow-up of breast cancer patients stage I-II: a baseline strategy.

In 430 stage I-II breast cancer patients the cost-benefit of investigations during follow-up have been studied. Median follow-up time was 8 years and 128 patients had relapsed, 91 with metastatic disease. High costs of routine chest X-ray, limited skeletal X-ray and bone scan examinations were associated with low incidence of diagnosed relapses not suspected otherwise. In the eight blood analyses examined, increases of more than 10 mm/h in erythrocyte sedimentation rate (ESR), 20 U/l in gamma-glutamyltransferase (GT) or 60 U/l in alkaline phosphatase (ALP) resulted in a combined sensitivity of 55% and specificity of 91% for relapses with distant metastases. Elevation of at least two blood tests gave a combined sensitivity of 31% and a specificity of 98%. The importance of using individual reference values in screening for recurrences is emphasised. Symptomatic relapse or relapse detected at interval visits were not independent prognostic factors. The blood tests ALP, ESR and GT were strong predictors of survival measured from relapse which increase their legitimacy in follow-up. A more frequent follow-up for patients with 4+ involved nodes is proposed: three visits annually the first 5 years vs. two visits annually for the others. We conclude that history, clinical examination, ALP, ESR and GT are sufficient as a baseline screening for relapse in breast cancer patients.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

Blood tests and prognosis in bladder carcinomas treated with definitive radiotherapy.

The value of some commonly recorded blood tests as prognostic factors in patients with bladder carcinomas treated with definitive radiotherapy has been assessed. This study included 202 consecutive patients (T2, n = 46; T3, n = 82 and T4, n = 74) treated during the period 1980-1987. The median total dose received was 56 Gy [50-67] and the median cumulative radiation effect was 1750 reu (radiation effect unit) (1515-1823). The blood tests examined in survival analyses were erythrocyte sedimentation rate (ESR), hemoglobin (Hb), leucocyte and thrombocyte count, alkaline phosphatase (ALP), gamma-glutamyltransferase (GT), lactate dehydrogenase (LD), creatinine and albumin. In the univariate survival analyses six blood tests were significant prognostic factors (ESR, albumin, creatinine, Hb, ALP and GT). In the multivariate analysis of all 202 patients, the following five variables were significantly associated with shorter survival: T4 tumors, ESR > 30 mm/h, albumin < 35 g/l, LD > 400 U/I and age > 75 years. Our conclusion is that several commonly recorded blood tests are powerful prognostic factors in bladder cancer treated with definitive radiotherapy. These tests can replace other more expensive laboratory investigations used for prognostication.

Pregnancy and breast cancer: a population-based study.

The incidence of pregnancy-associated breast cancer, i.e. during pregnancy and lactation, and of pregnancy subsequent to a breast-cancer diagnosis will increase as more women choose childbearing at a later age. Few larger series are published on pregnancy-associated breast cancer. In a population-based study, we evaluated the outcome and prognostic factors in 173 breast-cancer patients. One hundred and twenty-two patients had pregnancy-associated breast cancer (20 coincident with pregnancy and 102 during lactation) and 51 patients had pregnancy subsequent to breast cancer. The median follow-up time was 151 months. Histopathological parameters and immunoreactivity for oestrogen and progesterone receptors c-erbB-2 and c-erbB-4 were studied. All three groups had tumours with high histological grade, low frequency of hormone receptors and high expression of c-erbB-2. The pregnancy and lactation groups were near identical with regard to all histopathological parameters and outcome. In the two pregnancy-associated breast-cancer groups, tumours were significantly larger, with more extensive lymph-node involvement. For node-negative tumours the respective 5- and 10-year survival rates were 62% and 50% in the pregnancy group and 60% and 50% in the lactation group. For node-positive tumours, respective 5- and 10-year survival rates were 50% and 34% in the pregnancy group and 50% and 33% in the lactation group. In the subsequent group, overall survival was high in both node-negative and -positive groups, with 5- and 10-year survival rates of 80% and 73% and 86% and 76%, respectively. Tumour size, lymph-node status, histological grade, progesterone receptor, oestrogen receptor and c-erbB-2 were significant prognostic factors in the pregnancy-associated breast-cancer patients.

Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients.

The search for better prognostic indicators and new treatment modalities in node-negative breast carcinoma patients is important. The aim of this study was to determine the immunohistochemical expression of central cell regulator proteins in relation to hormone receptor status, tumour-cell differentiation and prognosis. We investigated the immunoreactivity of p27, p21, cdk4, cyclin D1 and p53 in 77 node-negative breast carcinomas, with long-term follow-up (mean 163 months; range 20-227). Nuclear staining for p27 was seen in 87% of the carcinomas, for cdk4 in 92%, for p21 in 68%, for cyclin D1 in 58% and for p53 in 18%. Oestrogen receptor (ER) and progesterone receptor (PgR) nuclear staining was seen in 69% and 65% of the tumours, respectively. No correlation between the levels of p21 and p53 was observed. p21 overexpression was, however, associated with positive ER status. Elevated levels of p27 and cyclin D1 correlated with positive hormone status (both ER and PgR). We did find a significant correlation between p27 and cyclin D1 and histological grade of the tumours, with extensive positive immunostaining of p27 and cyclin D1 in well-differentiated carcinomas. The only significant prognostic factor in our series was histological grading. Ten-year relapse-free survival was significantly prolonged in patients with histological grade I tumours versus histological grade II and III tumours. Our results suggest that the expression of p27 and cyclin D1 is closely linked to hormone receptor status in breast carcinomas and to tumour differentiation, a finding that may be of importance in the treatment of hormone-dependent tumours.

Combined intra-arterial and systemic chemotherapy for recurrent malignant brain tumors.

Seventy-nine patients harboring recurrent brain tumors received four cycles of infraophthalmic carotid injections of 160 mg of carmustine. Two milligrams of intravenous vincristine and 50 mg of oral procarbazine was also administered three times daily for 1 week in conjunction with each BCNU treatment. The response rate was 60% with a median survival for patients with astrocytomas, anaplastic astrocytomas, and glioblastomas of 32, 20, and 6.5 months, respectively. The median survival of the responding patients was 20 months, and the survival at 30 months was 45%. The survival in patients not responding to treatment was 5 months, reflecting the natural history of the tumor. There have been no deaths related to the treatment procedure. No incidents of severe or permanent eye complications or leukoencephalopathy were observed. Based on multivariate survival analysis, only patients with a good performance status who are not steroid dependent are candidates for this treatment.

Erythrocyte sedimentation rate as a prognostic factor in renal cell carcinoma.

In a follow-up study of 193 adult patients with renal cell carcinoma diagnosed in northern Norway 1974-1980, ESR as a prognostic factor was studied with the Cox regression model. In 71 patients (37%) metastatic disease was known at diagnosis. In patients without metastatic disease an elevated ESR greater than 15 mm/h and renal vein involvement were significant prognostic factors indicating short survival. Multivariate survival analyses of all patients showed the presence of metastatic disease and elevated ESR (greater than 15 and greater than 30 mm/h) as significant prognostic factors indicating high-risk patients. This study concludes that ESR deserves attention as a prognostic discriminator in renal cell carcinoma.

Colony-forming ability of human ovarian carcinomas in the Courtenay soft agar assay.

One hundred and twenty-one ovarian carcinomas were cultivated in soft agar according to the Courtenay & Mills (C-M) soft agar method. 71% of the tumours formed colonies, and 54% formed more than 30 colonies. Tumour cells from malignant fluids grew more frequently than did solid tumours, whereas the plating efficiencies (PEs) were higher in the case of solid tumours. In general, the PEs were higher and more tumours formed colonies in the C-M method compared to the Hamburger-Salmon (H-S) method. The colony-forming ability did not show statistically significant correlation to histopathological type and grade, previous treatment and S-phase fraction, but was related to DNA ploidy. In poorly differentiated tumours a high colony-forming ability was associated with a poor prognosis, whereas the opposite was found in well and moderately differentiated tumours. Differential dose-response relationships were obtained after in vitro treatment with anticancer agents.

Flow cytometric DNA analysis as prognostic factor in human breast carcinoma.

Fresh tumour tissue from 198 primary invasive breast carcinomas was analysed by DNA flow cytometry. 108 tumours were non-diploid. A significantly higher proportion of non-diploid tumours was found among node-positive patients, patients with oestrogen receptor negative tumours and among patients with ductal carcinomas. The survival of patients with diploid and non-diploid tumours was not significantly different (p = 0.1). Totally, 145 tumours were analyzed with respect to S-phase fraction (SPF). The distribution of SPF was different in diploid and non-diploid tumours. A low SPF group, defined as the lower SPF quartile (< or = 4.6% in diploid and < or = 8.5% in non-diploid tumours), was associated with highly differentiated tumours and oestrogen receptor positive tumours. Histological grading revealed a highly significant correlation to SPF. 57% of ductal carcinomas grade I (8 out of 14), 30% of ductal carcinomas grade II (20 out of 67) and 5% of ductal carcinomas grade III (2 out of 37) had a low SPF. Patients within the low SPF group had a significantly longer survival than had patients within the high SPF group (p = 0.006). In a multivariate analysis the SPF was found to be an additional prognostic factor next to node status and ER status.

Clinical research in a hospital--from the lone rider to teamwork.

Clinical research of high international standard is very demanding and requires clinical data of high quality, software, hardware and competence in research design and statistical treatment of data. Most busy clinicians have little time allocated for clinical research and this increases the need for a potent infrastructure. This paper describes how the Norwegian Radium Hospital, a specialized cancer hospital, has reorganized the clinical research process. This includes a new department, the Clinical Research Office, which serves the formal framework, a central Diagnosis Registry, clinical databases and multicentre studies. The department assists about 120 users, mainly clinicians. Installation of a network software package with over 10 programs has strongly provided an internal standardization, reduced the costs and saved clinicians a great deal of time. The hospital is building up about 40 diagnosis-specific clinical databases with up to 200 variables registered. These databases are shared by the treatment group and seem to be important tools for quality assurance. We conclude that the clinical research process benefits from a firm infrastructure facilitating teamwork through extensive use of modern information technology. We are now ready for the next phase, which is to work for a better external technical framework for cooperation with other institutions throughout the world.

[Taxicabs for patient transport to national hospitals]. / Drosjer som syketransport til statlige sykehus.

The use of taxis to transport patients to and from the Norwegian Radium Hospital has been studied. 36% of the patients travelled by taxi. This frequency gives an estimated 70,000 trips by taxi annually at a cost of NOK 60 million for four national hospitals in Oslo. Since at present most of the patients travel one in a taxi. There seems to be a large potential for reducing costs.

Regression analyses of prognostic factors in colorectal cancer.

In a follow-up study of 110 patients with colorectal cancer, age, sex, erythrocyte sedimentation rate (ESR), hemoglobin (Hb), leukocyte count, emergency operation, tumor site, Dukes' stage, and histologic grade were tested in survival analyses. Dukes' stage was a highly superior prognostic discriminator. In multivariate survival analysis (Cox model) elevated ESR and leukocytosis were significant prognostic factors in addition to the Dukes' stage, indicating high-risk patients with shorter survival.

Blood analyses as prognostic factors in primary lung cancer.

The prognostic value of some pretreatment blood tests was analysed in a follow-up study of 189 patients with non-small cell lung cancer diagnosed in West-Norway between 1976 and 1985. At diagnosis 100 patients had stage III/IV disease. Five-year survival calculated with the life-table method was 12%. In univariate survival analyses significant prognostic factors were stage III/IV disease, weight loss, elevated lactate dehydrogenase, gamma glutamyl transferase, erythrocyte sedimentation rate and alkaline phosphatase, thrombocytosis, leukocytosis and anaemia. In multivariate survival analyses with the Cox's regression model stage III/IV disease, elevated lactate dehydrogenase, thrombocytes and erythrocyte sedimentation rate were significant prognostic factors. It is concluded that these blood analyses at diagnosis in non-small cell lung cancer patients may give additional prognostic information. The need for multivariate analyses is also demonstrated.

Blood analyses and survival in symptom- and survey-detected lung cancer patients.

Commonly recorded blood analyses as indicators of low- and-high risk patients with lung cancer were studied by comparing symptom- and survey-detected patients. During the period 1976-1985, in 41 of 189 non-small-cell lung cancer patients in Western Norway, lung cancer was detected by chest X-ray survey performed in the preventive tuberculosis screening programme. After adjusting for other variables, including developmental stage, erythrocyte sedimentation rate (ESR) was the only blood analysis which discriminated symptom-detected patients (high ESR) from survey-detected patients (low ESR). Survey-detected patients had a better short-term survival. In multivariate survival analyses leucocyte count, lactate dehydrogenase activity and ESR were significant prognostic factors, in addition to advanced stage and detection due to symptoms. We conclude that common blood analyses such as ESR provide supplementary information concerning low- and high-risk lung cancer patients.

[Use of personal computers for statistical analyses]. / Bruk av personlige datamaskiner til statistiske analyser.

We report the range in elapsed time for various statistical analyses and for the same logistic regression analysis in 23 different personal computers (PCs). Without a floating-point coprocessor, the elapsed time increased from ten to 113 minutes in the same PC. Elapsed time ranged from two to 45 minutes from 80486 to 8086 PCs with a floating-point coprocessor. The PC equipment we need strongly depends on the type and frequency of the statistical analyses we are to perform. If a floating-point coprocessor is installed, the 80286/80287 PC family may be fast enough for most users.