Per Dombernowsky

Tumor markers in the management of patients with ovarian cancer

Epithelial ovarian cancer constitutes one-quarter of the gynecologic malignancies, but is the leading cause of death among women with gynecologic cancer. In 6070% of the women, the disease is detected at a late stage when 5-year survival is poor. The recommended primary therapeutic approach for ovarian cancer is aggressive primarydebulking surgery followed by combination chemotherapy. The efficacy is routinely evaluated by repeated vaginal examination and transabdominal ultrasonography. However, these methods are unreliable for monitoring as progressive and recurrent disease often remains hidden until the patient presents with a large tumor mass. Over the last few decades a variety of serological tumor markers has been proposed as a supplement to other non-invasive diagnostic methods. The main issue with tumor marker measurements is to obtain reliable information about changes in tumor mass before the changes are detectable by other methods. However, despite several attempts to identify useful serological markers for epithelial ovarian cancer, the results have not been as encouraging as for germ-cell tumors. The purpose of this paper is to review the applicability of CA 125, CEA, TPA, TATI, CASA, and tetranectin in screening, diagnosis, prognosis, and monitoring of ovarian carcinoma. Several compounds other than those mentioned above are being investigated as markers in the early detection and management of ovarian cancer. Some ofthese potential tumor markers listed in Table 1 will not be discussed further in this review.

Toremifene and tamoxifen in advanced breast cancer - a double-blind cross-over trial

SummaryToremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study.66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40mg/day or TOR 240mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10–41%) and with TAM 42% (95% confidence limits 25–61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of overlooking a response rate of 20% or more is less than 1%.In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.

Predictors of central nervous system metastasis in patients with metastatic breast cancer. A competing risk analysis of 579 patients treated with epirubicin-based chemotherapy

SummaryIn order to identify factors predictive of central nervous system (CNS) metastasis, we reviewed the histories of 579 patients treated with epirubicin-based chemotherapy for metastatic breast cancer. Statistical analysis included Kaplan–Meier survival plots, Cox’s regression analysis and competing risk analysis using the cumulative incidence. Median follow-up-time was 137xa0months (range 0–183+). In this period, one hundred and twenty-four patients (21.4%) developed CNS metastasis. Lung, liver, and lymph node metastases and oestrogen receptor negative or unknown tumor were predictive as well. However, increased pretreatment lactate dehydrogenase (LDH) concentration in serum above the upper normal limits was the strongest single risk factor and should therefore be measured. The risk of CNS metastasis differed considerably among risk groups. Patients without risk factors had a cumulative incidence on 9%, compared to a cumulative incidence of 42%, when the serum LDH concentration was elevated to more than twice the upper normal limits.

Histologic malignancy grading of invasive ductal breast carcinoma. A regression analysis of prognostic factors in low-risk carcinomas from a multicenter trial

In a prospective adjuvant trial including patients with primary operable breast cancer, invasive carcinomas of ductal type were subjected to histological malignancy grading. The parameters investigated were tubule formation, number of mitoses and cell pleomorphism. A Cox regression model for survival data was applied to evaluate the impact of the histological parameters on prognosis in 1809 patients with low‐risk carcinomas. Cell pleomorphism proved superior to the other histologic tumor characteristics. It was found that low‐risk invasive ductal carcinomas with severe cell pleomorphism had an excess recurrence intensity of 209% relative to carcinomas with no pleomorphism. It is therefore suggested that polymorphous invasive ductal breast carcinomas, other things being equal, should be regarded as high‐risk tumors in future clinical trials. Finally it was found that the tripartite malignancy grading 1, 2 and 3 characterizing each of the histological parameters was not equidistant. Consequently, the traditional tripartite histologic scoring needs reconsideration.

Combination chemotherapy with 4′Demethylepipodophyllotoxin 9-(4,6-0-ethylidene-β-d-glucopyranoside), VP 16–213 (NSC 141540) in L1210 Leukemia☆

Abstract The epipodophyllotoxin derivative VP 16–213 (NSC 141540), an antineoplastic agent of high activity against transplantable leukemia in mice and of proven activity in human tumours, was studied in combination therapy with actinomycin D, 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU), cyclophosphamide (CTX), cytosine arabinoside, daunorubicin, 5-fluorouracil, 6-mercaptopurine, methotrexate or vincristine against L1210 leukemia in mice. With one treatment on day 1 after transplantation, the therapeutic results of the combination of VP 16–213 with actinomycin D, cytosine arabinoside, daunorubicin, 5-fluorouracil, 6-mercaptopurine, methotrexate and vincristine, were in the same range or inferior to the effect of the single agents. Combination of VP 16–213 with CTX or BCNU led to remarkably good results, which were of the “more than additive” type. Thus, in equitoxic doses, for example, the combination of VP 16–213+CTX (ratio 1:1) at the 0·5 ld 10 level gave 75% cures compared with 5% for VP 16–213 alone and 0% for CTX. When treatment was started on day 6 after transplantation, no advantage of the VP 16–213+CTX combination could be demonstrated, while the VP 16–213+BCNU combination still proved superior to the single agents, with respect to increase in life-span and cure rate.

PROGNOSTIC VALUE OF SERUM TETRANECTIN IN PATIENTS WITH METASTATIC BREAST CANCER

To evaluate serum tetranectin as a prognostic marker before first-line chemotherapy, serum levels were studied in 67 patients with metastatic breast cancer. In the Cox analyses, the relative risk (RR) for death of cancer varied with the cut-off level of serum tetranectin. A maximal RR of 5.0 was found for patients with serum tetranectin < or = 5.4 mg/l. The maximal RR of death for the other prognostic variables were multiple metastases 2.8, and for a poor performance status 2.0. Testing for the outcome, progressive disease, a maximal RR of 3.8 was found for patients with serum tetranectin < or = 5.3 mg/l, a maximal RR of 3.7 for multiple metastases and a maximal RR of 1.8 for a poor performance status. Significantly lower serum tetranectin values were found in patients with a poor treatment response compared to well responding patients. Serum tetranectrin seems to be useful as an additional prognostic factor in metastatic breast cancer.

The value of yearly chest X-ray in patients with stage I breast cancer

In 263 patients with stage I breast cancer, i.e. tumour less than 5 cm in diameter, no invasion of skin and deep fascia, and no involvement of axillary lymph nodes, X-rays of the chest were performed at 6, 12 months and yearly thereafter to the 6th year or until recurrence, another cancer was detected, the patient refused further follow-up or died. Among 1599 examinations, in only 0.25% (four patients) were unsuspected malignant changes observed. Due to this low cost/benefit ratio a fixed routine schedule of repeated chest X-rays in stage I cancer patients, otherwise apparently free of disease, is not justified.

Interpretation of sequential measurements of cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) based on analytical imprecision and biological variation in the monitoring of ovarian cancer

Abstract The main objective with cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) monitoring of ovarian cancer patients is to detect an early change of disease activity with high reliability. We hypothesized that a monitoring scheme for ovarian cancer patients with serological tumor markers should take into account the stochastic variation, i.e. the probability that observed increases and decreases may solely be due to analytical imprecision and normal intra-individual biological variation. The aim of this study was to provide a detailed characteristic of the within-subject mean steady state concentrations and the associated variability in healthy individuals with an age distribution representative for ovarian cancer patients. Thirty-one healthy women with a median age of 55 years comprised the study population. Sixteen blood samples were collected from each subject in four series, with four samples per series, over a period of approximately 1 year. We found that, i) natural logarithmic-transformed concentrations were more homogeneously distributed between individuals than the original concentrations, ii) the within-subject mean steady state levels, the standard deviations, and the coefficients of variation differed among subjects, and iii) the steady state variability differed among the markers. In conclusion, our data indicate that the assessment of sequential CA 125, CEA, and TPA concentrations is more complex than hitherto recognized. We suggest that it is necessary to adjust the assessment criteria to the type of marker, and that assessment may be facilitated if based on natural logarithmic transformed concentrations.

Assessment of CA 15.3, CEA and TPA Concentrations during Monitoring of Breast Cancer

Abstract The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) during steady state concentrations and the rate of increase during progression is described. One hundred and ninety-two patients were monitored during first-line chemotherapy for metastatic breast cancer and during follow-up. Blood specimens were sampled approximately every four weeks. Steady state concentrations were registered for 77 (CA 15.3), 96 (CEA), and 127 (TPA) patients with below cutoff level values and for 28 (CA 15.3), 25 (CEA), and 11 (TPA ) patients with above cutoff level values. Clinical and marker progression was registered for 75 (CA 15.3), 62 (CEA), and 57 (TPA) patients. The coefficients of total variation of steady state concentrations (comprising the intra- and interassay analytical imprecision and the within subject biological variation) were higher below (14.9% CA 15.3, 15.4% CEA, 25.9% TPA) than above cutoffs (9.6% CA 15.3, 6.0% CEA, 19.9% TPA). The variability was similar for CA 15.3 and CEA but higher for TPA. During progression the rates of increase in concentrations were similar for CA 15.3 (0.0257) and CEA (0.0214) and lower than for TPA (0.0346). Our data indicate that criteria for assessment of sequential tumor marker concentrations should consider the marker in question, the steady state variability, the cutoff value, and the rate of increase during disease progression.

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age.

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N=94), the TAM+AG+H (N=83), and the TAM+FLU (N=81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p=0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are −9–19% and for TAM vs. TAM+FLU −4–25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM+FLU group, respectively (p=0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG+H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.