Aron Goldhirsch

Receptor heterogeneity of human breast cancer as measured by multiple intratumoral assays of estrogen and progesterone receptor

Multiple intratumoral tissue samples from the primary mass of 30 consecutive invasive breast cancer patients were assayed for estrogen receptor (ER) and progesterone receptor (PR) by the dextran-coated charcoal method following frozen section histopathological examination. Steroid receptor status of each sample was classified as positive (R+) or negative (R-), based only upon quantitative guide lines from the ER/PR results. Four out of 32 (12.5%) of the invasive cancers had an intratumoral sample classified as R+ and one sample as R-. R+ invasive ductal carcinomas has a highly significant degree of tubule formation (P = 0.005) when compared with R- invasive ductal cancers. While the quantitative ER content (r = 0.18) and the degree of quantitative variation in ER content (P = 0.04) did not correlate with the tumor cellularity of the individual samples, tumor cellularity (P = 0.005) and ER content (P = 0.005) were lower in the samples from the tumor border than from the central tumor samples. Variations in ER and PR content may be found on a regional basis within a breast tumor mass resulting from heterogeneity of tumor subpopulations and/or differences in tumor cellularity.

The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial

PURPOSEnA wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorectal cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting survival benefit as opposed to FU alone (J Clin Oncol 1989; 7: 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both treatment arms.nnnPATIENTS AND METHODSnPatients with inoperable or metastatic colorectal cancer were randomized to receive monthly FU 400 mg/m2/day plus LV 20 mg/m2/day as intravenous push daily for five days, or FU alone.nnnRESULTSnThree hundred nine of the 310 patients randomized were eligible and included in the analysis. The objective response rate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO > 2 toxicity, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), was more pronounced for FU-plus-LV, without fatal events.nnnCONCLUSIONSnThis is the largest published randomized trial to compare FU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survival benefit obtained from biomodulating monthly FU with low-dose LV. The toxic effects of FU-plus-LV were acceptable to most patients, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dose LV provides a simple and economical means by which to achieve adequate FU efficacy in the treatment of advanced colorectal cancer.

A quality control study to assess the inter-laboratory variability of routine estrogen and progesterone receptor assays

The steroid hormone receptor laboratories of Bern, Basel, Zürich, Locarno, Lausanne and Geneva have participated in a quality control study to assess potential inter-laboratory variability in results of tests for determination of steroid hormone receptor status in human breast tumor biopsies. Homogeneous breast tumor powders containing low, medium and high concentrations of estrogen receptors (ER) and progesterone receptors (PR) were prepared in Bern and dispatched on solid CO2 to each laboratory within 1 day of preparation. Each laboratory was requested to assay each powder for ER and PR by their usual procedures. The results revealed that the quantitative discrepancies in ER and PR binding values among the participants could be attributed in part to variations in the methods used for measuring cytosol protein content and also to the differences in hormone receptor assay methods. Nevertheless, all of the laboratories were able to identify the samples containing low, medium and high concentrations of ER and PR.

Estrogen receptor in malignant melanoma: Fact or artefact?

A model system is presented to explain how tyrosinase, an enzyme unique to pigmented cells such as normal and malignant melanocytes can oxidize [3H]-estradiol to radiolabeled products which closely resemble the tight binding of [3H]-estradiol to estrogen receptor. In the model system studied, tyrosinase oxidized [2,4,6,7-3H]-estradiol to [3H]-water and [3H]-estradiol metabolites, the latter of which formed ring-substituted conjugates with nucleophiles like monothioglycerol and BSA. Radiolabeled estradiol without tritium in the C-2 position (i.e. [6,7-3H]-estradiol) failed to liberate [3H]-water when exposed to tyrosinase but, nevertheless, did form ring-substituted [3H]-estradiol adducts with nucleophiles. The [3H]-water and the ring-substituted radiolabeled products possessed several characteristics of a genuine estrogen receptor protein in that they were resistant to dextran-coated charcoal (DCC) adsorption and their enzymatic formation was inhibited with non-steroidal estrogens like diethylstilbestrol. Other natural (estradiol) and synthetic (hydroxytamoxifen) estrogens which contain the phenol grouping also inhibited the enzymatic oxidation of [3H]-estradiol. Although it was difficult to differentiate estrogen receptor from tyrosinase using the conventional DCC assay system, several differences in these two proteins permitted a distinction to be made between them. First, tyrosinase oxidation of [3H]-estradiol was markedly inhibited by sulfhydryl reducing agents (monothioglycerol) that stabilize [3H]-estradiol binding to estrogen receptor. Second, estrogen receptor adsorbed by hydroxylapatite whereas tyrosinase did not, thus permitting the separation of these two proteins prior to incubation with [3H]-estradiol. We conclude that the [3H]-estradiol binding components in melanoma previously reported to be estrogen receptor probably represent instead the radiolabeled products of the tyrosinase-catalyzed oxidation of [3H]-estradiol.

A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule

SummaryCarboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200–550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50–155) ml/min and dropped to a median lowest creatinine clearance of 69 (23–171) ml/min on day four (p < 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42–155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200–500

Phase II study of oral VP-16-213 in hepatocellular carcinoma

In a disease-oriented phase II study, 26 patients with hepatocellular carcinoma were treated with oral VP-16-213 at 120 mg/m2/day for 5 consecutive days, repeated every 3 weeks. Of 24 evaluable patients, 3 achieved partial remission (PR) for 12, 16 and 35 weeks respectively. Minor regression or stabilization of the disease (NC) was achieved in 8 patients for a median duration of15 weeks. Patients with PR and NC experienced similar median survival (22 weeks), whereas non-responders had a median survival of less than8 weeks. Results of this trial indicate that VP-16-213 has limited but definite anti-tumor activity in hepatocellular carcinoma.

Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer

We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens.

Whole-abdomen radiation in patients with advanced ovarian carcinoma after surgery, chemotherapy and second-look laparotomy

SummaryForthy-three patients with ovarian carcinoma were treated with whole-abdomen radiation (moving strip±pelvic radiation), 15 patients had not received prior chemotherapy, and 28 patients were irradiated following chemotherapy and second-look laparotomy. Ten of these had been treated with a variety of chemotherapy regimens (L-PAM, CHAD, Hexa-CAF). Eighteen patients were treated in an ongoing prospective trial with combination chemotherapy consisting of melphalan, cis-platinum, and hexamethylmelamin (HexaPAMP). Thrombocytopenia was the limiting toxicity. A temporary pause in the radiation schedule allowing platelets to recover made it possible to complete treatment in 80% of the patients. The acute toxic effects, which included the expected side effects of radiation therapy on intestine, liver and lung, were not more frequent or more severe in the patients who had received prior chemotherapy than in those who had radiation therapy alone. Thirty-four of 43 patients (stage I, seven patients; stage II, seven patients; stage III, 27 patients; stage IV, two patients) are alive and without evidence of disease 26+ months (range 7 to 64 months) after entering the postsurgical treatment program.

Complete Remission following Endocrine or Combined Cytotoxic and Hormonal Treatment in Advanced Breast Cancer

Among 422 patients with advanced breast cancer treated in a randomized trial we observed 60 complete responses (CR). Sixteen were achieved among 206 patients treated with endocrine therapy alone and 37 among 216 patients treated with concomitant chemotherapy and endocrine therapy. The incidence of CR in women treated with the concomitant modality was higher in those with dominant soft tissue disease, intermediate in those with osseous or pulmonary involvement, and low in patients with liver metastases. Bone was shown to be the organ most responsive to therapy among patients treated with hormonotherapy, while patients with soft tissue metastases had an unexpectedly low rate of complete remission with this modality. The probability of achieving a CR was inversely proportional to the tumor burden in the patients treated with concomitant chemotherapy and endocrine therapy. For complete responders on hormone treatment alone and for those on combined endocrine and cytotoxic therapy, both median time to progression (26 and 29 months, respectively) and survival (52 and 53 months, respectively) were similar and statistically significantly longer than in partial or minor responders. This observation leads us to the conclusion that the hormonal component is the determinant for the length of a CR.

Ovarian Cancer and Tumor Markers: Sialic Acid, Galactosyltransferase and CA-125

In an effort to correlate the serum values of potential markers, including CA-125, galactosyltransferase, and total sialic acid, with residual tumor mass after initial surgery, 43 patients with FIGO stage IIb and c, III and IV ovarian cancer were studied. The sensitivity of galactosyltransferase and sialic acid levels was sufficient to correlate their serum values with the corresponding residual tumor mass. Furthermore, 28 patients were histopathologically evaluated for their response to chemotherapy. Determination of these tumor markers did not permit discrimination between small residual disease (less than or equal to 1 cm) and a state of no evidence of disease. Conversely, progression of disease has been associated with a sensitive increase in the level of all three markers. CA-125 has been found to be the most useful of the three for distinguishing between responders and nonresponders.