Primary breast cancer: the effect of primary ovarian irradiation.

Between November 1957 and December 1963, 169 premenopausal and 177 postmenopausal patients were included in a randomized clinical trial. In the experimental group ovarian irradiation was given shortly after mastectomy. In the control group ovarian irradiation was planned for the time of first recurrence. The last published follow-up in 1974 [1] revealed a significant effect on disease-free survival both in premenopausal and postmenopausal patients. The latest results from a follow-up conducted in 1989 demonstrate a significant effect also on crude survival in both age groups. As expected, long-term effects are observed exclusively in the premenopausal cohort.

Perioperative adjuvant chemotherapy in breast cancer. The Scandinavian Adjuvant Chemotherapy Study 1.

In a randomized study of operable primary breast cancer patients initiated January 1965, 507 patients received one single course with cyclophosphamide 5 mg/kg/day for six days, first dose given immediately after mastectomy. The 519 control patients received no adjuvant chemotherapy. In other respects both groups were treated equally. Median follow-up time is 17.1 years. In terms of relapse-free percentage, the difference between the groups after 20 years is 13.5% in favour of the cyclophosphamide group. The difference is statistically highly significant. This benefit is observed in node positive as well as in node negative patients, and over as well as under 50 years. The immediate side effects of the cyclophosphamide course have been very moderate. No late complications have been observed. In a parallel randomized study with 110 patients where the same course was given 2-4 weeks after mastectomy, no benefit could be observed.

Prolonged adjuvant chemotherapy in breast cancer. The Scandinavian Adjuvant Chemotherapy Study 2.

Eleven hundred and sixteen primary female breast cancer patients received one short perioperative chemotherapy course. The node negative patients were randomised between immunotherapy (corynebacterium parvum s.c. around the scar 2 weeks after mastectomy), or no further adjuvant therapy. A moderate, but significant delaying effect was observed, without side effects. The node positive patients were randomised to four groups: 1) the same immunotherapy as in the node negative patients, 2) CMF for 1 year, 3) combination of these two treatments, or 4) no further adjuvant therapy. The prolonged chemotherapy had a significant positive effect, but also considerable and distressing side effects. The immunotherapy had a non-significant negative effect in the node positive patients, but without side effects.

Is there a role for perioperative adjuvant therapy in the treatment of early breast cancer?

Despite having been investigated for many years, the role of adjuvant perioperative chemotherapy in the treatment of early breast cancer has still to be fully defined. This paper reviews the early trials of perioperative cytotoxic therapy and overviews the two largest trials; the Scandinavian Adjuvant Chemotherapy Study Group (SACSG) Trial, which began in 1965 and recruited 1026 patients, and the Cancer Research Campaign (CRC) Adjuvant Trial with 2230 patients entered between 1981 and 1985. Overview analysis of these two trials clearly shows a small but highly significant increase in time to first event (P less than 0.001). Increased survival, although significant in the SACSG trial, has not yet been demonstrated in the CRC study, but at this stage of follow-up (median 2.5 years) this is not surprising.

Treatment of node-negative breast cancer patients with short course of chemotherapy immediately after surgery.

In our first study, one short course of chemotherapy (cyclophosphamide, 5 mg/kg/day for 6 days iv) was given perioperatively to 507 patients with operable primary breast cancer; there were 519 control subjects. Randomization was done by telephone from the operating theater, and stratification was by hospital only. The side effects were negligible. With 20-year follow-up, the relapse rate was 60.5% in the control group and 48% in the treatment group (P less than 0.001). The overall survival benefit was marginally significant, but with correction for deaths not related to cancer, P was less than 0.02. A total of 309 patients in the treatment group and 301 in the control group were histologically node negative. The observed benefit in this subgroup was as good as in the node-positive subgroup, but the relapses were too few for testing of meaningful significance. In our second study, all patients received one short perioperative course, and the node-positive patients were randomized between control or continued chemotherapy for 1 year. This improved the beneficial results but also considerably increased the side effects.

Short perioperative versus long-term adjuvant chemotherapy.

A single course of cyclophosphamide IV 5 mg/kg daily for 6 days was given immediately after mastectomy to 507 patients (519 randomized controls). The relapse-free rates were significantly increased, and after 16 years the difference was 12%. In a parallel series the same adjuvant course was given 2-4 weeks after mastectomy to 52 patients (58 randomized controls). No effect of this delayed course was found. In a second study a short multidrug course was given to all patients immediately after mastectomy. One-half of the axillary node-positive cases were randomized to continue with IV CMF for 1 year. The preliminary observations show that the prolonged treatment improved the relapse-free rates significantly during the first few years. One year after mastectomy the difference was 10%; after 2 years, 9%; after 3 years, 11%; and after 4 years, 9%. The side-effects of the short course were negligible, but the side-effects of prolonged treatment were considerable and increased with increasing treatment duration. More trials are needed to find the optimum duration of adjuvant chemotherapy.

Adjuvant chemotherapy in breast cancer.

One single course of i.v. cyclophosphamide (30 mg/kg) was given over a 6-day period to 559 mastectomized patients. During a follow-up period of up to 15 years, 241 recurrence and 234 deaths are registered in this group, and 294 recurrences and 283 deaths in the randomized control group of 577 patients. Analysis of the life-table curves shows an increased cure rate of about 10%.

Orchiectomy combined with cyproterone acetate or prednisone in the treatment of advanced prostatic carcinoma. A randomized clinical and endocrine study.

Thirty-four previously untreated patients with advanced prostatic carcinoma, histologically graded as being of intermediate differentiation, were randomized in three groups. All patients were treated with primary orchiectomy, group I was observed without additional therapy, group II treated with oral administration of prednisone and group III treated with cyproterone acetate per os. The clinical results with the combination orchiectomy and prednisone was encouraging both when initial and secondary remissions were considered. Cyproterone acetate treatment induced a highly significant raise in plasma prolactin, a fact which may explain the less favourable clinical results in this group.

Surgical adjuvant chemotherapy: results with one short course with cyclophosphamide after mastectomy for breast cancer.

One single six-day course with cyclophosphamide (total dose 30 mg/kg) was given immediately after mastectomy to 507 breast cancer patients, with 519 randomized controls receiving no adjuvant chemotherapy. The control group now has 234 recurrences and 196 deaths, and the treatment group 175 recurrences and 146 deaths. The differences of 59 recurrences and 50 deaths in favour of the treatment group are significant with p values less than 0.001 and less than 0.01 respectively. The differences in recurrence rates increased gradually, reached 10.71% four years after mastectomy (p less than 0.001), and remained at the same level for another 6 years. The differences in death rates increased until 6 years after mastectomy, and was 10.48% after 10 years. With this pattern, the mechanism is probably not a delay in onset of clinical recurrences, but a definite reduction of recurrence rates due to tumoricidal chemotherapy. Prognostic factors or menstrual state had apparently no influence on the effect of this type of adjuvant chemotherapy. Side effects were of short duration and very moderate. Since there was a good effect in the prognostically most favourable groups of patients, treatment of such cases seems therefore also justified. The same chemotherapy course given 3 weeks after mastectomy seemed without effect.

On gestagen treatment of advanced prostatic carcinoma.

Depostat treatment was found to reduce plasma testosterone and to have a gonadotrophin suppressive effect in males. In our study the clinical effect on prostatic cancer was, however, disappointing when compared to the well established effect of orchiectomy. The therapeutic failure of Depostat might be related to the incomplete suppression of plasma testosterone compared to that observed after orchiectomy.