Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.

The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the adequacy of tumor margins defined as 'no ink on invasive tumor or DCIS' and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online.

Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII.

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.

Interaction of tamoxifen with concurrent cytotoxic adjuvant treatment affects lymphocytes and lymphocyte subsets counts in breast cancer patients.

The effects and interaction of endocrine and cytotoxic adjuvant treatment on measures of cellular immunity were assessed in 41 stage I-II breast cancer patients from International Breast Cancer Study Group trials. Counts of lymphocytes and lymphocyte subsets [(T, T4, T8, B, natural killer (NK) and activated T (AT) cells] were assessed by flow cytometry immediately before adjuvant therapy at baseline and on day 1 of the 3rd cycle. Twenty-two patients received cyclophosphamide, methotrexate and 5-fluorouracil (CMF), 7 CMF and tamoxifen (TAM), and 12 TAM alone. On day 1 of the 3rd cycle the counts of total lymphocytes (P = 0.003) and all lymphocyte subsets (P<0.05) except AT cells were significantly lower than baseline in the CMF treatment group. There was no significant change in the CMF+TAM or in the TAM treatment group. The combination of CMF and TAM resulted in less pronounced decrease in lymphocyte and subset counts from baseline to day 1 of the 3rd cycle. It seems possible that there is an interaction between TAM with CMF that affects lymphocyte and lymphocyte subset counts during cytotoxic treatment.

Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI.

Adjuvant chemotherapy-induced amenorrhoea has been shown to be associated with reduced relapses and improved survival for premenopausal breast cancer patients. Amenorrhoea was, therefore, studied to define features of chemotherapy (i.e. duration and timing) and disease-related factors which are associated with its treatment effects. We reviewed data from IBCSG Trial VI, in which accrual was between July 1986 and April 1993. 1196 of the 1475 eligible patients (81%) were evaluable for this analysis. The median follow-up was 60 months. Women who experienced amenorrhoea had a significantly better disease-free survival (DFS) than those who did not (P = 0.0004), although the magnitude of the effect was reduced when adjusted for other prognostic factors (P = 0.09). The largest treatment effect associated with amenorrhoea was seen in patients assigned to receive only three initial CMF courses (5-yr DFS: 67% versus 49%, no amenorrhoea; hazard ratio, 0.55; 95% confidence interval, 0.38 to 0.81; P = 0.002). DFS differences between amenorrhoea categories were larger for patients with ER/PR positive tumours (hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80; P = 0.0001). Furthermore, patients whose menses returned after brief amenorrhoea had a DFS similar to those whose menses ceased and did not recover (hazard ratio, 1.10; 95% confidence interval, 0.75 to 1.62; P = 0.63). The effects associated with a permanent or temporary chemotherapy-induced amenorrhoea are especially significant for node-positive breast cancer patients who receive a suboptimal duration of CMF chemotherapy. Cessation of menses, even for a limited time period after diagnosis of breast cancer, might be beneficial and should be prospectively investigated, especially in patients with oestrogen receptor-positive primaries.

Adjuvant chemotherapy in operable breast cancer: cyclophosphamide, methotrexate, and fluorouracil versus chlorambucil, methotrexate, and fluorouracil--11-year results of Swiss Group for Clinical Cancer Research trial SAKK 27/82.

PURPOSE: To compare two adjuvant combination chemotherapies, cyclophosphamide, methotrexate, and fluorouracil (CMF) and chlorambucil, methotrexate, and fluorouracil (LMF), for patients who had undergone potentially curative surgery for unilateral breast cancer, in terms of relapse, survival, and toxicity. PATIENTS AND METHODS: Selection criteria was as follows: stage pT1-3a, N+ or N-, M0, less than 72 years of age. Eligible patients were randomized to receive either CMF (cyclophosphamide 100 mg/m2 orally on days 1 to 14, methotrexate 40 mg/m2 intravenously (I.V.) on days 1 and 8, fluorouracil 600 mg/m2 I.V. on days 1 and 8) or LMF (Leukeran [Wellcome A.G., Bern, Switzerland] 5 mg/m2 orally on days 1 to 14 with the some I.V. cytostatic drugs). Follow-up examinations were performed every 3 months during the first 3 years after mastectomy, and every 6 months thereafter. RESULTS: A total of 246 patients were randomized, of whom 232 who were fully eligible and contribute to the analyses presented here. No statistically significant difference in favor of adjuvant CMF over LMF emerges after a median follow-up duration of 11.2 years, for either overall survival (P = .15) or disease-free survival (P = .14). A consistent trend suggestive of a possible relative benefit associated with CMF should be pointed out. However, CMF presents a significantly worse toxicity profile as concerns hematologic parameters as well as alopecia, nausea, and vomiting. CONCLUSION: This prospective trial has not identified a statistically significant difference in disease-free survival or overall survival between the two adjuvant regimens LMF and CMF. Although a trend in favor of CMF has been observed in premenopausal patients, this has to be weighted against its definitely more pronounced toxicity profile.

Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy. The International Breast Cancer Study Group.

Breast cancer metastases appearing soon after adjuvant chemotherapy (within 12 months of its completion) are usually resistant to retreatment with the same cytotoxic agents, while relapses occurring later (beyond 12 months) regress when rechallenged with the same agents, showing similar response rates observed in non-pretreated patients with advanced disease. The International Breast Cancer Study Group (IBCSG) prospectively explored the efficacy of retreatment for patients upon relapse using the same therapy administered during the adjuvant programme. 87 patients previously treated with an adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) combination chemotherapy (with or without the addition of low-dose prednisone and tamoxifen), who had measurable first breast cancer relapse, usually after at least 6 months of completion of the adjuvant treatment, were treated with CMF. Pretreatment consisted of 1-3 CMF courses in 27 patients and 4 or more courses in 60 patients. 17 patients were retreated with additional tamoxifen or had tamoxifen stopped at relapse. The data of these patients are shown separately. 47 of the 86 fully evaluable patients (55%) had an objective response, which was complete in 25 (29%). The dominant metastatic type and the number of involved sites were the most important factors influencing response to retreatment. Patients with soft tissue metastases had a high response rate (36/52, 69%) compared with those who had visceral involvement (9/24, 38%) or those with bony disease (2/10, 20%) (P = 0.002). In conclusion, response rates to retreatment with CMF were similar to those expected in a non-pretreated population. The patterns of relapse and the number of metastatic sites were the most important factors predicting response to retreatment, while treatment-free interval (usually longer than 6 months due to the study design) did not influence response rates. This study supports the hypothetic effectiveness of late reintroduction of adjuvant cytotoxic therapy (prior to evidence of systemic relapse), upon which several current trials are based.

The effect of adjuvant prednisone combined with CMF on patterns of relapse and occurrence of second malignancies in patients with breast cancer. International (Ludwig) Breast Cancer Study Group.

BACKGROUND: The addition of low-dose prednisone (p) to the adjuvant regimen of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) allowed patients to receive a larger dose of cytotoxics when compared with those on CMF alone. However, disease-free survival and overall survival were similar for the two groups. To test the hypothesis that low-dose prednisone might influence the efficacy of the cytotoxic regimen used, the toxicity profiles of the two treatment regimens and the patterns of treatment failure (relapse, second malignancy, or death) were examined. PATIENTS AND METHODS: 491 premenopausal and perimenopausal patients with one to three positive axillary lymph nodes included in International (Ludwig) Breast Cancer Study Group (IBCSG) trial I from 1978 to 1981 and randomized to receive CMF or CMFp were analyzed for differences in long-term outcome and toxic events. The 250 patients assigned to CMF and prednisone received on the average 12% more cytotoxic drugs than those who received CMF alone. RESULTS: The 13-year DFS for the CMFp group was 49% as compared to 52% for CMF alone, and the respective OS percents were 59% and 65%. Several toxic effects such as leukopenia, alopecia, mucositis and induced amenorrhea were reported at a similar incidence in the two treatment groups. Using cumulative incidence methodology for competing risks, we detected a statistically significant increase in first relapse in the skeleton for the CMFp group at 13 years follow-up with a relative risk (RR) of 2.06 [95% confidence interval (CI), 1.23 to 3.46; P = 0.004]. Patients with larger tumors in the CMFp regimen were especially subject to this increase with a RR for failure in the skeleton of 3.32 (95% CI, 1.57 to 7.02; P = 0.0005). CMFp-treated patients also had a larger proportion of second malignancies (not breast cancer), with RR of 3.34 (95% CI, 0.91 to 12.31; P = 0.09). CONCLUSIONS: Low-dose continuous prednisone added to adjuvant CMF chemotherapy enabled the use of higher doses of cytotoxics. This increased dose had no beneficial effect on treatment outcome, but was associated with an increased risk for bone relapses and a small, not statistically significant increased incidence of second malignancies. The effects of steroids, which are widely used as antiemetics (oral or pulse injection) together with cytotoxics, should be investigated to identify their influence upon treatment outcome.

Paracelsus, scientific research and supportive care--500 years after!

The 500th anniversary of the birth of the famous Swiss physician and philosopher, Theophrastus Bombastus von Hohenheim--called Paracelsus, in the fall of 1993 provides an excellent opportunity to review some of his thoughts and teachings and to reflect upon their timeless meaning for present-day medical research and patient care, especially in the sometimes controversial field of supportive care in oncology. Most probably Paracelsus' call for the abandonment of the encrusted dogmatic Galenism and his fight for a new spirit of experimental investigation by sound empirical studies was well ahead of his time in the early Renaissance. However, his concept of diseases as specific entities, relating to specific anatomical sites and possessing distinct and reproducible natural courses, was nearly prophetic, while still leaving room enough for individual variations. His views are somehow illustrative of modern psychosomatic medicine and comprehensive "holistic" supportive and palliative care, realized only after a very long "doctor's delay" at the close of the twentieth century.

Swiss adjuvant trials in women with node-negative breast cancer. OSAKO.

Women with node-negative breast cancer have a 30% chance of relapse 5 years after mastectomy. If it is possible to prevent or defer recurrent disease with adjuvant systemic therapy, node-negative patients, with their low tumor burden, should theoretically benefit most from such treatment. In 1974 we started a randomized adjuvant trial in eastern Switzerland, using a subjectively less toxic regimen [chlorambucil, methotrexate, and fluorouracil (LMF)]. Two hundred fifty-four patients were randomly assigned after standardized modified radical mastectomy to observation only or to treatment with oral LMF for 6 months followed by BCG skin scarifications monthly for up to 2 years. While we find no significant statistical difference between the control group and the treated group in terms of relapse-free survival, there is a strong and consistent trend toward prolongation of overall survival within the treated group.

[Why do cancer patients use alternative medicine?]. / Warum benützen Tumorpatienten Alternativmedizin?

160 patients (53.3%) replied to an anonymous questionnaire distributed to 300 consecutive patients of our Outpatient Oncology Clinic. 83 patients (53%) mentioned some experience of one or more alternative methods of cancer treatment. Most often cited were various herbal teas (35 instances), beetroot juice (16), Vogel plant extracts (15), laying-on of hands (14), homeopathic medicine (13), the mistletoe extract Iscador (13), magnetopathy (12), various diets (10), acupuncture (10) and psychological methods (9). Resort to alternative methods of treatment correlated significantly with lower age (51.5 years vs 59.8 years, p = 0.001). The reasons for using alternative medicine were the desire to do everything possible to regain health (49), to use one's psychological forces as well (35), reports of successful cancer cures (28), desire for a holistic approach (23), hope of "softer" medicine with less severe side effects (18) and, in 7 cases only, disappointment with conventional university medicine. The major source of information was relatives and friends, not the mass media. The physician should be aware of the locally available alternative medicine options and be able to advise his patients accordingly. He should also recognize and give due consideration to the patient's underlying desire for better control of his disease and a more holistic approach to care.

Adjuvant chemoimmunotherapy with LMF + BCG in node-negative and node-positive breast cancer patients: 10 year results.

A total of 254 patients with stages T1-3a/N0-1/M0 operable breast cancer were randomized to either surgery alone or surgery plus adjuvant chemoimmunotherapy (LMF + BCG). Ten-year results are presented for RFS (relapse-free survival) and OAS (overall survival) in the whole patient population as well as in the most important menopausal and nodal subgroups. LMF + BCG significantly increased RFS in the whole patient population as well as in node-positive women. The earlier impressive RFS and OAS gains for node-negative patients were fading after 5 and 8 years respectively, leaving marginal trends in favour of the LMF + BCG treated women. Node-positive patients treated with LMF + BCG continue to demonstrate a marginal gain in RFS up to 10 years. This gain is nearly exclusively expressed in postmenopausal node-positive women, an observation which can be made in the node-negative patient group as well. Despite the still continuing increase in RFS,' no OAS benefit was observed for node-positive women with LMF + BCG at any time of the study. Dose still remains a critical factor in cancer therapy. However, at 10 years of follow-up, a full dose of LMF (greater than or equal to 90%) during the six cycles no longer affects OAS favourably. There was no indication of any adverse long-term toxicity of LMF + BCG in our study after a median follow-up of 10 years, especially no increase of second tumours. In the node-negative patient population, the presence or absence of intramammary lymphatic infiltration seems to be a significant prognostic factor within this nodal subgroup.

Swiss adjuvant trial (OSAKO 06/74) with chlorambucil, methotrexate, and 5-fluorouracil plus BCG in node-negative breast cancer patients: nine-year results.

Between 1974 and 1977, a total of 254 patients with stages T1-3a, N0-1, and M0 operable breast cancer (node negative and node positive, stratified) were randomized to either modified radical mastectomy alone or the same surgery and adjuvant chlorambucil, methotrexate, 5-fluorouracil (LMF) plus BCG. After a median follow-up of 9 years (January 1985), we concluded that LMF plus BCG significantly increased relapse-free survival (RFS) in 240 fully evaluated patients, especially postmenopausal women. This gain in RFS ceased to transform into a gain in overall survival (OAS) after 7 years of median follow-up for the whole patient group. In the 122 node-negative patients studied, LMF plus BCG produced a marked increase in RFS up to the fifth year and in OAS up to 8 years after initial surgery, thus prolonging significantly the median disease-free interval compared with surgical control patients. This trend favoring LMF plus BCG-treated patients continues. Although median time to first relapse and to generalized disease were increased in relapsing patients by LMF plus BCG, the subsequent intervals from local relapse to distant disease and from distant metastases to death were equal for both treatment regimens. Subjective and objective acute toxicity from LMF plus BCG was mild. At 9 years of median follow-up, fewer second tumors were noted in the node-negative group receiving LMF plus BCG than in surgical controls.

A randomized study of combination chemotherapy (VAC-FMC) with or without immunostimulation by Corynebacterium parvum in metastatic breast cancer.

A total of 156 patients with metastatic breast cancer were entered into a prospective multi-center trial in September 1975. All patients were treated monthly with vincristine, adriamycin and cyclophosphamide (VAC) six times, followed by 5-fluorouracil, methotrexate and cyclophosphamide (FMC) until progression was documented. By random assignment, the patients received 5 mg/m2 Corynebacterium parvum (CP) subcutaneously on day 1, in addition to VAC/FMC. Of the 150 evaluable patients, 33 of 76 (45%) and 36 of 74 (49%) had complete or partial response to VAC/FMC plus CP, respectively. The Kaplan-Maier curves of duration of remission and survival were almost identical (medians 14.5 vs 12.1 months and 22.2 vs 21.1 months, respectively). The hematologic and gastrointestinal toxicity were also similar in the two study groups. However, 19 of 74 (26%) patients developed skin ulcers after repeated injections of CP. These patients showed prolonged survival (P = 0.002, log rank test). These results suggest that adding nonspecific immunostimulation with CP to currently available chemotherapy on day 1 is of no benefit to most patients with metastatic breast cancer, but may select an "immunoreactive subgroup with increased local toxicity and survival.

Adjuvant chemoimmunotherapy with LMF plus BCG in node-negative and node-positive breast cancer - intermediate report at 4 years.

A randomized surgical adjuvant trial in 242 evaluable patients with T1-3a, N0-1, and M0 breast cancer was initiated 4 years ago. The well-tolerated, oral combination chemotherapy with six cycles of Leukeran plus methotrexate plus fluorouracil (LMF) plus repeated BCG skin scarifications was used. After 4 years, the following results were seen: (1) significant increase of relapse-free (RFS) and also overall survival (S) in both pre- and postmenopausal node-negative patients versus surgical controls (RFS 91.1 vs. 701%, P = 0.003; S 96 vs. 88%, P = 0.03); (2) no significant increase of RFS or S in pre- and postmenopausal node-positive patients versus surgical controls (RFS 50.1 versus 44%, P = 0.49; S 70 versus 68 %, P = 0.9, respectively); (3) Patients receiving greater than 90% of the planned LMF dose showed significantly better survival after 4 years; and (4) Nonrandomized comparison with concurrent Swiss adjuvant studies with LMF alone indicate no beneficial or harmful effect of BCG skin scarifications in addition to the six-cycle LMF.