Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.     

Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An Eastern Cooperative Oncology Group trial

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.     

Postoperative chemotherapy and chemohormonal therapy in women with node-positive breast cancer

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Integration of full-dose adjuvant chemotherapy with definitive radiotherapy for primary breast cancer: four-year update

Controversy exists over the effect of definitive radiotherapy on the ability to administer full doses of adjuvant chemotherapy in primary breast cancer. Ninety-six consecutive women with clinical stage I and II breast cancer were treated with radiotherapy plus chemotherapy. Three combinations of drugs were used: cyclophosphamide and 5-fluorouracil (CF); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); or cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP). Chemotherapy consisted of two cycles of CF (cyclophosphamide at a dosage of 100 mg/m2 orally on days 1-14+5-fluorouracil at 600 mg/m2 iv on days 1 and 8) during concurrent radiotherapy, followed by six cycles of CMFP (same CF dosages+methotrexate at 40 mg/m2 iv on days 1 and 8+prednisone at 40 mg/m2 orally on days 1-14). The study included 63 premenopausal and 33 postmenopausal patients; 72 had 1-3 positive nodes, had greater than or equal to 4 positive nodes, and 9 had negative nodes and negative estrogen receptors. The mean CF doses delivered during concurrent radiotherapy were 95% of the optimal doses, and the mean CMF doses administered during the six cycles after radiotherapy were 89%. The CMF was delivered at level I (greater than or equal to 85% of optimal doses) to 73% of the patients. With a median follow-up of 36 months, 16 relapses have been observed. Two of these patients had treatment failure only in the breast or axilla and are disease free after mastectomy. Of the 72 patients with 1-3 positive nodes, 10 relapsed in distant sites, while 4 of 15 patients with greater than or equal to 4 positive nodes have had distant failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.     

Chemotherapy versus observation in high-risk node-negative breast cancer patients.

Postoperative women with breast cancer but without histopathological evidence of metastases to the axillary lymph nodes or clinical evidence of metastases were studied. Six hundred fifty-five "good-risk" patients who were estrogen receptor positive (ER+) with primary tumors less than 3 cm were registered for observation. Twenty-four of these patients were treated with chemotherapy. Five hundred thirty-six "poor-risk" patients who were either ER+ with primary tumors greater than or equal to 3 cm or estrogen receptor negative (ER-) with any primary tumor size were randomly assigned between chemotherapy and observation. Randomization was stratified by type of surgical procedure, number of lymph nodes examined, menopausal status, tumor size, and ER status. The chemotherapy (CMFP) consisted of six 4-week cycles of cyclophosphamide, 100 mg/m2 orally days 1-14; methotrexate, 40 mg/m2 intravenously (IV) days 1 and 8; fluorouracil, 600 mg/m2 IV days 1 and 8; and prednisone, 40 mg/m2 orally days 1-14. Treatment arms in the randomly assigned patients were balanced with respect to pretreatment characteristics. This analysis includes 445 eligible patients entered in the registration arm and 425 eligible patients entered into the randomized treatments. The median follow-up is 4.5 years in the randomly assigned cohort and 4.8 years in the registered cohort. The overall 5-year disease-free survival (DFS) among the randomly assigned patients was 83% with CMFP and 61% with observation (P less than .0001). A DFS treatment benefit was observed in premenopausal and postmenopausal patients as well as in patients with ER+ or ER- tumors. There were fewer local-regional and distant relapses among the CMFP-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adjuvant chemohormonal therapy on the ovarian and adrenal function of breast cancer patients

Ovarian and adrenal function were studied in premenopausal breast cancer patients before and at intervals during adjuvant therapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). Amenorrhea developed within 10 months of starting therapy in 13 of 15 patients given CMF, 8 of 10 receiving CMFP, and all of 13 CMFPT-treated patients. The amenorrheic patients receiving CMF showed a reduction in their plasma total estrogens and an increase in plasma luteinizing and follicle-stimulating hormones, indicating that these cytotoxic drugs directly suppressed ovarian function. Plasma androstenedione levels, which are derived equally from the ovaries and adrenals before the menopause, were also reduced. Plasma dehydroepiandrosterone sulfate, a steroid predominantly of adrenal origin, was unaffected. CMFP-induced amenorrhea was associated with similar changes in the plasma estrogens and gonadotropins, but patients receiving this combination showed significantly greater reductions in plasma androstenedione and also decreased levels of plasma dehydroepiandrosterone sulfate. Suppression of androstenedione secretion from both the ovaries and adrenals did not affect the total plasma estrogen concentrations. Initially, CMFPT-treated patients showed significant elevations in plasma total estrogens, without a change in the gonadotropin levels. Although the plasma sex hormone-binding capacity was increased during CMFPT therapy, there was only a small reduction in the percentage of free plasma estradiol, with the result that the level of circulating unbound estrogen was increased. The plasma estrogens declined, with a corresponding increase in gonadotropins, after the onset of CMFPT-inducted amenorrhea.     

Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors

One hundred fifty-five eligible women with metastatic breast cancer were randomly allocated to receive monthly cycles of either CMFP (cyclophosphamide, methotrexate, 5-fluorouracil, prednisone) or CAF (cyclophosphamide, doxorubicin, 5-fluorouracil), and 12 patients were studied to evaluate the effects of additional Corynebacterium parvum immunotherapy. Overall response rates of 53% were seen with CMFP and CAF. CAF was associated with significantly more complete responses than CMFP (17% v 5%). However, CAF therapy was administered for eight months and CMFP for six months. Only 13% of the CAF patients had a complete response during the first six months of chemotherapy, and this was not significantly different from the complete response rate on CMFP. The median response durations (CMFP, 6.3 months; CAF, 11.0 months), times to treatment failure (CMFP, 5.7 months; CAF, 7.8 months), and survival times (CMFP, 15.8 months; CAF, 18.6 months) were not statistically different. Other investigators who have compared CAF to CMF-containing regimens have reported a large advantage in CAF therapy among patients with "good risk" sites of metastases (local-regional recurrence, bone, lung nodules). Such a finding was not confirmed by our study: in multivariate analyses the groups associated with an advantage for CAF tended to have a poorer prognosis than the groups associated with an advantage for CMFP. There was significantly more nausea and vomiting after CAF treatment, and CMFP treatment was associated with significantly more edema, Cushingoid features, fever, and eye symptoms.     

Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, node-positive breast cancer

Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tomoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.     

Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study

A prospectively controlled randomized trial to compare the adjuvant efficacy of 12 cycles of cyclophosphamide, methotrexate, fluorouracil, prednisone, and tamoxifen (CMFPT) followed by observation or a total of 5 years of continuous tamoxifen versus four cycles of CMFPT followed by observation in postmenopausal women with operable node-positive breast cancer was started by the Eastern Cooperative Oncology Group (ECOG) in 1982. In 1986 the study was modified to allow patients on CMFPT X 12 plus continuous tamoxifen to be rerandomized after completing 5 years of tamoxifen to either continue for life or to stop therapy. Patients were stratified for number of involved nodes and estrogen-receptor (ER) status and randomized to receive one of three treatments: CMFPT X 4, CMFPT X 12, or CMFPT X 12 plus continuous tamoxifen. Of 962 patients entered on the study, 803 were eligible. Life-threatening toxicity occurred in 75 and lethal toxicity in seven patients. Median follow-up is 4.1 years; 279 patients had recurrent disease. Time to relapse (TTR) is significantly longer for patients on CMFPT X 12 plus continuous tamoxifen than for CMFPT X 4 (P = .002), or CMFPT X 12 (P = 0.05). Differences between four or 12 cycles of CMFPT are not significant; relapse-free rates at 5 years are 61% for CMFPT X 12 plus continuous tamoxifen, 51% on CMFPT X 12, and 52% on CMFPT X 4. Treatment differences in overall survival are not significant. Hormone receptor status and number of involved nodes were found to be significant prognostic parameters.     

The effect of adjuvant chemotherapy on cosmesis and complications in patients with breast cancer treated by definitive irradiation

From 1978 to 1981, 46 patients received primary radiotherapy following excisional biopsy and axillary staging procedure for Stages I and II carcinoma of the breast. The patients were divided into 2 groups: 27 patients who received radiation and completed 12 cycles of adjuvant chemotherapy (CMF or CMFP) and 19 patients who received radiation alone. All patients received radiation to the breast and regional nodes (4600-5000 rad) and a boost to the site of the primary tumor (1500-2000 rad). Median follow-up from completion of radiation was 26 months in the non-adjuvant and 24 months in the adjuvant group with a range of 12 to 49 months. Cosmesis was judged to be good to excellent in 89% (17/19) of the patients receiving radiation alone and 81% (22/27) of the patients receiving adjuvant chemotherapy. Fair to poor cosmesis in the adjuvant group was attributed primarily to increased fibrosis and reduction of breast size. The single complication for which there was an increased incidence in the adjuvant group was arm edema (22 vs. 0%). The incidence of arm edema was unrelated to T stage, type of axillary surgical procedure, number of positive nodes, addition of prednisone or sequencing of chemotherapy. Further efforts should be directed towards minimizing complications and maximizing cosmesis without sacrificing relapse-free survival in patients receiving primary radiotherapy and adjuvant chemotherapy for early breast cancer.     

Natural history of human cancer and prognostic factors. The example of breast cancer

The most important event during the growth of a human cancer is the occurrence of distant spread. A model of the natural history of breast cancer was developed which was used for several aims. It has been possible to study the relationship between the size of the breast tumor and the probability of dissemination either in regional lymph nodes or in distant sites. It was found that the distribution of tumor volume at metastatic dissemination is log normal with a median (termed V50) of 23.6 ml (diameter 3.5 cm). The number of involved axillary lymph nodes and the histological grade have both an impact on the dissemination probability and the size of the V50. It is also possible to estimate the median volume of the primary at the involvement of the first axillary node, of the second, of the third... On average, the V50 for distant metastatic dissemination is greater than the volume of the tumor at the initiation of the second axillary node but smaller than the volume at the initiation of the third. Another study was the assessment of the time at which the metastases were initiated. The results concerning age of metastases at the time of initial treatment allow to estimate the reduction in the incidence of distant metastases which can be obtained by an earlier diagnosis; these estimations are consistent with data of screening programs. The size of the occult metastases at the time of treatment of primary tumor was calculated. It was found that this size is much larger in the subset of patients with pejorative prognostic factors which probably explains the relatively low effectiveness of adjuvant chemotherapy in these patients. The maximum size of the metastases which are controlled by adjuvant chemotherapy was found equal to 1.5.10(6) cells. Finally the model was used to investigate the possible dissemination arising from loco-regional recurrence. The discrepancy between the great reduction in the incidence of loco-regional recurrences obtained with post-operative radiotherapy and its relatively small impact on survival is probably due to the fact that a recurrence has an impact on survival only in patients without distant metastases at the time of initial treatment and in whom the recurrence was not detected and treated before it reached the size at which it can initiate a metastasis. This situation is likely to occur only in patients with tumors of the inner quadrants in whom the internal mammary chain has a great likelihood of being involved.     

Natural history of human breast cancer: Recent data and clinical implications

Summary This study of the natural history of human breast cancer was based on the analysis of a series of 3000 patients treated by radical mastectomy at a single institution (Institut Gustave Roussy) at a time when adjuvant chemotherapy was not prescribed. The follow-up of the patients ranged from 15 to 30 years; for each patient the tumor size, the number of involved axillary nodes, and the histological grade were prospectively registered.A highly significant correlation was found between tumor size and the probability of distant metastatic dissemination. The distribution of tumor sizes at metastatic spread was log-normal with a median diameter equal to 3.5 cm.The patients were subdivided into 3 groups according to the histological grade. In each subgroup there was a significant correlation between tumor size and the probability of distant spread; the distributions were log-normal and the median size was markedly larger for grade 1 tumors. Moreover the proportion of grade 1 tumors was higher in small tumors than in large ones while the reverse was observed for grade 3 tumors; these data suggest that during their growth tumors progress towards higher grades.One of the chief fundamental characteristics of a tumor seems to be its propensity for axillary node invasion. The orderly pattern of nodal involvement makes it possible to calculate the tumor size at invasion of the first axillary node in each subset of patients. A strong and highly significant correlation exists between the size of the tumor at initation of distant metastasis and at invasion of the first lymph node. However the capacity for lymphatic spread is, on average, acquired much earlier than the capacity for metastatic spread.With a simple model based on these data it was possible to compute the proportion of patients with occult metastases as a function of tumor size, histological grade, and number of involved axillary nodes.Early invasion of axillary nodes is associated with a rapid growth rate of the primary tumor (or a high S-phase fraction). However each of these variables has an independent prognostic significance; the S-phase fraction appears as one of the strongest prognostic indicators.A model of tumor growth was used to assess the impact of screening procedures on the proportion of patients with distant metastases. The predictions of the model are consistent with the results of the screening programs. The model was used to predict the influence of the interval between mammographies on the proportion of patients with distant metastases and on the size of these metastases. Since the curability of distant metastases by adjuvant chemotherapy is, to a large extent, governed by their size, the model can predict the cumulative effect of screening procedures and adjuvant chemotherapy on the proportion of patients with overt distant metastases.     

A phase I/II study of high-dose megestrol acetate in the treatment of metastatic breast cancer

Summary Thirty four patients treated with mastectomy and axillary node dissection for potentially curable breast cancer received a seven month combined adjuvant chemotherapy and radiation therapy program. These patients were considered to be at high risk for recurrence because they had either three or more positive axillary lymph nodes or their primary tumor was greater than 5 cm in diameter. The chemotherapy given at 3-week intervals consisted of cyclophosphamide, 600 mg/m², Adriamycin 40mg/m², and methotrexate 40 mg/m² during cycles 1 through 3 and 7 through 9. Radiation therapy was administered during cycles 4 through 6 with concomitant administration of 5-fluorouracil 600 mg/m², vincristine 1.4 mg/m², and prednisone 40 mg/m² for 7 days. Median follow up time from initiation of study is 60 months (range 36–93). Seventeen of 34 patients (50%) remain free of recurrent breast cancer. Distant metastases and local-regional recurrence have occurred in 16 (47%) and 4 (12%) patients, respectively. Significant myelosuppression and infections requiring hospitalization were seen in 4 patients, with 1 treatment-related death. Adriamycincontaining chemotherapy and post-operative radiotherapy can thus be combined in an adjuvant treatment program with acceptable toxicity.     

Adjuvant chemotherapy of breast cancer.

One hundred women with primary breast cancer with 4 or more metastatic axillary nodes were treated for 9 months postoperatively with vincristine, prednisone, cyclophosphamide, methotrexate, and fluorouracil (VPCMF). Sixty-five women have been observed for a minimum of 5 years or until failure and the rest for 3 years or more. For 73 women who received adjuvant chemotherapy only, observed for 5 1/2 years median, disease-free status by life table analysis is 68% at 8 years. No significance difference was found between response of pre- and postmenopausal women in disease-free interval or survival. Mortality compared to expectation was sharply reduced; only 9 of 73 have died. These findings demonstrate the long term effectiveness of relatively short-term surgical adjuvant combination chemotherapy in pre- and post-menopausal patients with breast cancer at high risk.     

Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study

Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together, p = 0.11. Local recurrence (LR) was observed in 24 of the 86 patients (28%) who had reached complete remission (CR). LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. In arm III, the CR rate after 4 cycles AV plus CMF and RT hardly changed after another 8 cycles of chemotherapy. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results, p = 0.04. In conclusion: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.     

Adjuvant treatment for early breast cancer: the Ludwig breast cancer studies

The Ludwig Breast Cancer Study Group conducted four concomitant trials involving adjuvant chemotherapy and endocrine therapy. In Ludwig I, adjuvant combination chemotherapy was used with or without prednisone to treat premenopausal and perimenopausal women with metastases in 1-3 axillary lymph nodes. The impact of adding low-dose, continuous prednisone (7.5 mg/day) to an adjuvant, chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was investigated in a randomized trial of 491 premenopausal and perimenopausal patients with operable breast cancer and metastases in 1-3 axillary lymph nodes. As a consequence of lower hematologic toxicity, a significantly higher dose of CMF could be administered with added prednisone (P less than 0.0001). However, at the 4-year median follow-up, no significant improvement was observed in disease-free survival (DFS) (73% vs. 77%; P = 0.35) or overall survival (OS) (both 86%; P = 0.73). Induced amenorrhea was associated with a longer DFS for younger patients, those who received lower CMF doses, and those with tumors that were estrogen receptor (ER) positive. In Ludwig III, adjuvant therapy was administered to younger postmenopausal women in a study of chemotherapy plus endocrine therapy versus endocrine therapy alone versus mastectomy alone. In this randomized trial of 463 postmenopausal women 65 years of age or younger with axillary node metastases, treatment with the combination of CMF plus low-dose prednisone and tamoxifen (CMFp + T), was compared to endocrine therapy alone (p + T) or to no further treatment after total mastectomy and axillary clearance. At a median follow-up of 4 years, the DFS was 61% for the CMFp + T group, compared with 48% for the p + T group (P = 0.01) and 31% for the observation group (P less than 0.0001). The 4-year OS rates were not statistically different (76%, 67%, and 68%, respectively; P = 0.30). Treatment with CMFp + T reduced local, regional, and distant metastases and was equally effective in improving DFS in patients with ER-positive or ER-negative tumors. In Ludwig II, chemotherapy was given with or without oophorectomy in premenopausal and perimenopausal patients with metastases in 4 or more axillary nodes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Long-term results of combined-modality therapy for inflammatory breast carcinoma

Sixty-eight patients with inflammatory breast carcinoma (IBC) received treatment in 2 prospective randomized trials of multimodality therapy for locally advanced breast cancer. The treatment plan consisted of 3 courses of neoadjuvant chemotherapy with CAF (cyclophosphamide/doxorubicin/5-fluorouracil [5-FU]) or CEF (cyclophosphamide/epirubicin/5-FU) followed by surgery and 6 adjuvant courses of CAF or CEF alternated with CMF (cyclophosphamide/methotrexate/5-FU). Radiation therapy was administered at the end of adjuvant treatment. All patients with estrogen receptor-positive tumors received tamoxifen 20 mg daily for 5 years. The response rate to induction chemotherapy was 73.6% (95% CI, 61.4%-83.5%): 4 of 68 patients (6%) exhibited a pathologic remission of primary breast tumor (persistent disease in the axilla), and 2 patients (3%) exhibited a pathologic complete response. Median follow-up was 10 years (range, 5 months to 14.7 years). Disease-free survival (DFS) rates at 5 and 10 years were 29% and 20%, respectively, and median DFS was 2.2 years (range, 3.8 months to 11.5 years). Overall survival (OS) rates at 5 and 10 years were 44% and 32%, respectively, and median OS was 4 years (range, 5 months to 14.7 years). Significant prognostic factors for DFS and OS were the number of axillary nodes and residual disease in the breast at surgery. This analysis confirmed that patients with IBC obtained significant long-term survival benefit from combined-modality therapy.     

The Efficacy of Neoadjuvant Chemotherapy Compared to Postoperative Therapy in the Treatment of Locally Advanced Breast Cancer

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, MA, and MB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, Cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.     

Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer

The management of rectal cancer presents substantial challenges. Patients with T3 and/or node-positive rectal cancers are at high risk for local failure and distant metastases (DM). Adjuvant radiation has been shown to decrease local recurrence (LR) rates; however, this local therapy has not been demonstrated to improve survival when compared to surgery alone. In several prospective randomized trials adjuvant chemoradiation with 5-fluorouracil-(5-FU)-based chemotherapy improved LR rates, DM rates, and overall survival (OS). The optimal chemotherapeutic regimen has not been determined; however, studies comparing standard IV bolus 5-FU administration with continuous infusion (CI) 5-FU demonstrated that CI administration was superior. Preoperative therapy has potential advantages over adjuvant therapy such as less acute bowel toxicity and improved sphincter preservation. Preoperative chemoradiation has been shown in several studies to improve LR rates and OS when compared to surgery alone. Our current approach to patients with resectable T3 or N1 cancer in the distal two-thirds of the rectum on preoperative staging is preoperative chemoradiation with planned postoperative chemotherapy. This regimen offers the best chance for local control and disease-free survival while potentially downstaging the tumor and improving sphincter preservation.