ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.

BACKGROUND: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. RESULTS: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. CONCLUSIONS: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).

Recurrence and mortality dynamics for breast cancer patients undergoing mastectomy according to estrogen receptor status: different mortality but similar recurrence.

(Cancer Sci 2010; 101: 826-830) The purpose was to ascertain whether the recurrence risk patterns for patients with estrogen receptor (ER)-positive (P) and ER-negative (N) breast cancer support the ER-related clinical divergence suggested by the observed different mortality patterns and gene expression profiles. Both recurrence and death were considered in a series of 771 patients undergoing mastectomy. ER status was available for 539 patients. The hazard rates for recurrence and mortality throughout 15 years of follow-up were assessed. The recurrence dynamics displays a bimodal pattern for both ERP and ERN tumors with comparable peak timings. The two curves cross during the 3rd year. By contrast, the mortality dynamics are definitely different for ERP and ERN tumors: during the early follow-up period ERN patients have their highest mortality risk, while ERP patients have their lowest mortality risk. The two curves cross during the 5th year. In spite of the different mortality dynamics, the recurrence dynamics do not demonstrate a major distinction in timing between ERP and ERN breast cancers, suggesting that the metastasis development process following mastectomy is apparently similar for both ER categories. The observed differences in the mortality risk are plausibly attributable to ER-related factors influencing the clinical course from recurrence to death. These clinical findings apparently contradict the occurrence of two different types of breast cancer, notwithstanding the distinct epidemiological, clinical, and molecular features linked to ERP and ERN tumors, although ER levels may concur to establish the event risk levels.

Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy.

PURPOSE: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin-->CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel-->CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate. METHODS: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C. RESULTS: Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P<0.0001). PTS induced a significant axillary downstaging (P<0.001), and breast sparing surgery was feasible in 65% versus 34% (P<0.001). CONCLUSIONS: Doxorubicin/paclitaxel-->CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.

Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer.

PURPOSE: To assess the clinical relevance of different sequences of doxorubicin (DOX) and cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of disease relapse. PATIENTS AND METHODS: Two randomized trials were activated in the early 1980s. The first study, in patients with one to three involved nodes, was intended to assess the effectiveness of intravenous (i.v.) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose DOX (CMF-->DOX). The second study, in patients with more than three involved nodes, compared four courses of full-dose DOX sequentially followed by eight courses of i.v. CMF (DOX-->CMF) versus alternating two courses of the same CMF regimen with one course of DOX (CMF/DOX) for a total of 12 courses. RESULTS: After a median observation of 210 months, no statistically significant difference was documented in the first study (relapse-free survival hazard rate [HR], 1.06; total survival HR, 1.03). In contrast, the delivery of DOX first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54 to 0.87; P =.0017) and death (HR, 0.74; 95% CI, 0.57 to 0.95; P =.018) compared with the alternating regimen. CONCLUSION: Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.

Menopausal status dependence of early mortality reduction due to diagnosis of smaller breast cancers (T1 v T2-T3): relevance to screening.

PURPOSE: To provide data relevant to the paradoxical mortality excess for women age 40 to 49 years observed during the first 6 to 8 years in the invited group in all mammography screening studies. PATIENTS AND METHODS: In 1,173 patients undergoing mastectomy alone as primary treatment, allocated to subsets according to menopausal status and tumor size, hazard rates for death were calculated. The ratios between the hazard rate for T2-T3 patients and the corresponding value for T1 patients were assessed over time. RESULTS: For postmenopausal patients, the ratio appeared to be time-dependent, dropping from the maximum value of approximately 5 at the first year after surgery to a near constant value of approximately 2 after 5 to 6 years. Premenopausal patients, on the contrary, showed a nearly constant ratio of approximately 3. Therefore, although in each T-category the 10-year survival of premenopausal and postmenopausal patients was similar, its time distribution was menopause-dependent. In particular, the difference between cumulative survival of premenopausal and postmenopausal T2-T3 patients attained statistical significance after 3 years. CONCLUSION: The mortality reduction due to the diagnosis of smaller tumors is significantly higher for postmenopausal women than for premenopausal women during early postsurgery time. According to the hypothesis that primary tumor surgical removal, occurring sooner in the invited group than in the control arm of screening trials, results in some acceleration of metastasis development, a greater number of unfavorable events (recurrence and death) should occur in the invited group. We suggest that for younger women, the early balance between benefit from tumor downsizing and harm from surgery-induced metastasis acceleration results in harm. This disadvantage does not occur in postmenopausal women.

ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results.

PURPOSE: Radiation therapy (RT) alone can cure more than 80% of all patients with pathologic stage IA, IB, and IIA Hodgkin's disease, but some prognostic factors unfavorably affect treatment outcome. Combined-modality approaches improved results compared with RT, but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation. PATIENTS AND METHODS: In February 1990, we activated a prospective trial in patients with early, clinically staged Hodgkin's disease to assess efficacy and tolerability of four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy (IFRT). RESULTS: Main patient characteristics were fairly well balanced between the two arms. Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild. CONCLUSION: Present long-term findings suggest that, after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin's disease with both favorable and unfavorable presentation.

Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial.

PURPOSE: Prognosis of patients with advanced oral cavity cancer is worth improving. Chemotherapy has been reported to be especially active in oral cavity tumors. Here we repeat the results of a randomized, multicenter trial enrolling patients with a resectable, stage T2-T4 (> 3 cm), N0-N2, M0 untreated, squamous cell carcinoma of the oral cavity. PATIENTS AND METHODS: Patients were randomly assigned to three cycles of cisplatin and fluorouracil followed by surgery (chemotherapy arm) or surgery alone (control arm). In both arms, postoperative radiotherapy was reserved to high-risk patients, and surgery was modulated depending on the tumor's closeness to the mandible. Patients' accrual was opened in 1989 and closed in 1999. It included 195 patients. RESULTS: In the chemotherapy arm, three toxic deaths were recorded. No significant difference in overall survival was found. Five-year overall survival was, for both arms, 55%. Postoperative radiotherapy was administered in 33% of patients in the chemotherapy arm, versus 46% in the control arm. A mandible resection was performed in 52% of patients in the control arm, versus 31% in the chemotherapy arm. CONCLUSION: The addition of primary chemotherapy to standard surgery was unable to improve survival. However, in this study, primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo mandibulectomy and/or radiation therapy. Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results, but there appears to be room for using preoperative chemotherapy to spare destructive surgery or radiation therapy in patients with advanced, resectable oral cavity cancer.

HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression was found to predict a good response in breast carcinoma patients treated with doxorubicin (Adriamycin [ADM]). Evidence from our recent study indicates that node-positive patients respond to cyclophosphamide, methotrexate, and fluorouracil (CMF) regardless of HER2 status. We address the issue of whether therapy regimens including CMF and ADM versus CMF alone have the same therapeutic effect in patients with HER2+ and HER2- tumors in terms of relapse-free survival (RFS) and overall survival (OS). METHODS: Archival specimens of the primary tumors from 506 patients in a prospective clinical trial were stained with the anti-HER2 monoclonal antibody CB11. Originally, patients were randomly allocated to receive either 12 courses of intravenous CMF or eight courses of the same regimen followed by four cycles of ADM. RFS and OS were analyzed by a Cox model taking into account treatment, HER2 status, and the interaction between treatment and HER2 status, adjusting for the effect of other known clinical and biopathologic factors. RESULTS: Analysis of survival rates indicates a possible differential effect of treatment in the patients grouped according to HER2 status. Improved RFS and OS were observed in the HER2+ subgroup after treatment with CMF plus ADM versus CMF alone. With a median follow-up of 15 years, the hazard ratio (HR) for RFS was 0.83 in HER2+ tumors and 1.22 in HER2- tumors. The effect of treatment was more evident on OS in HER2+ patients (HR = 0.61; CI, 0.32 to 1.16) than in HER2- patients (HR = 1.26). CONCLUSION: Our data indicate that adding ADM to CMF might be beneficial for patients with HER2+ tumors.

CD20 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin's disease: associations with presenting features and clinical outcome.

PURPOSE: CD20 can be expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's disease (HD), but its clinical significance remains controversial. Therefore, we correlated CD20 expression with presenting features and clinical outcome of untreated patients with classical HD. PATIENTS AND METHODS: Patients were eligible if they were previously untreated and human immunodeficiency virus-1 negative, had biopsy-proven classical HD, and if pretreatment paraffin-embedded tumor tissue was available. CD20 expression was determined by immunohistochemistry without knowledge of clinical outcome. A tumor was considered positive if any HRS cells expressed CD20, but other cutoffs for number of CD20-positive HRS were also investigated. RESULTS: We identified 598 patients whose median age was 30 years and of whom 55% were male. HRS cells expressed CD20 in 132 (22%) of 598 patients with classical HD. When any percentage of CD20 expression in HRS cells was used as a cutoff, the 5-year failure-free survival (FFS) for positive versus negative tumors was 86% versus 84%, respectively, for 302 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens (P =.7 by log-rank test), 74% versus 77%, respectively, for 181 patients treated with mitoxantrone, vincristine, vinblastine, and prednisone and radiotherapy (P =.7 by log-rank test), 74% versus 84%, respectively, for 54 patients treated with MOPP (P =.4 by log-rank test), and 77% versus 88% for 53 patients treated only with radiotherapy (P =.5 by log-rank test). The 5-year FFS was not statistically different when cutoffs of 5% up to 50% for CD20-positive HRS cells were used. CONCLUSION: CD20 is expressed by HRS cells in 22% of patients with classical HD but is not associated with different FFS after treatment with equivalent regimens.

Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute.

The aim of this study was to assess the long-term therapeutic outcome and risk of treatment-related complications in Hodgkin's disease. From May 1973 to September 1990, four randomised studies have been activated at the Milan Cancer Institute using nitrogen mustard, vincristine, procarbazine and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimens, with or without irradiation, involving a total of 811 patients with intermediate and advanced Hodgkin's disease. Overall, ABVD contributed to significantly reduce the relative risk of lymphoma progression and death compared with the MOPP regimen. With a prolonged follow-up, a total of 106 patients (75 of whom were in continuous complete remission after first-line chemotherapy) developed a variety of cancers, resulting in a total risk of 22.2%. Our 25 years of experience re-emphasises that ABVD can cure a high fraction of patients with Hodgkin's disease. However, patients in continuous complete remission, are at a high risk of developing second cancers, especially when the treatment strategy includes extensive irradiation. The main focus of future trials should be on reducing treatment sequelae to improve the quality of life of long-term survivors.

Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome.

PURPOSE: EBV-latent membrane protein-1 (LMP-1) is often expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL), but its clinical significance is controversial. We correlated LMP-1 with presenting features, including serum interleukin 10 levels and clinical outcome. EXPERIMENTAL DESIGN: Patients were eligible if they had biopsy-proven cHL, were untreated, HIV-1 negative, and had available archival tissue. LMP-1 expression was determined by immunohistochemistry. RESULTS: We identified 577 patients with cHL with a median age of 30 years, 55% of whom were male. LMP-1 was expressed in HRS cells of 124 patients (21%) and was detected in 78 of 461 (17%) patients with nodular sclerosis compared with 44 of 112 (39%) with mixed cellularity (P < 0.001 by Fisher's exact test). Patients with tumors with LMP-1-positive HRS cells had higher serum interleukin 10 levels (P = 0.009 by Mann-Whitney test). For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test). Overall survival (OS) at 5 years for patients with LMP-1-positive tumors was 90 versus 91% for patients with LMP-1-negative tumors (P = 0.8 by log-rank test). Expression of LMP-1 was not associated with different FFS and OS in patients treated with other regimens or with radiotherapy alone. CONCLUSIONS: LMP-1 was expressed by HRS cells in 21% of cHL and correlated with mixed cellularity type and higher serum interleukin 10 levels. The presence of LMP-1 was not associated with FFS or OS in uniformly treated patients.

BAX expression in Hodgkin and Reed-Sternberg cells of Hodgkin's disease: correlation with clinical outcome.

PURPOSE: BAX, a proapoptotic member of the BCL-2 family of proteins, has been detected in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD), but its clinical significance is unknown. Therefore, we correlated BAX expression with presenting features and clinical outcome in untreated patients with HD. DESIGN: Patients with biopsy-proven HD were eligible if they were untreated previously and if pretreatment paraffin-embedded tumor tissue was available. BAX was detected by immunohistochemistry without knowledge of clinical features or outcome. A tumor was considered as positive if any number of HRS cells expressed BAX, but other cutoffs of BAX expression were examined for analysis of clinical outcome. RESULTS: We identified 260 patients with HD. The median age was 31 years, and 55% were male. HRS cells expressed BAX in 181 of 195 (93%) nodular sclerosis, 47 of 48 (98%) mixed cellularity, 1 case of lymphocyte depletion, all 6 unclassified classical HD, and all 10 lymphocyte predominance tumors. Using a cutoff of 50% positive HRS cells for BAX expression, the 5-year failure-free survival (FFS) for patients with high versus low BAX expression was 83 versus 93%, respectively (P = 0.19 by Log-rank) for 116 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens; it was 78 versus 79%, respectively, for 79 patients treated with mitoxantrone, vincristine, vinblastine, and prednisone and radiotherapy (P = 0.45 by Log-rank); it was 71 versus 81%, respectively, for 26 patients treated with nitrogen mustard, vincristine, prednisone, and procarbazine (P = 0.6 by Log-rank); and it was 72 versus 82% for 29 patients treated only with radiotherapy (P = 0.57 by Log-rank). The 5-year FFS was not statistically different when we used cutoffs of 20, 30, and 75% for BAX expression. CONCLUSION: BAX is often expressed by HRS cells in HD and does not correlate with FFS.

Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour.

INTRODUCTION: Information on the metastasis process in breast cancer patients undergoing primary tumour removal may be extracted from an analysis of the timing of clinical recurrence. METHODS: The hazard rate for local-regional and/or distant recurrence as the first event during the first 4 years after surgery was studied in 1173 patients undergoing mastectomy alone as primary treatment for operable breast cancer. Subset analyses were performed according to tumour size, axillary nodal status and menopausal status. RESULTS: A sharp two-peaked hazard function was observed for node-positive pre-menopausal patients, whereas results from node-positive post-menopausal women always displayed a single broad peak. The first narrow peak among pre-menopausal women showed a very steep rise to a maximum about 8-10 months after mastectomy. The second peak was considerably broader, reaching its maximum at 28-30 months. Post-menopausal patients displayed a wide, nearly symmetrical peak with maximum risk at about 18-20 months. Peaks displayed increasing height with increasing axillary lymph node involvement. No multi-peaked pattern was evident for either pre-menopausal or post-menopausal node-negative patients; however, this finding should be considered cautiously because of the limited number of events. Tumour size influenced recurrence risk but not its timing. Findings resulting from the different subsets of patients were remarkably coherent and each observed peak maintained the same position on the time axis in all analysed subsets. CONCLUSIONS: The risk of early recurrence for node positive patients is dependent on menopausal status. The amount of axillary nodal involvement and the tumour size modulate the risk value at any given time. For pre-menopausal node-positive patients, the abrupt increase of the first narrow peak of the recurrence risk suggests a triggering event that synchronises early risk. We suggest that this event is the surgical removal of the primary tumour. The later, broader, more symmetrical risk peaks indicate that some features of the corresponding metastatic development may present stochastic traits. A metastasis development model incorporating tumour dormancy in specific micro-metastatic phases, stochastic transitions between them and sudden acceleration of the metastatic process by surgery can explain these risk dynamics.

Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients.

BACKGROUND: We suggest that surgical extirpation of primary breast cancer among other effects accelerates relapse for some premenopausal node-positive patients. These accelerated relapses occur within 10 months of surgery for untreated patients. The mechanism proposed is a stimulation of angiogenesis for distant dormant micrometastases. This has been suggested as one of the mechanisms to explain the mammography paradox for women aged 40-49 years. We could imagine that it also plays a role in adjuvant chemotherapy effectiveness since, perhaps not coincidentally, this is most beneficial for premenopausal node-positive patients. HYPOTHESIS: We speculate that there is a burst of angiogenesis of distant dormant micrometastases after surgery in approximately 20% of premenopausal node-positive patients. We also speculate that this synchronizes them into a temporal highly chemosensitive state and is the underlying reason why adjuvant chemotherapy works particularly well for that patient category. Furthermore, this may explain why cancer in younger patients is more often 'aggressive'. TESTING THE HYPOTHESIS: Stimulation of dormant micrometastases by primary tumor removal is known to occur in animal models. However, we need to determine whether it happens in breast cancer. Transient circulating levels of angioactive molecules and serial high-resolution imaging studies of focal angiogenesis might help. IMPLICATIONS: Short-course cytotoxic chemotherapy after surgery has probably reached its zenith, and other strategies, perhaps antiangiogenic methods, are needed to successfully treat more patients. In addition, the hypothesis predicts that early detection, which is designed to find more patients without involved lymph nodes, may not be a synergistic strategy with adjuvant chemotherapy, which works best with positive lymph node patients.

Elevated serum levels of IL-10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy.

Elevated pretreatment serum interleukin-10 (IL-10) is associated with inferior progression-free survival (PFS) in patients with Hodgkin's disease (HD) treated with ABVD or equivalent regimens. Therefore, we explored the association of serum IL-10 with presenting features and PFS in HD patients treated only by radiotherapy (RT) with curative intent. Eligible patients were previously untreated, had biopsy-proven HD, were older than 16 years, HIV-negative, and had unthawed pretreatment serum. Serum IL-10 levels were measured with ELISA and were considered high if > or = 10 pg/ml. We identified 69 patients with median age of 34 years (range 16 - 74), of who 52% were males, and 3% had B-symptoms. Ann Arbor Stage was I in 35%, II in 58%, and III in 7% of the patients. Histology was lymphocyte predominance in 26%, and classical HD in 74% of the patients. Serum IL-10 was elevated in 35% of the patients. After a median follow-up of 67 months for survivors, the 5-year PFS of patients with high vs. normal serum IL-10 was 50% vs. 81% (all patients, P = 0.006), and 43% vs. 77% for the subset with classical HD (P = 0.008). Multivariate analysis revealed that high serum IL-10 and beta2-microglobulin were independently associated with inferior PFS. Patients with none, 1, or 2 adverse features comprised 57%, 36%, and 7% of the population, and their 5-year PFS was 80%, 63%, and 0%, respectively (P < 0.0001). In conclusion, high serum IL-10 is independently associated with inferior PFS in patients with HD treated with RT.

Role of anthracyclines in the treatment of early breast cancer.

PURPOSE: To review data relating to anthracyclines in the adjuvant treatment of early breast cancer. DESIGN: This is a report from a seminar in which the future of anthracyclines in the adjuvant treatment of breast cancer was considered. In particular, the question of whether anthracyclines should now be discarded and replaced by taxanes was addressed. RESULTS: Accumulating data from large randomized trials indicate that genetic markers may have a role in predicting sensitivity to cytotoxic drugs. However, no reliable, validated test is available for predicting sensitivity to anthracyclines in particular. Topoisomerase IIalpha amplification and/or deletion, especially in conjunction with human epidermal growth factor receptor-2 amplification, has been proposed to fulfill this role but more data are needed. Currently, only one published trial has shown that a taxane-based regimen may be superior to an anthracycline-based regimen, but several trials indicate that combinations including both anthracyclines and taxanes may be better still. Further studies aimed at optimizing anthracyclines and taxanes in combination, and integrating biologic agents, seem to be the way forward. There is no validated test that can determine whether anthracyclines can be of greater benefit than other agents for individual patients. CONCLUSION: Anthracyclines have been extensively tested in clinical trials spanning several decades; currently, there are insufficient data to recommend replacing them in the adjuvant treatment of breast cancer.

Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer.

PURPOSE: To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. PATIENTS AND METHODS: A total of 1,355 women with operable breast cancer were randomly assigned to one of three treatments: surgery followed by adjuvant doxorubicin (75 mg/m(2)) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; arm A); surgery followed by adjuvant paclitaxel (200 mg/m(2)) plus doxorubicin (60 mg/m(2)), followed by CMF (arm B); or paclitaxel (200 mg/m(2)) plus doxorubicin (60 mg/m(2)) followed by CMF followed by surgery (arm C). The two coprimary objectives were to assess the effects on relapse-free survival (RFS) of the addition of paclitaxel to postoperative chemotherapy (arm B v arm A) and primary chemotherapy versus adjuvant chemotherapy (arm B v arm C). RESULTS: Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy. The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF (hazard ratio [HR], 0.73; P = .03). Distant RFS was similarly improved (HR, 0.70; P = .027). There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery (HR, 1.21; P = .18). However, the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy (63% v 34%; P < .001). CONCLUSION: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significant improvement in RFS and distant RFS. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients.

30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study.

OBJECTIVE: To assess the long term effectiveness of adjuvant treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of relapse, on the basis of three successive randomised trials and one observational study conducted from June 1973 to December 1980. DESIGN: Cohort study. SETTING: Istituto Nazionale Tumori in Milan, Italy. MAIN OUTCOME MEASURES: Relapse free and overall survival, measured by univariate and multivariate analyses. RESULTS: After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04). Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years. CONCLUSIONS: When delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups.