Andrea Veronesi

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

BACKGROUND Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING F Hoffmann-La Roche, Michelangelo Foundation.

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.

RADIOTHERAPY VERSUS RADIOTHERAPY ENHANCED BY CISPLATIN IN STAGE III NON-SMALL CELL LUNG CANCER

Abstract Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m 2 ) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment.

Early Start of Adjuvant Chemotherapy May Improve Treatment Outcome for Premenopausal Breast Cancer Patients With Tumors not Expressing Estrogen Receptors

PURPOSE The proper time to commence adjuvant chemotherapy after primary surgery for breast cancer is unknown. An analysis of the International (Ludwig) Breast Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested that early initiation of adjuvant chemotherapy might improve outcome for premenopausal, node-positive patients whose tumors did not express any estrogen receptor (ER). PATIENTS AND METHODS We investigated the relationship between early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788 premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The disease-free survival for 599 patients (84 with ER-absent tumors) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for 1,189 patients (142 with ER-absent tumors) who started chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years. RESULTS Among patients with ER-absent tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group (226 patients; hazard ratio [HR], 0. 49; 95% confidence interval [CI], 0.33 to 0.72; P =.0003). This difference remained statistically significant in a Cox multiple regression analysis controlling for study group, number of positive nodes, tumor size, age, vessel invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P =.019). Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P =.40). CONCLUSION In premenopausal patients with ER-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. Further confirmatory studies are required before any widespread modification of current clinical practice. In premenopausal patients with tumors expressing some ER, gains from early initiation are unlikely to be clinically significant.

Breast Cancer in the Elderly

Screening and adjuvant postoperative therapies have increased survival among women with breast cancer. These tools are seldom applied in elderly patients, although the usually reported incidence of breast cancer is close to 50% in women 65 years or older, reaching 47% after 70 years in the updated Surveillance, Epidemiology, and End Results (SEER) database. Elderly breast cancer patients, even if in good medical health, were frequently excluded from adjuvant clinical trials. Women age 70 years who are fit actually have a median life expectancy of 15.5 years, ie, half of them will live much longer and will remain exposed for enough time to the potentially preventable risks of a relapse and specific death. In the last few years, a new concern about this issue has developed. Treatment now faces two major end points, as in younger women: to improve disease-free survival in the early stages, and to palliate symptoms in advanced disease. However, in both settings, the absolute benefit of treatment is critical because protecting quality of life and all its related aspects (especially functional status and independence), is crucial in older persons who have more limited life expectancy. Furthermore, the new hormonal compounds (aromatase inhibitors) and chemotherapeutic drugs (capecitabine, liposomal doxorubicin), are potentially less toxic than and equally as effective as older more established therapies. These new treatments bring new challenges including higher cost, and defining their benefit in elderly breast cancer must include an analysis of the cost/benefit ratio. These issues emphasize the urgent need to develop and support clinical trials for this older population of breast cancer patients both in the adjuvant and metastatic settings, a move that will take us from a prejudiced, age-based medicine to an evidence-based medicine.

Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding

Purpose: After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment. Experimental Design: We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed. Results: WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients. Conclusions: Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.

Identifying Breast Cancer Patients at High Risk for Bone Metastases

PURPOSE To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates. PATIENTS AND METHODS We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10. 7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence. RESULTS For the entire population with operable disease, the cumulative incidence of bone metastases at any time was 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years). CONCLUSION Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue.

Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study

Between June 1980 and December 1983, 111 patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were entered into a randomized trial comparing radiotherapy alone versus radiotherapy and combination chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), methotrexate, and procarbazine. Thirty‐five of 62 (56.4%) patients treated with 4500 rad in 15 fractions in 3 weeks and 19 of 49 (38.8%) patients treated with the same radiation treatment and chemotherapy had an objective response. The difference in response rate was not significant (P = 0.900). Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. The toxicity was acceptable and no treatment‐related death occurred in either treatment schedule. In this study no significant superiority of combined radiotherapy and chemotherapy treatment over radiation therapy alone was evidenced. Whether different chemotherapy regimens may prove more effective in this context should be clarified by further studies.

Etoposide (VP-16-213) in malignant brain tumors: a phase II study.

Twenty-two consecutive patients with recurrent malignant brain tumors after radiation therapy and systemic combination chemotherapy with BCNU and vincristine, four of whom were not evaluable due to early death, were treated with etoposide (VP-16-213) (50-100 mg/m2 for five days every three weeks). Response, defined as improvement in both clinical examination and computed tomography scan in absence of glucocorticoids dosage increase, was observed in three (17%) of 18 evaluable patients, lasting greater than 21, seven, and two months, respectively. Six additional patients had stable disease for greater than 10, seven, four, four, three, and two months: all of them had improvement of clinical symptoms but no variation in their scans. Overall median survival from the start of VP-16-213 was 4.5 months (range, 1-23 + months), whereas patients with response or stable disease had a median survival of eight months. Overall, treatment was well tolerated. In 10 patients concomitant plasma and cerebrospinal fluid samples were evaluated with a high-performance liquid chromatographic method for drug assay. The concentration of VP-16-213 in cerebrospinal fluid was less than 1% that found in plasma, even in the two patients with response. The activity of etoposide in patients with malignant, lomustine-vincristine-resistant brain tumors suggests an interesting potential use for this drug.

Hormone replacement treatment and breast cancer risk: a cooperative Italian study.

The relationship between hormone replacement treatment (HRT) and breast cancer risk was analysed using data from a case-control study conducted between June 1991 and February 1994 in six Italian centres on 2569 patients aged below 75 with histologically confirmed breast cancer and 2588 controls admitted to hospital for a wide spectrum of acute, non-neoplastic, non hormone-related diseases. Ever HRT use was reported by 7.5% of cases and 7.5% of controls, corresponding to a multivariate odds ratio (OR) of 1.2 [95% confidence interval (CI), 0.9-1.5]. The risk increased with increasing duration of use: the ORs were 1.0 for use lasting less than 1 year, 1.3 for 1-4 years and 1.5 for 5 years or more. There was no clear pattern of risk with reference to time since starting use, but the OR was significantly elevated (OR = 2.0, 95% CI 1.3-2.9) for women who had stopped HRT within the last 10 years. No association was observed in those who had stopped HRT more than 10 years ago (OR = 1.0). The increased OR for women who had stopped HRT within the last 10 years was consistent across strata of identified covariates, and was significantly related to duration of use. This study confirms the absence of a strong association between HRT and breast cancer risk, although the risk estimate was above unity for women who had used HRT for 5 years or longer. However, the risk was significantly elevated in the short to medium term after use, particularly for long-term use. This short-term increased risk is consistent with an effect of HRT on one of the later stages of the process of breast carcinogenesis. The flattening of risk with increasing time since stopping, and hence the absence of a long-term cumulative excess in breast cancer risk after stopping HRT exposure, has relevant implications on individual risk assessment and public health.