Impact of body mass index (BMI) on the prognosis of high-risk early breast cancer (EBC) patients treated with adjuvant chemotherapy.

The association between obesity and prognosis in early breast cancer (EBC) is unclear, especially when aggressive phenotypes are considered. We evaluated the influence of BMI on the prognosis of women with high-risk EBC enrolled in a phase III trial of adjuvant chemotherapy (CT). The association was assessed in 1066 patients with rapidly proliferating tumors, randomized to receive adjuvant CT with or without anthracyclines. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier; multivariate analysis was performed according to age, tumor size, nodal, estrogen receptor (ER), and HER2 status and type of CT. Information on BMI was available for 959 women. Of these, 529 (55.2 %) were overweight or obese. Median age was 52 years. A total of 457 (47.7 %) patients had nodal involvement. Centralized pathology was performed in 850 cases: 522 (61.4 %) were ER positive, and 194 (22.8 %) were HER-2 positive. At a median follow-up of 103 months (range 1-188), 5-year DFS was 81 % (95 % CI 77-85), 82 % (95 % CI 77-86), and 76 % (95 % CI 70-83), in normal, overweight, and obese women, respectively (p = 0.44). Five-year OS was 92 % (95 % CI 89-95), 94 % (95 % CI 91-96), and 89 % (95 % CI 84-93), respectively (p = 0.60). BMI was not associated by multivariate analysis with differences in DFS or OS. Higher BMI had no influence on prognosis in high-risk EBC patients treated with CT. These data are consistent with prior observations and suggest that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor.

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer.

AIM: To evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC). PATIENTS AND METHODS: The relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin→cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF→epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size. RESULTS: At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02-1.30, p=0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p=0.043): 8-year OS 88% (95% CI 85-90) for patients with a TTC <7 weeks and 78% (95% CI 68-87) for the other group. CONCLUSIONS: Our results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.

Post-relapse survival in patients with Ewing sarcoma.

BACKGROUND: Post-relapse survival (PRS) was evaluated in patients with Ewing sarcoma (EWS) enrolled in chemotherapy protocols based on the use of high-dose chemotherapy with busulfan and melfalan (HDT) as a first-line consolidation treatment in high-risk patients. PROCEDURE: EWS patients enrolled in ISG/SSG III and IV trials who relapsed after complete remission were included in the analysis. At recurrence, chemotherapy based on high-dose ifosfamide was foreseen, and patients who responded but had not received HDT underwent consolidation therapy with HDT. RESULTS: Data from 107 EWS patients were included in the analysis. Median time to recurrence (RFI) was 18 months, and 45 (42%) patients had multiple sites of recurrence. Patients who had previously been treated with HDT had a significantly (P = 0.02) shorter RFI and were less likely to achieve a second complete remission (CR2). CR2 status was achieved by 42 (39%) patients. Fifty patients received high-dose IFO (20 went to consolidation HDT). The 5-year PRS was 19% (95% CI 11 to 27%). With CR2, the 5-year PRS was 48% (95% CI 31 to 64%). Without CR2, median time to death was six months (range 1-45 months). According to the multivariate analysis, patients younger than 15 years, recurrence to the lung only, and RFI longer than 24 months significantly influenced the probability of PRS. CONCLUSIONS: Age, pattern of recurrence, RFI, and response to second-line chemotherapy influence post-relapse survival in patients with recurrent Ewing sarcoma. No survival advantage was observed from chemotherapy consolidation with HDT.

Benefit from anthracyclines in relation to biological profiles in early breast cancer.

There are no validated predictors of benefit from anthracyclines. We compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF), and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers. Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations. Patients with N- or 1-3N+ tumors, were randomized to receive (a) epirubicin (4 cycles) followed by CMF (4 cycles); (b) CMF (4 cycles) followed by epirubicin (4 cycles), or (c) CMF (6 cycles) alone. Immunohistochemical assessments of estrogen (ER) and progesterone (PgR) receptors, HER2 and Ki67 were available for 705 patients (arm A/B/C: 276/269/160). Prognostic and predictive relevance was analyzed by log-rank tests and Cox models. Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free (DFS) and overall survival (OS). In patients with triple negative tumors (ER-, PgR-, HER2-), epirubicin-containing regimens yielded better DFS (HR 0.33, 95 % CI 0.17-0.62, P = 0.0007) and OS (HR 0.24, 95 % CI 0.10-0.57, P = 0.001) compared with CMF alone, whereas no differences were found in patients with HER2-positive (HER2+, ER-, PgR-) subtype. Treatment by subtype interaction (HER2-positive vs. others) was significant for DFS (χ (2) = 6.72, P = 0.009). In triple unfavorable (ER-, PgR-, Ki67 > 20 %) tumors, the use of epirubicin yielded better DFS (HR 0.45,95 % CI 0.26-0.78, P = 0.005) and OS (HR 0.30, 95 % CI 0.15-0.63, P = 0.001). Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating, triple negative or triple unfavorable tumors.

High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study.

BACKGROUND: Patients with metastatic osteosarcoma at diagnosis or axial primary tumors have a poor prognosis. The aim of the study was to evaluate the feasibility and efficacy of intensified treatment with high-dose chemotherapy (HDCT) and stem cell rescue in this group. METHODS: From May 1996 to August 2004, 71 patients were included in a Scandinavian-Italian single arm phase II study. Preoperative chemotherapy included methotrexate, doxorubicin, cisplatin and ifosfamide, and postoperative treatment consisted of two cycles of doxorubicin, one cycle of cyclophosphamide and etoposide and two courses of high-dose etoposide and carboplatin with stem cell rescue. RESULTS: Twenty-nine patients (43%) received two courses and 10 patients (15%) received one course of HDCT. HDCT was associated with significant toxicity, but no treatment-related deaths were recorded. Fourteen patients (20%) had disease progression before completion of the study protocol, and only 29/71 patients (41%) received the full planned treatment. Median event-free survival (EFS) was 18 months, and estimated 5-year EFS was 27%. Median overall survival (OS) was 34 months, and estimated 5-year OS was 31%. When patients who did not receive HDCT due to disease progression were excluded, there was no difference in EFS (P = 0.72) or OS (P = 0.49) between patients who did or did not receive HDCT. CONCLUSIONS: The administration of high-dose chemotherapy with stem cell rescue was feasible, but associated with significant toxicity. Patient outcome seemed comparable to previous studies using conventional chemotherapy. We conclude that HDCT with carboplatin and etoposide should not be further explored as a treatment strategy in high-risk osteosarcoma.

Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer.

Adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have proven highly effective in rapidly proliferating breast cancer (RPBC). It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant epirubicin (E) followed by CMF is superior to the inverse sequence in RPBC. Patients with node-negative or 1-3 node-positive RPBC (Thymidine Labeling Index > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%) were randomized to receive E (100 mg/m(2) i.v. d1, q21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m(2) i.v. d1 and 8, q28 days for 4 cycles) (E â†’ CMF) or CMF followed by E (CMF â†’ E) or CMF for 6 cycles. From November 1997 to December 2004, 1066 patients were enrolled: E â†’ CMF 440, CMF â†’ E 438, and CMF 188. At a median follow-up of 69 months, 5-year OS was 91% (95% CI 88-94) for E â†’ CMF and 93% (95% CI 90-95) for CMF â†’ E, with adjusted hazard ratio of 0.88 (95% CI 0.58-1.35), and DFS was 80% in both arms, with adjusted hazard ratio of 0.99 (95% CI 0.73-1.33, Cox model). Adverse events were similar, apart from a higher rate of neutropenia in the CMF â†’ E arm. No important differences in clinical outcome were observed between the two different sequences, making both a valid option in early breast cancer. Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence.

Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival.

PURPOSE: To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide. RESULTS: The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P <.0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P =.006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P <.06), RFI (5-year PRS at < or = 24 months, 20%; at > 24 months, 60%; P <.0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P <.0001) but not by the use of a second-line chemotherapy treatment. CONCLUSION: RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.