Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer.

BACKGROUND: This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. PATIENTS AND METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100 mg/m(2)) or six cycles of TAC (75/50/500 mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. RESULTS: In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). CONCLUSIONS: With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.

Reliability of receptor assessment on core needle biopsy in breast cancer patients.

We compared the breast core needle biopsy and the resection specimen with respect to estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (HER2) status to identify predictors for discordant findings. We retrospectively collected data from 526 newly diagnosed breast cancer patients. ER, PR and HER2 status had been assessed in both the core needle biopsy and resection specimen. The assessment of ER by immunohistochemistry (IHC) in core needle biopsy was false negative in 26.5% and false positive in 6.8% of patients. For the PR status the false negative and false positive results of core needle biopsy were 29.6% and 10.3%, respectively. The results of the HER2 status, as determined by IHC and silver in situ hybridization (SISH), were false negative in 5.4% and false positive in 50.0%. We need to be aware of the problem of false negative and false positive test results in ER, PR and HER2 assessment in core needle biopsy and the potential impact on adjuvant systemic treatment. With current techniques, we recommend using the resection specimen to measure these receptors in patients without neoadjuvant treatment. A better alternative might be the use of tissue microarray, combining both core needle biopsy and resection specimen.

Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.

An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ≥ 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined.

Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study.

BACKGROUND: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. PATIENTS AND METHODS: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. RESULTS: In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. CONCLUSIONS: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.

The effect of optimal treatment on elderly patients with aggressive non-Hodgkin's lymphoma: more patients treated with unaffected response rates.

A substantial part of elderly patients (with good performance) with intermediate or high-grade non-Hodgkin's lymphoma (NHL) are not treated with the standard chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). If NHL patients are not treated with CHOP, the outcome is inferior. By adding granulocyte colony-stimulating factor (G-CSF) to CHOP chemotherapy, we aimed at treating more patients with less toxicity. We performed a multicenter population-based study (in the southeast of the Netherlands) in which elderly patients (> or = 60 years) with intermediate or high-grade stage > or = IIB NHL were treated with CHOP chemotherapy and growth factor G-CSF to increase the number of patients treated according to standard protocols. We also evaluated elderly NHL patients who were not treated with CHOP chemotherapy. Adequate therapy was defined as > or = six cycles or a total of five cycles when complete remission was achieved after three cycles. Seventy-nine NHL patients fulfilled the selection criteria. The patients were treated with CHOP plus G-CSF (n=46), CHOP (n=19), cyclophosphamide, vincristine, and prednisone (COP) (n=2), chlorambucil and prednisone (n=2), or prednisone (n=1). Nine patients were not treated with chemotherapy. The median age was 72 years (60-87). Of the 79 NHL patients, 65 were treated with CHOP chemotherapy (82%); 38 of 65 patients (59%) were adequately treated. The complete remission rate in the NHL group treated with CHOP was 65% (42 of 65 patients). The overall 3-year survival was 50%. Most of the patients died from progressive NHL (53% in the CHOP and 77% in the group not treated with CHOP). The treatment-related mortality was 15% in the CHOP group. The most important reason for not treating patients with CHOP (with or without G-CSF) was poor performance (WHO > or = 2). A significant subset of patients can be treated with CHOP chemotherapy with acceptable toxicity. The combination of CHOP plus G-CSF increased the absolute number of treatable elderly patients, resulting in more (absolute) patients with complete remission and overall survival compared to our previous study.

Treatment of elderly patients with intermediate- and high-grade non-Hodgkin's lymphoma: a retrospective population-based study.

PURPOSE AND METHODS: Nowadays more people are becoming older. The median age of a patient with non-Hodgkin's lymphoma (NHL) at diagnosis is over 60 years. The incidence of NHL in elderly has increased in the last decades. Therefore, in the future, NHL will be diagnosed more often in the elderly. Data of all patients in the south-east of the Netherlands with newly diagnosed NHL between January 1991 and January 1995 were analysed in a retrospective multicentre population-based study to investigate if and how elderly patients (> 60 years) with advanced NHL (Ann Arbor Staging > or = IIB) of intermediate- and high-grade malignancy were treated. Treatment modalities applied, outcome, and causes of death were evaluated. Treatment was considered inadequate if it deviated from the standard anthracycline-containing chemotherapy (CNOP/CHOP) for a minimum of six cycles. RESULTS: The entry criteria were met by 68 patients. Of these patients, 57 (83.8%) were treated and 11 (16.2%) were not treated. The treatment consisted of CHOP (36 patients), CNOP (6 patients), chlorambucil (13 patients), or COP (2 patients). Forty-two of 68 patients had adequate treatment, but 14 of 42 (33.3%) patients had a suboptimal numbers of cycles (< 6). Of 28 patients with adequate chemotherapy, only 16 had the optimal number of cycles and dose; the result is that the treatment of 76.5% (52/68) of patients differed from that of their younger counterparts. The most important reason for treatment not being optimal was high age (23%) or poor performance (35%). In the appropriately treated patients, 62.5% (10/16) had a complete response. Survival in the CHOP/CNOP-treated group was better than in other groups. The main cause of death in the total study group was NHL. The results cannot be explained by the different international prognostic index. CONCLUSION: A significant subset (76.5%) of elderly people with intermediate/high-grade NHL received suboptimal therapy, mainly because of a suboptimal performance status. However, a significant part of the patients (23%) were not treated optimally because of high age, despite a good performance. For improving the overall survival in the elderly, it is not only the schedule that is important, but also the intention to treat the elderly patient.

Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer.

Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called 'shortening of cycle time'. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m(-2) followed by paclitaxel 135 mg m(-2) (3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m(-2). The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m(-2) and paclitaxel 175 mg m(-2) could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m(-2) per week, respectively.

Cyclophosphamide, epirubicin and cisplatin (CEP) versus epirubicin plus cisplatin (EP) in stage Ic-IV ovarian cancer: a randomized phase III trial of the Gynecologic Oncology Group of the Comprehensive Cancer Center Limburg.

Cisplatin is the most important drug in the treatment of advanced ovarian cancer. The role of anthracyclines is controversial. We compared a combination of epirubicin plus cisplatin (EP) with a regimen of cyclophosphamide, epirubicin and cisplatin (CEP). Patients with stage Ic-IV ovarian cancer were randomized to receive either epirubicin 100 mg/m2 plus cisplatin 75 mg/m2 q 4 weeks or cyclophosphamide 500 mg/m2 plus epirubicin 75 mg/m2 plus cisplatin 50 mg/m2 q 4 weeks, which we considered the reference treatment based on our previous experience. Patients were initially debulked, followed by six cycles of chemotherapy, or in case primary debulking was insufficient or considered inappropriate, secondary debulking was attempted in selected cases after sufficient chemotherapy-induced regression. Optimal debulking was defined as residual lesions < or = 2 cm. A total of 210 patients (191 eligible) were randomized. Results did not show significant differences in all major endpoints (pathologically documented complete response and survival). The median survival for all patients was 34 months, for patients with stage III 26 months, for patients with stage IV 20 months and it has not been reached for patients with stage Ic-II. As no significant differences between an equitoxic regimen of EP and CEP were detected, it might be more useful to look again at the anthracyclines as part of combination chemotherapy instead of the alkylating agents.

Efficacy of carboplatin plus primary prophylactic filgrastim (granulocyte colony stimulating factor) in relapsed ovarian cancer: a study of the Gynecologic Oncology Group of the Comprehensive Cancer Center Limburg.

A total of 34 patients with advanced ovarian cancer, who relapsed 1-72 months after at least one first-line cisplatin-based chemotherapy protocol, were treated with carboplatin, 350 mg/m2 q 4 weeks, with the adjunct of primary prophylactic granulocyte colony stimulating factor (G-CSF; filgrastim), 300 or 480 microg daily, days 5-9. Over 90% of the anticipated dose of carboplatin could be administered. Partial response, defined as a decline in CA-125 of 50% or more on two consecutive samples, occurred in 42%, while 15% of patients achieved a complete response (no clinical signs of disease with normalization of CA-125). Survival from start of carboplatin treatment was 23 months. Myelosuppression was the most important toxicity with 35% of patients experiencing grade 4 thrombocytopenia of short duration. Grade 4 leucopenia occurred in only one patient. It is concluded that single-agent carboplatin, with the adjunct of prophylactic G-CSF, can be administered with adequate dose intensity, and is an effective and acceptable palliative treatment for patients with relapse after first-line cisplatin-based chemotherapy.