A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

PURPOSE: To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. METHODS: A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. RESULTS: Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. CONCLUSIONS: High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen.

BACKGROUND: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). PATIENTS AND METHODS: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). RESULTS: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2-4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P<0.03). CONCLUSIONS: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.

Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study.

BACKGROUND: A prospective randomized clinical trial was implemented to assess whether the concomitant or the sequential addition of tamoxifen to chemotherapy provides improved clinical benefit in the adjuvant treatment of breast cancer in postmenopausal patients. PATIENTS AND METHODS: Four-hundred and eighty-five patients with node-positive operable disease were randomized to receive tamoxifen (20 mg/day) concomitantly (CON) or sequentially (SEQ) to EC chemotherapy (epirubicin 75 mg/m(2) + cyclophosphamide 600 mg/m(2) on day 1, every 21 days for four cycles). RESULTS: In the 474 fully evaluable patients there were 96 events; eight being second neoplasms and 88 being related to the breast cancer. Of these, 48 of 88 occurred in the CON arm and 40 of 88 in the SEQ arm. The Kaplan-Meier estimation of disease-free survival (DFS) at 5 years was 70% in the CON and 75% in the SEQ group (log-rank test, P = 0.43). Adjusted hazard ratio for treatment was 1.11 (95% confidence interval 0.71-1.73; P = 0.64). CONCLUSION: This study fails to show an advantage of one treatment arm over the other, but a trend, albeit non-significant, appears to favor the sequential addition of tamoxifen to epirubicin + cyclophosphamide and, as such, warrants further investigation.

Sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer: a GEICAM-9801 phase II study.

PURPOSE: To evaluate the efficacy and the toxicity profile of the sequential administration of doxorubicin and docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Eighty-one patients received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m2) and 200 of docetaxel (100 mg/m2 every 21 days). The first 35 patients received doxorubicin every 14 days with G-CSF support, and in the other 46 cases doxorubicin was administered every 21 days without G-CSF. RESULTS: After entire treatment the overall response rate was 65% (18 complete responses). With a median follow-up of 19 months (range, 1-48 months), the median time to progression was 11.3 months and the median survival time was 31 months. As expected, febrile neutropenia was the most important toxicity and it appeared in 26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin every 14 days, the febrile neutropenia incidence was higher during docetaxel treatment, especially after its first administration. CONCLUSIONS: The dose and schedule of doxorubicin and docetaxel used in this trial seems to be active in first-line treatment of patients with MBC. The toxicity profile appears to be better than observed with concomitant schedules.

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study.

PURPOSE: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

A multicenter randomized Phase II trial of granulocyte-colony stimulating factor-supported, platinum-based chemotherapy with flexible midcycle cisplatin administration in patients with advanced ovarian carcinoma. PSAMOMA Cooperative Group, Spain.

BACKGROUND: The purpose of this study was to analyze whether the addition of granulocyte-colony stimulating factor (G-CSF) to platinum-based combination chemotherapy could increase platinum dose intensity and response rates and decrease hematologic toxicity in patients with advanced epithelial ovarian carcinoma. METHODS: Patients with untreated advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage IIC-IV) were treated after maximum debulking surgery with cyclophosphamide, 750 mg/m2, and carboplatin, 350 mg/m2, on Day 1 plus cisplatin, 75 mg/m2, on Day 14 when clinically indicated (adequate bone marrow and renal function). Patients were randomized to receive chemotherapy alone (Arm A) or chemotherapy supported with G-CSF (5 microg/kg subcutaneously on Days 2-13; Arm B). RESULTS: Between November 1993 and April 1995, 80 patients were included. Seventy-eight patients were evaluable for dose intensity calculations. Both groups were well matched with regard to age, Eastern Cooperative Oncology Group performance status, histopathologic subtype, tumor grade, FIGO stage, and residual tumor after surgery. The dose intensities calculated in mg/m2/week for cyclophosphamide and carboplatin were similar in both groups; however, the dose intensity of cisplatin was higher in Arm B (5.7 mg/m2 vs. 10.3 mg/m2). The occurrence of Common Toxicity Criteria Grade 3-4 neutropenia was less common in the G-CSF arm (55% vs. 7.7%). Response rates (52% vs. 68%) and pathologic complete responses (32% vs. 25%) were similar in both groups. CONCLUSIONS; The addition of G-CSF to this platinum-based chemotherapy regimen in patients with advanced ovarian carcinoma resulted in a modest increment in platinum dose intensity and appeared to reduce the incidence of Grade 3-4 neutropenia.

Central venous brachial catheter (P.A.S. Port TM) and catheter scanning system (Cath-Finder TM).

To assess the effectiveness and safety of an implanted portal with a central venous brachial implanted catheter, P.A.S. Port TM(P-P), and the accuracy of its Cath Finder TM tracking system (C-F), (Pharmacia Deltec) vs. radiology, a phase II multicentric study was designed. The catheter was implanted in 53 oncologic patients treated with chemotherapy and the performance of the catheter was evaluated for 3 months. No problems arose during the implantation in 77% of the cases and in all cases radiologic location of the catheter tip coincided with the C-F. We can conclude that P-P is easy to implant and to maintain in the arm and that it is well tolerated by the patients. C-F is an accurate and reliable system for locating the catheter tip. The use of both systems is an attractive alternative to the standard ones.

Phase I study of mitonafide with a 3-day administration schedule: early interruption due to severe central nervous system toxicity.

Eleven patients with solid tumors for whom effective therapy was not available entered a phase I study of mitonafide given as a short intravenous (i.v.) infusion daily for 3 consecutive days. The initial dose level was selected according to the experience from another phase I study using a 5-day administration schedule. Six patients entered the first dose level (180 mg/m2/day x 3 days) and 4 of them had grade 3-4 leukopenia. This level was considered to be the maximum tolerated dose (MTD) and no further dose escalations were attempted. The following 5 patients received a dose approximately 10% inferior to the previous one (160 mg/m2/day x 3 days). Three of them had grade 3-4 neutropenia. Three partial responses were observed in total. After inclusion of 11 patients, an unexpected toxicity, central nervous system (CNS) toxicity, consisting of severe loss of memory, temporospatial disorientation and high integrative function impairment was observed in 5 patients (46%). A median patients' follow-up of 3 months after treatment discontinuation showed that these alterations were progressive and not reversible. This disabling toxicity prompted us to an early study interruption. In conclusion, mitonafide, when administered as a short 3-day i.v. infusion, can induce severe and irreversible CNS toxicity. Nevertheless, since antitumor activity has been observed, further development of the drug is recommended with different schedules of administration that have shown not to produce neurotoxicity, i.e., 5-day continuous infusion.

Multiple primary tumors and familial cancers. A case report.

We herein report the case of a patient who had 4 primary tumors, 3 of which were malignant. His family had a high rate (26%) of cancer. The possible genetic factors that con produce these events are briefly discussed.

Ifosfamide in advanced epidermoid head and neck cancer.

A total of 37 men with epidermoid head and neck cancer whose disease had recurred following primary treatment (surgery and/or radiotherapy) received first-line chemotherapy with ifosfamide at i.v. doses of 3 g/m2 given daily on 3 consecutive days in combination with mesna (600 mg/m2 x 3 oral daily doses on days 1-3) every 3 weeks. In all, 7 patients showed a partial response and 2 patients achieved a complete response, for an overall objective response rate of 26% (9 of 35 eligible patients; 95% confidence interval, 12.5%-43%). Excluding the 5 early nontoxic deaths observed during the first 3 weeks of therapy, the objective response rate was 30% (9 of 30 patients; 95% confidence interval, 15%-49.5%). Responses were seen in lung metastases (2 patients), lymph nodes (2 patients), skin (3 patients), and cases of local recurrence (5 patients). The median duration of responses was 3 months (range, 2-5 months). The main side effects of ifosfamide were alopecia (83% of patients), emesis (80%), granulocytopenia (23%), and mild mucositis (20%). Two poor-risk patients suffered severe CNS complications that were probably related to treatment. Three patients died due to chemotherapy-related complications (2 patients with CNS toxicity and 1 patient with granulocytopenic sepsis). In conclusion, ifosfamide appears to be an active drug in epidermoid head and neck cancer and merits further evaluation in this disease.

Intravenous and oral magnesium supplementations in the prophylaxis of cisplatin-induced hypomagnesemia. Results of a controlled trial.

The effects of oral and intravenous magnesium supplementation on cisplatin (CDDP)-induced hypomagnesemia were investigated in 41 patients treated with 100 mg/m2 CDDP. Patients were randomly allocated to receive no magnesium supplementation, intravenous magnesium supplementation (magnesium sulphate, 3 g before each CDDD administration) or oral magnesium supplementation (magnesium pidolate, 2 g orally every 8 hours on days 2 to 21 of each CDDP course) during the first 4 courses of CDDP treatment. Patients in both supplementation arms showed significantly higher magnesium levels than control patients from the second course on (oral magnesium arm) or from the third course on (intravenous magnesium arm). Three of the 9 patients (33%) in the intravenous magnesium arm and 4 of the 9 (44%) in the oral magnesium arm developed hypomagnesemia after the fourth course of CDDP, compared with 9 of the 10 (90%) unsupplemented patients. There were no magnesium-related side effects in patients on intravenous magnesium supplementation. Two patients treated with oral magnesium developed mild gastrointestinal symptoms (emesis and diarrhea), probably from magnesium therapy. Our study showed that both intravenous and oral magnesium supplementations appear to be safe and efficacious in the prevention of CDDP-induced hypomagnesemia. Since patients were not completely protected, and since the analysis was limited to the first four courses of chemotherapy, additional studies are needed to determine the best schedule of magnesium supplementation, especially in patients who receive more than four courses of CDDP chemotherapy.

Carboplatin: an active drug in metastatic breast cancer.

PURPOSE: The study was undertaken to assess the antitumor activity of carboplatin 400 mg/m2 intravenously every 4 weeks in metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-four MBC patients without any prior exposure to chemotherapy entered the study. All patients had measurable disease in at least one site and were assessable for response and toxicity. RESULTS: Of 34 assessable patients, 12 obtained a complete (one) or partial (11) response to carboplatin, resulting in an overall response rate of 35% (95% confidence interval, 19.8% to 53.5%). The median duration of response was 8 months (range, 2+ to 12 months). Responses were seen in lymph nodes (four of six), lung (five of nine), skin and soft tissues (four of nine), breast (two of eight), and liver (three of 11), but not in measurable lytic lesions of the bone. Toxicity was mild, mainly consisting of emesis (81% of the patients; 66% of the courses), leukopenia of World Health Organization (WHO) grade 1 to 2 (47% of the patients; 18% of the courses), and thrombocytopenia (12% of the patients; 3% of the courses). There were no cases of life-threatening toxicity, although one patient developed grade 4 thrombocytopenia without bleeding. Of 22 patients who did not respond to carboplatin, 18 received salvage therapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF; 15 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; one patient); or hormones (two patients). Objective responses to CAF and hormonal therapy were seen in 11 of 15 and two of two patients, respectively. The remaining patient did not respond to CMF salvage chemotherapy. Overall, the response rate to either first-line carboplatin or second-line salvage therapy was 73.5% (25 of 34 patients). After a median follow-up time of 22 months, the median survival was 19 months. CONCLUSIONS: Carboplatin is an active drug in MBC patients without previous exposure to chemotherapy. In our study, the use of an experimental drug as first-line single-agent treatment in MBC did not have a negative influence on patient survival, as the majority of the carboplatin nonresponding patients could be salvaged with a conventional therapeutic regimen.

Phase II study of carboplatin in advanced breast cancer: preliminary results.

The antitumor activity of carboplatin (400 mg/m2 intravenously every 4 weeks) in advanced breast cancer was evaluated in two consecutive trials enrolling patients with and without prior exposure to chemotherapy, respectively. All patients had measurable disease in at least one site. The first trial included patients who had received prior chemotherapy (adjuvant, neoadjuvant, or chemotherapy for metastatic disease). All but one of these patients had previously received doxorubicin-containing combinations. There were no objective responses among the first 14 evaluable patients, although 7 of them had stable disease, including 2 with minor responses. The second trial, carried out with patients who had no prior exposure to chemotherapy, is ongoing. Currently, 6 of 19 evaluable patients have obtained a complete (1) or partial (5) response to carboplatin, resulting in an overall response rate of 32%. In both studies, toxicity was mild, mainly consisting of emesis (88%), leukopenia (22%), and thrombocytopenia (12%). Thus, by standard criteria, carboplatin was not found to be active in breast cancer patients with prior exposure to chemotherapy. Preliminary results in patients without such exposure are encouraging, although additional patients are needed to confirm these data.

The natural course of emesis after carboplatin treatment.

Twenty-eight patients receiving their first cycle of carboplatin treatment (300-400 mg/m2) entered a prospective study in which the natural course and intensity of postchemotherapy emesis was evaluated. Twenty-five patients (89%) experienced nausea at some time after carboplatin treatment and twenty-three patients (82%) vomited. The median number of emetic episodes was 13.5. In the 23 patients who experienced vomiting, the mean period of latency of vomiting (time from start of carboplatin administration to onset of vomiting) was 6.25 h. The period of maximum incidence of vomiting was between 8 and 12 h (71% of patients with vomiting). Between 6 and 14 h after the start of carboplatin treatment, more than 50% of patients were continuously vomiting. Vomiting declined significantly after 24 h. According to these data, carboplatin is a severely emetic drug. Prospective antiemetic trials are necessary in order to obtain antiemetic schedules which are able to increase the tolerance to carboplatin treatment.

Treatment of advanced ovarian cancer with cisplatin, adriamycin and cyclophosphamide (PAC).

Forty two ovarian cancer patients with residual disease after the first laparotomy were treated with the combination of cisplatin (80 mg/m2 day 1), adriamycin (50 mg/m2 i.v. day 2) and cyclophosphamide (500 mg/m2 i.v. day 2) (PAC). Forty women were considered evaluable for analysis, with an overall response rate (partial, plus complete responses) of 62.5%. Twelve patients (30%) obtained a complete response (histologically confirmed after second look surgery in 6 cases, surgical complete response, residual tumor completely resected in the second look-in 5 cases and maintained complete clinical remission without second look confirmation in 1 case). Main side effects were nausea and vomiting (90%), leukopenia (70%), mucositis (45%), and anemia (37%). Seventeen percent of the patients were free of disease at 60 months, after a median follow-up of 48 months. The prognostic factors that showed significant influence on survival were the Karnofski index (90-100 vs 80 or less), stage of the disease (II + III vs IV) and the volume of residual tumor after the first surgical procedure (less than or equal to 2 cms vs greater than 2 cms). Patients who achieved a complete remission have not reached the median 5 years survival, which was 10 months for the remaining patients. These results confirm the activity of PAC in ovarian cancer, mainly in those patients with residual tumor of less than 2 cms and good performance status.

Motor neuron disease in Cantabria.

Sixty-two patients with motor neuron disease (MND), encompassing amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA), were selected from within a defined area (Cantabria) in northern Spain, from 1974 to 1985. The annual incidence of MND was 1.01 per 100,000 inhabitants and the prevalence rate was 3.52 per 100,000. The male to female ratio was 1.78:1. Age-specific incidence rates increased with advanced age, with a maximum between 60 and 69 years for males and over 70 years for females. The median age at onset was 60.5 years. The average interval between the onset symptoms and diagnosis was 11 months. Fifty-three per cent of the patients had conventional or pseudopolyneuritic ALS, 36% had PBP and 11% had PMA. There were three familial cases. Two PMA patients had had acute poliomyelitis. The mean duration of the disease was 26.6 months and was significantly longer in males aged under 60 years. The survival rates in 50 patients with adequate follow-up were 18% after 5 years from onset and 6% after 10 years.