High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer.

BACKGROUND: The mesenchymal-epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors. METHODS: We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors. RESULTS: Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65-7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65-8.46; P=0.002). CONCLUSION: These results provide further evidence that the MET pathway could be exploited as a target for TNBC.

Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial.

PURPOSE: It is well recognized that breast cancer is a heterogeneous disease. The purpose of the current study was to classify patients according to the immunohistochemical phenotype of their tumors in an effort to evaluate the outcome of the respective groups of patients and specifically of those with triple-negative breast cancer (TNBC) following dose-dense sequential adjuvant chemotherapy. METHODS: A total of 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel in the context of a randomized study. ER, PgR, HER2, Ki67, EGFR, and CK5 protein expression were evaluated in 298 formalin-fixed paraffin-embedded tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH). HER2 status and Ki67 protein expression differentiated luminal IHC subtypes (luminal B tumors being HER2 and/or Ki67-positive). RESULTS: Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2 enriched, and 36 (12%) as TNBC. The median follow-up time was 97 months. Patients with luminal A tumors had the best prognosis, with improved disease-free survival (log-rank, P = 0.033) and overall survival (P = 0.006) compared with the other three tumor subtypes. The three subtypes had an increased risk for relapse and death compared with luminal A in multivariate analysis, as well. No benefit from paclitaxel treatment was detected in any of the four subtypes or the total cohort. Hierarchical clustering based on mRNA expression of ER, PgR, and HER2 by quantitative RT-PCR identified patient groups that were comparable to the subtypes identified by IHC. CONCLUSIONS: The results of this study confirm that triple negative, luminal B and HER2-enriched phenotypes identified by IHC are of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy.

Tumor dissemination after laparoscopic surgery for an unsuspected endometrial stromal tumor.

BACKGROUND: The use of laparoscopic surgery in gynecologic oncology might be complicated by unsuspected side-effects for the patient. Experimental data suggest that the risk of tumor dissemination in the non traumatized peritoneum may be higher after pneumoperitoneum than after laparotomy, and they also show the importance of the surgeon's experience and technique. CASES: We present two cases of uterine endometrial stromal tumors which were laparoscopically excised. In both cases, intraperitoneal tumor seedings were identified shortly after the initial operation. The first patient had a low-grade endometrial stromal sarcoma and succumbed from the disease two years after the initial operation, while the second patient who was diagnosed with endometrial stromal tumor remains disease free two years later. CONCLUSIONS: The laparoscopic excision of an endometrial stromal tumor might result in tumor dissemination into the abdominal cavity. A careful second-look examination of the abdomen or a radical surgical approach is proposed.

Molecular markers in epithelial ovarian cancer: their role in prognosis and therapy.

Epithelial cancer of the ovary is the most lethal malignancy of all gynaecological cancers. Various clinical and pathological features of ovarian cancer are used as predictors of clinical outcome. The use of molecular markers in common clinical practice seems promising for the diagnosis and prognostication. The aim of this review article is to describe current theories regarding the pathogenesis and molecular evolution of epithelial ovarian cancer. With respect to the molecules involved, this article focuses on whether they are associated with poor prognosis or not. This evaluation is performed in light of the progress made and the potential usefulness in treatment decisions without overlooking existing controversies that should be further studied. It is tempting to anticipate the gradual integration of molecular profiling in clinical practice.

Paclitaxel chemotherapy and vascular toxicity as assessed by flow-mediated and nitrate-mediated vasodilatation.

BACKGROUND: Antitumor activity of paclitaxel is based on promotion of abnormal microtubule (MT) assembly but it is also considered to have significant pro-inflammatory and anti-angiogenic effects in vivo and thus may cause vascular dysfunction. METHODS: We studied 27 women treated with paclitaxel-containing combinations for breast or ovarian cancer. The control group was represented by 10 women with carcinoma of the uterine cervix who received low doses of weekly cisplatin as radiation sensitizer. We measured endothelial-dependent flow-mediated dilatation (FMD) and nitrate-mediated dilatation (NMD) of the right brachial artery by ultrasonography, as well as levels of the inflammatory cytokines TNF-alpha and IL-6 before and after chemotherapy. RESULTS: Patients who received paclitaxel and an anthracycline had the most marked reduction in both FMD (p=0.005) and NMD (p=0.027). A significant reduction in FMD was also observed in patients treated with weekly paclitaxel (p=0.045), whereas NMD was not affected (p=0.421). Although TNF-alpha and IL-6 levels were different among chemotherapy groups after treatment, no significant differences were observed between levels of both markers before and after chemotherapy. CONCLUSION: Treatment with paclitaxel-containing combinations impairs endothelial function in vivo but endothelial function deterioration is not related to the serum levels of inflammation markers.

Low frequency of somatic mutations in uterine sarcomas: a molecular analysis and review of the literature.

OBJECTIVE: The rarity of uterine sarcomas along with their pathological and molecular heterogeneities render their study particularly challenging. We evaluated a panel of somatic mutations principally centering on the tyrosine kinase gene family and their downstream signaling cascades in an attempt to identify potential candidate markers that may assist in diagnostic or therapeutic decisions in these tumors. METHODS: We performed mutational analysis of 20 exons from 9 genes (EGFR, CDKN2A, MET, KIT, RAS, BRAF, PI3KCA, HER-2 and PDGFR-alpha) on biopsy material from 25 patients who underwent primary surgery for uterine sarcoma between October 1995 and October 2003. Due to the limited number of studies conducted we have also undertaken a literature review of somatic mutations in uterine sarcomas. RESULTS: A total of 3 different somatic mutations were identified: one KRAS (codon G12D) in a carcinosarcoma and two exon 20 PI3KCA mutations (H1047R and H1047Y) both in carcinosarcomas. Mutational status of all mutations was confirmed using germline DNA extracted from peripheral blood. Consistent with the literature data, no other mutations regarding the rest of the genes of the panel were identified. Due to the low number of somatic mutations in our series, we did not perform further clinicopathological correlations. CONCLUSION: The absence of somatic mutations in the majority of genes that are considered critical in neoplastic transformation hampers the identification of potential therapeutic targets in patients with uterine sarcoma.

Management of advanced stage uterine sarcomas: a bone of contention.

Uterine sarcomas constitute a rare group of neoplasms characterized by an aggressive clinical course and poor prognosis. It is this rarity that has resulted in clinical-trial reports and literature reviews including a broad range of histological subtypes of sarcoma. This has a detrimental effect on interpretation and application of the results; the pathological subtype demands a tailored approach. Surgical resection remains the mainstay of treatment for non metastatic uterine sarcomas. Although adjuvant radiation therapy has reportedly been of little survival value, it appears to improve local control and may delay recurrence. The role of adjuvant chemotherapy has yet to be established; however, bearing in mind the limitations and assumptions in the pooling of data the therapeutic options should be based on the pathological subtype. Considering the poor overall survival in uterine sarcomas, the need for new therapeutic agents is critical. New drugs with possible activity in uterine sarcomas include trabectedin, temozolomide, liposomal doxorubicin and gemcitabine.

Effectiveness of ozonation and chlorination on municipal wastewater treatment evaluated by a battery of bioassays and biomarkers.

A battery of bioassays, including biological toxicity as well as in vitro mouse spleen lymphoproliferative responses and cytokine production, was conducted to compare the effectiveness of tertiary treatment methods such as coagulation (Coag) and absorption on granular activated carbon (GAC) and disinfection processes such as chlorination and ozonation in removing toxic or stress inducing agents from reclaimed wastewater. Whole effluent toxicity (WET) testing of secondary treated (ST) wastewater using as test species Vibrio fischeri, Daphnia magna and Tetrahymena thermophila as well as phytotoxicity revealed moderate toxicity effects that depend on the organism used. All bioassays exhibited decrease of the ecotoxicological responses after tertiary treatment. However, mitogenic responses were proved to be more sensitive. Endotoxin present in ST samples may be responsible for the increased strong lymphoproliferative activity as well as interleukin-1 (IL-1) production by mouse splenocytes. Tertiary treatment of ST with coagulation and/or adsorption on granular activated carbon (GAC) in combination with ozonation reduced WET to control levels. Ozonation alone or in combination with any other treatment removed endotoxin more efficiently than chlorination and thus reduced spleen lymphoproliferative responses and IL-1 production.

Clinicopathological features of primary fallopian tube carcinoma: a single institution experience.

PURPOSE OF INVESTIGATION: Primary fallopian tube carcinoma (PFTC) is a rare malignancy with only few data existing on the impact of prognostic factors. METHODS: We retrospectively analyzed 26 patients. Tissue blocks were reviewed and sections were stained for vascular endothelial growth factor (VEGF), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2), c-erbB-2, estrogen (ER), and progesterone receptors (PgR). RESULTS: Reactivity for VEGF, ER, PgR, MMP-2, MMP-9, TIMP-1, TIMP-2 and c-erbB-2 was observed in 85%, 46%, 27%, 11.5%, 58%, 0%, 23% and 8% of specimens, respectively. None of the markers studied displayed prognostic significance. Regarding clinical prognostic factors, the hazard ratio (HR) for progression and death for patients with tumor residuum > 2 cm was 5.24 (p < 0.01) and 11.19 (p < 0.005), respectively. Patients with advanced stage disease had a HR of 12.55 (p < 0.05) for progression, while the HR for death was not found to be statistically significant. CONCLUSION: None of the biomarkers studied seems to influence survival. Early-stage disease and optimal debulking are associated with improved outcome.

Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: We undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix. PATIENTS AND METHODS: One hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m(2), daily, on days 1-3 and cisplatin 70 mg/m(2) on day 2) or the same combination with the addition of paclitaxel 175 mg/m(2) on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis. RESULTS: A modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet. CONCLUSION: The ITP combination merits further investigation in randomized phase III studies.

Bioassays and biomarkers for ecotoxicological assessment of reclaimed municipal wastewater.

The aim of this work was to examine the ecotoxicity of reclaimed wastewater by the use of bioassays and the determination of immunological parameters. Secondary and tertiary mucicipal wastewater samples were examined for their physicochemical and microbiological characteristics as well as for their endotoxin concentrations. The ecotoxicological characteristics were assessed by a battery of bioassays, using Vibrio fischeri, Daphnia magna and Tetrahymena thermophilla as test species and phytotoxicity. The mitogenic responses of mouse splenocytes were as well used as bioassay. The cytokines of IL-1, IL-2, IL-10, IFNgamma and TNFalpha, were also determined in the supernatant of splenocyte cultures and served as molecular biomarkers. All bioassays exhibited decrease of the ecotoxicological responses after tertiary treatment. However, mitogenic responses were proved to be more sensitive. IL-1 increased, while IL-2 production was unaffected. The fact that IL-10 production increased in response to secondary treated effluents in conjunction with the increased endotoxin levels, suggest Th2 type immune responses. Although results obtained from the toxicity bioassays after the tertiary treatment showed comparable results to those of controls, cytokine levels indicated the induction of immune response even after tertiary treatment. Consequently, cytokine production could be used as a sensitive biomarker for the evaluation of treatment efficiency of the reclaimed wastewaters intended for reuse.

Anthracycline-based adjuvant chemotherapy in early-stage uterine sarcomas: long-term results of a single institution experience.

PURPOSE OF INVESTIGATION: Uterine sarcomas are rare neoplasms characterized by a high rate of local recurrences and distant metastases. The role of chemotherapy in early-stage completely resected disease remains controversial. METHODS: Thirty-one patients with Stage I or II uterine sarcomas, referred to our center for adjuvant chemotherapy, received anthracycline-based regimens. Seventeen (54.8%) patients received ifosfamide, etoposide and epirubicin, six (19.4%) were treated with doxorubicin and carboplatin, three (9.6%) were administered doxorubicin and ifosfamide, while five (16.1%) patients received various anthracycline-based regimens. RESULTS: With a median follow-up of 82 months disease recurred in 12 (38.7%) patients. Five-year survival probability is estimated at 54%. Both median overall survival and time to progression for all patients have not been reached yet. Patients who received ifosfamide-containing regimens had a statistically significant benefit in overall survival (p < or = 0.05) when compared with those treated with non-ifosfamide-containing regimens. CONCLUSION: Our data suggest a potential role for anthracycline- and ifosfamide-containing chemotherapy in the adjuvant setting for early-stage uterine sarcomas.

Adjuvant chemotherapy with paclitaxel and carboplatin in non-endometrioid carcinoma of the uterus.

PURPOSE OF INVESTIGATION: Uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) represent more aggressive tumors than the more common endometroid cancers, exhibiting a propensity for distant metastasis. The aim of this study was to investigate the activity and safety of paclitaxel/carboplatin chemotherapy as the only adjuvant treatment in patients with surgically resected UPSC and UCCC. METHODS: Fifteen patients with Stage IB-IV UPSC or UCCC were treated with a mean of six courses of paclitaxel 175 mg/m3 plus carboplatin AUC 5 at three-week intervals, three to six weeks after undergoing surgery with curative intent. No patient had residual disease after surgery and none underwent pre- or post-chemotherapy irradiation. RESULTS: With a median follow-up of 29.4 months, six patients (40%) relapsed and two (13%) died of disease. Mean time to recurrence was 16.9 months. Recurrence rate per Stage was 17% for Stage IB/C, 57% for Stage IIIA/C and 50% for Stage IV. Projected 5-year overall survival and progression-free survival was 79.7% and 55.7%, respectively. All relapses were abdominopelvic whereas in one case pelvic recurrence was accompanied by lung metastasis. The most frequent grade 3-4 toxicity was neutropenia. CONCLUSION: Chemotherapy with paclitaxel plus carboplatin is feasible and possibly prevents distant metastasis when used as adjuvant in UPSC and UCCC.

Ifosfamide, paclitaxel and cisplatin first-line chemotherapy in advanced, suboptimally debulked epithelial ovarian cancer.

BACKGROUND: The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS: Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m(2), as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m(2) intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m(2) intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 microg/kg/day on Days 7-11. RESULTS: Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION: The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens.

Non-cryopreserved peripheral blood progenitor cells collected by a single very large-volume leukapheresis: a simplified and effective procedure for support of high-dose chemotherapy.

High-dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) support has become a widely used treatment strategy. In order to simplify the procedure, a single very large-volume leukapheresis programme combined with short-term refrigerated storage of the PBPC was developed. Seventy-two patients suffering from various relatively chemosensitive malignancies received high-dose chemotherapy, consisting of agents with short in vivo half-lives and 24 to 48 hours later, the refrigerated PBPC were reinfused. A single very large-volume apheresis was sufficient to obtain at least 2 x 10(6)/kg CD34+ cells in 58 patients (81%), and 63% had at least 2.5 x 10(6) CD34+ cells/kg. Only two patients (3%) were transplanted with less than 1 x 10(6) CD34+ cells/kg. In three patients (4%) leukapheresis was repeated because of insufficient number of PBPC. The median CD34+ cell count was 3 x 10(6)/kg. A median of 38.5 L blood (range, 21 to 59) was processed, which accounted for a median of 9 x patient's total blood volume. Very large-volume leukapharesis was well tolerated with symptomatic hypocalcemia being the most common (18%) side-effect. The median time to neutrophils >1.5 x 10(9)/L, and to self-supporting platelet count >25 x 10(9)/L, was 10 and 12 days after reinfusion of PBPC graft, respectively. There were no treatment-related deaths. Our results indicate that this simplified approach of PBPC transplantation can be associated with prompt hematologic recovery in most patients and that it can be useful in settings where facilities are limited or for certain diseases where conditioning regimens with short half-life are appropriate. J. Clin. Apheresis, 15:236-241, 2000.

Paclitaxel, cisplatin, and epirubicin first-line chemotherapy in stage III and IV ovarian carcinoma: long-term results of a phase II study.

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has become the preferred chemotherapy regimen in the treatment of epithelial ovarian carcinoma. Anthracyclines also have activity in this disease. We conducted a Phase II study by using the combination of paclitaxel, cisplatin, and epirubicin for the treatment of advanced ovarian carcinoma. METHODS: Forty consecutive patients with optimally (n = 7) or suboptimally (n = 33) debulked advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV) were treated with paclitaxel, 135 mg/m(2), as a 3-hour intravenous infusion, cisplatin 75 mg/m(2) intravenously (i.v.), and epirubicin 50 mg/m(2) i.v. every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was administered at a dose of 5 microg/kg/day on Days 5-9. RESULTS: Among 28 patients with measurable disease, 24 (86%%) achieved an objective response including 19 complete and 5 partial responses. Among 18 patients who underwent reassessment laparotomy, pathologic complete response was confirmed in 9 patients. At a minimum follow-up of 40 months, the median overall survival had not been reached whereas the median time to progression for all patients was 18.7 months. The median remission duration for women with measurable disease who responded to treatment was 14 months. The treatment was well tolerated without toxic deaths; the most common toxicity was Grade 3/4 neutropenia that occurred in 30% of patients. Significant neuropathy (Grade 2 or higher) developed in only 8% of patients. CONCLUSIONS: The combination of paclitaxel, cisplatin, and epirubicin is a well tolerated outpatient regimen with significant activity in the treatment of advanced epithelial ovarian carcinoma.

Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study.

OBJECTIVES: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent carcinoma of the endometrium, and the combination of these two agents has shown activity in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. METHODS: Twenty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m(2) administered intravenously over a 3-h period followed by cisplatin 75 mg/m(2) administered intravenously with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 3 weeks for a maximum of six courses. RESULTS: Sixteen patients (67%; 95% confidence interval, 45-84%) achieved an objective response, including seven complete responses and nine partial responses. The median duration of response was 7 months, and the median times to progression and survival for all patients were 8.4 and 17.6 months, respectively. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 22% of patients and peripheral neuropathy in 9%. CONCLUSION: The combination of paclitaxel with cisplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium. The significant incidence of neurotoxicity is of concern and alternative methods of administration of the two agents could be evaluated.

Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix.

PURPOSE: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity. PATIENTS AND METHODS: Thirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-hour period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses. RESULTS: Sixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse. CONCLUSION: The combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.

Sequential administration of doxorubicin and paclitaxel followed by cyclophosphamide, methotrexate and 5-fluorouracil combination (CMF) in women with metastatic breast cancer.

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.