High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin, and cisplatin before radiotherapy.

Undifferentiated carcinoma of nasopharyngeal type (UCNT) is a geographically endemic, Epstein-Barr virus-related carcinoma of epidermoid origin with reported 5-year survival rates of 15%-40% when treated with radiotherapy alone. Although UCNT can be well controlled locally by radiation therapy, in advanced nodal stage N3 [International Union Against Cancer-American Joint Committee on Cancer (UICC-AJCC, 1987)] the survival rate is below 20%, primarily because of metastatic spread in 80% of the fatalities. We report a pilot study of 41 patients with nonmetastatic, locoregionally advanced disease (85% of the patients had a nodal status greater than or equal to N2C-N3; 43% had T4 primaries), during which we used a combination of 100 mg of cisplatin/m2 on day 1, 15 mg of bleomycin by intravenous push and 12 mg/m2 by continuous infusion on days 1-5, and 70 mg of epirubicin/m2 on day 1 every 21 days for three cycles before definitive radiation therapy with 70 Gy for 7 weeks. Twenty-seven of 41 patients (66%; 95% confidence interval = 52.5%-80.5%) achieved a clinical complete response, and 40 of 41 (98%) had a major objective response after chemotherapy. Two deaths were treatment related, but side effects were moderate, and the overall treatment sequence was feasible. At the end of radiation therapy, all 39 assessable patients were in complete response, with a median follow-up of 21+ months (greater than 10-greater than 31); 33 (80%) patients had no evidence of disease. We believe that such a complete response rate in a high-volume disease with the use of combined modality treatment indicates a therapeutic gain in UCNT. Researchers performing a multicenter international controlled trial will test this hypothesis and compare local control, disease-free, and overall survival of the therapeutic sequence presented here with radiotherapy alone.

Leukemoid reaction, bone marrow invasion, fever of unknown origin, and metastatic pattern in the natural history of advanced undifferentiated carcinoma of nasopharyngeal type: a review of 255 consecutive cases.

PURPOSE: This study is an analysis of frequency and relationship regarding two undifferentiated carcinoma of nasopharyngeal type (UCNT)-associated paraneoplastic syndromes (PNS): leukemoid reaction (LR) and fever of unknown origin (FUO) with bone marrow invasion (BMI) and metastatic pattern. PATIENTS AND METHODS: A consecutive UCNT patient cohort (N = 255) with locally advanced (n = 142) or metastatic (n = 113) disease receiving chemotherapy alone or in combination with radiotherapy was studied. All patients had a complete baseline work-up that included bone marrow biopsy. RESULTS: UCNT has distinctive features among head and neck squamous cell cancers (HNSCC). These include early subclinical dissemination, with 70% of metastases appearing within 18 months of first symptoms. Metastases are common in bone (65% v 25% in HNSCC), liver (29% v 23%), and lung (18% v 84%), and BMI is observed in 25% of UCNT patients with metastases. Metastases likelihood is related to lymph node involvement, with 64% of patients with metastases having N3 disease. Involved lymph nodes in contrasted CT scans revealed hypodensity in 26% of UCNT patients versus 79% in patients with other HNSCC. Hypercalcemia was observed in one case. LR was identified in 41 patients (16%); in 26 of the 41 patients (64%) it was observed concomitant with N3 and/or metastatic disease. FUO was found in 23 patients (9%) and was associated in four instances with BMI and in 17 with LR (in four instances with both). Brain metastases or meningeal carcinomatosis were not observed despite the high rate of skull base compromise. Paraneoplastic signs were observed in 47 of 255 cases (18.5%) and were more frequent in patients with metastases. However, PNS were observed in 15 patients with negative metastases work-up. CONCLUSION: The PNS described could help in the diagnosis and follow-up of UCNT patients because they may be the first manifestation of the disease or may reappear with relapse. BMI is a frequent finding in patients with metastases and is unrelated to PNS.

Clinical implications of the serum level of CD23 in patients with undifferentiated nasopharyngeal carcinoma.

PURPOSE: In contrast with other carcinoma cells, cells from nude mice transplanted undifferentiated carcinoma of nasopharyngeal type (UCNT) release the soluble fragment of the CD23 antigen (sCD23). We sought to study the level of sCD23 in sera of untreated UCNT patients. PATIENTS AND METHODS: Pretherapeutic sera from 65 consecutive, locally advanced, initially nonmetastatic UCNT patients were assayed for sCD23. Patients were treated with a neoadjuvant chemotherapy/full-dose radiotherapy sequence. The mean follow-up duration is 50.5 months (range, 28 to 77). The Cox proportional hazards model was used to study the association between sCD23 levels and clinical signs and disease evolution. RESULTS: sCD23 levels showed an association with disease-free survival (DFS; P = .08) and overall survival (OVS; P = .08). Patients with sCD23 levels greater than a cutoff value of 0.6 ng/mL (greater cutoffs were found to be equally significant, but less sensitive), have a relative risk (RR) of relapse of 3.3 (95% confidence interval, 1.6 to 6.9; P = .002), and an RR of death of 2.9 (95% confidence interval, 1.2 to 7.3; P = .02), when taking other prognostic factors into account. CD23 does not correlate with either the response to treatment or the development of metastases, but appears to be related to local control (cutoff, 0.6 ng/mL; RR = 5.1 [95% confidence interval, 1.2 to 21.7]; P = .02). CONCLUSION: The serum level of sCD23 appears to be an independent prognostic factor for initially nonmetastatic, locally advanced UCNT patients, treated with chemotherapy and radiotherapy. Our data indicate an association between this marker and local relapses. Thus, a simple enzyme-linked immunoadsorbent assay (ELISA) could help to identify a high-risk group among nonmetastatic UCNT patients. CD23 could be a marker for two groups of UCNT tumors, with distinct biologic characteristics and clinical behaviors.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.

Long-term disease-free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type.

PURPOSE: To review incidence and analyze profile of long-term complete responders among patients with undifferentiated carcinoma of nasopharyngeal type (UCNT) treated at a single institution. PATIENTS AND METHODS: We present a cohort of 20 long-term unmaintained complete responders to chemotherapy for metastatic UCNT treated at the Institut Gustave Roussy between April 1978 and November 1996. A patient was considered a long-term survivor if he or she was disease-free for more than 36 months without treatment after obtaining a complete response by chemotherapy. Patient characteristics were as follows: sex, 17 men and three women; median age, 28 years (range, 9 to 62 years); median World Health Organization performance status, 1; and initial tumor-node-metastasis stage (International Union Against Cancer-American Joint Committee on Cancer, 1987) of T3 to T4, 60%, and of N2b to N3, 75%. Epstein-Barr virus serology was characteristic in 19 patients. Of 16 pretreated patients, 11 were pretreated by radiotherapy alone and five by chemotherapy and radiotherapy. Thirteen patients had metastatic relapses of locally controlled UCNT. Tumor sites were bone in 15 patients, lung in four, and liver (biopsy-proven) in two. Chemotherapy included the following: cisplatin, bleomycin, and fluorouracil in five patients; bleomycin, epirubicin, and cisplatin in seven patients; fluorouracil, mitomycin, epirubicin, and cisplatin in four patients; and fluorouracil, bleomycin, epirubicin, and cisplatin in one patient. Three patients were treated with platinum-based regimens before 1985. Patients received a median of six cycles (range, three to 13). Thirteen patients with bone metastases received consolidating radiotherapy. RESULTS: As of June 1999, 14 of 20 patients were still alive with no evidence of disease after treatment (disease-free survival time, 82+ to 190+ months), three patients died of other causes while in complete response at 61, 109, and 208 months after treatment, and three patients died of disease at 42, 89, and 115 months after treatment. Long-term complete responses were obtained in both bone and visceral disease. CONCLUSION: Our data support a curative role for chemotherapy in metastatic UCNT and are a major incentive to continue research for better combinations to increase the percentage of patients with metastatic UCNT who attain complete responses and long-term survival.

Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil.

Undifferentiated nasopharyngeal carcinoma (UCNT) is known to be radiosensitive and chemosensitive, but the latter has never been studied prospectively with phase II methodology. After an intensive work-up, 49 patients with recurrent (REC) and/or metastatic (MTS) UCNT were treated with three monthly cycles of cisplatin (CDDP) 100 mg/m2 day 1; bleomycin 15 mg intravenously (IV) day 1, and 16 mg/m2/d continuous infusion (CI) days 1 to 5; and fluorouracil (5FU) 650 mg/m2/d CI days 1 to 5 (PBF). Of the 49 patients, 33 were North African. The sex ratio was three males:one female, and the median World Health Organization (WHO) performance status was 1.6. In the 48 patients assessable for response, we observed nine (19%) complete responses (CRs) and 29 (60%) partial responses (PRs) (60%), for a 79% overall response rate (95% confidence interval, 68% to 90%) in the assessable group and a 78% global rate. There were eight CRs (24%) observed in the group without previous chemotherapy (33 patients) compared with one CR in the chemotherapy pretreated group (16 patients). Four patients are still alive without evidence of disease after 52+, 54+, 58+, and 58+ months, respectively. All of them had less than three bone MTS sites, and received radiation therapy in these sites. The results confirm the chemosensitivity of UCNT, and the observation of unmaintained long-term responders makes curability a possible consideration.

Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer.

PURPOSE: This trial investigated the toxicity and efficacy of docetaxel as first-line chemotherapy in women with heavily pretreated advanced breast cancer. PATIENTS AND METHODS: From April 1992 to August 1992, 35 patients with advanced breast cancer from 29 to 65 years of age with a performance status of 0 to 2 were entered onto the study. Docetaxel 100 mg/m2 was administered every 3 weeks as a 1-hour infusion on day 1 without routine premedication for hypersensitivity reactions. Thirty-one patients were assessable for response. Previous adjuvant chemotherapy had been given to 11 patients. RESULTS: Five complete responses (CRs) and 16 partial responses (PRs) were observed, for an overall response rate of 67.7% (95% confidence interval, 49% to 83%). A CR occurred at 13 of 45 assessable sites (four liver, two lung, three breast, three lymph node, and one skin). The median duration of response was 44+ weeks, the median time to disease progression 37+ weeks, and the median overall survival time 16+ months. Among 34 patients assessable for toxicity (177 cycles; median, five cycles per patient), the following side effects were reported: nadir neutropenia grade 3 (three patients); grade 4 (31 patients); no grade 3 to 4 infection, acute hypersensitivity-like reaction (10 patients); grade 2 to 3 alopecia (all patients); and grade 2 to 3 nausea and vomiting (six patients). Fluid retention occurred in 26 patients and consisted of weight gain, edema alone (15 patients), or edema associated with serous effusion (11 patients). This side effect led to treatment discontinuation in 16 of 21 responding patients after a median of five cycles and a median cumulative dose of docetaxel of 574 mg/m2. CONCLUSION: Our data suggest that docetaxel has major antitumor activity when used as a single cytotoxic agent as first-line chemotherapy in advanced breast cancer.

Docetaxel in combination with doxorubicin or vinorelbine.

The rationale for the development of a new drug combination is to combine optimal doses of drugs with single-agent activity that are not cross-resistant or have similar toxicities. Docetaxel, with its unique mechanism of action and its high response rates in metastatic breast cancer, provides both opportunities and challenges for the development of combination chemotherapy. Anthracyclines are widely accepted as the agents of choice for first-line treatment of metastatic breast cancer and they have been studied in combination with taxoids. Preliminary results with a combination of docetaxel and doxorubicin indicate an overall response rate of 74%, with the dose-limiting toxicities being neutropenia and infection. Vinorelbine also has single-agent activity against metastatic breast cancer and preclinical studies have demonstrated synergism when vinorelbine and docetaxel are combined. The dose-limiting toxicities of the vinorelbine-docetaxel combination are febrile neutropenia and mucositis. The overall response rate to treatment with this combination is 67%. We therefore conclude that docetaxel can be combined with doxorubicin or vinorelbine to provide high response rates and acceptable toxicity.

Alternating chemo-radiotherapy with cisplatin and 5-fluorouracil plus bleomycin by continuous infusion for locally advanced undifferentiated carcinoma nasopharyngeal type.

UNLABELLED: More than 80% of undifferentiated carcinoma nasopharyngeal type patients with N3 disease (AJC-UICC 1987) will die with or from distant metastases within 3 years after the first symptom. From February 1986 to November 1987 30 consecutive patients with very advanced local disease were entered in a programme with chemotherapy-radiotherapy (CT-RT) alternation after a thorough work-up to eliminate the possibility of distant metastases. PROTOCOL: two cycles of cisplatin 100 mg/m2 day 1, bleomycin 15 mg intravenously day 1 and 16 mg/m2 per day by continuous infusion days 1-5; 5-fluorouracil (5-FU) 650 mg/m2 per day by continuous infusion days 1-5 4 weeks apart. This was followed by two series of high-energy radiotherapy, 35 Gy/3.5 weeks, with a third chemotherapy cycle in between. 27 men and 3 women were treated, the median age was 37 years (range 17-71) and the mean WHO performance status was 1 (range 0-3). TNM classification: 15 T4, 9 T3, 6 T2, 28 N3 and 2 N2c. 18 patients had nodes larger than 8 cm and 24 had bulky bilateral cervical nodes. Toxicity for this protocol was moderate, nausea and vomiting being the main side-effects. Results after two CT cycles were 3 complete responses (CR; 10%), 22 partial responses (PR; 73%), 2 disease stabilizations, 2 progressions, and 1 patient inevaluable. Of the 30 patients, 27 patients completed the CT-RT protocol, 2 patients died before radiotherapy and 1 refused treatment after 2 days on protocol. 25 patients were in CR 3 months after the end of radiotherapy. As of August 1991, with a median follow-up of 55 months (range 43-63), there are 17 patients alive, 2 of them with active disease and 15 are NED (2 after salvage therapy).

Docetaxel combined with vinorelbine: phase I results and new study designs.

This was a phase I dose-finding and pharmacokinetic study of vinorelbine (Navelbine) and docetaxel (Taxotere) as first-line chemotherapy for metastatic breast cancer. Vinorelbine dose, 20 or 22.5 mg/m2, on days 1 and 5, was followed on day 1 by docetaxel every 21 days, in doses increasing from 60 to 100 mg/m2. Two maximum tolerated doses were reached, the first at 75 mg/m2 of docetaxel and 22.5 mg/m2 of vinorelbine, and the second at 100 mg/m2 of docetaxel and 20 mg/m2 of vinorelbine. Symptomatic peripheral neuropathy was not observed. The recommended doses for phase II studies are 75 to 85 mg/m2 of docetaxel on day 1 and 20 mg/m2 of vinorelbine on days 1 and 5, every 3 weeks. The treatment regimen, which included 3-day corticosteroid prophylaxis, resulted in only mild fluid retention. Responses were seen at all dose levels, with an 80% overall response rate at the higher recommended dose; the overall response rate for patients at all dose levels was 66%. A high rate of response, including a complete response, was observed in patients with liver metastases.

Undifferentiated carcinoma of nasopharyngeal type of tonsil.

A review of 2262 squamous cell carcinomas of the tonsillar region seen at the Institut Gustave-Roussy, Villejuif, France, from 1970 to 1986 showed 1837 well- and poorly differentiated squamous cell carcinomas and 425 undifferentiated squamous cell carcinomas. Eighteen patients with undifferentiated squamous cell carcinomas presented histologic characteristics of undifferentiated carcinomas of nasopharyngeal type. Radiosensibility and radiocurability (complete sterilization with 70 Gy administered) was found in this group with an excellent long-term control of local disease (77% at 10 years actuarial). Epstein-Barr virus-related serologic tests were performed for seven patients. Four of them presented the serologic anti-Epstein-Barr virus titer patterns, generally associated with undifferentiated carcinomas of nasopharyngeal type (1280 to 5120 for viral capsid antigen/IgG and 40 to 320 for viral capsid antigen/IgA). These observations confirm that undifferentiated carcinomas of the nasopharyngeal type may arise outside the nasopharynx.

Phase I-II trial of recombinant interferon alpha-2b with cisplatin and 5-fluorouracil in recurrent and/or metastatic carcinoma of head and neck.

The aims of this study were to establish the feasibility and toxicity of the biochemical modulation of the cisplatin (CDDP)-5FU combination by interferon alpha-2b (INF), and to assess its therapeutic efficacy in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The mandatory eligibility criteria included histologically proven SCCHN; a performance status <2; adequate bone marrow, hepatic, renal, and cardiac functions; and measurable and/or evaluable disease. The protocol was CDDP, 100 mg/m2 i.v. day 1; 5-FU, 1,000 mg/m2 in a c.i.v. infusion over 96 h; and INF 3.10(6) U/day s.c., begun 2 h before cisplatinum for 5 consecutive days, repeated every 3 weeks. Twenty patients were included and received 76 cycles (median number cycles/patient = three). Eighteen patients were evaluable for activity with an overall response rate (RR) of 30% [2 complete responses (CR) + 4 partial responses (PR)], which was 55% (5/9) in previously untreated and 9% (1/11) in previously treated patients. Myelosuppression (50%), mucositis (40%), loss of electrolytes (15%), and asthenia (20%) were the most frequent severe toxic effects. Notwithstanding, the protocol was feasible and well tolerated in this overall population with a poor prognosis. Median duration of response was 8 months, and median survival for the overall population was 8.5 months. This schedule is the test arm of an ongoing international multicentric phase III trial versus standard CDDP-5FU in the same SCCHN population.

[Undifferentiated carcinoma of the nasopharynx: epidemiological, clinical and therapeutic aspects]. / Carcinomes indifférenciés du nasopharynx: aspects épidémiologique, clinique et thérapeutique.

Undifferentiated carcinoma of the nasopharynx (UCNT) is a particular head and neck epidermoïd lineage tumor related to the Epstein-Barr Virus (EBV). It has geographically selective endemic epidemiologic features, without relation to external carcinogens. Its systemic agressiveness is the source of most disease related demises, since radiotherapy achieves excellent local control and a significant percentage of cure in patients with exclusive locoregional disease. Differences in the staging systems currently in use, the recent changes in imaging and radiotherapy technology, and the lack of distinction between UCNT and SCC of the nasopharynx in Western literature reports make for some difficulty in therapeutic results evaluation when analyzing available literature. Its chemosensitivity is a relatively recent acknowledged fact, and its use in metastatic patients results in a high percentage of objective responses, many of long duration. Neoadjuvant cisplatin based chemotherapy seems to be of benefit, but outstanding controversies in this regard will be soon answered through ongoing phase III trials. After a review of the current literature of all the above mentioned aspects of this fascinating nosologic entity, our own experience in over 250 patients seen during the past 8 years, both in metastatic and locoregional disease patients is analyzed.

How long do routine dental restorations last? A systematic review.

OBJECTIVE: To conduct a systematic review of the literature on the longevity of routine dental restorations in permanent posterior teeth, and to identify and examine factors influencing its variability. METHOD: Accepted guidelines were followed. An advisory group oversaw the project. Simple Class I and Class II amalgam, composite resin, glass ionomer and cast gold restorations were covered. Comprehensive searching of electronic databases, hand-searching, and location of 'grey' literature, generated 124 research reports. Those considered relevant were assessed for validity and quality according to agreed criteria. The analysis was descriptive. RESULTS: Eight of 58 relevant research reports were categorised, according to agreed criteria, as being of satisfactory validity and quality. They suggested that 50% of all restorations last 10 to 20 years, although both higher and lower median survival times were reported. The findings were supported by the totality of studies reviewed. However, variability was substantial. Restoration type, materials, the patient, the operator, the practice environment and type of care system appeared to influence longevity. CONCLUSIONS: Many studies were imperfect in design. Those considered to be the most appropriate for analysis were too limited to undertake a formal statistical exploration. Therefore there remains a need for definitive randomised controlled trials of restoration longevity, of sound design and adequate power, employing standardised assessments and appropriate methods of analysis.

Taxoids in combination chemotherapy for metastatic breast cancer.

The rationale for the development of new drug combinations is to combine optimal doses of drugs with single agent activity which are not cross-resistant and have non-overlapping toxicities. Anthracyclines are widely accepted as the agents of choice for first-line treatment of metastatic breast cancer and have been tested in combination with the taxoids, docetaxel (Taxotere) and paclitaxel (Taxol). Toxicity problems have emerged using anthracyclines and paclitaxel, with sequence- and schedule-dependent toxic effects including dose-limiting typhlitis and mucositis, as well as febrile neutropenia and, in one study, cardiomyopathy. The dose-limiting toxicities of the combination of docetaxel and doxorubicin are neutropenia and infection, and preliminary results indicate a response rate of 89%. There is a need to develop a combination treatment regimen which is non-cross-resistant with anthracyclines. Vinorelbine (Navelbine) has single agent activity against metastatic breast cancer and has been used in combination with taxoids. The dose-limiting toxicities of the vinorelbine-paclitaxel combination are febrile neutropenia, pelvic pain, fatigue and paraesthesias. The dose-limiting toxicities of the combination of docetaxel and vinorelbine are febrile neutropenia and mucositis. The overall response rate for this combination was 67% and studies are ongoing.