Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.     

Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer

PURPOSE: A multiinstitutional trial was performed to confirm the clinical activity, in terms of response rate and toxicity (primary objectives) and duration of responses and survival (secondary objectives), of an intensive weekly regimen in advanced gastric cancer. PATIENTS AND METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma received 1-day per week administration of cisplatin (CDDP) 40 mg/m2, fluorouracil (5FU) 500 mg/m2, epi-doxorubicin (epi-ADR) 35 mg/m2, 6S-stereoisomer of leucovorin 250 mg/m2, and glutathione 1.5 g/m2. On the other days, filgrastim was administered by subcutaneous injection at a dose of 5 mg/kg. One cycle of therapy consisted of eight 1-week treatments. Patients who showed a response or stable disease received a further 6 weeks of therapy. RESULTS: Of 105 enrolled patients, 11 had locally advanced unresectable disease only; 33 had primary nonresected and metastatic disease; 48 had metastatic disease and primary tumor resected; 10 had locoregional recurrence and metastatic disease; and three had locoregional recurrence only. After one cycle, 18 complete responses (CRs) and 47 partial responses (PRs) were achieved, for an overall response rate of 62% (95% confidence interval [CI], 53% to 71%). Twenty patients had stable disease and 20 progressed on therapy. The median survival duration of all 105 patients was 11 months, with 1- and 2-year survival rates of 42% and 5%, respectively. World Health Organization (WHO) grade III to IV toxicity, in terms of anemia, neutropenia, thrombocytopenia, and mucositis, was experienced by 40 patients (38%). There were no treatment-related deaths. CONCLUSION: These data support the results of the pilot study and confirmed the high activity of the regimen, with acceptable toxicity. This schedule deserves evaluation in the adjuvant setting.     

The role of chemotherapy in the management of nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy (RT). However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor. METHODS: A review of retrospective and prospective clinical studies was performed to assess the role of chemotherapy in three settings: metastatic disease; neoadjuvant and/or adjuvant; and concurrent chemotherapy with radiotherapy. RESULTS: Cisplatin-based combination chemotherapy results in a high response rate in patients with metastatic NPC, and a subgroup may achieve long term disease free survival. The use of neoadjuvant and adjuvant chemotherapy to treat locoregionally advanced disease has resulted in consistently high response rates, but no randomized trial to date has demonstrated an improvement in overall survival. A recent Head and Neck Intergroup study randomized patients in the United States to receive concurrent chemotherapy (cisplatin) and radiotherapy or radiotherapy only. Although this approach demonstrated significant benefit in overall survival favoring the use of concurrent chemotherapy and radiotherapy, its applicability in geographic areas of high NPC incidence remains to be proven. CONCLUSIONS: NPC is a chemosensitive tumor, and patients with metastatic disease have a high response rate. Further prospective studies will define the standard approach to treating locoregionally advanced NPC, which is likely to incorporate into the primary treatment some form of systemic chemotherapy.     

Effectiveness of paclitaxel and carboplatin combination in heavily pretreated patients with head and neck cancers

A phase II study was conducted to evaluate the activity of paclitaxel and carboplatin in advanced head and neck cancer. Twenty-four patients with measurable locoregional squamous cell carcinoma and metastatic disease were entered. All had been heavily pretreated with radiotherapy, surgery and chemotherapy and were at second recurrence or disease progression when they entered the trial. Patients received Paclitaxel 200 mg/m2 with carboplatin 7 AUC once every 3 weeks with premedication with dexamethasone and diphenyldramine and ranitidine. Twenty-three patients were evaluable for response. Four patients (17%) achieved a complete response and 5 (22%) a partial response for an overall response rate of 39%. Duration of response was 3-9 months. Toxicity was tolerable. Four patients showed Grade III (WHO) and 6 Grade II neutropenia. Nineteen (79%) of patients who received more than two courses of chemotherapy presented neurotoxicity. The combination of paclitaxel and carboplatin was effective in heavily pretreated patients with squamous cell carcinoma of the head and neck.     

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).     

Perspectives on the role of the lateral pterygoid muscle and the sphenomandibular ligament in temporomandibular joint function

This is a phase II study to evaluate the efficacy and toxicity of short-course carboplatin in advanced-stage nasopharyngeal carcinoma (NPC). Thirty-three previously untreated stage III-IV NPC patients were studied. Carboplatin was given as a rapid intravenous injection every 3 weeks. The dose of carboplatin was calculated according to the individual patient's creatinine clearance and desired platelet nadir of 75,000/microliter according to the Egorin formula. Response and toxicity were evaluated. Thirty-two patients were evaluated for response. The median age was 54 years, range 30-70 years. Twenty-four patients had local regional disease and 8 patients had metastatic disease. The median dose of carboplatin given was 415 mg/m2 (range 91-791 mg/m2). Fourteen (44%) patients had a partial response with a 95% confidence interval of 26-62%. Fifteen (47%) patients had stable disease and 3 (9%) progressive disease. The overall median survival rate was not reached at 43 months. Overall toxicity was tolerable. Grade III-IV myelosuppression occurred in 4 (12%) patients. There were no other major toxicity- or treatment-related deaths. We conclude that carboplatin has a significant anticancer effect in advanced NPC. Thus carboplatin combination chemotherapy for the treatment of NPC is worthy of future clinical investigations.     

Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck

BACKGROUND: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks. RESULTS: Twenty-four patients with a median age of 59 years (range 42-74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%-42%). The main toxicity was hematological: neutropenia grade 3-4 in 28% of the cycles and thrombocytopenia grade 3-4 in 16%. The most significant non-hematological toxicity was asthenia grade 2-3 in 24% of the cycles. CONCLUSIONS: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.     

Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design

PURPOSE: To identify characteristics that predict response to chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Between January 1986 and May 1996, 190 chemotherapy-naive patients with advanced or recurrent squamous cell carcinoma of the cervix not amenable to curative radiation therapy or surgery were treated on 14 different chemotherapy protocols at M.D. Anderson Cancer Center. Patient's charts were retrospectively reviewed for patient demographics, tumor and treatment characteristics, and patterns of response and survival. RESULTS: Of 190 patients, 22 had advanced or persistent disease and 168 had recurrent disease. Patients were treated with platinum-based (n=95) and non-platinum-based (n=95) regimens. The overall response rate was 20.0% (4.2% complete response; 15.8% partial response), with a median response duration of 4.8 months. Race, socioeconomic class, tumor stage and grade, mode of primary treatment, time from primary diagnosis to disease recurrence, initial performance status, and use of platinum-based therapy were not significant predictors of response. Age at time of chemotherapy (P=.001) and site of recurrence (P=.044) were significant determinants by multivariate analysis. Patients who were older were more likely to respond to therapy, and the response rate for patients in whom disease recurred outside the irradiated field was 25.2%, compared with a 5.3% response rate for patients with recurrent disease limited to a previously irradiated field. CONCLUSION: The site of disease recurrence and patient age should be taken into account when designing chemotherapy trials and also when considering chemotherapy in the patient with recurrent cervix cancer.     

The fate of patients with locally advanced bladder cancer treated conservatively with neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy: 10-year experience

PURPOSE: We assess the results of bladder preservation for infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive transurethral resection and radiotherapy was evaluated in 40 patients with T2-T4a G2-G3 bladder carcinoma. MATERIALS AND METHODS: From 1983 to 1995, 40 patients with bladder cancer underwent bladder sparing treatment, consisting of neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy. Most patients had T3G3 cancer. A deep transurethral resection biopsy was performed before and after chemotherapy, and an extensive transurethral resection was repeated at the end of radiotherapy. Of the patients 30 received cisplatin and methotrexate and 10 also received vinblastine. Total dose of radiotherapy was 60 to 65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy was considered for persistent or recurrent invasive disease. RESULTS: Complete response occurred in 19 patients (47.5%) after chemotherapy, and in 8 patients after transurethral resection and radiotherapy (67.5%). Within 10 years 8 responding patients (30%) had local recurrences and 3 underwent cystectomy. Of the patients 14 (35%) are alive, including 13 with no evidence of disease (mean survival 65 months), 5 died of unrelated disease and 21 (52.5%) died of distant metastases (mean survival 28 months). Of the 21 patients 14 had residual tumor after radiotherapy, 3 presented with distant metastases after vesical infiltrating recurrence and 4 had distant metastases in the absence of locoregional recurrence. In 22 patients (55%) the bladder was salvaged. Patients with complete response to chemotherapy had a low risk for recurrent infiltrating tumors and metastases. CONCLUSIONS: Complete tumor control was maintained at 5 years in more than 50% of the patients treated conservatively. Bladder salvage is feasible in select patients.     

Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy

We assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and 16alpha-[18F]fluoro-17beta-estradiol (FES) in women with breast cancer for predicting response to systemic therapy. Results of FES-PET were correlated with estrogen receptor (ER) status. Forty-three women with locally advanced or metastatic breast cancer underwent FDG-PET and FES-PET prior to institution of systemic therapy. All patients had measurable disease and had tumors submitted for ER determination. Cancers were considered functionally hormone sensitive if the standardized uptake value of the lesion on FES-PET was >/=1.0 (FES+) and hormone resistant if the standardized uptake value was <1.0 (FES-). Information obtained by FES-PET was compared with the results of ER assays. The tumor response to chemotherapy and hormonal therapy was correlated with intensity of uptake by both FDG-PET and FES-PET. The ER status of the breast cancers was negative (ER-) in 20 patients, positive (ER+) in 21 patients, and unknown in 2 patients. All 20 of the ER- tumors were also FES-. However, of the 21 ER+ tumors, 16 were FES+ and 5 were FES-. Thirty patients were treated initially with chemotherapy, and 21 (70%) demonstrated objective responses. We were unable to correlate the response to chemotherapy with information obtained by FDG-PET or FES-PET. Thirteen patients were treated with hormone therapy, and 8 (61%) responded to that therapy. Only 1 of the 5 patients whose tumors were ER+ but FES- received hormone therapy, and this treatment resulted in disease stabilization only. Multiple sites of disease were assessed by FES-PET in 17 patients with metastatic breast cancer. Functional hormone sensitivity, defined by FES-PET, was concordant with multiple lesions in 13 (76%). Ten patients with locally advanced breast cancer developed recurrent disease. The initial site of recurrence was the breast in 5 patients. Of the 5 patients with systemic recurrence, 4 had disease detected at the site of recurrence on the pretreatment FDG-PET study but not detected on pretreatment computed tomography. In our experience, FDG-PET imaging is more sensitive than conventional imaging methods, including computed tomography, in staging women with breast cancer. When compared with the in vitro assay of ER status, FES-PET has an apparent sensitivity of 76% and specificity of 100%. Our finding of a subset of patients who have tumors that are ER+ and FES- suggests that the functional assessment of hormone sensitivity by PET imaging can identify patients with ER+ disease whose tumors are likely to be hormone refractory.     

Localization of recurrent disease after extended lymph node dissection for carcinoma of the thoracic esophagus

BACKGROUND: The role of aggressive locoregional dissection in the treatment of carcinoma of the thoracic esophagus is controversial. The extent of disease spread for which resection can be performed is not yet fully established. STUDY DESIGN: Of 230 patients who underwent extended lymph node dissection, including the cervical nodes, the overall hospital mortality rate was 4.8 percent. Recurrent carcinoma was clinically confirmed by periodic follow-up examination with diagnostic imaging in 83 patients. We examined the exact anatomic sites of recurrent lesions and the clinical courses of patients. Recurrence patterns were classified into locoregional, distant, and mixed types. RESULTS: Recurrence of the carcinoma was locoregional in 35 patients, distant in 38 patients, and mixed in ten patients. The frequency of locoregional recurrence was significantly lower in patients with less than eight positive nodes and in patients without invasion of neighboring organs. Locoregional recurrence in the dissected area was mainly found in the region around the recurrent nerves and the main bronchi. Lymph nodes outside of the dissected area developed recurrence only in cases of markedly advanced disease apart from the abdominal para-aortic nodes. The group with locoregional recurrence and the group with distant recurrence had similar clinical courses over time. In patients in whom recurrent lesions could be treated with resection and adjuvant therapy, the one-year survival rate after recurrence was 83 percent. CONCLUSIONS: Unless the disease was markedly advanced, systematic lymph node dissection in our procedures yielded good locoregional control. The relatively low rate of distant recurrence with acceptable hospital mortality rates favors an extensive operation. When recurrent lesions were localized macroscopically, surgical removal of the recurrent lesions offered good palliation.     

Head and neck cancer: guidelines for chemotherapy

Head and neck cancer is estimated to be one of the most prevalent cancers in the world. This tumour type accounts for 5% of all new cancer cases in the US and Europe each year. Patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck have a poor prognosis, with a median duration of survival between 4 and 6 months. During the past few years, screening for potentially active new compounds, new associations and new modalities of chemotherapy administration have had some degree of success. Clinical investigations have also focused on the addition of chemotherapy to locoregional treatment for patients with locally advanced disease. Induction chemotherapy or concomitant chemo- and radiation therapy can result in high response rates, and reduced incidence of distant metastases. However, there is no clear demonstration of any benefit from the addition of chemotherapy to locoregional therapy on overall survival in patients with resectable disease. In patients with resectable laryngeal or hypopharyngeal cancer, chemotherapy combined with radiotherapy can be considered as a standard treatment option for larynx preservation, keeping total laryngectomy reserved for salvage therapy. In patients with unresectable head and neck cancer, simultaneous chemoradiotherapy has been shown to improve locoregional control and survival, at the cost of greater toxicity. Outside clinical trials, this approach can also be considered as a standard therapy for unresectable disease.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

Nasopharyngeal carcinoma in childhood and adolescence

BACKGROUND: This study reviews the authors' experience from 1979 through 1996 in the management and outcome of 56 patients with nasopharyngeal carcinoma who were under 20 years of age. PROCEDURE: There were 33 males and 23 females, their ages ranging from 7 to 19 years (median: 16 years). Forty patients had World Health Organization type III carcinomas, 16 had T4 tumors, 41 had metastatic cervical lymph nodes, and 50 were at stage III or stage IV. Thirty-two patients were treated with radiation therapy alone and 24 with the addition of chemotherapy. Cumulative radiation dose to the primary tumor ranged from 18 to 70 Gy (median: 66 Gy) and radiation dose to metastatic cervical lymph nodes ranged from 18 to 70 Gy (median: 66 Gy). RESULTS: Follow-up ranged from 0.1 to 16.8 years (mean: 9 years). Locoregional tumoral complete response was achieved in 49 patients. Locoregional tumoral failure was observed in 12 patients and systemic failure in 11. Overall, locoregional failure-free, metastases-free, and disease-free survival rates at 5 years were 49%, 62%, 79%, and 47%, respectively, for the entire group of patients, 42%, 61%, 72%, and 42%, respectively, for patients treated with radiation therapy alone, and 58%, 63%, 87%, and 54%, respectively, for patients treated with the addition of chemotherapy. Advanced T-stage and lower radiation doses worsened locoregional failure-free survival, whereas advanced N-stage and exclusion of chemotherapy worsened metastases-free survival. CONCLUSIONS: In children and adolescents with nasopharyngeal carcinoma, radiation therapy alone results in an improved locoregional tumoral response rate and a reduced locoregional tumoral failure rate at higher radiation doses, while the addition of chemotherapy results in a reduced systemic failure rate.     

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.     

Short-course induction chemoradiotherapy with paclitaxel for stage III non-small-cell lung cancer

BACKGROUND: This study assessed toxicity, tumor response, disease control, and survival after short-course induction chemoradiotherapy and surgical resection in patients with stage III non-small-cell lung carcinoma. METHODS: Forty-five patients with stage III non-small-cell lung carcinoma received 12-day induction therapy of a 96-hour continuous infusion of cisplatin (20 mg/m2 per day), 24-hour infusion of paclitaxel (175 mg/m2), and concurrent accelerated fractionation radiation therapy (1.5 Gy twice daily) to a dose of 30 Gy. Surgical resection was scheduled for 4 weeks later. Postoperatively, a second identical course of chemotherapy and concurrent radiation therapy (30 to 33 Gy) was given. RESULTS: Induction toxicity resulted in hospitalization of 18 (40%) patients for neutropenic fever. No induction deaths occurred. Of 40 (89%) patients who underwent thoracotomy, resection for cure was possible in 32 (71%) patients. Pathologic response was noted in 21 (47%) patients, and 14 (31%) were downstaged to mediastinal node negative (stage 0, I, or II). At a median follow-up of 19 months, 24 patients were alive, 10 with recurrent disease. Of 21 deaths, 16 were from recurrent disease, three were from treatment, and two were unrelated. Recurrent disease was distant in 21 patients, distant and locoregional in 2, and locoregional in 3. The Kaplan-Meier projected 24-month survival is 49%. Projected 24-month survival is 61% for stage IIIA, 17% for stage IIIB (p = 0.035); 84% for pathologic responders, 22% for nonresponders (p<0.001); 83% for downstaged patients (stage 0, I, or II), 33% for those not downstaged (p = 0.005); and 63% for resectable patients, 14% for unresectable patients (p = 0.007). CONCLUSIONS: We conclude that short-course neoadjuvant therapy with paclitaxel (1) has manageable toxicity and a low treatment mortality, (2) results in good tumor response and downstaging, (3) provides excellent locoregional control with most recurrences being distant, and (4) has improved the median survival compared with historical controls. Survival was better in stage IIIA patients, resectable patients, pathologic responders, and patients downstaged to mediastinal node negative disease (stage 0, I, or II).     

Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma

PURPOSE: Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS: Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS: Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION: The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.     

Management of recurrent meningeal hemangiopericytoma

BACKGROUND: Meningeal hemangiopericytoma is an uncommon neoplasm with a high propensity for recurrence. The purpose of this study was to analyze the efficacy of different treatment options in patients with recurrent disease. METHODS: The records of all patients with recurrent meningeal hemangiopericytoma treated at the study institution between 1976 and 1996 were reviewed. RESULTS: Thirty-four consecutive patients were studied. The mainstay of treatment was brain surgery in 21 patients (62%); the median time to recurrence from surgery was 12 months. Ten patients (29%) had 20 recurrent central nervous system (CNS) lesions treated by stereotactic radiosurgery. Of these, 3 previously nonirradiated patients (all with lesion size < 25 mm) achieved a complete response, which persisted at a median of 3 years. In 14 lesions (70%) a partial response (PR) occurred with a median duration of 12 months, whereas 3 lesions (15%) remained stable. Two patients with inoperable CNS lesions received external beam radiation therapy and both had PRs lasting 14 and 24 months, respectively. Nine patients (26%) received radiation therapy for metastatic disease. Of these, seven patients remained stable with good symptomatic relief, and two patients experienced tumor progression. Chemotherapy with doxorubicin-containing regimens was administered in 7 patients (21%); there was only 1 PR that lasted 8 months. The median survival from first recurrence was 4.6 years. CONCLUSIONS: Surgical management is important for the successful treatment of patients with recurrent meningeal hemangiopericytoma. Radiosurgery plays a definite role in the treatment of smaller recurrent CNS lesions. Radiation therapy is helpful in the management of inoperable tumors. More effective chemotherapeutic agents are needed.     

Combination chemotherapy of Hodgkin's disease in children

Forty-five children with advanced Hodgkin's disease (stages III and IV) received combination chemotherapy in three schedules: MOPP (mustargen, Oncovin, procarbazine, prednisolone); COPP (cyclophosphamide was substituted for mustargen); and CVPP (cyclophosphamide, vinblastine, procarbazine, prednisone). The results showed the efficacy of all drug combinations (93% complete and partial remissions). However, the superiority of the MOPP program in prolonging the duration of the complete remission rate was demonstrated. Of 29 patients who showed complete response, 24 continued in complete remission from 8 to 53 months (median duration, 21 months). The other five patients relapsed within 2 to 6 months. Thirty-six of the 45 treated patients are still alive after an average period of follow-up of 19 months. The nine patients who died were followed for an average of seven months. The histologic type, prior chemotherapy, and the age of the patients influenced the results of treatment. The role of maintenance therapy is not discussed in this series     

Regional chemotherapy with hemofiltration: a rationale for a different treatment approach to advanced pancreatic cancer

BACKGROUND/AIMS: Since 1989, thirty-two patients with advanced, intra-abdominal pancreatic cancer were treated with regional chemotherapy in combination with extracorporeal hemofiltration. PATIENTS and METHODS: Eleven patients had locally advanced, unresectable cancer, and ten had advanced disease with liver metastases. Three patients had developed liver metastases following a radical resection. One patient had an incomplete resection with local residual disease, and a second had developed a local recurrence after a radical resection. One patient had an unresectable cystadenocarcinoma. Five patients had failed prior systemic therapies for unresectable pancreatic cancer. The patients underwent 85 treatments with regional chemotherapy plus hemofiltration, an average of 2.7 treatments per patient. RESULTS: Of 21 patients treated primarily with regional chemotherapy plus hemofiltration, there were two complete responses (9%) and eight partial responses (38%), an overall total response rate of 47%. The average survival for patients with Stage II/III localized, unresectable disease is 13 months and that for Stage IV unresectable disease with liver metastases is 9 months. CONCLUSIONS: Patients with recurrent disease following a radical resection or having failed prior systemic therapies generally had no benefit from regional chemotherapy plus hemofiltration.