Long term complications and prognostic factors in locally advanced nasopharyngeal carcinoma treated with docetaxel,cisplatin, 5-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy: A retrospective cohort study

This study was conducted to evaluate the long term complications and their risk factors including of survival outcomes in patients with locally advanced nasopharyngeal cancer (NPC) treated with docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT).Among the patients who were diagnosed as NPC, we consecutively evaluated the late complications in 104 patients who completed 3 cycles of TPF induction chemotherapy followed by CCRT and received regular follow-up by otolaryngologist and oncologist. The prognostic factors for overall survival, relapse free survival and each complication were analyzed based on clinical characteristics.Over a median follow-up of 54 months (range, 7.9–152.9 months), 5-year overall survival rate was 87% for stage II, 89% for stage III, 87% for stage IV patients. The significant prognostic factor for survival is complete response rate after CCRT in multivariate analysis. The most frequent toxicity was ear complication (29.8%) including of hearing loss requiring hearing aid (6.7%) and bone necrosis (3.8%). Decreased renal function over grade 2 was occurred in only 4 patients (3.8%) regardless of the cumulative dose of cisplatin. The long term complications did not affect the survival outcome. Patients who received radiation therapy more than 5400 cGy had better survival outcome than those who did not. However, ear complication was significantly related to radiation dose (≥ 6,600 cGy) and type of radiation therapy (conventional). Age over 65 years was a significant risk factor for both ear and renal toxicity. In conclusion, close follow-up to monitor long-term complications should be performed in patients treated with TPF induction chemotherapy followed by CCRT treatment, especially in elderly patients. Reestablishing the optimal chemotherapeutic agent during CCRT and adjustment of radiation dose after induction chemotherapy could be helpful to reduce the toxicity associated with the subsequent treatment strategy for locally advance NPC patients.     

Primary central nervous system lymphoma: the clinical features and treatment of 22 cases

OBJECTIVE: To clarify the efficacy of chemotherapy after radiation therapy in immunocompetent patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: A retrospective analysis of 22 PCNSL patients was performed. Twenty-two patients were divided into a combined treatment (chemotherapy after radiation) group and a radiation group. The survival curves, calculated according to the Kaplan and Meier method, were compared using the Log-rank and Wilcoxon statistical analyses. RESULTS: Eight patients were treated with radiation therapy alone, and their median survival time (MST) after diagnosis was 21.9 months. Fourteen patients were treated with chemotherapy after radiotherapy. Six patients received chemotherapy consisting of cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP), while 6 patients received carboplatin-based chemotherapy and 2 patients received methotrexate-based chemotherapy. The MST of these 14 patients was 34.4 months, which was not significantly better than that of the radiation therapy group (p=0.159). Leukoencephalopathy occurred in 3 patients, who received whole brain radiation. CONCLUSION: The use of chemotherapy after radiation has up to now been thought to be a standard treatment modality but CHOP or carboplatin-based chemotherapy did not improve the survival time.     

Treatment of metastatic germ-cell tumors in men with adriamycin, vincristine, and bleomycin.

Twenty-five patients with metastatic germ-cell tumors were treated with a combination of adriamycin, vincristine, and bleomycin. Fifteen patients (60%) had previously received radiation therapy, chemotherapy, or both. Twenty patients (80%) responded to treatment, with eight (32%) patients achieving a complete remission (CR) and 12 (48%) patients achieving a partial remission (PR). The median duration of response for the patients with PR was 4 months, whereas four patients with a CR remain alive without evidence of disease for greater than 3 years after the initiation of treatment. Responses were observed in all tumor categories and apparently were not influenced by prior therapy. Side effects included gastrointestinal toxicity, alopecia, neuropathy, skin changes, mucositis, and myelosuppression (more severe in previously treated patients). Though moderate success was demonstrated for this chemotherapy regimen, it does not appear as effective as more recent regimens including vinblastine and bleomycin.     

Combined modality therapy for stage IIIMO non-oat cell bronchogenic carcinoma.

Thirty-nine patients with stage IIIMO non-cell bronchogenic carcinoma (NOBC) were treated with combined modality therapy: radiation therapy and chemotherapy with cyclophosphamide, adriamycin, methotrexate, and procarbazine. The median survival for all patients treated was 9.6 months compared to 6.4 months for historical controls (P = 0.015). Patients who responded to the treatment program had a significantly longer survival (median, 15.2 months) compared to nonresponders and historical controls (P less than 0.005). It is concluded that combined modality therapy is moderately effective therapy in stage IIIMO NOBC.     

A prospective clinical trial comparing chemotherapy,radiotherapy and combined therapy in the treatment of early stage Hodgkin‘s disease with bulky disease

We performed a randomized clinical trial to assess the usefulness and toxicity of combined therapy compared with chemotherapy and radiotherapy in the treatment of early stage Hodgkin‘s disease with bulky disease as an adverse prognostic factor. Three-hundred and seven patients were enrolled into the study. They were randomized to receive either radiotherapy (extended field, generally mantle, 3500 cGy), or chemotherapy (adriamycin, bleomicin, vinblastine and dacarbazine: ABVD, 6 monthly) cycles or combined therapy (three cycles of ABVD, followed by irradiation therapy and three more cycles of chemotherapy). The median follow-up duration from start of treatment was 11.4 years. Complete response rates were similar in the three arms: 83% for radiotherapy (95% confidence interval [CI] 67–92%), 80% for chemotherapy (CI 69–88%) and 87% for combined therapy (CI 74–94%). However, disease-free survival and overall survival were better in the patients treated with combined therapy. At 12 years 76% (CI 51–93%) of the patients treated with combined therapy remained alive in the first complete remission compared with 42% (CI 26–61%) in patients treated with radiotherapy and 48% (CI 31–57%) in patients who had received chemotherapy alone (P < 0.01). Improvement in overall survival was also evident at 12 years: 88% (CI 59–93%) in those who had received combined therapy, compared with 53% (CI 36–67%) in the radiotherapy arm and 59% (CI 35–67%) in the chemotherapy group. Acute toxicity was more frequent in patients treated with combined therapy, but no death related treatment was observed in the three groups. Late toxicity was similar in the three treatment groups. Combined therapy with extended field radiotherapy and six cycles of chemotherapy is an effective treatment of patients with early stage bulky Hodgkin‘s disease compared with chemotherapy or radiotherapy alone.     

Combination chemotherapy for ovarian carcinoma with cyclophosphamide, adriamycin, and cis-dichlorodiammineplatinum(II) after failure of initial chemotherapy

Twenty-four patients who had stage III or IV ovarian adenocarcinoma and had failed prior chemotherapy were treated with cyclophosphamide, adriamycin, and cis-dichlorodiammineplatinum(II) every 3 weeks. Twelve patients had objective responses and an additional six had subjective improvement. The median duration of survival for responders is 9 months. There were no instances of nephrotoxicity. Fluid management consisted of 1000-2000 ml of iv fluid without Lasix- or mannitol-induced diuresis. Patients responded after having failed radiotherapy or multiple-drug chemotherapy, including some who were 70-75 years of age or were greater than 50% bedridden. Patients with one- or two-drug prior chemotherapy had a higher response rate (ten responses among 17 patients) than those previously treated with three or more drugs (two responses among seven patients).     

Treatment of advanced squamous cell carcinoma of the head and neck with cisplatin, bleomycin, and methotrexate (PBM)

Twenty-nine of 32 patients with advanced squamous cell carcinoma of the head and neck were treated with two courses of an intensive chemotherapy regimen consisting of cisplatin, bleomycin, and methotrexate (PBM). The frequency of toxic effects (in 29 evaluable patients) associated with this regimen was low. Serious neutropenia occurred in 17% and thrombocytopenia in 10% of the courses. Nausea (50%) and severe vomiting (6%) were easily managed. All 26 (100%) evaluable patients with squamous cell carcinoma had significant reduction (less than 50%) of measurable tumor. Complete regression was noted in seven patients (27%). Fifteen patients were treated with PBM prior to receiving radiation therapy or surgery as definitive treatment for their disease. Antitumor response in these patients was rapid, occurring within 3 weeks from the initiation of chemotherapy. Maximal antitumor effect was achieved by Week 6 of induction chemotherapy. No patient showed tumor regrowth prior to the institution of radiation therapy or surgery. Twelve patients with recurrent disease following previous radiotherapy and/or surgery also received PBM chemotherapy. In our study, previous radiotherapy or surgery did not diminish the antitumor effect of PBM, but toxicity was more severe.     

Radiation therapy for the treatment of unresected stage I-II non-small cell lung cancer

STUDY OBJECTIVES: Radiotherapy is considered to be the standard treatment for patients with stage I or II non-small lung cancer who refuse surgery or who are not surgical candidates because of significant comorbidities. To determine whether radiotherapy benefits these patients, we compared the survival of those treated with radiation alone to those left untreated. METHODS: Using the Surveillance, Epidemiology, and End Results registry, we identified all patients in whom histologically confirmed, stage I and II non-small cell lung cancer had been diagnosed between 1988 and 2001. Among these patients, 4,357 did not undergo surgical resection. Kaplan-Meier survival curves were compared among patients who received and who did not receive radiation therapy. We used Cox regression analysis to evaluate the effect of radiation on survival after adjusting for potential confounders. RESULTS: The survival of patients with lung cancer who did not undergo resection and had been treated with radiation therapy was significantly better compared to the untreated patients (stage I cancer, p = 0.0001; stage II cancer, p = 0.001). The median survival time of patients with stage I disease who underwent radiotherapy was 21 months compared to 14 months for untreated patients. Stage II patients who received and did not receive radiation therapy had median survival times of 14 and 9 months, respectively. The survival of treated and untreated patients was not significantly different approximately 5 years after diagnosis (stage I disease, 15% vs 14%, respectively; stage II disease, 11% vs 10%, respectively). In multivariate analysis, radiation therapy was significantly associated with improved lung cancer survival after controlling for age, sex, race, and tumor histology. CONCLUSIONS: These results suggest that radiotherapy is associated with improved survival in patients with unresected stage I or II non-small cell lung cancer. The observed improvement in median survival time was only 5 to 7 months, and radiotherapy did not offer the possibility of a cure.     

Dysphagia in Patients with Nasopharyngeal Cancer After Radiation Therapy: A Videofluoroscopic Swallowing Study

This study evaluated swallowing status and the factors influencing swallowing in patients with nasopharyngeal carcinoma (NPC) after radiation therapy. During the period from July 1995 to June 1999, this cross-sectional study used videofluoroscopic swallowing study (VFSS) to evaluate 184 NPC patients who had completed radiation therapy [113 cases had completed radiation therapy 12 months prior to evaluation (acute group) and 71 cases had completed radiation therapy >12 months prior to evaluation (chronic group)]. The numbers of patients with tumors in each of the four stages were as follows: 24 in stage I, 45 in stage II, 41 in stage III, and 74 in stage IV. Swallowing abnormalities of the acute and chronic groups were correlated with multiple variables, including gender, age, the stage of the tumor, use of either neoadjuvant chemotherapy or radiosensitizer, and radiation modality. The analytical results indicated that the chronic group had a significantly higher proportion of swallowing abnormalities. Radiation modality, chemotherapy, and tumor staging were not significantly associated with swallowing dysfunction. Trend analysis revealed a progressive deterioration of most parameters of swallowing function in this group of patients. These findings indicate that swallowing function continues to deteriorate over time, even many years after radiation therapy in patients with NPC. Our results indicate that the time elapsed since radiation therapy correlates with the severity of dysphagia in NPC patients. This work was conducted at National Taiwan University Hospital.     

Combination chemotherapy used prior to radiation therapy for locally advanced squamous cell carcinoma of the head and neck

Thirty-three patients with locally advanced squamous cell carcinoma of the head and neck were scheduled to receive two courses of chemotherapy prior to radical radiotherapy. Chemotherapy consisted of moderate-dose methotrexate with leucovorin rescue, bleomycin by infusion, and cisplatin. Loss of body weight and the duration of membrane formation at a specified region of the oral cavity during radiation therapy were used as indices of radiation toxicity: there was no excessive loss of body weight or mucosal reaction in patients who received combined treatment compared to patients in a nonrandomized control group who received radiotherapy alone. Twenty patients (60%) had a greater than or equal to 50% decrease of measurable disease prior to starting irradiation, but only eight patients (24%) are alive and disease-free at a median followup of 16 months. Aggressive chemotherapy does not prevent delivery of subsequent full-dose radiotherapy for squamous cell carcinoma of the head and neck, but this study does not suggest that chemotherapy has a great beneficial effect on long-term survival.     

Treatment of advanced endometrial carcinoma with doxorubicin and cisplatin: effects on both untreated and previously treated patients

Sixteen patients with advanced (International Federation of Gynecology and Obstetrics stage III and IV) adenocarcinoma of the endometrium were treated with twelve 28-day cycles of doxorubicin and cisplatin. Response was achieved in 92% of patients (11 responses among 12 patients) who had received no prior chemotherapy and in 50% (two responses among four patients) of previously treated patients. Median survival was 10 months. Doxorubicin and cisplatin were readily administered on an outpatient basis with comparatively low major toxic effects, primarily hematologic, renal, and gastrointestinal. These results indicate that doxorubicin and cisplatin combination therapy is effective with acceptable toxicity in patients with advanced endometrial carcinoma.     

Upper hemibody and local chest irradiation as consolidation following response to high-dose induction chemotherapy for small cell bronchogenic carcinoma--a pilot study

Encouraging results of the combination of upper hemibody irradiation (UHBI) and local chest irradiation (LCI) combined withh standard-dose chemotherapy in patients with extensive small cell bronchogenic carcinoma led us to a second pilot study utilizing the same radiation program combined wit high-dose induction chemotherapy. Fourteen patients with small cell bronchogenic carcinoma, five with extensive disease and nine with localized disease, were treated with cyclophosphamide (1.5 g/m2 iv, Days 1 and 22), lomustine (70 mg/m2 orally, Day 1), and methotrexate (15 mg/m2 twice weekly during Weeks 2, 3, 5, and 6). UHBI (600 rads) was given during Week 6 in a single dose and LCI was given during Week 7 (2000 rads/five fractions) to the tumor and mediastinum. Maintenance chemotherapy began in Week 12 with cyclophosphamide (700 mg/m2 iv every 3 weeks) and lomustine (70 mg/m2 orally every 6 weeks). Twelve patients were evaluable for response and toxicity (eight with limited disease). There were three complete response and seven partial responses after induction chemotherapy. After completion of the consolidation radiation therapy, all 12 patients had a response: six complete responses and six partial responses. Acute toxic effects included nausea and vomiting in eight patients, fever in five, and hypotension and angina in one. Subacute toxic effects included nausea, vomiting, and dehydration in two patients who required hospitalization, prolonged aplasia in one, reversible radiation esophagitis in three. Three patients had radiation pneumonitis including one with bilateral diffuse disease that led to death from respiratory failure. Only two of 12 patients received their maintenance therapy on schedule. Treatment failures occurred within the LCI field in seven patients and in distant metastatic sites in six. The median time to first relapse was 7 months and the median survival was 9 months. Because of toxicity, treatment delays, and poor survival in this group of patients, we cannot recommend this combined modality approach.     

Use of cisplatin, doxorubicin, and cyclophosphamide to treat advanced and recurrent adenocarcinoma of the endometrium

Eighteen patients with recurrent or advanced adenocarcinoma of the endometrium were treated with the combination of cisplatin, doxorubicin, and cyclophosphamide between January 1981 and December 1983. Sixteen of the 18 had received prior irradiation. None of the patients had received prior chemotherapy. Fifteen patients had previously received hormones without response. No patients received concurrent hormone treatments. Ten of the 18 patients (56%) achieved an objective response: five (28%) achieved complete response and five (28%) achieved partial response. Myelosuppression was present in seven patients, and two developed neurotoxicity. Combination chemotherapy using cisplatin, doxorubicin, and cyclophosphamide is active in patients with adenocarcinoma of the endometrium, including those who have received prior irradiation and have failed hormonal therapy.     

Critical value of laparotomy with splenectomy in stage III Hodgkin's disease as restaging procedure after chemotherapy

38 patients with stage III Hodgkin's disease underwent laparotomy with splenectomy as restaging procedure after first line chemotherapy which included MOPP, ABVD, or both. 28 patients were judged to be in clinical complete remission (CR) and 10 were resistant or had relapsed. Among patients in CR, 27 (96%) were confirmed to be in pathological CR; among patients resistant or relapsed, 9 (90%) were confirmed to have disease in the abdomen or retroperitoneum. The therapy for patients in clinical remission before laparotomy consisted of TNI or sTNI in 19 patients, mediastinal radiation in 6 patients and no further therapy in the remaining 3 patients. No significant differences were seen in survival and relapse-free survival between those patients treated by extensive and those treated by local radiotherapy or no further therapy. Instead, among those patients who received extensive radiotherapy 3 developed acute non-lymphoid leukemia (ANLL). The therapy for this group of patients consisted of further chemotherapy in 7 who had concomitant liver involvement and TNI in the remaining 3 who had the disease confined to the spleen and/or lymph nodes. Among these patients, only 3 obtained CR; 2 with radiation and 1 who was resistant to MOPP, with ABVD. This study leads us to re-consider the role of laparotomy in stage III HD which should be used as non-routine procedure only in selected patients without poor prognostic factors who may be cured by radiotherapy alone. In patients resistant to chemotherapy, an early evaluation of disease in the abdomen may be useful for a better salvage treatment.     

The Treatment of Metastatic Breast Cancer with Aminoglutethimide

Abstract: Thirty-eight patients with advanced breast cancer, resistant to prior endocrine therapy and in most cases prior chemotherapy, were treated with aminoglutethimide, 250 mg qds. Seven of 30 evaluable patients (23%) responded. Six have subsequently relapsed with a mean duration of response of 17 weeks, while one continues to respond after 50 weeks of therapy. Six additional patients (20%) had stable disease during aminoglutethimide therapy (mean duration of 16 weeks). Three of the seven responders had shown a partial response, two had stable disease and two had progressive disease on prior endocrine therapy (including tamoxifen); six of the seven patients responding to aminoglutethimide had received prior combination chemotherapy, to which ail had responded.
Aminoglutethimide was generally well tolerated, although three patients withdrew from treatment within the first two weeks because of intolerable drowsiness. Aminoglutethimide offers a useful alternative to surgical adrenalectomy for women with advanced breast cancer responsive to previous endocrine and cytotoxic chemotherapy.     

Phase 2 trial of pegylated liposomal doxorubicin in advanced endometrial cancer

Purpose To evaluate the efficacy and toxicity of pegylated liposomal doxorubicin in patients with advanced endometrial cancer.Methods Pegylated liposomal doxorubicin was administered at a dose of 40 mg/m², and repeated on an every 28-day schedule.Results A total of 19 patients were enrolled in this phase 2 trial. Fourteen patients had received prior chemotherapy (carboplatin/paclitaxel-9; cisplatin/paclitaxel-3; single agent paclitaxel-2), seven prior radiation therapy, and three prior hormonal therapy. No patients had previously received doxorubicin. Two patients (11%) developed grade 1 hand-foot syndrome following treatment with pegylated liposomal doxorubicin. There were no episodes of cardiac dysfunction (>10% reduction in baseline ejection fraction). Three patients required hospitalization for nausea, vomiting, anemia, and dehydration. Only 2 (11%) patients required dose reduction. Four of 19 patients (21%; 95% CI: 3–39%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy (duration of responses: 2 months, 3 months, 4 months, 6+ months).Conclusion The pegylated liposomal doxorubicin regimen employed in this trial exhibited an acceptable toxicity profile (cardiac dysfunction, hand-foot syndrome). Definite, although modest, antineoplastic activity in a patient population with recurrent or advanced endometrial cancer was documented.     

Non-Hodgkin's lymphoma in a population with or at risk for acquired immunodeficiency syndrome: indications for intensive chemotherapy

PURPOSE: An increased risk of malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma, is found in patients infected with the human immunodeficiency virus type 1 (HIV-1). Treatment of such patients may be complicated by their underlying immunodeficiency, especially when aggressive regimens are used. Clinical presentation and treatment outcomes were assessed in 31 patients with non-Hodgkin's lymphoma who had or were at risk for infection with HIV-1 at a single community institution. PATIENTS AND METHODS: Lymphomas presented in advanced stages and involved extranodal sites. Twenty-six patients received therapy (two radiation, one surgery), and a total of 23 patients received chemotherapy. RESULTS: A 52 percent response rate was seen with the use of chemotherapy. A history of opportunistic infections, or Kaposi's sarcoma, or both impacted negatively on the ability to achieve a complete response. Sixty-four percent of the 11 patients who received an intensive chemotherapeutic regimen, MACOP-B (methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) had complete remissions. Overall median survival for 23 patients who received chemotherapy was seven months. Patients achieving complete responses had a median survival of 20 months. CONCLUSION: Our results support intensive chemotherapy for patients with lymphoma and HIV-1 infection.     

Ophthalmologic outcomes after chemotherapy and/or radiotherapy in non-conjunctival ocular adnexal MALT lymphoma

In the present study, we evaluated the ophthalmologic outcomes of 24 patients who received chemotherapy and/or radiotherapy for the treatment of non-conjunctival ocular adnexal mucosa-associated lymphoid tissue-type (MALT) lymphoma. Ophthalmologic outcomes were assessed in patients who received chemotherapy and/or radiotherapy from March 2004 until May 2010. Outcomes were determined according to common symptoms following chemotherapy and/or radiotherapy, which consisted of decreased visual acuity, dry eye symptoms, retinopathy, optic neuropathy, increased intraocular pressure, and blepharitis. Nine patients received chemotherapy alone, eight patients received radiotherapy alone, and seven patients received chemotherapy with additional radiotherapy (chemoradiation therapy). Patients treated by chemotherapy alone showed better ophthalmologic outcome scores (mean score, 1.56) than those treated by radiation alone or chemoradiation therapy (mean score, 4.01). In conclusion, the treatment of ocular adnexal lymphoma including radiotherapy showed poor ophthalmologic outcomes due to radiation-induced complications. Recently, many new treatment options have emerged, such as immunotherapy or radioimmunotherapy. In the future study, to select a better treatment modality with fewer complications, well-designed prospective trials with ophthalmologic outcomes are needed.     

ADVANCED BREAST CANCER: RESPONSE TO HIGH DOSE ORAL MEDROXYPROGESTERONE ACETATE

We treated 105 patients with advanced breast cancer, using the progestational agent medroxyprogesterone acetate (MPA), 200 mg orally tds in a non-randomised trial. In general they were a poor risk population, since 78 had received prior endocrine therapy (21 more than one type) and 58 prior chemotherapy. Treatment was well tolerated. Side effects included weight gain, muscle cramps, fine tremor and fluid retention, but these were usually mild, resolved if the dose of drug was reduced, and only one patient stopped treatment because of toxicity. Seventeen patients died within six weeks of starting MPA, and disease progression occurred in a further 58. Nine have had stable disease for periods ranging from two to 11 months, and there were 21 who showed disease regression. Response to treatment continues in 13 of these patients, and at the time of writing the median duration of response is 10 months. Response rates were similar in pre- and post-menopausal patients. The dose of MPA was doubled to 400 mg tds in 16 patients whose disease had progressed on 200 mg tds, but no additional responses were seen in this group. Seven out of 24 (29%) patients who had not received prior endocrine therapy responded to high dose oral MPA, a response rate similar to that seen following other hormonal manipulations, but because the drug also has activity against hormone-resistant tumours and is well tolerated, it should have a role in the treatment of advanced breast cancer.     

Chemotherapy for colorectal cancer with 5-fluorouracil, cyclophosphamide, and CCNU: comparison of oral and continuous iv administration of 5-fluorouracil.

Forty-six adult patients with colorectal cancer were treated with cyclophosphamide and CCNU administered orally and 5-fluorouracil (5-FU) administered either orally or by continuous iv infusion (FCC-CIF), depending on the availability of hospital beds. The overall response rate in 37 patients with measurable disease was 25%. The response was greater in patients who had had no prior treatment (seven of 20 versus two of 17) and in patients treated with FCC-CIF (six of 19 versus three of 18). Among patients receiving FCC-CIF, response was also greater in those who had received no prior therapy (five of nine versus one of ten). The overall median survival was 7.5 months, regardless of the route of administration of 5-FU. Further investigations are indicated to study the efficacy of 5-FU administered by continuous iv infusion in combination with other agents in patients who have had no prior treatment.