5-fluorouracil,leucovorin, hydroxyurea,and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study

Summary Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m² 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m² daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m² 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m² daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m² daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.Supported in part by an American Cancer Society Clinical Oncology Cancer Development Award (to M. J. R.) and by National Cancer Institute grant CA-14599-17     

5-Fluorouracil with oral leucovorin and hydroxyurea and concomitant radiotherapy for stage III non-small cell lung cancer

Twenty-three patients with regionally advanced non-small cell lung cancer (NSCLC) (Stage III) were treated with continuous infusion 5-fluorouracil (5-FU) augmented by high-dose oral leucovorin and hydroxyurea and concomitant radiotherapy. This chemoradiotherapy regimen was administered during 5 days of every other week for six cycles (total radiation dose, 6000 cGy). Three patients (13%) had stable disease, 13 patients (57%) had a partial response (PR), and 1 patient (4%) had a complete response (CR). The overall response rate was 61% (95% confidence interval, 41% to 81%). At a median follow-up time of 19 months, the median survival time for all 23 patients was 12 months. The median time to disease progression was 6 months. Twelve patients have had disease progression outside of the chest, and only 3 patients have had intrathoracic disease progression as the site of first failure. The toxicities of this regimen consisted of mild to moderate myelosuppression and moderate degree dermatitis and mucositis. It was concluded that concomitant chemoradiotherapy with this regimen results in high local activity at acceptable toxicity. However, the systemic activity of this regimen was low, resulting in a high distant recurrence rate and a median survival time that was not different from that achieved with standard therapy. Therefore, its use, as defined in this study, cannot be recommended.     

Pilot study of 6 weeks of chemoradiotherapy with 5 FU and hydroxyurea in malignant gliomas

Summary In an attempt to improve the primary treatment of malignant gliomas we used a concomitant 6-week course of chemoradiotherapy with 5 fluorouracil (5 FU) and hydroyxurea (HU) in 24 adults with anaplastic astrocytoma (AA) (7 cases) or glioblastomas (GLB) (17 cases). This patient population was characterised by a poor prognostic profile; 50% of cases had biopsic or subtotal surgery and 70% had GLB. Patients received 2 Gy/day 18 MV photons with 300m² of 5 FU in continuous infusion and 500 mg x 4/day per os of HU, five days per week during 6 weeks. Treatment was poorly tolerated in terms of toxicity and implied heavy logistics (hospitalization, central venous access) worsening the quality of life which is already bad in malignant gliomas. Unfortunately we did not improve median survival which does not exceed 26 weeks with 7 long survivors (> 49 weeks). This pilot study does not offer any benefits over current standard approaches. Aggressive locoregional approaches such as this should perhaps be attempted in patients with a better profile.     

Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy

PURPOSE: To report the results of a Phase I/II clinical trial for patients with malignant gliomas, treated with combined X-ray radiotherapy (XRT), chemotherapy, and carbon ion radiotherapy (CRT). METHODS AND MATERIALS: Between October 1994 and February 2002, 48 patients with histologically confirmed malignant gliomas (16 anaplastic astrocytoma (AA) and 32 glioblastoma multiforme (GBM) were enrolled in a Phase I/II clinical study. The treatment involved the application of 50 Gy/25 fractions/5 weeks of XRT, followed by CRT at 8 fractions/2 weeks. Nimustine hydrochloride (ACNU) were administered at a dose of 100 mg/m(2) concurrently in weeks 1, 4, or 5 of XRT. The carbon ion dose was increased from 16.8 to 24.8 Gray equivalent (GyE) in 10% incremental steps (16.8, 18.4, 20.0, 22.4, and 24.8 GyE, respectively). RESULTS: There was no Grade 3 or higher acute reaction in the brain. The late reactions included four cases of Grade 2 brain morbidity and four cases of Grade 2 brain reaction among 48 cases. The median survival time (MST) of AA patients was 35 months and that of GBM patients 17 months (p = 0.0035). The median progression-free survival and MST of GBM showed 4 and 7 months for the low-dose group, 7 and 19 months for the middle-dose group, and 14 and 26 months for the high-dose group. CONCLUSION: The results of combined therapy using XRT, ACNU chemotherapy, and CRT showed the potential efficacy of CRT for malignant gliomas in terms of the improved survival rate in those patients who received higher carbon doses.     

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study

PURPOSE: To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. METHODS AND MATERIALS: Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. RESULTS: Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). CONCLUSION: In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.     

恶性脑胶质瘤术后三维适形放射治疗

 【摘要】　目的　探讨恶性脑胶质瘤术后三维适形放射治疗（3DCRT）的临床疗效及患者不良反应。方法　将62例恶性脑胶质瘤术后患者随机分为两组，3DCRT组32例，常规放疗组30例，照射剂量均为DT 60 Gy／30次，6周。结果　3DCRT组近期有效（CR+PR）率为87.5 %（28／32），常规放疗组为73.3 %（22／30），两组比较差异无统计学意义（P = 0.158）。3DCRT组1、2年生存率分别为90.6 %（29／32）、81.3 %（26／32），常规放疗组1、2年生存率分别为80 %（24／30）、56.7 %（17／30），两组间差异有统计学意义（P＜0.05）。3DCRT组放射性脑水肿发生率为15.6 %（5／32），常规放疗组为40 %（12／30），两组间差异有统计学意义（P＜0.05）。放射性脑水肿经脱水治疗后好转，未发生严重并发症。主要死因是局部未控和肿瘤复发。结论　恶性脑胶质瘤术后行3DCRT比常规放疗有较好的疗效，其有较高的肿瘤局部控制率和1、2年生存率，无严重不良反应。     

Escalating doses of interferon alpha-2A with cisplatin and concomitant radiotherapy: a phase I study

In this phase I study, we added escalating doses of interferon-alpha2A (IFN) to cisplatin and twice-daily radiotherapy based on the following rationale. Radiation enhancement has been shown for both interferon and cisplatin; in addition, potentiation of the cytotoxic activity of cisplatin by interferon has been demonstrated. A total of 48 patients with advanced solid tumors were treated with radiotherapy in 2 daily fractions of 125 cGy plus cisplatin at 8–10 mg/m² per day delivered on 3 different schedules (continuous infusion, daily short-term infusion, and single short-term infusion of 50 mg/m²). IFN was injected s.c. 2h preceding the first daily fraction of radiation. IFN doses ranged from 0 to 5.0×10⁶ U/m² per day. All therapy was given over 5 days of every other week until completion of the radiotherapy. Treatment at all dose levels was well tolerated during cycles 1 and 2, with no instance of acute grade 3 or 4 toxicity being noted. However, cumulative myelosuppression in patients receiving more than two treatment cycles was seen at all dose levels and was attributed to the repeated administration of cisplatin. Alteration of the cisplatin schedule did not allow for further dose escalation of cisplatin. Our recommended doses are cisplatin given at 8 mg/m² per day as a continuous infusion with IFN at 5.0×10⁶ U/m² per day. Among 24 patients with non-small-cell lung cancer, 2 had a complete response, 9 had a partial response, and 7 had stable disease. We conclude that this concomitant cisplatin-IFN-radiotherapy regimen is feasible. Activity was seen in non-small-cell lung cancer, and further studies of this regimen in that disease appear indicated.     

替莫唑胺联合放射治疗治疗恶性脑胶质瘤的疗效观察

目的探讨替莫唑胺(TMZ)联合放射治疗治疗恶性脑胶质瘤的临床疗效和安全性评价。方法收集56例病理学诊断为恶性脑胶质瘤的患者,其中III级患者为32例,IV级患者为24例。根据不同的治疗方法将患者分为TMZ联合放疗(TMZ-RT)组(30例)和单纯放疗(RT)组(26例)。TMZ-RT组患者采用放疗联合TMZ化疗(75 mg·m-2·d-1)治疗6周,放疗后继续给予TMZ序贯/辅助(150²00 mg·m-2·d-1)化疗2200 mg·m-2·d-1)化疗2⁴周。RT组患者接受立体定向适形放射治疗1.84周。RT组患者接受立体定向适形放射治疗1.8³Gy/d,部分患者接受超分割放射治疗,总剂量为603Gy/d,部分患者接受超分割放射治疗,总剂量为60⁷5 Gy。治疗结束后评估两组患者的生存率和近期疗效。结果影像学结果显示,TMZ-RT组完全缓解8例,部分缓解9例,稳定10例,进展3例;RT组完全缓解6例,部分缓解8例,稳定8例,进展4例,两组差异无统计学意义(P>0.05)。TMZ-RT组患者的1、2、3年生存率分别为86.7%、80.0%和56.7%。RT组患者的1、2、3年生存率分别为73.1%、30.8%和11.5%,两组患者的2年和3年生存率比较,差异有统计学意义(P<0.05)。TMZRT组和RT组患者的中位复发时间分别为(23.1±8.7)个月和(15.8±8.9)个月,两组差异有统计学意义(P<0.05)。TMZ-RT组和RT组患者化疗后KPS评分别为(89.8±9.7)分和(65.4±10.3)分,两组间差异有统计学意义(P<0.05)。TMZ-RT组患者的不良反应发生率较低且,患者的生活质量水平显著高于RT组患者(P<0.05)。结论 TMZ联合放疗与单纯放疗治疗恶性脑胶质瘤的近期疗效相当,但TMZ联合放疗能够显著提高2年和3年的生存率并延缓复发时间。TMZ联合放疗治疗不良反应轻,安全性高,能够改善患者的生活质量,值得临床进一步推广。     

Simultaneous chemotherapy and radiotherapy with escalating doses of chemotherapy in patients with advanced esophageal carcinoma.

From January 1992 to January 1995, 39 patients were diagnosed with esophageal carcinoma at the Department of Veterans Affairs Medical Center in Washington, D.C. All of the patients were men aged 44 to 78, and the median age was 66. Staging included a physical examination, serum chemistries, barium swallow, endoscopy with biopsy, and computed tomographic scans of the chest and abdomen. Seven patients were ineligible for the study because they had poor performance status, refused treatment, or received treatment at another medical center. All the patients treated had a performance status of 1 to 2. In 1992, 15 patients received 400 mg/m2/d 5-fluorouracil; in 1993, eight patients received 500 mg/m2/d 5-fluorouracil; and in 1994, nine patients received 600 mg/m2/d 5-fluorouracil as a continuous intravenous infusion during radiotherapy, which consisted of 60 Gy over 6 to 8 weeks. The complete response rates were 26%, 25%, and 22% for 1992, 1993, and 1994, respectively. The median survival was 11 months, 14 months and 9 months for those same years, respectively. The major toxicities were hematologic. Three patients died of pneumonia during treatment. Simultaneous chemotherapy and radiotherapy is an effective mode of therapy for localized esophageal carcinoma. However, escalating doses of chemotherapy did not increase the complete response rate.     

Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma

BACKGROUND: Although temozolomide is active against recurrent malignant glioma, responses in many patients are modest and short-lived. Temozolomide may prove more effective in combination with other agents. Therefore, combination oral chemotherapy for these patients is a particularly attractive approach. METHODS: The authors conducted a Phase I study of temozolomide in combination with escalating doses of oral etoposide (VP-16) to determine the maximum tolerated doses of these two agents when given together. The temozolomide dose was fixed at 150 mg/m(2) per day on Days 1-5. The oral VP-16 was escalated in cohorts of 3 to 6 patients by numbers of days of VP-16 administered: 50 mg/m(2) per day, Days 1-5 (dose level 1), Days 1-8 (dose level 2), Days 1-12 (dose level 3), Days 1-16 (dose level 4), and Days 1-20 (dose level 5). Therapy was given in 28-day cycles. RESULTS: Of the 29 patients enrolled, 26 were fully evaluable and 3 were partially evaluable for toxicity. The 29 patients received a total of 92 cycles. The median age of the patients was 49 years (range, 28-76 years). Diagnoses included glioblastoma (n = 19), gliosarcoma (n = 3), anaplastic astrocytoma (n = 5), and anaplastic oligoastrocytoma (n = 2). The median time from diagnosis to disease recurrence was 8 months (3-188 months). Twenty patients were treated at the first disease recurrence, seven at the second, and two at the third. Twenty-four patients (83%) were receiving anticonvulsants and 24 were receiving dexamethasone. All patients had received previous radiation, and 25 of 29 had been treated with chemotherapy previously. Of the 3 patients at dose level 1, none had dose-limiting toxicity (DLT). Of the 6 patients at dose level 2, 1 patient had DLT: Grade 3 thrombocytopenia resulting in a > 2-week delay in starting the next cycle of chemotherapy. Of the 6 patients at dose level 3, 1 patient had DLT: death due to pneumonia. There were 2 DLTs in the 7 patients at dose level 4: fever, neutropenia, and herpes zoster infection in 1 patient and death due to pneumonia in another. Seven patients had been started at dose level 5 when DLT was established at dose level 4: of the 5 fully evaluable and 2 partially evaluable patients at dose level 5, there was no DLT. CONCLUSIONS: The maximum tolerated dose of temozolomide and oral VP-16 in this heavily treated group of patients with recurrent malignant glioma is temozolomide 150 mg/m(2) per day for 5 days and oral VP-16 50 mg/m(2) per day for 12 days.     

Combination chemotherapy with carmustine and cisplatin before,during, and after radiotherapy for adult malignant gliomas

Summary Twenty-two patients, aged 16 to 67, who had malignant gliomas after surgical resection were treated with carmustine and cisplatin intravenous infusion before, during, and after radiotherapy. All patients had subtotal or total resection, or biopsy as the initial procedure. Twenty-one patients who had at least 2 cycles of chemotherapy and finished the whole course of radiotherapy were considered to be evaluable for responses. Among them, 5 had glioblastoma multiforme, 16 had anaplastic astrocytoma. The median time to tumor progression was 35 weeks (range 12–130 weeks) and median survival time was 66 weeks (range 10–156 weeks). Early progression occurred more frequently in patients with biopsy only and subtotal resection, and in patients with glioblastoma than in those with anaplastic astrocytoma. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients, and with ototoxicity in 1 patient, nephrotoxicity in 2 patients. Combination of carmustine and cisplatin with cranial irradiation for malignant gliomas is moderately toxic and appears to offer no obvious survival advantage compared with radiation therapy plus BCNU alone.     

A randomized phase II study of 5-fluorouracil,hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil,hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers

IntroductionWe conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC).Patients and methodsEligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m²/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy.ResultsTwenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen.ConclusionsLocoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.     

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas

Purpose Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients and method Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Results Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1–7) and the median number of prior treatment regimens was 3 (range, 1–8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Conclusion Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG. Supported by National Institutes of Health grant nos. 1-P50-CA108786-01, NS20023 and CA11898 and by grant no. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.     

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.     

Hypofractionated stereotactic radiotherapy for unifocal and multifocal recurrence of malignant gliomas

To evaluate the efficacy and safety of stereotactic radiotherapy (SRT) for unifocal and multifocal recurrence of malignant gliomas. Between June 2007 and October 2010, 35 consecutive patients with 47 recurrent lesions were treated with salvage SRT at the University of Cincinnati. Thirty-three patients treated had a diagnosis of high grade glioma, four Grade III and twenty-nine Grade IV, while two patients initially were diagnosed with grade II tumors but recurred as high grade lesions. All patients had previously received a median dose of 59.4 Gy. Twenty-six patients were treated for a single lesion, and nine patients were treated for multiple lesions. Using SRT, patients were re-treated with a median total dose of 30 Gy in a median of five fractions. Median survival from diagnosis was 22 months and median survival following SRT was 8.6 months. The median survival following SRT for those patients treated for multifocal recurrence was 7.9 versus 10 months for those treated for unifocal recurrence (p = 0.7). Multivariate analysis showed local control of the SRT treated lesion(s) 6 months after SRT was associated with a significant improvement in survival (p ≤ 0.01). All patients tolerated their treatment well and completed their prescribed SRT as planned. Three patients (9 %) were felt to possibly have developed radiation necrosis following therapy. SRT was both well tolerated and efficacious with the local control provided by SRT resulting in improved overall survival. This benefit also seems to be apparent for patients with multi-focal recurrence.     

A dose escalating study of oxaliplatin and high dose weekly leucovorin and 5-Fluorouracil in patients with advanced solid tumors

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of L-OHP plus 5-FU and LV in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalated doses of L-OHP (starting dose 50 mg/m2) as a 2-hour IV infusion on Days 1 and 15, and LV (500 mg/m2 as a 2-hour IV infusion) followed by escalated doses of 5FU (starting dose 1,800 mg/m2) as a 22-hour continuous IV infusion on Days 1, 8, 15, 21 every 6 weeks. DLTs were evaluated in the first cycle. RESULTS: Fifty-two patients [median age: 66 years; PS (ECOG) 0-1 in 90 percent] were treated on 12 dose-levels. Five (10 percent) patients had received 2 prior chemotherapy regimens, 24 (46 percent) one, and 23 (44 percent) were chemo-na?ve. The DLT was reached at the dose of LOHP 100 mg/m2 and 5FU 2,200 mg/m2. Dose-limiting events were G3 diarrhea, G3 asthenia, G4 neutropenia, and G4 thrombocytopenia. Grade 3 diarrhea was observed in 6 (12 percent) patients and Grade 3 fatigue in 6 (12 percent). One (2 percent) patient developed Grade 4 neutropenia and another (2 percent) Grade 4 thrombocytopenia. CONCLUSION: The MTD were L-OHP 95 mg/m2 on d1 and d15 and 5FU 2,200 mg/m2/week for 4 consecutive weeks every 6 weeks.     

Continuous infusion 5-fluorouracil with escalating doses of intermittent cisplatin and etoposide. A phase I study

Continuous infusion 5-fluorouracil (CI 5-FU) and the combination of cisplatin (CDDP) plus etoposide (VP-16) have emerged as salvage regimens for metastatic breast carcinoma (MBC). In this study, 18 patients (15 with MBC) were entered into a Phase I study to determine the maximum intermittent doses of CDDP and VP-16 that could be added to 200 mg/m2/d CI 5-FU. The maximum tolerated dose of the combination was 40 mg/m2 of CDDP and 60 mg/m2 of VP-16 weekly for the first 8 weeks and every other week thereafter. The dose-limiting toxicities of the regimen were myelosuppression and thrombocytopenia. Two complete responses (both patients had received no previous chemotherapy) and one partial response were noticed. This regimen at the doses described here is appropriate for Phase II trials as an alternative to doxorubicin-based regimens for MBC.     

Concurrent hypofractionated radiotherapy and 5-Fluorouracil for advanced sarcomas of the bone

Purpose. 5-Fluorouracil (5-FU) has shown radiosensitizing properties in vitro. This paper reports the effects of radiotherapy and concomitant intravenous 5-FU radiosensitization in the treatment of advanced bone sarcomas.Subjects/methods. Four patients with large inoperable bone sarcomas (three chondrosarcomas and one fibrosarcoma) were treated with hypofractionated radiotherapy and concomitant 5-FU bolus injection (300 mg m(-2)) before each fraction of radiotherapy. A radiation fraction of 5 Gy was given twice a week to a normalized total dose (alpha/beta=4 Gy) of 75 Gy.Results. The regimen was well tolerated, the main toxicity being grade I/II diarrhoea in two cases with pelvic irradiation. Treatment interruption for 1 week was necessary in two cases with pelvic disease but not in two patients treated for sarcoma of the extremities. A complete symptomatic relief was obtained in all cases immediately after the third to the fifth fraction and the median duration was 10 months. Computed tomography scan documented a partial response in 2/4 cases.Discussion. Hypofractionated radiotherapy combined with potential lethal damage inhibitors for bone sarcomas requires further investigation.