Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m²/day, with planned escalations to 250, 300, 350, and 400 mg/m²/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m²/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m² level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m²/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.     

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.

Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m² days 1–3, cisplatin 30 mg/m² days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m² every 8 weeks × 4 cycles was given after radiation therapy.

Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m² days 1–3, cisplatin 20 mg/m² days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m² every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.

Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.     

Etoposide and Mitoxantrone as a Second Cycle of Consolidation Therapy Following High Dose Cytosine Arabinoside and Daunorubicin in Patients with Acute Non-Lymphocytic Leukemia in Remission: A Pilot Study

High dose cytosine arabinoside (ARA-C) has produced long term relapse free survival in 26% to 49% of patients when used as consolidation therapy of acute non-lymphocytic leukemia (ANLL) in first remission. However, the optimal consolidation regimen has not been defined. In this pilot study we attempted to confirm and extend our previous studies of high dose consolidation therapy by administering two cycles of consolidation chemotherapy to patients with ANLL in first remission. The first cycle was high dose ARA-C 3 gm/m² over 1 hour every 12 hours for 12 doses followed by daunorubicin 45 mg/m²/day for three days. The second cycle was etoposide 75 mg/m²/day for 10 days and mitoxantrone 12 mg/m²/day for three days.

Twenty-three patients received high dose consolidation chemotherapy, 13 of whom received the proposed two cycles. The major reason for not receiving the planned second consolidation cycle was life threatening toxicity, primarily fungal infection, during the first consolidation cycle. By actuarial estimate, 46% of patients receiving consolidation chemotherapy were projected to be relapse free at 36 months. There were no deaths during consolidation. Survival was not improved in patients receiving etoposide and mitoxantrone as the second cycle of consolidation therapy as compared to patients receiving only one cycle of consolidation therapy.     

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m², etoposide 100 mg/m², and cisplatin 50 mg/m² on day 1; vincristine 1 mg/m² on day 8; and ifosfamide 1.2 gm/m² on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.     

A Phase I—II Study of Cyclophosphamide, Epidoxorubicin, Levofolinic Acid/5-Fluorouracil and Recombinant Human Granulocyte Colony Stimulating Factor in Metastatic Breast Carcinoma

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m² on day 1, levofolinic acid 100 mg/m² plus 5-fluorouracil 375 mg/m² on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m²/day until the dose limiting toxicity (DLT) was reached. At the dose of 40mg/m²/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent partients were treated at the maximal tolerated dose of EDXR (35 mg/m²/day). In the group of 18 patients treated at 35 mg/m²/day the overall response rate was 78%, with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent.     

High Dose Chemotherapy with G-CSF in Refractory Hodgkin's Disease

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non- myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with hih doses: BCNU, 300 mg/m², on day 1, vincristine 1.4 mg/m², and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m², iv, on days 14 and 15; and ifosfamide 4 g/m², and epirubicin 180 mg/m², on day 29. G-CSF Sug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m², iv, on days 1 and 8; vincristine 1.4 mg/m², iv on days 1 and 8; prednisone 60 mg/rn², PO, daily, days 1 to 14 and procarbazine 100 ng/m², PO, daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58 % (50 out of 86 patients) being 38 and 76 % in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44 % of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autolo-gous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.     

A Phase I Trial of Combination Chemotherapy Employing Carboplatin, Vinca Alkaloids, with or without Bleomycin in Patients with Advanced Malignant Tumors

A Phase I trial of three carboplatin-based combination chemotherapy regimens was conducted. These included: carboplatin plus vindesine; carboplatin, vindesine, plus bleomycin; and, carboplatin plus vinblastine. Carboplatin was administered every 28 days as an intravenous bolus. The initial dose was 150 mg/m² and doses were escalated by 50 mg/m² in each successive group of patients. Vindesine was given at a dose of 3 mg/m² weekly for 5 doses, then every other week thereafter. Bleomycin, 10 units/m² IV bolus, was followed by 10 units/m²/day infusion for 4 days (3-7 and 31-35). Vinblastine was given at 5 mg/m² every other week. Doses of vindesine, vinblastine, and bleomycin were not escalated. The maximum tolerated dose (MTD) of the carboplatin, vindesine bleomycin regimens was reached at a carboplatin dose of 250 mg/m² and the MTD was influenced by the weekly vindesine in the initial 4 weeks of therapy. The MTD of the carboplatin and vinblastine regimen was reached at a carboplatin dose of 500 mg/m². Dose-limiting toxicity of all three regimens was leukopenia. Although nonhematological toxicity of the carboplatin and vinblastine regimen included peripheral neuropathy and emesis, therapy was easily administered in an outpatient setting. The recommended Phase II dose of carboplatin is 450 mg/m² in combination with vinblasrine at this dose and schedule for previously untreated patients. Twelve patients demonstrated major responses with the various regimens including 5 of 24 patients with adenocarcinoma of the upper gastrointestinal tract.     

Concurrent Cisplatin, Prolonged Oral Etoposide, and Vincristine plus Chest and Brain Irradiation for Limited Small Cell Lung Cancer: A Phase II Study of the Southwest Oncology Group (SWOG-9229)

Purpose: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting.

Methods and Materials: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m² i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m² (days 1–14, 29–42, and 57–70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m² i.v., doxorubicin 50 mg/m² i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy.

Results: Among 56 eligible patients, 93% had SWOG performance status 0–1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimun follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3).

Conclusion: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

A Phase I Pilot Study of BCNU plus Thymidine in Patients with Refractory Cancer

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m²/day to 105.5 g/m²/day for 48 hr, along with 100 mg/m²/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m²/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m /day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.     

Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction.[8] This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m² over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m² bolus, followed by infusional 5-FU 600 mg/m² over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m² bolus, followed by cisplatin 50-75 mg/m² over 30 minutes and then infusional 5-FU 600 mg/m² over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m² inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.     

A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma

The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m²) combined with a fixed dose of docetaxel (60 mg/m²) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m²) was determined to be 90 mg/m². Docetaxel 60 mg/m² plus nedaplatin 90 mg/m² induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.     

Phase I and pharmacodynamic study of Triapine,a novel ribonucleotide reductase inhibitor,in patients with advanced leukemia

In a phase I study, 24 patients with refractory leukemia received Triapine^®, a novel ribonucleotide reductase (RR) inhibitor, as a continuous intravenous infusion over 96 h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120 mg/m² per day, and the maximum tolerated dose (MTD) was 160 mg/m² per day. Three of eight patients receiving 160 mg/m² per day in the first course, and one patient escalated to this dose in a second course, developed hepatic dose-limiting toxicity (DLT). For the days 1 and 8 regimen, the first 96 h infusion was administered at a fixed dose of 140 mg/m² per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160 mg/m² per day without observing DLT. No objective responses occurred. Over 70% of patients had a >50% reduction in white blood cell counts. The steady-state levels of Triapine were between 0.6 and 1 μM. As expected from the in vitro studies, at these plasma concentrations there was a decline in dATP and dGTP pools and a decrease in DNA synthetic capacity of the circulating leukemia cells. Based on these clinical, pharmacokinetic, and pharmacodynamic data, Triapine warrants further study in patients with hematologic malignancies.     

Long-term Maintenance Combination Chemotherapy with OPECMPEC (Vincristine or Methotrexate, Prednisolone, Etoposide and Cyclophosphamide) or with Daily Oral Etoposide and Prednisolone Can Improve Survival and Quality of Life in Adult T-cell LeukemiaLymphoma

Acute leukemia and lymphoma varieties of adult T-cell leukemiallymphoma (ATL) usually cany a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination rotocol, OPEClMPEC (weekly doses of vincnstine, 0.7 mg/m² or methotrexate, 14 mg/m; prednisolone, 20 mg/m²; etoposide, 70 mg/m² and cyclophosphamide, 200 mg/m²). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPECNPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting.     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non–small-cell lung cancer

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of twice-weekly gemcitabine and concurrent thoracic radiation in patients with Stage IIIa/IIIb non–small-cell lung cancer (NSCLC).

Methods and Materials: Seventeen patients with histologically confirmed Stage IIIa and IIIb NSCLC were studied. Gemcitabine was administered via a 30-min i.v. infusion twice weekly for 6 weeks concurrent with 60 Gy of thoracic radiation. Gemcitabine, starting at a twice-weekly dose of 10 mg/m² (20 mg/m²/week), was escalated in 10–15 mg/m² increments in successive cohorts of 3 to 6 patients until dose-limiting toxicity was observed.

Results: Of the 17 patients entered, 16 were evaluable for toxicity. The dose-limiting toxicity at 50 mg/m² given twice weekly (100 mg/m²/week) was Grade 3 pneumonitis observed in 1 patient, Grade 3 pulmonary fibrosis in a second patient, and Grade 4 esophagitis observed in two additional patients. Twice-weekly gemcitabine at a dose of 35 mg/m² was determined to be the MTD. The overall response rate for the 16 evaluable patients was 88%. The median survival for the entire group is 16.0 months.

Conclusions: The MTD of twice-weekly gemcitabine is 35 mg/m² (70 mg/m²/week) given with thoracic radiation. A Phase II study within the Cancer and Leukemia Group B to ascertain the potential efficacy of this treatment regimen is in development.     

A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer

In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m²/day to 1.5 mg/m²/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m²/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/m²/day continuous IV infusion combined with tamoxifen 200 mg/kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer.     

Pentostatin, chlorambucil and prednisone therapy for B-chronic lymphocytic leukemia: a phase I/II study by the Eastern Cooperative Oncology Group study E1488

Pentostatin is a purine nucleoside analog with demonstrated activity in low-grade lymphoid malignancies. The purpose of this study was to determine the dose of pentostatin (dCF) that could be combined with chlorambucil and prednisone to treat chronic lymphocytic leukemia (CLL), evaluate the toxicity of the resulting regimen and to estimate its efficacy. This was a multi-institutional Eastern Cooperative Oncology Group (ECOG) phase I - II study. Individuals with active B-CLL were eligible if they had no prior treatment or were in sensitive first relapse, provided they had normal renal and hepatic function. Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m² and prednisone 80 mg/day, 1 - 5 of each 14-day cycle. The pentostatin dose was 2 mg/m² IV, day 1 for the first 6 patients; 3 mg/m² IV, day 1 for the next 6 patients; and 4 mg/m² IV, day 1 for the last set of 6 patients. Fifty-five patients were entered. Because of increasing toxicity with no apparent improvement in clinical efficacy on escalation of the pentostatin dose, 2 mg/m² was chosen as the phase II dose, and 43 patients were treated at this level. Thirty-nine of these patients were eligible, of which 38 were evaluable for response, 36 of these 38 had no prior treatment. Complete response (CR) manifested by normal bone marrow morphology, peripheral blood counts and resolution of any lymphadenopathy or hepatosplenomegaly occurred in 17 patients (45%). The overall objective response rate was 87%. The median response duration was 33 months and the median survival 5 years. The median time to treatment failure is 32 months. Severe (Grade 3 + ) infections were seen in 31% of patients and included bacterial pneumonia (n = 4), Pneumocystis pneumonia (n = 1), fungal pneumonia (n = 2), urinary tract infection with sepsis (n = 1) and Herpes Zoster (n = 5). Overall, 11 patients had H. Zoster while on study. Due to toxicity, 33% of patients stopped therapy. Pentostatin, chlorambucil and prednisone is a highly active regimen in CLL but cannot be recommended in present form because of an unacceptable incidence of opportunistic infections. These findings add to other recent reports which suggest combination therapy with pentostatin and alkylators are active in B-CLL. However, these combination chemotherapies will need to be combined with appropriate addition of anti-bacterial and anti-viral prophylaxis to reduce infection risk for B-CLL patients.     

Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100 mg/m² days 1, 3, 5 and cisplatin 80 mg/m² day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m² resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m². The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m² without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.     

Treatment of Advanced Gastric Cancer with a Modified Regimen of Etoposide/Leucovorin/5-Fluorouracil

The efficacy and toxicity of a combination of etoposide 100 mg/m²/day iv on day 2-4, leucovorin 300 mg/m²/day iv, and 5-FU 500 mg/m² day iv on day 1-5 every 4 weeks were assessed in 21 patients with advanced gastric cancer with measurable or evaluable diseases. Eight patients had an objective response, including 3 in CR. The overall response rate was 38.1% (95% CI 33.4-42.8%). Five of 8 patients who exhibited locally advanced and unresectable diseases had an objective response (2 CR, 3 PR). The response rate in patients with metastatic disease was 23.0% (95% CI 14.4-31.6%). The median progression-free interval and overall survival time were 7 and 10 months, respectively. The most frequent side effect was alopecia (Gr I/II 71.4%). No treatment-related death occurred. Modified ELF is a relatively effective and tolerable combination regimen for advanced gastric cancer and can be safely administered to elderly patients and patients with systemic diseases.