洛铂联合固定剂量多西紫杉醇二线及以上治疗晚期实体肿瘤的剂量递增研究

背景与目的：恶性肿瘤一线化疗后多出现复发或转移,需要二线及以上治疗。本研究旨在确定洛铂联合固定剂量多西紫杉醇治疗化疗后进展的实体肿瘤时洛铂的最大耐受剂量(maximum-tolerated dose,MTD),并评价其不良反应。方法：应用改良的Fibonacci法进行洛铂剂量递增,固定多西紫杉醇剂量为60 mg/m²,洛铂初始剂量为30 mg/m²,组间递增剂量为5 mg/m²,每21天重复。每组至少3例,如1个剂量组中3例均无剂量限制性毒性(dose-limiting toxicity,DLT)出现,则进入下1个剂量组,直至出现DLT,DLT的低一剂量水平即为MTD。结果：17例患者共完成58个周期化疗,进行3个剂量组的研究(洛铂分别为30、35、40 mg/m²),完全缓解(complete response,CR)0例,部分缓解(partial response,PR)1例,疾病稳定(stable disease,SD)10例,疾病进展(progression disease,PD)3例;有效率(response rate,RR,CR+PR)为7.1%(1/14),疾病控制率(disease control rate,DCR,CR+PR+SD)为78.6%(11/14)。主要不良反应为白细胞下降,3例出现DLT,其中2例发生在洛铂40 mg/m²组。确定洛铂35 mg/m²组为MTD。结论：本组洛铂联合固定剂量多西紫杉醇的MTD为35 mg/m²,其不良反应可耐受。     

Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia

: Indolent non-Hodgkin’s lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the palliative effect of this regimen in patients with disseminated INHL or CLL.

: Twenty-two patients (11 men, 11 women, median age 62 years, range 30–89) with disseminated INHL (n = 15) or CLL (n = 7) were treated with local low-dose RT, 2 Gy × 2 within 3 days, with the aim of achieving palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3–26).

: All patients and all irradiated sites were assessable for response. Of the 22 patients, 18 responded to the treatment, corresponding to an overall response rate (RR) of 82%; 12 patients (55%) achieved a complete response (CR), 5 patients (22%) a partial response (PR), and 1 patient had a CR at three sites and a PR at one site. Of the 31 irradiated sites, 27 responded to treatment, corresponding to an overall RR of 87%; in 20 sites (65%) a CR was achieved and in 7 sites (22%) a PR. Patients with disseminated INHL had an overall RR of 87% (74% CR, 13% PR); patients with CLL had an overall RR of 71% (29% CR, 42% PR). The median duration of response was estimated at 22 months. None of the patients had significant side effects from the treatment.

: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects.     

Combination Therapy with Platinum and Etoposide of Brain Metastases from Breast Carcinoma

Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m² day 1) and etoposide (100 mg/m² days 4,6,8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12 + 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.     

Evaluation of Two Consecutive Regimens in Advanced Gastric Cancer

Treatment of gastric cancer still presents a challenge in cancer chemotherapy. In our Institute, from January 1981 to November 1984, 45 patients were given 5-fluorouracil (5FU) 600 mg/m² Days 1, 8, 29, and 36; doxorubicin (A) 30 mg/m² Days 1 and 29; mitomycin-C 10 mg/m² Day 1 (FAM regimen) every 8 weeks. From December 1984 to October 1986, 26 patients were treated with 5FU 300 mg/m² on Days 1-5, A 40 mg/m² on Day 1, cisplatin (P) 100 mg/m² on Day 1 (FAP regimen) every 3 weeks. In the FAM group, 42 patients are evaluable for response; 5 (12%) partial remission (PR), 9 stable disease (SD), and 28 progressions (PRO) were observed. Median duration of response (MDR) was 21 weeks (range 13-45) and the median survival (MS) in the whole group was 27 weeks. In the FAP group, 23 patients are evaluable: 2 CR (9%), 11 PR (47%), 2 SD (9%), and 8 PRO (34%) were observed; CR duration was 24 and 107+ weeks, respectively, MDR of PR was 22 weeks (5-35). The MS of all patients was 16 weeks. Toxicity (WHO criteria) was mild in the FAM group and severe in the FAP group. In spite of a higher objective response rate, the short MS and the severe toxicity observed in the FAP group do not merit recommendation of this regimen in patients with gastric cancer; therefore neither FAM nor FAP appear to be an ideal standard therapy.     

A Phase II Study of Carboplatin and Prolonged Administration of Oral Etoposide in Patients with Small-Cell Lung Cancer

Prolonged oral administration of etoposide may have a theoretical advantage over intravenous infusion, and carboplatin has a more favorable toxicity profile than cisplatin. A combination of carboplatin 300 mg/m² and oral etoposide 40 mg/m²/day for 21 days was assessed in 74 (42 limited, 32 extensive disease) previously untreated patients with small-cell lung cancer. Response rate was 69% (CR 19%, PR 50%) for limited disease and 72% (CR 9%. PR 63%) for extensive disease. Median response duration and overall survival was 6.6 and 10.1 months for limited disease, and 5.3 and 9.1 months for extensive disease, respectively. One-year and two-year survival was 36 and 10% for limited disease and 31 and 2% for extensive disease, respectively. The major toxicity was hematological with grade 4 or greater neutropenia in 36% and grade 4 thrombocytopenia in 16% and one patient died of neutropenic fever. Non-hematologic toxicities were mild and grade 3 emesis was observed in 5% of patients. Carboplatin combined with 21-day oral etoposide showed only modest activity against small-cell lung cancer with high toxicity and did not merit further evaluation.     

Phase I-II Trial of High-Dose Melphalan in Previously Untreated Stage III Multiple Myeloma: Cancer and Leukemia Group B Study 8512

To study the efficiency of high-dose melphalan in previously untreated patients with advanced myeloma, we performed a Phase I-U trial. Twenty-eight patients were treated at dose level of 60-140 mg/m². Each patient was first treated with a priming dose of cyclophosphamide (300 mg) followed by high-dose melphalen 1 week later. One course of therapy was given. Patients were then followed without further therapy until relapse. Clinical and laboratory features of the 28 patients in this study included: median age 63, performance status 0-2, hypercalcemia 21%, bone pain 82%, paraprotein types: IgG 76%, Iga 20%, and paraproteinuria 71%. Because none of the patients acheived complete remission (CR) at 60 mg/m², despite life-threatening toxicity in all patients, the dose level was rapidly increased to 140 mg/m², a dose previously reported to induce a high percentage of CR. At this dose, CR was achieved in only 1 of 11 patients (9%). This patient had multiple plasmacytomas without generalized bone marrow involvement. One additional patient at 100 mg/m² achieved CR Of the whole group, 12 achieved PR. Durations of remissions were generally short: CR 6.3 and 18+ months and PR 2.3-18 month, median 6.9 months. Life-threatening myelosuppression was universal with prolonged pancytopenia. Treatment-related deaths from sepsis were observed in 29% of patients. The median survival of the entire group was 15.6 months. Older patients in this trial did not tolerate high-dose melphalen therapy well; this resulted in a high proportion of toxic deaths and poor overall survival.     

Concomitant Radiotherapy and Daily Low-Dose Carboplatin in Locally Advanced, Unresectable Head and Neck Cancer Definitive results of a phase I-II study

The combination of daily low-dose carboplatin and radiotherapy was studied in 55 patients with inoperable head and neck cancer. All patients were planned to receive 70 Gy plus carboplatin i.v. daily, 45-60 min before radiotherapy. A starting schedule of 30 mg/m² on days 1 through 5, weeks 1, 3, 5 and 7 was administered to 17 patients; an escalating daily dose, up to 55 mg/m² was given to 38 additional patients. Up to a daily dose of 45 mg/m² only 4.4% of the patients developed grade 3 leukopenia; on the contrary, grade 3 and 4 leukopenia was seen in 62.5% of patients receiving 50 mg/m² or more. Mucositis was the major nonhaematologic toxicity and seemed to be dose-dependent. At the end of the loco-regional treatment there were 33 (61.1%) CR and 17 PR; the most effective total carboplatin dose seemed to be 40-45 mg/m². After surgical salvage the number of CRs increased to 37 (68.5%). One-and 2-year loco-regional control rates were 64% and 53% respectively. One- and 2-year actuarial survival rates were 71% and 53% respectively; the corresponding rates of disease-free survival were 60% and 43%. There was a strong correlation nodal status and both survival and disease-free survival.     

Recombinant interferon Gamma Treatment in Non-Small Cell Lung Cancer Antitumour Effect and Cardiotoxicity

Fifteen patients with previously untreated, inoperable non-small cell lung cancer were treated with r-IFN-gamma 2mg/m², on alternate days three times a week for a maximun of 12 weeks. After IFN treatment patients with stage III a + b disease received radiotherapy (55 Gy/44 F/32 d b.i.d.), and 4/5 patients with stage IV disease received chemotherapy (cisplatin-vindesine). Ten patients were evaluable for response at 4 weeks; 9 had stable disease and one had progressive disease. At 12 weeks 7 patients were evaluable; one had a partial response, and 6 had stable disease. of 10 patients subsequently given radiotherapy 2 achieved CR, 5 PR, and 3 SD. of the 3 evaluable patients receiving chemotherapy 1 PR, 1 SD and 1 PD were observed. IFN-gamma treatment was discontinued due to toxicity in 7/15 of patients. Main toxicities were the 'flu'-like syndrome (in 15 patients) and cardiovascular events (in 13 patients). Three patients were withdrawn because of cardiotoxicity. Our results suggest that high dose r-IFN-gamma might have some biological activity in NSCLC and does not interfere with subsequent conventional therapies given with a curative intent.     

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.     

Idarubicin and High Dose Cytarabine: A New Salvage Treatment for Refractory or Relapsing Non-Hodgkin's Lymphoma

Twenty three patients with relapsing (n = 11) or refractory (n = 12) non-Hodgkin's lymphoma (NHL) to one or two prior anthracycline based combination chemotherapy regimens were treated as second or third line regimen with 3 induction cycles of Idarubicin (IDA) (7 mg/m²/d IV dl-d3) and high dose cytarabine (HD Ara-C) (1 g/m²/12 h IV dl-d3), each cycle was repeated every 3 weeks. Responding patients received a maintenance therapy with monthly cycles of IDA : 15 mg/m² dl-d3, Etoposide 100 mg/m² dl-d3, both by oral route. Twenty two patients are evaluable and we observed 13 CR and 1 PR with an overall response rate of 61 % (14/23; 95% Cl = 38.5% 80.3%). The median time to progression was 32 months (6.5 - 63 + m.). The response rate to IDA-HD Ara C was not different for patients with (n = 14) or without (n = 9) objective response to the last prior therapy. The main toxicity was hematological: all patients experienced grade 4 neutropenia and 22 patients had grade 4 thrombopenia, but there were no toxic deaths. IDA and HD-Ara-C combination is highly effective in refractory or relapsed NHL. As hematological toxicity was the limiting factor for further escalation of dose-intensity, further studies might include hematopoietic growth factors support in the therapeutic scheme.     

Phase II study of gemcitabine plus paclitaxel in metastatic breast cancer patients with prior anthracycline exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m² was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m² was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9-61.4) with 16.7 percent (95 percent CI: 1.7-31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6-42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3-4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.     

Results of A trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer

: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA).

: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m². Two additional dose levels of 0.75 mg/m² and 1.0 mg/m² were tested.

: Six patients were accessioned to the 0.5 mg/m² dose level, three patients to the 0.75 mg/m² dose level, and three patients to the 1.0 mg/m² dose level. At the 0.5 mg/m² dose level, zero of six patients had ≥Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m² dose level, two of three patients had ≥Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced ≥Grade 4 hematologic toxicity. At the 1.0 mg/m² dose level one of three patients had ≥Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease.

: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m² days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.     

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer

To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC).

Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m²/day)/carboplatinum (70 mg/m²) on days 1–5 and 29–33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 μg, days 15–19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1–3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors).

This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: ± G-CSF, p = 0.0072).

With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.     

3D打印模板插植后装放疗联合深部热疗对盆腔复发性宫颈癌的疗效分析

目的:探讨3D打印模板插植后装放疗(brachytherapy,BT)联合深部热疗(hyperthermia,HT)对盆腔复发性宫颈癌的近期疗效.方法:选取2017年1月至2021年3月河北省沧州中西医结合医院收治的复发性宫颈癌患者73例临床病理资料,其中单独行3D打印模板插植后装放疗39例为对照组、联合深部热疗34例...     

Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil

To assess safety, tolerance, and disease control of transurethral resection of the bladder tumor (TURB) plus concurrent cisplatin, 5-fluorouracil (5-FU), and radiation therapy (RT) with selective organ preservation in patients with bladder cancer.

Forty-five patients with muscle-invading or high-risk T1 (G3, associated carcinoma in situ, multifocality, >5 cm) bladder cancer were entered into a protocol of TURB followed by concurrent cisplatin (20 mg/m²/day, 20-min infusion) and 5-FU (600 mg/m²/day, 120-hour continuous infusion), administered on Day 1–5 and 29–33 of RT (single dose 1.8 Gy, total dose to the bladder 54–59.4 Gy). Response was evaluated by restaging TURB 6 weeks later. In case of invasive residual or recurrent tumor, salvage cystectomy was recommended. Median follow-up was 35 months (range: 8–80 months).

Thirty-nine patients (87%) had no detectable tumor at restaging TURB; 29 patients (64%) have been continuously free of tumor in their bladders. A superficial relapse occurred in 4 patients, a muscle-invasive relapse in 6 patients. Overall survival and survival with preserved bladder was 67% and 54%, respectively, at 5 years. Hematologic Grade 3/4 toxicity occurred in 10%/4%; Grade 3 diarrhea occurred in 9%. Thirty-four patients (76%) completed the protocol as scheduled or with only minor deviations. One patient required salvage cystectomy because of a shrinking bladder.

Conclusion: This protocol of concurrent cisplatin/5-FU and RT has been associated with acceptable toxicity. The complete response rate of 87% and the 5-year survival with intact bladder of 54% are encouraging and compare favorably with our historical control series using RT with carboplatin and cisplatin alone.     

Radiotherapy vs. radiotherapy and razoxane in the treatment of soft tissue sarcomas: Final results of a randomized study

The effect of the sensitizer razoxane on soft tissue sarcomas (STS) was prospectively evaluated in a randomized, controlled trial. The main purpose of the study was to determine the response rates and local control under the combined treatment compared to irradiation alone.

Between 1978 and 1988, 144 patients entered the study; 130 were evaluable for response, toxicity, or survival. The patients were randomized to receive with gross disease (unresectable primaries, recurrent disease, or metastatic disease). The median radiation dose was 60 Gy postoperatively, and 56–58 Gy in patients with gross disease. The dose difference has palliative reasons. Razoxane was given orally at a daily dose of 150 mg/m² during the time of the radiotherapy, starting 5 days before the first irradiation. In general, the groups were comparables as to their prognostic factors. There was some imbalance, however, in favor of the postoperative group reveiving radiotherapy alone.

Between the patient groups treated postoperatively in an adjuvant form, there were no substantial differences in local control and survival. Among 82 patients with gross disease, the treatment with radiotherapy and razoxane led to an increased response rate compared to photon irradiation alone (74 vs. 49%). The local control rate was likewise improved (64 vs. 30%; p = 0.05). The acute toxicity was somewhat higher in the sensitizer arm, but there was no difference in the occurrence of late complications.

Radiotherapy combined with razoxane seems to improve the local control in inoperable, residual, or recurrent STS compared to radiotherapy alone. The combined treatment is a fairly well tolerated procedure at low costs. It can be recommended for inoperable primary STS or gross disease after incomplete resection, conditions which are still associated with limited local control and a grave prognosis.     

A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients

To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC.

Between November 1994 and March 1999, 157 patients with Stage IV, M₀ (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35–40 fractions, 1.8–2.0 Gy/fraction/day, 5 days/week, to a total dose 70–72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m² cisplatin, 2,200 mg/m² 5-fluorouracil, and 120 mg/m² leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.

With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p VALUE = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (≥ Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (≥ Grade 3).

We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.     

A phase I study of gemcitabine and docetaxel for advanced stage solid tumors

Background: We conducted a phase I study to determine the maximum tolerated dose of docetaxel in combination with gemcitabine for patients with refractory solid tumors. Methods: From January 1998 to November 1999, we treated 28 patients on a phase I protocol with gemcitabine given at a constant dose of 800 mg/m² IV over 30 minutes on days 1, 8, and 15. Docetaxel was administered by a phase I schedule over 1 hour on day 1 of a 28-day cycle with a starting dose of 50 mg/m² and increased by increments of 10 mg/m² based on dose-limiting toxicity (DLT) that occurred in the first cycle. Results: Neutropenia and thrombocytopenia were the dose-limiting toxicities. The maximum tolerated dose was 60 mg/m². The most significant nonhematologic toxicities included fatigue, nausea, vomiting, mucositis, and hypersensitivity reactions. There was one partial response at 15 months in a patient with gastric cancer and six patients with stable disease for 4.0 to 15.0 months. Conclusions: The maximum tolerated dose of docetaxel with gemcitabine is 60 mg/m². A phase II study in selected primary sites is planned.     

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 Phase I dose-finding study using an innovative sequential biweekly schedule of irinotecan followed 24 hours later by capecitabine

Background: Irinotecan and capecitabine have a broad spectrum of activity in human malignancy and are synergistic in an animal model when irinotecan precedes capecitabine. Patients and Methods: A Phase I design of the combination of irinotecan IV Day 1 with capecitabine on Days 2-8 every 2 weeks was evaluated in 27 adult patients with solid tumors. Two sequential schema were used: Arm A fixed the dose of irinotecan at 100 mg/m² and escalated capecitabine in cohorts, and arm B fixed the dose of capecitabine at 750 mg/m² PO BID and escalated the dosage of irinotecan. Results: Neutropenia was dose limiting with nausea and diarrhea as the most common nonhematological toxicities. Significant interpatient variation in toxicity occurred despite uniform dosing. No Grade IV toxicities were encountered. Grade III toxicity occurred in first cycle in 15 percent (3/20) patients in arm A and 29 percent (2/7) of patients in arm B. All toxicities were reversible. Repetitive dosing was feasible with prolonged disease stabilization in 8 patients. Conclusions: The suggested Phase II dose of this combination and schedule is irinotecan 100 mg/m² and capecitabine 1000 mg/m² BID. Some patients tolerated a capecitabine dose as high as 1250 mg/m² BID.