Radiation Therapy and Simultaneous Chemotherapy for Recurrent Cervical Carcinoma

Purpose: To evaluate the efficacy and toxicity in patients with recurrence of cervical cancer treated with radiotherapy and simultaneous chemotherapy.Patients and Methods: Between 1987 and 2001, 24 patients with recurrent cervical carcinoma were treated with concurrent chemoradiotherapy. Nine patients had incomplete tumor resection prior to radiation therapy. Irradiation was delivered to a total dose of 60 Gy, in three patients with central recurrences supplemented by brachytherapy. One patient was treated with brachytherapy alone. Simultaneous chemotherapy was done as a combined therapy of 5-fluorouracil-(5-FU, 600 mg/m²/d1–5, 29–33) and cisplatin (20 mg/m²/d1–5, 29–33; 16/24 patients) or of 5-FU (1,000 mg/m²/d1–5, 29–33) and mitomycin C (10 mg/m²/d2, 30; 1/24 patients). Cisplatin alone (25 mg/m²/d1–5) and carboplatin alone (800 mg/m²/d1–5) were administered in 5/24 patients (21%) and 2/24 patients (8%).Results: The 5-year local recurrence-free survival rate was 37%, disease-free survival 33%, and overall survival 34%. Grade 3 toxicity (NCI-CTC grade 3) occurred mainly as diarrhea (38%), leukopenia (33%), and nausea (21%). Severe toxicity (grade 4) was not seen in any of the patients.Conclusion: Radiation therapy with simultaneous chemotherapy for recurrences of cervical cancer is an effective treatment with acceptable toxicity.     

Weekly gemcitabine and cisplatin concurrent with pelvic irradiation for primary therapy of cervical cancer: report of the first seven cases in Thai women

Purpose The aim of this study was to evaluate the compliance, response, and side effects of weekly gemcitabine (125 mg/m²) given concomitantly with standard weekly cisplatin (40 mg/m²) and pelvic radiotherapy for primary treatment of cervical cancer stage IB2–IVA in the first seven Thai cases. Materials and methods Weekly gemcitabine at a dose of 125 mg/m² was given concomitantly with cisplatin at 40 mg/m² for six cycles with concurrent radiotherapy in primary therapy of stage IB2–IVA cervical cancer. Radiation consisted of 5000 cGy in 25 daily fractions combined with brachytherapy to take point A to about 8600 cGy. Results Using weekly gemcitabine at a dose of 125 mg/m² with cisplatin at a dose of 40 mg/m², five of seven patients demonstrated a dose-limiting toxicity (DLT). DLTs consisted of nephrotoxicity in three cases and bone marrow suppression in two cases. Only one of seven patients could go through six cycles. All 5 living patients had a clinically complete response. Conclusions Weekly gemcitabine at a dose of 125 mg/m² with cisplatin at a dose of 40 mg/m² given concurrently with primary pelvic radiotherapy resulted in an excellent response but unacceptable toxicities for Thai women. The trial protocol was changed by reducing the cisplatin dosage to 20 mg/m².     

Simultaneous chemoradiation with cisplatin in a patient with recurrent cervical cancer undergoing hemodialysis

Purpose

To prove the feasibility and toxicity of platinum-based chemoradiation in a patient with recurrent cervical cancer undergoing concomitant hemodialysis.

Patient and Methods

We report a patient with a renal transplant because of chronic renal failure who then underwent radical hysterectomy and lymphadenectomy due to cervical cancer FIGO stage IB1. One year after primary therapy, a 53 × 54 × 68 mm vaginal stump recurrence was treated by total translevatoric exenteration with lymphadenectomy, explantation of the transplant, and the right residual kidney. Because of microscopically involved margins, chemoradiation was recommended. Radiation was performed to the tumor region and pelvic lymph nodes up to 50.4 Gy. A boost was given to the clip-marked region to 66.6 Gy. Neurological, gastrointestinal and genitourinary toxicity was evaluated once a week, while hematological toxicity twice per week. Samples to evaluate cisplatin concentrations were taken from blood and dialysate.

Results

The patient completed chemoradiation with 5 cisplatin applications with a decreased dose (20 mg/m²) without any high grade toxicity. Hemodialysis was performed three times a week. Within 30 min after cisplatin application, the cisplatin serum concentration reached the highest level with 1,179.6 ??g/l and showed nearly stable concentrations over 120 min. There was an accumulation of cisplatin from week 1 (100%) to week 5 of application (219%). The corresponding concentration in the dialysate also showed a rapid increase within the first hour of hemodialysis and decreased to 50% within 2 h.

Conclusion

Cisplatin application with a modified dose (20 mg/m²) is feasible and safe in a patient with cervical carcinoma undergoing chemoradiation and hemodialysis.     

Transcatheter Arterial Chemoembolization Using Cisplatin Powder Mixed with Degradable Starch Microspheres for Colorectal Liver Metastases after FOLFOX Failure: Results of a Phase I/II Study

PurposeTo report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol.Materials and MethodsA fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m², 65 mg/m², and 80 mg/m². In phase II, tumor response, toxicity, and survival times were assessed.ResultsThe study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m². In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval [CI], 4.06–13.5 mo) and 21.1 months (95% CI, 8.37–33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%).ConclusionsThis study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m² mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.     

局部晚期直肠癌术前同步放化疗中卡培他滨联合奥沙利铂剂量递增的I期临床研究

目的 探讨局部晚期直肠癌术前同步放化疗基于5-Fu类药物的联合方案中奥沙利铂的最大耐受剂量。方法 本试验设计为前瞻性研究,自2015年3月至2015年10月,入组经病理确诊的局部晚期（T₃、T₄/N+）直肠癌患者15例,接受调强放疗以及卡培他滨联合奥沙利铂方案的同步化疗。放疗采用同步局部加量, 总剂量GTV为50.6 Gy,CTV 41.8 Gy,共22次,30 d内完成。同期化疗,卡培他滨为固定剂量825 mg/m²,2次/d,每周1~5服用,伴随放疗全程;奥沙利铂剂量分别为100、110、120、130 mg/m²,共4个递增剂量水平组,每21天为1个周期。15例患者,前12例按随机数字表法分为4组,每组3例,最后一组因出现剂量限制性毒性又入组了3例患者,因此,第4组为6例。治疗后充分评估不良反应和有效率。结果 近期治疗相关不良反应主要表现为放射性肠炎、皮肤反应、恶心、乏力、泌尿系不良反应和骨髓抑制,并随奥沙利铂剂量的提高而增多、加重。观察100、110 和120 mg/m²组中未出现3级以上不良反应,130 mg/m²组中则出现了剂量限制性毒性：1例3级血小板减少和1例3级恶心,该剂量为最大耐受剂量。手术后病理显示,所有患者均达到降期,4组患者分别有0、1、2、3例达到完全缓解。结论 局部晚期直肠癌调强放疗同步联合卡培他滨及奥沙利铂方案安全有效。奥沙利铂的最大耐受剂量为130 mg/m²,1次/3周。     

Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck

Background

Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART).

Patients and methods

Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400?mg/m²) and then with a weekly dosage of 250?mg/m² during HART. HART was started with a prescribed dosage of 2.0?Gy per day for 3 weeks, followed by 1.4?Gy twice daily to a total dose of 70.6?Gy to the gross tumour volume. CIS (40?mg/m²) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2?year progression-free survival (PFS).

Results

Between November 2007 and November 2010, a total of 74?patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2? and 5?year overall survival rates were 64 and 41%, the 2? and 5?year PFS rates were 45 and 32%, and the 2? and 5?year locoregional control rates were 47 and 33%, respectively.

Conclusion

The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

     

Aggressive Simultaneous Radiochemotherapy with Cisplatin and Paclitaxel in Combination with Accelerated Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Tumors

BACKGROUND: Simultaneous radiochemotherapy (sRCT) is the treatment of first choice in locally advanced head and neck cancers. We have tested a very aggressive combination protocol with cisplatin and escalated paclitaxel in combination with accelerated hyperfractionated radiotherapy to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), overall toxicity, and response rate. PATIENTS AND METHODS: The trial recruited 24 patients (21 males, three females, mean age 57 years) treated at our department from 1998 through 2001. Irradiation was administered in daily doses of 2 Gy up to 30 Gy followed by 1.4 Gy twice daily up to 70.6 Gy to the primary tumor and involved nodes and 51 Gy to the clinically negative regional nodes. The chemotherapy schedule included cisplatin in a fixed dose of 20 mg/m(2) on days 1-5 and 29-33 and paclitaxel at increasing dose levels of 20, 25, 30 mg/m(2) twice weekly over the whole treatment time. Patients were recruited in cohorts of three to six, and the MTD was reached if two out of six patients in one cohort developed DLT. DLT was defined as any grade 4 toxicity or any grade 3 toxicity requiring treatment interruption or unplanned hospitalization or any grade 3 neurotoxicity. We recruited mainly patients with large tumors for this protocol; all patients were stage IV, and the mean tumor volume (primary + metastases) amounted to 72 +/- 61 cm(3). The mean follow-up was 30 months (range 4-39 months). RESULTS: One early death (peritonitis and sepsis at day 10) occurred, and 23 patients were evaluable for acute toxicity and response. The MTD of paclitaxel was reached at the third dose level (30 mg/m(2) paclitaxel twice weekly). The DLT was severe mucositis grade 3 (n = 1) and skin erythema grade 4 (n = 2). After determining the MTD, another 14 patients were treated at the recommended dose level of paclitaxel with 25 mg/m(2) twice weekly. In summary, 13/23 patients (57%) developed grade 3 and 10/23 (43%) grade 2 mucositis. Two patients (9%) had grade 4, five (22%) grade 3, and 16 (69%) grade 2 dermatitis. One patient died at day 30 of neutropenic infection. In one patient, a grade 2 nephrotoxicity appeared requiring cessation of cisplatin chemotherapy. 18/23 patients (78%) required blood transfusion (1-3 units) and 16/23 (70%) i.v. antibiotics. 14 patients (61%) achieved a complete and nine (39%) a partial remission, yielding an overall response rate of 100%. In summary, six patients died of local tumor progression (n = 2), distant metastases (n = 2), or therapy-related complications (n = 2) during follow-up. The 3-year overall survival was 71%. Tumor volume was not a risk factor for failure in this protocol (mean tumor volume in relapse-free vs. progressive patients 71 +/- 65 cm(3) vs. 64 +/- 38 cm(3)). All patients have, so far, developed only slight late effects (fibrosis, lymphedema) with no grade 3-4 late sequelae. CONCLUSIONS: This very aggressive sRCT protocol yielded excellent response and survival figures but was associated with a very high rate of acute toxicity (8% therapy-related deaths). A maximal supportive treatment is therefore required.     

Induction chemotherapy followed by simultaneous hyperfractionated radiochemotherapy in advanced head and neck cancer

Purpose

To evaluate the feasibility of induction chemotherapy followed by concomitant chemotherapy and hyperfractionated irradiation in locally advanced, inoperable head and neck cancer.

Methods

A pilot study was undertaken comprising 3 cycles of cisplatinum (100 mg/m², day 1) and 5-fluorouracil (1000 mg/m² in continuous intravenous infusion over the first 120 h) followed by bifractionated radiotherapy applied to tumor/involved lymph nodes up to the dose of 74.4 Gy given in 2 fractions of 1.2 Gy daily for 5 days a week combined with concomitant weekly cisplatinum infusion (50 mg/m²).

Results

Six patients were enrolled in the study. All of them completed the protocol therapy. Severe mucositis and myelotoxicity were the most common acute side effects observed in all and in 5 of the patients, respectively. Acute toxicity required interruption of concomitant chemotherapy in 5 cases and in 2 interruption of radiotherapy was necessary. Opioid analgesic parenteral therapy was administered in 4 patients. Three of them had to be hospitalized. One patient experienced cerebral stroke 1 day after the completion of therapy and died 7 days later. Due to high acute toxicity, patient accrual was terminated after 6 patients. At the mean follow-up of 17 months, 4 patients are alive, 3 of them are free of disease and in 1 local progression has been diagnosed.

Conclusions

High acute toxicity of induction cisplatinum and 5-fluorouracil followed by concomitant cisplatinum and hyperfractionated irradiation calls for less toxic treatment schedules in locally advanced inoperable head and neck cancer.     

Selective intraarterial chemoradiation therapy for oropharyngeal carcinoma with high-dose cisplatin

Purpose

Cisplatin has shown a high tumor response rate among head and neck carcinomas, and the tumor response is related to the cisplatin dosage. The purpose of this study was to evaluate the efficacy and toxicity of selective intraarterial chemoradiation therapy for oropharyngeal carcinomas with high-dose cisplatin.

Materials and methods

This retrospective study consisted of 21 patients with oropharyngeal carcinoma, stages II-IVB, in whom intraarterial chemoradiation therapy was performed between 2000 and 2008. All patients were given two courses of selective intraarterial infusions of cisplatin (300 mg/m²), systemic chemotherapy with 5-fluorouracil, and simultaneous radiation therapy (58?C61 Gy/30 fractions), with a 1-week rest period.

Results

The 2-year overall survival rate of the 15 patients who completed the therapeutic regimen was 71.3%. The 2-year locoregional control rate and disease-free survival rate were 95.0% and 67.7%, respectively.

Conclusion

Selective intraarterial high-dose cisplatin chemotherapy with concomitant radiation therapy shows results similar to those of original methods in terms of survival and locoregional control with a reduction in the number of procedure times.     

Comparison of cisplatin and 5-fluorouracil chemotherapy protocols combined with concurrent radiotherapy for esophageal cancer

Purpose  The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. This study was performed to identify the differences in toxicity and completion rates of various chemotherapy protocols with that goal in mind. Materials and methods  A total of 61 patients with esophageal cancer were enrolled in this study between June 2002 and January 2004. The total radiotherapy dose was 64 Gy. Three chemotherapy protocols were used. Arm A comprised daily low-dose cisplatin (CDDP) and 5-fluorouracil (5FU) (CF protocol) (3 mg/m² and 180 mg/m², respectively). Arm B was intermediate between arm A and C (CDDP 7 mg/m² and 5FU 250 mg/m² on days 1–5, 8–12, 29–33, and 36–40). Arm C comprised two courses of standard CF (CDDP 70 mg/m² on day 1 and 5FU 600 mg/m²/24 h on days 1–4). Results  Although there were no significant differences in hematological toxicity between the protocols, leukocytopenia was slightly milder in arm A. Nausea was significantly more severe in arm C. The completion rate was higher in arm A. The 3-year survival rates were 40%, 31%, and 62%, respectively. Conclusion  The daily low-dose CF protocol showed a trend of mild toxicity regarding leukocytopenia. However, we could not find statistical difference between arms. It also showed a better completion rate than the other two arms.     

Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma

Introduction

Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach.

Materials and methods

Between December 2008 and March 2010, 22?patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4?out of 22?patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45?Gy and 69.96?Gy in 33?fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1?week before RT at a loading dose of 400?mg/m² body surface area over a period of 120?min, follow by a weekly 60?min infusion of 250 mg/m² for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria.

Results

All but 2?patients completed treatment and achieved the minimum follow-up of 12?months after the end of the treatment. Of the 22?patients, 18% (4?patients) showed grade?1, 36% (8?patients) grade?2, and 36% (8?patients) showed grade?3 dermatitis, while 9% (2?patients) had grade?1, 36% (8?patients) grade?2, and 45% (10?patients) had grade?3 mucositis/stomatitis. No grade?4 toxicities were recorded. Considering blood parameters, 3?cases of grade?1 anemia and 1?case of grade?2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment.

Conclusion

The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.     

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck

Background

Close resection margins <?5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article.

Methods

Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1–36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m², days 1–5 and days 29–33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m², days 1–5 + days 29–33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m² followed by weekly doses of 250 mg/m². Maintenance cetuximab began after radiochemotherapy at 500 mg/m² every 2 weeks for 6 months.

Results

Of the 55 patients (46 male, 9 female, mean age 55.6, range 29–70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3–4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14?% of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22?% of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80?% were still on cetuximab at 3 months and 63?% at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48?% of patients.

Conclusion

Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3–5 months is moderate.     

伽玛刀联合吉西他滨治疗局部晚期胰腺癌的Ⅰ期临床观察

 目的 探索吉西他滨联合伽玛刀治疗局部晚期胰腺癌的最适剂量。方法 采用“3+3”试验设计模式,患者接受伽玛刀和吉西他滨治疗,伽玛刀治疗计划52 Gy/13F,吉西他滨初始剂量700 mg/m²,每周1次,连续3周,剂量按照100 mg/m²依次递增,直至出现剂量限制性毒性反应。结果 入组9例患者,700 mg/m²和800 mg/m²组完成治疗计划,当吉西他滨的剂量递增至900 mg/m²时出现剂量限制性的血液学毒性反应,试验中止。结论 伽玛刀联合吉西他滨治疗局部晚期胰腺癌,吉西他滨的推荐剂量为800 mg/m²,每周1次,连续3周。     

Concurrent chemoradiotherapy using protracted infusion of low-dose CDDP and 5-FU and radiotherapy for esophageal cancer]

PURPOSE: We evaluated the effects and safety of concurrent chemoradiotherapy for patients with esophageal cancer. MATERIALS AND METHODS: Between March 1994 and April 1998, concurrent chemoradiotherapy using protracted infusion of low-dose cisplatin (CDDP: 3-6 mg/m2/24h), 5-fluorouracil (5-FU: 200 mg/m2/24h) and radiotherapy was given to 26 patients. The median age was 70 yr, with a range from 58 to 86 yr. With regard to TNM classification (1987), six patients were stage II, five stage III, and 15 stage IV. Radiotherapy was performed by external irradiation alone in 23 patients and external irradiation plus brachytherapy in three patients. One patient underwent surgery after a dose of 40 Gy owing to the possibility of idiopathic bleeding from the stomach. RESULTS: Locally, primary effects resulted in complete response in 11 patients (42.3%) and partial response in 15 (57.7%). Acute toxicity was primarily hematologic. Leukopenia and thrombocytopenia of grade 3 or 4 occurred in eight (30.7%) and six (23.0%) of 26 patients, respectively. In patients administered CDDP at more than 5 mg/m2/day, hemotoxicity was severe because in five of the 10 patients administered 5 mg/m2 CDDP and one of the two patients administered 6 mg/m2 CDDP, thrombocytopenia of grade 3 or 4 occurred. CONCLUSION: Protracted infusion of low-dose CDDP and 5-FU with concomitant radiation therapy is effective, but from the point of acute toxicity, the optimal dose of CDDP and 5-FU needs further investigation.     

Yttrium-90 DOTATOC: first clinical results

In a pilot study, DOTA-d-Phe¹-Tyr³-octreotide (DOTATOC), which can be labelled with the β-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of ⁹⁰Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of ⁹⁰Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120±1347 MBq/m²) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of ≥3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity ≤ grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of ≤7400 MBq/m². Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m² and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. ⁹⁰Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment – at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during ⁹⁰Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing. Received 12 February and in revised form 16 May 1999     

Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer

Purpose

In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated.

Patients and methods

From 2000–2002, 38 patients with stage III (5.3?%) and stage IV (94.7?%) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m² on days 1–5 and 6 cycles of weekly cisplatin (30 mg/m²). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial.

Results

Median follow-up was 11.4 years (95?% CI 8.6–14.2) and mean dose 71.6 Gy. Of the patients, 82?% had 6 (n?=?15) or 5 (n?=?16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6?%, respectively. Grade 3 mucositis in 50?%, grade 3 and 4 dysphagia in 55 and 13?%. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2?%, the MFS was 77.5, 66.7, and 57.2?% and the OS 59.6, 29.2, and 15?%, respectively.

Conclusion

Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups.     

Weekly paclitaxel and carboplatin with concurrent radiation therapy in locally advanced non-small cell lung cancer: phase I study

PURPOSE: The optimal dose of weekly paclitaxel in combination with carboplatin and concurrent radiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC) is not well defined in Japan. The purpose of this study was to define the maximum-tolerated dose (MTD) of paclitaxel in this combination. MATERIALS AND METHODS: Treatment consisted of weekly paclitaxel plus carboplatin fixed AUC 2 and CRT for a total 60 Gy at 2 Gy/fraction/day 5 times weekly for 6 weeks. The dose of paclitaxel was 25 mg/m2 in the first cohort and escalated by 5 mg/m2 per cohort. RESULTS AND CONCLUSION: A total of 18 patients were enrolled and analyzed. The dose limiting toxicity of this study was considered to be pulmonary toxicity, and the MTD of it was determined to be 45 mg/m2 of paclitaxel in patients with NSCLC. Further evaluation of this regimen in a phase II trial is underway.     

Optimizing Cancer Radiotherapy with 2-Deoxy-D-Glucose

Background and Purpose: Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of γ-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients.Patients and Methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of ⁶⁰Co γ-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200–250–300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients.Results: Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who received complete treatment and survived between 11 and 46 months after treatment.Conclusion: Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.     

Chemoradiation in Cervical Cancer with Cisplatin and High-Dose Rate Brachytherapy Combined with External Beam Radiotherapy Results of a Phase-II Study

Background: In 1999, five randomized studies demonstrated that chemoradiation with cisplatin and low-dose rate (LDR) brachytherapy has a benefit in locally advanced cervical cancer and for surgically treated patients in high-risk situations. We evaluated the safety and efficacy of concomitant chemoradiation with cisplatin and high-dose rate (HDR) brachytherapy in patients with cervical cancer. Patients and Method: 27 patients were included in our phase-II trial: 13 locally advanced cases (group A) and 14 adjuvant-therapy patients in high-risk situations (group B). A definitive radiotherapy was performed with 25 fractions of external beam therapy (1.8 Gy per fraction/middle shielded after eleven fractions). Brachytherapy was delivered at HDR schedules with 7 Gy in point A per fraction (total dose 35 Gy) in FIGO Stages IIB-IIIB. The total dose of external and brachytherapy was 70 Gy in point A and 52-54 Gy in point B. All patients in stage IVA were treated without brachytherapy. Adjuvant radiotherapy was performed with external beam radiotherapy of the pelvis with 1.8 Gy single-dose up to 50.4 Gy. Brachytherapy was delivered at HDR schedules with two fractions of 5 Gy only in patients with tumor-positive margins or tumor involvement of the upper vagina. The chemotherapeutic treatment schedule provided six courses of cisplatin 40 mg/m² weekly recommended in the randomized studies GOG-120 and -123. Results: A total of 18/27 patients (66.7%) completed all six courses of chemotherapy. Discontinuation of radiotherapy due to therapy-resulted morbidity was not necessary in the whole study group. G3 leukopenia (29.6%) was the only relevant acute toxicity. There were no differences in toxicity between group A and B. Serious late morbidity occurred in 2/27 patients (7.4%). 12/13 patients (92.3%) with IIB-IVA cervical cancer showed a complete response (CR). 13/14 adjuvant cases (92.8%) are free of recurrence (median follow up: 19.1 months). Conclusion: Concomitant chemoradiation with cisplatin 40 mg/m² weekly 2 6 using HDR brachytherapy represents a promising treatment of cervical cancer with an acceptable toxicity. Hintergrund: 1999 zeigten fünf randomisierte Studien, dass die simultane Radiochemotherapie mit Cisplatin und einer Low-Dose-Rate-Brachytherapie für Patientinnen mit einem lokal fortgeschrittenen Zervixkarzinom und in der adjuvanten Hochrisikosituation einen Überlebensvorteil bringt. Wir untersuchten die Sicherheit und Effektivität der simultanen Radiochemotherapie mit Cisplatin und High-Dose-Rate-Brachytherapie bei diesen Patientinnen. Patientinnen und Methode: 27 Patientinnen wurden in unsere Phase-II-Studie eingeschlossen: 13 mit lokal fortgeschrittenen Zervixkarzinomen (Gruppe A) und 14 adjuvante Hochrisikopatientinnen (Gruppe B). Die primär radiochemotherapierten Fälle erhielten 25 Fraktionen einer perkutanen Hochvolttherapie des Beckens (1.8 Gy pro Fraktion/Einbringen eines Mittelblocks nach elf Fraktionen). Die Brachytherapie wurde bei den FIGO-Stadien IIB-IIIB nach dem High-Dose-Rate-Afterloading-Prinzip mit 7 Gy pro Fraktion in Punkt A (Gesamtdosis 35 Gy) appliziert. Die Gesamtdosis der kombinierten Therapie war 70 Gy in Punkt A und 52-54 Gy in Punkt B. Bei den FIGO-Stadien IVA erfolgte keine Brachytherapie. Bei der adjuvanten Strahlentherapie wurde die perkutane Hochvolttherapie des Beckens mit Fraktionen von 1,8 Gy bis zu einer Gesamtdosis von 50,4 Gy appliziert. Die High-Dose-Rate-Afterloading-Brachytherapie mit zwei Fraktionen von 5 Gy erfolgte nur bei Patientinnen, bei denen sich im Operationspräparat tumorbefallene Resektionsränder oder ein Befall der Scheide fanden. Das Chemotherapieregime mit 6 wöchentlichenGaben von 40 mg/m² Cisplatin entsprach dem der Studien 120 und 123 der GOG. Ergebnisse: 18 von 27 Patientinnen (66,7%) erhielten alle sechs Cisplatingaben. Eine Unterbrechung der Strahlentherapie aufgrund von Nebenwirkungen war in keinem Fall erforderlich. Die G3-Leukozytopenie (29,6%) war die einzige relevante Akuttoxizität; Toxizitätsunterschiede zwischen Gruppe A und B konnten nicht gesehen werden. Erhebliche späte Nebenwirkungen traten bei zwei der 27 Patientinnen (7,4%) auf. Zwölf von 13 Patientinnen (92,3%) mit einem Zervixkarzinom FIGO IIB-IVA zeigten eine Komplettremission (CR). 13 von 14 adjuvanten Fällen (92,8%) sind nach einer medianen Nachbeobachtungszeit von 19,1Monaten rezidivfrei. Schlussfolgerung: Die simultane Radiochemotherapie des Zervixkarzinoms mit 6 wöchentlichen Cisplatingaben 40 mg/m² und High-Dose-Rate-Afterloading-Brachytherapie stellt eine sichere und effektive Therapieform dar.     

Phase I/II Multicenter Study of Transarterial Chemoembolization with a Cisplatin Fine Powder and Porous Gelatin Particles for Unresectable Hepatocellular Carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401

PurposeA multicenter phase I/II study of transarterial chemoembolization with a fine cisplatin powder and gelatin particles (GPs) for multifocal hepatocellular carcinoma (HCC) was conducted. Primary endpoints were dose-limiting toxicity (DLT) and recommended dose (RD). Secondary endpoints were the incidence and severity of adverse events and tumor response.Materials and MethodsNonselective transarterial chemoembolization was performed until all tumor enhancement disappeared. Lipiodol was not used. In the phase I study, the cisplatin dose was escalated from 35 mg/m² to 65 mg/m² in 15-mg/m² increments to determine DLT and RD. In the phase II study, 40 patients were treated with the RD. Toxicity was assessed by Common Toxicity Criteria for Adverse Effects (version 3.0), and tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and European Association for the Study of the Liver (EASL) criteria.ResultsA total of 46 patients were enrolled. As no DLT occurred at any dose level in the phase I study, RD was determined as 65 mg/m². In the phase II study, the treatment was discontinued in one patient as a result of vasovagal response. Toxicities of grade 3 or higher included nausea (2.2%), pancreatitis (2.2%), cholecystitis (2.2%), thrombocytopenia (8.7%), hyperbilirubinemia (2.2%), and increased aspartate aminotransferase (28.3%) and alanine aminotransferase (21.7%) levels. Tumor response rates under RD were 25.6% and 64.1% by RECIST and EASL criteria, respectively.ConclusionsNonselective transarterial chemoembolization with fine cisplatin powder and GPs was well tolerated and effective in patients with multifocal HCC at the RD of 65 mg/m².