Combined concomitant boost radiotherapy and chemotherapy in stage III-IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone

Background: Alteration of radiation therapy (RT) fractionation and thecombination of chemotherapy (CT) with RT represent two predominant fields ofcurrent research in the treatment of head and neck carcinomas. To assess thepotential integration of these two fields, a retrospective comparison oftoxicity and treatment outcome was carried out in stage III–IV patientstreated with a concomitant boost RT schedule with or without CT.Patients and methods: Fifty-two patients were treated by RT alone and 35by RT and CT. In the RT group, there were significantly fewer T3–4tumors(56% vs. 88%, P = 0.002) and higher proportion of planned neckdissections (35% vs. 14%, P = 0.047). The planned total dose was69.9 Gy delivered over 5.5 weeks. In 10 cases CT was given before RT and in25 concomitantly with RT, either alone or with neoadjuvant and/or adjuvant CT.All patients but two had cisplatin-based (CDDP, 100mg/m²) CT, associated in 28 patients with 5-fluorouracil(5-FU, 1000 mg/m²/24 h × 5). The median follow-upfor the surviving patients was 21 and 31 months for the RT and RT–CTgroupsrespectively.Results: Grade 3–4 acute toxicity (RTOG) was observed in 73%and86% of patients, and grade 3 dysphagia in 31% and 57% (P=0.02) respectively in the RT and RT–CT groups. The rates of grade3–4 late complications were similar in the two groups (5% vs.12%). At three years, actuarial loco-regional control (LRC) was57% and 66% (P = 0.66) and overall survival was 56% and47% (P = 0.99) in the RT and RT–CT groups respectively.Conclusions: While acute toxicity was higher compared with RT alone, thisaccelerated RT schedule was feasible in association with 5-FU/CDDP, evenadministered concomitantly. Despite the significant proportion of moreadvanced disease in the RT–CT group, LRC was similar to that obtainedby RTalone. Combinations of concomitant boost RT and chemotherapy merit furtherinvestigation in prospective trials.     

Pathologic downstaging of T3–4Nx rectal cancer after chemoradiation: 5-fluorouracil vs. Tegafur

Purpose: To describe downstaging effects in locally advanced rectal cancer induced by 2 fluopirimidine radiosensitizing agents given through different routes in conjunction with preoperative radiotherapy.Methods and Materials: From March 1995 to December 1999, two consecutive groups of patients with cT_3–4N_x rectal cancer (94% CT scan, 71% endorectal ultrasound) were treated with either (1) 45–50 Gy (1.8 Gy/day, 25 fractions) and 5-fluorouracil (5-FU) (500–1,000 mg/m² by 24-h continuous i.v. infusion on Days 1–4 and 21–25) or (2) oral Tegafur (1,200 mg/day on Days 1–35, including weekends). Surgery was performed 4 to 6 weeks after the completion of chemoradiation.Results: The total T downstaging rate was 46% in the 5-FU group and 53% in the Tegafur group. Subcategories were downstaged by the sensitizing agents (5-FU vs. Tegafur) as follows: pT_0–1, 14% vs. 23%; pT₂, 32% vs. 32%; pT₃, 49% vs. 37%; pT₄, 5% vs. 7%; and N₀, 74% vs. 86%. Analysis of residual malignant disease in the specimen discriminated mic/macsubgroups (mic: <20% of microscopic cancer residue), with evident superior downstaging effects in the Tegafur-treated group: pTmic 23% vs. 58% (p = 0.002).Conclusions: When administered concurrent with pelvic irradiation, oral Tegafur induced downstaging rates in both T and N categories superior to those induced by intermediate doses of 5-FU by continuous i.v. infusion. In this pilot experience, oral Tegafur reproduced the characteristics of downstaging described previously when full doses of 5-FU have been combined with radiotherapy.     

Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: A French cooperative study

Background: Chemotherapy (5-fluorouracil–mitomycin C) concomitant withradiotherapy (RT) increases local control and colostomy-free survival inadvanced anal canalcarcinomas (ACC). The purpose of this prospective trial was to analyse thetoxicity of and response to an induction chemotherapy combining 5-fluorouracil(5-FU) and CDDP administered concomitantly with irradiation.Patients and methods: Thirty patients (24 F/6 M, mean age 60, range38–74) with an advanced ACC >40 mm and/or with node involvement wereprospectively treated (1 T1, 16 T2, 8 T3, 5 T4, 10 N1, 1 N2, 8 N3) fromNovember 1994 to January 1996. Two induction and two concomitant cycles of5-FU(800 mg/m² D1–4 infusion) and CDDP (80mg/i.v./m² at D1) were delivered. RT consisted of 45 Gy (1.8Gy/fr, 5 fr/w) on pelvis ± inguinal nodes or 30 Gy (3 Gy/fr, 4 fr/w)by direct perineal field. A boost (15–20 Gy) was delivered six weekslater.Results: Toxicity: one patient died of a pulmonary embolism on D4.The remaining 29 received the entire treatment, with reduced 5-FU doses in 11patients because of acute toxicity. The RT boost was delayed for one patient(aplasia). In 109 cycles, 3 grade 4 and 17 grade 3 toxicities were observed;there were no toxic deaths. Tumor response: the complete response (CR)and partial response (PR) rates were, respectively, 11% and 61%after induction chemotherapy, 59% and 31% after concomitantradiochemotherapy and 96% and 0% two months after completion ofthe treatment. No tumor progression was observed.Conclusion: the treatment was well tolerated and there was good compliance.After induction chemotherapy, most of the patients were in PR, with some evenin CR. After completion of the treatment all but one were in CR. The tumorresponse and the long term results of 50 patients will be analysed beforeinitiation of a randomised trial is considered.     

T1N0/T2N0 glottic carcinoma: A comparison of two fractionation schedules

The aim of this paper is the retrospective comparison of accelerated/hypofractionated radiotherapy regimen (AHFX) with standard fractionation regimen (SFX) for patients with early glottic carcinoma. One hundred and forty‐five patients with T₁–T₂ glottic cancer between 1986 and 1998 were eligible. Before 1992, patients received 60–66 Gy in 30–33 fractions over 6–6.5 weeks (SFX) with ⁶⁰Co and 6‐MV beams. After 1992, patients received 52.5–55 Gy in 20 fractions over 4 weeks (AHFX) using 6‐MV beams. The end‐points were overall survival, laryngectomy‐free survival (LFS), loco‐regional control and toxicity. One hundred and two were stage T₁N₀; 43 were stage T₂N₀. Median follow up was 4.9 years. The 5‐year overall survival was 78%. Five‐year loco‐regional control in T₁N₀ patients was higher in AHFX than in SFX group (95 vs 75%, P = 0.002). Loco‐regional control in T₂N₀ patients was similar for AHFX and SFX (81 vs 80%, P = 0.813). Overall LFS was 88%. T₁N₀ AHFX patients had 5‐year LFS of 95% compared with 75% for SFX (P = 0.003). For T₂N₀ AHFX patients, overall LFS was 92% compared with 80% for the SFX group (P = 0.291). No grade 4 or 5 late toxicity occurred. One AHFX patient developed grade 3 toxicity; two of 51 SFX patients developed grade 2 toxicity versus five of 94 AHFX patients. AHFX using 6‐MV beams for treatment of early glottic cancer resulted in equivalent LFS and toxicity when compared with SFX.     

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

Purpose:The aim of this randomised trial was to evaluate theactivity and toxicity of a biweekly regimen including 6S-leucovorin-modulated5-fluorouracil (LFA–5-FU), combined with either irinotecan (CPT-11 +LFA–5-FU) or raltitrexed (Tomudex®) (TOM + LFA–5-FU), inadvanced colorectal cancer patients, and to make a preliminary comparison ofboth these experimental regimens with a biweekly administration ofLFA–5-FU modulated by methotrexate (MTX + LFA–5-FU). Patients and methods:One hundred fifty-nine patients withadvanced colorectal carcinoma previously untreated for the metastatic disease(34 of them previously exposed to adjuvant 5-FU) were randomly allocated toreceive: CPT-11, 200 mg/m² i.v. on day 1, followed on day 2 by LFA,250 mg/m² i.v. infusion and 5-FU, 850 mg/m² s i.v. bolus(arm A); TOM, 3 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 1050 mg/m² i.v. bolus (armB); or MTX, 750 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 800 mg/m² i.v. bolus (armC). Courses were repeated every two weeks in all arms of the trial. Responserate (RR) was evaluated after every four courses. The sample size was definedto have an 80% power to detect a 35% RR for each experimentaltreatment, and to show a difference of at least 4% in RR with thestandard treatment if the true difference is 15% or more. Results:The RRs were: 34% (95% confidence interval(95% CI): 21%–48%) in arm A, including 3 completeresponses (CRs) and 15 partial responses (PRs), 24% (95% CI:14%–38%) in arm B, including 2 CRs and 11 PRs, and24% (95% CI: 14%–38%), with 2 CRs and 11PRs, in arm C. After a median follow-up time of 62 (range 18–108) weeks,the median time to progression was 38, 25, and 27 weeks for arm A, B, and C,respectively. With 94 patients still alive, the one-year probability ofsurvival was 61%, 54%, and 59%, respectively. WHO grade3 or 4 neutropenia and diarrhoea affected 46% and 16%,respectively, of patients treated with CPT-11 + LFA–5-FU. Medianrelative dose intensity over eight cycles (DI₈) was 78% forCPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA–5-FU wereneutropenia (16%) and diarrhoea (16%), but median relativeDI₈ was 93% for TOM, and 82% for 5-FU. Conclusions:CPT-11 + LFA–5-FU compares favorably in termof activity and toxicity with other combination regimens including CPT-11 andcontinuous infusional 5-FU. The hypothesis of a RR 15% higher than theMTX + LFA–5-FU treatment can not be ruled out after this interimanalysis. The TOM + LFA–5-FU regimen showed a RR and a toxicity profilevery close to the MTX + LFA–5-FU combination, and dose not deservefurther evaluation in advanced colorectal cancer patients.     

Estrogen-receptor-directed neoadjuvant therapy for breast cancer: Results?of?a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy

Background:We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. Patients and methods:Two hundred ten patients with primary breast cancer (T₁–T₄, N₀, N_1–2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m²), mitozantrone (7 mg/m²) and mitomycin (7 mg/m²) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. Results:With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% ± 4.7% (neoadjuvant) and 87% ± 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T₁ and T₂ tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. Conclusion:In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.     

Pre-operative chemo-radiotherapy in locally advanced rectal cancer: Is this the way of future management?

The purpose of the present paper was to update a prospective analysis (H Elsaleh et al. unpubl. data, 1997) investigating the effectiveness and toxicity of pre-operative pelvic radiotherapy with modest dose 5-fluorouracil (5-FU) in locally advanced rectal cancer (T₃–T₄). A total of 31 patients were assessed (28 T₃ and three T₄ tumours). Pre-operative pelvic radiotherapy was delivered in four fields, 45 Gy to the International Commission on Radiation Units and Measurements (ICRU) point in 25 fractions over 5 weeks. A radiosensitizing dose of 5-FU was delivered at 500 mg/m² on days 1, 2 and 3, and days 22, 23 and 24. Mesorectal excision of the rectal tumour either by anterior or abdomino-perineal resection was planned at 4–6 weeks from completion of pre-operative treatment. Response to therapy was assessed by fresh macroscopic measurement of the surgical specimen. Patients had a low toxicity profile; an estimated 50% or greater response was seen in 24 out of 31 (two complete responses). There were no surgical difficulties achieving resection. No late complications were documented, although follow-up was short. In locally advanced rectal cancer, pre-operative chemo-radiotherapy had a low toxicity profile. Appropriately fractionated pre-operative chemo-radiotherapy is a reasonable option in this disease and should be further evaluated. The optimal method of delivery of the radiosensitizing agent (5-FU) is the subject of further investigation.     

Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma

We conducted a randomized, controlled trial comparing 5-fluorouracil (5-FU) with or without biological response modifiers (BRMs) as a maintenance therapy for hepatocellular carcinoma (HCC) after treatment with percutaneous ethanol injection (PEI), transcatheter arterial embolization (TAE) or arterial infusion of antitumor agents (AI). A total of 58 cases of HCC were classified into 4 groups as follows: group I, PSK with 5-FU (n=15); group II, lentinan with 5-FU (n=15); group III, OK-432 with 5-FU (n=12); and group IV, 5-FU alone as the control (n=16)., The mean survival time, mortality rate, time to progression, and T₄/T₈ ratio of lymphocytes in the peripheral blood were compared among the four groups. There was no significant difference in the background factors among the groups. In group I, the T₄/T₈ ratio of lymphocytes was reduced after the therapy. No significant difference was found among the groups in terms of the mean survival time, mortality rate, or time to progression. PEI for mitial therapy was superior to the other therapies in terms of the mean survival time and mortality rate. These results suggest that the addition of BRM to maintenance therapy with 5-FU exerts no prognostic benefit on HCC patients treated with PEI, TAE, or AI.Work presented at the Third International, Symposium on Treatment of Liver Cancer, Seoul, Korea, 12–13 February 1993     

Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pretreated advanced colorectal carcinoma

Background:Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC. Patients and methods:From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2–3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1–21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m² + 5-FU 200 mg/m² (21 patients); 2) OHP 100 mg/m² + 5-FU 250 mg/m² (3 patients); 3) OHP 130 mg/m² + 5-FU 200 mg/m² (10 patients); 4) OHP 130 mg/m² + 5-FU 250 mg/m² (16 patients). Results:Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months; 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade 1 and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9–17), with 32 patients still alive after a median follow-up of 8 months. Conclusions:This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m² and 5-FU 250 mg/m².     

A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer

Background:Dose limiting acute toxicity from chemoradiation for pancreatic cancer occurs in 15%–20% of patients treated with post-operative adjuvant therapy. Reported here is a pilot study using chronomodulated infusional 5-fluorouracil (5-FU) chemoradiation (CIC) for pancreatic cancer, a treatment designed to reduce normal tissue toxicity and maintain efficacy, with specific evaluation of acute and late morbidity, patterns of disease progression, and survival. Patients and methods:Twenty-three patients with adenocarcinoma of the pancreas were treated with 5-FU CIC between January 1997 and September 1999. The median age was 64, and there were 9 males and 14 females. Six patients were considered unresectable and seventeen others were treated post-operatively. The median external beam irradiation dose was 50.4 Gy. 5-FU infusion was given five days per week (300 mg/m²/d) and the median total dose was 8.4 g/m². The chronomodulated 5-FU infusion consists of a low basal infusion rate for 16 hours followed by an eight-hour escalating-deescalating infusion peaking at 10 p.m. All patients were followed from the time of initial diagnosis until last follow-up or death; the median follow-up was 16 months. Results:No RTOG grade 3 or 4 hematologic toxicity occurred. Twelve of seventeen patients treated postoperatively have been controlled locally, and seven patients have no evidence of disease. The median survival is 28 months and one-year actuarial survival is 88% in the group of resected patients. The 6 patients treated for unresectable disease have a median survival of 13 months. Conclusions:Acute toxicity of 5-FU CIC appears to be less frequent and less severe than that reported with flat infusional or bolus 5-FU based chemoradiation used for adjuvant post-operative therapy for pancreatic cancer. This method may warrant further examination, as it may be attractive for the elderly or those who cannot tolerate the toxicity associated with standard post-operative treatment protocols.     

Concomitant B.I.D. radiotherapy and chemotherapy with cisplatin and 5-fluorouracil in unresectable squamous-cell carcinoma of the pharynx: clinical and pharmacological data of a French multicenter phase II study

Purpose: The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)–5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic–pharmacodynamic relationships were analyzed.Methods and Materials: Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m² (day 1) and 5-FU was given as 5-day continuous infusion (day 2–day 6: 750 mg/m²/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care.Results: Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3–4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC_0-105h were significantly linked to grade 3–4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival.Conclusion: This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.     

First-line high-dose chemotherapy +/- radiation therapy in patients with metastatic germ-cell cancer and brain metastases.

Purpose:To examine the feasibility and efficacy of first-linehigh-dose chemotherapy (HD-CTX) in patients with advanced metastatic germ-celltumors (GCT) and brain metastases. Patients and methods:Twenty-two patients with brain metastasesat initial diagnosis were identified within a cohort of two hundred thirty-oneconsecutive patients with advanced metastatic disease, entered on a Germanmulticenter trial between January 1993 and July 1998. All patients receivedfirst-line HD-CTX with cisplatin–etoposide–ifosfamide (HD-VIP)followed by autologous stem-cell transplantation. Brain irradiation (BRT) with30–50 Gy ± 10 Gy boost was applied in patients with symptomaticCNS disease or as consolidation in case of residual CNS lesions after HD-CTX. Results:A median number of 4 HD-CTX cycles (range 2–5) wereapplied to the 22 patients. Ten patients received HD-CTX alone and twelvepatients were treated with HD-CTX plus BRT. Median duration of WHO grade 4granulocytopenia and thrombocytopenia was seven and five days after eachcycle, respectively. Non-hematologic toxicity consisted mainly ofmucositis/enteritis (WHO grade 3–4 32%). Two early deathsoccurred in twenty-two patients (one CNS-bleeding/one sepsis). Fourteen oftwenty patients achieved a CR/PRm– status. Twenty patients (91%)responded in the brain (55% CR/36% PR). Two-yearprogression-free and overall survival rates were 72% and 81%,respectively. These survival rates are substantially higher compared to theavailable data in the literature. Conclusions:High-dose chemotherapy with autologous stem-cellsupport ± BRT appears to be feasible without increased therapy-relatedmortality in patients with advanced metastatic GCT and brain metastases. Theresults achieved emphasize the high chemosensitivity of CNS metastases fromGCT and suggest a potential role for dose intensification. The dose of BRT inaddition to HD-CTX may be tailored to the presence of clinical symptoms andthe response of CNS metastases to chemotherapy.     

Radiation therapy,cisplatin and hyperthermia in combination in management of patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes

Twenty-one patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes were treated with radiation therapy, cisplatin and hyperthermia in combination, in an attempt to investigate any potential contribution in terms of safety, response, duration of palliation and quality of life. Patients not initially treated with radiation therapy were treated with a median dose of 70Gy and patients initially treated with radiation therapy with a median dose of 30Gy. The median number of weekly cisplatin courses was five and the median number of twice weekly local external ultrasound hyperthermia sessions was five. Average T₉₀, Average T₅₀ and Average T₁₀ were 39.9±1.2°C, 42.4±1.3°C and 44.5±0.8°C, respectively, and Average CEM 43°C T₉₀, Average CEM 43°C T₅₀ and Average CEM 43°C T₁₀ were 7.8±9.6min, 22.6*plusmn;18.8 min and 39.3±25.1 min, respectively. Mean follow-up was 1 year. Nodal complete response was achieved in eight patients and palliation of presenting symptoms in 19. Overall survival was 39% at 1 year. Grade 3 acute skin toxicity was observed in one patient and Grade 3 acute haematological toxicity in one. Radiation therapy, cisplatin and hyperthermia in combination appear to be safe and might improve response, prolong duration of palliation and reinstate quality of life in patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes.     

Accelerated Hyperfractionated Radiation Therapy and Concurrent 5-Fluorouracil/Cisplatin Chemotherapy for Locoregional Squamous Cell Carcinoma of the Thoracic Esophagus: A Phase II Study

Purpose: To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT).

Material and Methods: Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m², days 1–5) and cisplatin (CDDP) (10 mg/m², days 1–5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m², days 1–5) and CDDP (20 mg/m², days 1–5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6.

Results: The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths.

Conclusion: The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.     

A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer

Background:Gemcitabine (Gemzar®) and 5-fluorouracil (5-FU)plus folinic acid (FA) both have proven activity in the treatment of patientswith advanced pancreatic cancer. The present study was initiated toinvestigate the efficacy of gemcitabine in combination with 5-FU–FA. Patients and methods:Thirty-eight patients, median age 60 years(range 34–70) with inoperable, stage IV, pancreatic cancer were enrolledinto the study and treated on an outpatient basis. All except one patientreceived at least one cycle of treatment with gemcitabine (1000mg/m²), followed by FA (200 mg/m²) and 5-FU (750mg/m²) administered as a 24-hour continuous infusion on days 1, 8,15 and 22 of a 42-day schedule. No patient had received prior chemotherapy orradiotherapy. All 38 patients were assessed for efficacy, toxicity and timeto progressive disease. Results:Two patients (5%), achieved a partial response andthirty-four patients (89%) achieved stable disease. There were twoearly deaths (4 weeks). The median time to progression was 7.1 months(range 0.4–18.1+; 95% confidence interval (95% CI):5.3–7.9 months). Three patients had a progression-free interval ofgreater than 12 months and 12 of 38 patients (32%) survived longer than12 months. The median overall survival was 9.3 months (range 0.5–26.5;95% CI: 7.3–13.0 months). The incidence of grade 3 and 4toxicities was low. Conclusions:The combination of gemcitabine and 5-FU–FA isactive and well tolerated and seems to offer an improvement inprogression-free interval over both gemcitabine monotherapy and 5-FU–FAtherapy.     

Phase I study of a weekly schedule of oxaliplatin, high-dose leucovorin, and infusional fluorouracil in pretreated patients with advanced colorectal cancer

Purpose:To identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including fixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to define the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCRC). Patients and methods: Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered into this phase I study. Fixed doses of LV (500 mg/m²) followed by a 48-hour 5-FU 2600 mg/m² infusion (5-FU_48h) were administered with escalating doses of L-OHP, starting from 60 mg/m² and with stepwise increments of 5 mg/m². No intra-patient dose escalation was allowed. Treatment was given once a week for four consecutive weeks, followed by a one-week rest period. Results:Three dose levels were tested. The MTD was L-OHP 70 mg/m² since two of the three patients showed dose-limiting diarrhea and the third developed neutropenia during the first cycle of chemotherapy. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 42 cases, but only in 11 of 42 after the pre-arranged 10% dose reduction of 5-FU (2300 mg/m²). Sixteen patients were evaluable for response: seven (33%; 95% confidence interval (CI): 14.6%–57.0%) were considered to show a major response (one complete), six showed a stable disease, and in addition progressive disease was observed in three patients. Conclusions:Our results show that L-OHP, LV and 5-FU can be administered safely and repetitively using a weekly schedule. Diarrhea and neutropenia are the DLT of this regimen. Its activity and its manageable toxicity profile deserve further evaluation in chemotherapy-naïve MCRC patients. The doses recommended for phase II trials are: L-OHP 65 mg/m², LV 500 mg/m² and 5-FU_48h 2300 mg/m² infusion given on a weekly-times-four schedule followed by a one-week rest period.     

Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background:To determine the dose-limiting toxicity of CPT-11 incombination with oxaliplatin, and the maximal tolerated dose (MTD) and therecommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods:The study was designed to evaluate escalateddoses of CPT-11 starting at 100 mg/m² with a fixedclinically-relevant dose of 85 mg/m² oxaliplatin given every twoweeks. Results:Twenty-three patients and 186 cycles were evaluable fortoxicity (median per patient: 7, range: 1–13). Grade 3oxaliplatin-induced neurotoxicity was cumulative and limiting in 39%(9 of 23) of patients. The MTD of CPT-11 was 200 mg/m², withincomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175mg/m² of CPT-11): no grade 4 neutropenia was seen in the two firstcycles; 30% of patients experienced grade 3–4 diarrhea. Febrileneutropenia (3.2% of all cycles) was 3-fold more frequent inperformance status (PS) 2 than in PS 0–1 patients. Among elevencolorectal cancer (CRC) patients, three complete and four partial responseswere documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion:To combine CPT-11 175 mg/m² and oxaliplatin85 mg/m² every two weeks is feasible in an outpatient setting, andvery active in 5-FU resistant CRC patients. A dose of 150 mg/m²CPT-11 is recommended in PS 2 patients.     

Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option

Background:

Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC.

Methods:

One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m⁻²) on days 1–5 and 29–33, mitomycin C (MMC, 10 mg m⁻²) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m⁻² b.i.d. on weekdays), MMC (10 mg m⁻²) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity.

Results:

Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3–4) toxicity.

Conclusions:

Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.     

Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase I-II trial of the Southern Italy Cooperative Oncology Group (SICOG).

Background:The combination of cisplatin (CDDP) and 5-fluorouracil(5-FU) can be regarded as a reference regimen in squamous cell carcinoma ofthe head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specificthymidilate synthase (TS) inhibitor, which has shown clinical activity againstSCCHN in a previous phase I study, when combined with 5-FU and levo-folinicacid (LFA). Preclinical data support the combination of CDDP and raltitrexed.The aim of the present study was to evaluate the combination of cisplatin,raltitrexed, LFA and 5-FU in a phase I–II study. Patients and methods:Patients with locally advanced or metastaticSCCHN were treated with a combination of cisplatin at the starting dose of 40mg/m², followed by raltitrexed at the starting dose of 2.5mg/m² on day 1; levo-folinic acid at fixed dose of 250mg/m², followed by 5-fluorouracil at the starting dose of 750mg/m² on day 2. Doses of the three cytotoxic agents werealternately escalated up to dose-limiting toxicity (DLT). Treatment wasrecycled every two weeks and given up to a maximum of eight courses; afterchemotherapy, patients with locally advanced disease received a locoregionaltreatment. Results:Forty-five patients were entered into the study. Six doselevels were tested. At CDDP 50 mg/m², raltitrexed 3mg/m², 5-FU 900 mg/m², four out of six patients showedDLT, which was in all cases grade 4 neutropenia. Therefore, this dose levelwas defined as maximum tolerated dose (MTD). CDDP 60 mg/m²,raltitrexed 2.5 mg/m², LFA 250 mg/m², 5-FU 900mg/m² was the dose level recommended for phase II. CDDP,Raltitrexed and 5-FU mean actually delivered dose intensities at the selecteddose level were 26, 1.05, and 378 mg/m²/week, respectively.Neutropenia was the main side effect and was observed even at the lowest doselevels. Non-hematologic side effects were mild. Nine complete responses(20%) and twenty-one partial responses (47%) were observed, foran overall response rate of 67% (95% confidence interval(95% CI): 51%–80%), according to intention to treatanalysis. Fifteen of fifteen patients (100%) treated at the dose levelselected for phase II had an objective response (5 complete responses, 10partial responses). Conclusions:The results of our dose escalation clearlydemonstrate that it is possible to combine CDDP, raltitrexed, and modulated5-FU at effective doses, without unexpected toxicities. The response datapoint to an impressive clinical activity, which will be better defined by anongoing large phase II study.