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BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

BACKGROUND We evaluated the impact of center expertise, in terms of number of patients treated, on the overall survival (OS) and progression-free survival (PFS) of patients with head and neck squamous cell carcinoma (SCC). METHODS We performed a pooled analysis including data from 6 randomized trials in head and neck SCC conducted in Italy. We evaluated the association between OS or PFS and the number of patients recruited by the center. RESULTS The outcome of 903 patients who had received radiotherapy (RT) was analyzed (median follow-up 76 months). The hazard ratio (HR) comparing the third and the first quartiles of the distribution of number of patients per center showed an advantage in PFS (HR 0.59, range 0.53-0.65, P

Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease often presenting at an already advanced stage. Cisplatin chemoradiotherapy is the standard treatment for locally advanced disease, although its efficacy varies according to different studies. Thus, treatment selection is a challenge, especially in older patients, who frequently have several comorbidities. Moreover, the majority of patients with recurrent and/or metastatic disease are unsuitable for local treatment, either surgery or radiation therapy. The only treatment option for them is systemic therapy, but prognosis remains poor, with a median overall survival of less than 12 months. Methods: A group of Italian key opinion leaders in the field of HNSCC gathered several times in 2018 in order to retrieve a set of statements to help clinicians in their daily decision-making process for the treatment of patients with different scenarios of HNSCC. Results and Conclusion: The panel agreed on 22 statements that were identified as “good clinical points” based on the available literature or after discussion of the most relevant aspect of the underlying diseases when no international consensus was available. The panel identified a number of possible scenarios (namely 71) in which these statements may be helpful to guide decision-making for the best treatment selection.

Background Adjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown. Methods In the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS). Results From 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51–1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51–0.96). Conclusions Updated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed.We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate.A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p.001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce.This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated.Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Induction chemotherapy prior to planned definitive local therapy for head and neck squamous cell carcinoma has been studied for at least three decades but the debate on its role is still open. Recent landmark studies, including those presented at outstanding meetings and those still ongoing on induction chemotherapy in different clinical situations, are critically reviewed. Data confirm that a docetaxel, cisplatin and 5-fluorouracil (TPF) based induction chemotherapy may be considered in clinical practice as one of the possible options when a larynx preservation strategy is attempted. On the contrary, current data do not support the use of induction chemotherapy before a planned surgical intervention for advanced oral cavity and oropharyngeal tumors. Currently, for patients with locoregionally advanced unresectable disease, concomitant chemo-radiation remains the standard of care in waiting for results of the few ongoing studies that hopefully will clarify the role of induction TPF before either concomitant chemo-radiation or bio-radiation.

Background No evidence exists to recommend a specific chemotherapy regimen in young breast cancer patients. We performed a pooled analysis of two randomised clinical trials to evaluate the efficacy of adjuvant dose-dense chemotherapy in premenopausal breast cancer patients and its impact on the risk of treatment-induced amenorrhoea. Patients and methods In the MIG1 study, node-positive or high-risk node-negative patients were randomised to 6 cycles of fluorouracil/epirubicin/cyclophosphamide every 2 (dose-dense) or 3 (standard-interval) weeks. In the GIM2 study, node-positive patients were randomised to 4 cycles of dose-dense or standard-interval EC or FEC followed by 4 cycles of dose-dense or standard-interval paclitaxel. Using individual patient data, the hazard ratio (HR) for overall survival by means of a Cox proportional hazards model and the odds ratio for treatment-induced amenorrhoea through a logistic regression model were calculated for each study. A meta-analysis of the two studies was performed using the random effect model to compute the parameter estimates. Results A total of 1,549 patients were included. Dose-dense chemotherapy was associated with a significant improved overall survival as compared to standard-interval chemotherapy (HR, 0.71; 95% confidence intervals [CI], 0.54–0.95; p = 0.021). The pooled HRs were 0.78 (95% CI, 0.54–1.12) and 0.65 (95% CI, 0.40–1.06) for patients with hormone receptor-positive and -negative tumours, respectively (interaction p = 0.330). No increased risk of treatment-induced amenorrhoea was observed with dose-dense chemotherapy (odds ratio, 1.00; 95% CI, 0.80–1.25; p = 0.989). Conclusion Dose-dense adjuvant chemotherapy may be considered the preferred treatment option in high-risk premenopausal breast cancer patients.

Background: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. Patients and methods: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. Results: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. Conclusion: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

Background: A phase III trial demonstrated that cetuximab is the first agent in 30 years to improve survival when added to platinum-based chemotherapy (platinum-fluorouracil) first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). This analysis of the trial assessed the impact of treatment on quality of life (QoL). Patients and methods: The European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30 (QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35) module were used to assess QoL. Results: Of 442 patients randomly assigned, 291 (QLQ-C30) and 289 (QLQ-H&N35) patients completed at least one evaluable questionnaire. For QLQ-C30, cycle 3 and month 6 mean scores for platinum–fluorouracil plus cetuximab were not significantly worse than those for platinum–fluorouracil. Pattern-mixture analysis demonstrated a significant improvement in the global health status/QoL score in the cetuximab arm (P = 0.0415) but no treatment differences in the social functioning scale. For QLQ-H&N35, the mean score for the cetuximab arm was not significantly worse than that for the chemotherapy arm for all symptom scales at all post-baseline visits. At cycle 3, some symptom scores significantly favored the cetuximab arm (pain, swallowing, speech problems, and social eating). Conclusion: Adding cetuximab to platinum–fluorouracil does not adversely affect the QoL of patients with recurrent and/or metastatic SCCHN.

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.

Background In order to improve our cisplatin–5-fluorouracil (5-FU)-based alternating chemo-radiotherapy regimen, in 1996 we started an investigational program to explore a modified alternating regimen including gemcitabine given both with radiosensitizing and cytotoxic intent. Materials and methods Based on our previous feasibility trial, we conducted a second study testing the feasibility and activity of the following schedule: gemcitabine 800 mg/m2 on day 1 and cisplatin 20 mg/m2 on days 2–5 (weeks 1, 4, 7 and 10) alternated with three courses of radiotherapy (RT) (weeks 2–3, 5–6 and 8–9) with conventional fractionation up to 60 Gy. Gemcitabine 300 mg/m2 was also administered on the Monday of each week of RT. Results Forty-seven patients with stage IV (41 patients) unresectable squamous cell carcinoma of the head and neck (SCC-HN) or who had relapsed after surgery (6 patients) were enrolled. None had previously received chemotherapy or radiotherapy. Eight patients (18%) did not complete the treatment. Main grade 3–4 toxicities were as follows: neutropenia (44%); neutropenia with fever (12%); thrombocytopenia (37%); anemia (30% grade 3). One patient died in therapy due to sepsis. Most patients needed hospitalization and tube-feeding or parenteral nutrition. However, 44% of patients had a weight loss >10%. Thirty-four patients had a complete response (72%). Three partial responders were rendered disease-free by surgery (final complete response rate, 79%). At a median follow-up of 38 months actuarial 3-year overall survival, progression-free survival and loco-regional control are 43%, 39% and 64%, respectively. Data of locoregional control favorably compare with those from our database of patients treated with alternating cisplatin–fluorouracil and radiation within controlled clinical trials (64% versus 40%). Conclusions The inclusion of gemcitabine into an alternating regimen seems to improve the results achievable with the original alternating program in stage IV patients. However, due to the high acute toxicity correlated, this intensive regimen should be managed by institutions well trained in multidisciplinary treatments.

The aim of this study was to investigate the possible impact of the treating institution on the survival of patients with advanced squamous cell carcinoma of the head and neck treated with radiotherapy alone or concomitant alternating chemotherapy and radiation. The National Institute for Cancer Research of Genoa (IST) was the coordinator of two multicentre randomised trials comparing an alternating chemotherapy and radiation approach to radiotherapy alone with standard fractionation (HN-8 trial: 157 patients) or accelerated fractionation (HN-9 trial: 136 patients) in patients with advanced squamous-cell carcinoma of the head and neck. A single database of the two studies was created and a univariate analysis was performed. The Cox regression model, adjusted for the effect of other prognostic factors, was used to test the impact of the treating institution on survival. Three-year overall survival was 46% for patients treated with chemotherapy and radiation at the coordinating centre and 27% for those treated with the same approach at the affiliated centres (P=0.0001). No difference was detected between patients treated with radiation alone at the coordinating centre or outside (23% versus 21%: P=0.52). The hazard ratio of death for patients treated at the affiliated centres with concomitant alternating chemotherapy and radiation was 2.15 (95% Confidence Interval (C.I.) 1.45-3.18), while it was 1.003 (95% C.I. 0.65-1.55) for those treated with radiation alone. In our experience, the treating institution had a significant impact only on the prognosis of patients treated with the multidisciplinary approach. This finding has implications, both in terms of clinical research and clinical practice.

The adverse effects of radiation therapy, often integrated with chemotherapy and/or targeted therapies, on the skin include severe acute and chronic dermatitis associated with pain, discomfort, itching, and burning, and may heavily affect patients' quality of life. The management of these skin adverse effects in head and neck cancer patients (HNCPs) are very heterogeneous due to the lack of shared rigorous classification systems and evidence based treatments. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of dermatitis in HNCPs treated with radiotherapy with or without systemic therapies in order to improve skin toxicity management. The Delphi Appropriateness Method was used. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. This paper offers contains seven clusters of statements about the management of dermatitis in HNCPs and a review of recent literature on these topics. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Alternating chemoradiotherapy was shown by our institution to be superior to standard radiation in patients with nonsurgical squamous cell carcinoma of the head and neck (SCC-HN). Gemcitabine has shown in vitro and in vivo radiosensitizing properties, synergistic activity with cisplatin, and cytotoxic activity against SCC-HN. Thus, the authors tested the feasibility and antitumoral activity of a modified alternating chemoradiotherapy program that includes gemcitabine. Fourteen patients with stage IV (nine patients) or relapsed after surgery (five patients) unresectable SCC-HN were enrolled. None had previously received chemotherapy or radiotherapy. The treatment plan consisted of cisplatin, 20 mg/m2/day, days 1 to 5, weeks 1 and 5, and gemcitabine 800 mg/m2, day 5, weeks 1, 2, 3, and 5, 6, 7. Radiation was administered during weeks 2, 3, and 4 and 6, 7, and 8 with conventional fractionation up to 60 Gy. At the end of the combined therapy, patients had to receive two additional courses of cisplatin, 20 mg/m2/day, and fluorouracil, 200 mg/m2/day, for 5 days every 21 days. All the patients are evaluable for toxicity and 11 for response. Main grade III-IV toxicities and frequencies were: neutropenia (79%), neutropenia with fever (50%), thrombocytopenia (57%), anemia (35%), mucositis (100%), and cutaneous toxicity (14%). Ten patients (71%) had a weight loss greater than 10%. All but two patients needed hospitalization and tube feeding or parenteral nutrition. The median relative dose intensity of gemcitabine actually delivered was 83%. Two patients died 1 month after the end of treatment before the final evaluation. One patient died of sepsis during the additional cisplatin and fluorouracil courses before response assessment. Ten patients reached a complete response (intention to treat: 71%), and 1 patient had a partial response (9%). At a median follow-up of 34 months, the actuarial 3-year progression-free survival and overall survival are 41% and 63%, respectively. The estimated 3-year locoregional control is 70%. Considering the expected poor prognosis of the enrolled patients, this combined regimen showed an impressive antitumoral activity, but the severity of acute local and hematologic toxicity correlated makes the exportation of this regimen unproposable. However, the activity observed warrants the exploration of different, less toxic, chemo-radiotherapy programs including gemcitabine.

BACKGROUND The authors previously have found that in patients with locally advanced squamous cell carcinoma of the head and neck (SCC-HN), alternating chemoradiotherapy (ALT) was superior to low-total-dose conventional radiotherapy alone. The purpose of this randomized trial was to compare the same chemoradiotherapy approach with high-total-dose partly accelerated radiotherapy. METHODS During 6 years, 136 consecutive patients with previously untreated unfavorable Stage II or Stage III–IV (International Union Against Cancer) SCC of the oral cavity, pharynx, and larynx were enrolled. They were randomly assigned to chemotherapy consisting of 4 cycles of intravenous cisplatin (20 mg/m2 of body surface area per day for 5 consecutive days) and 5-fluorouracil (200 mg/m2 per day for 5 consecutive days; weeks 1, 4, 7, and 10) alternated with three 2-week courses of radiotherapy (20 grays [Gy] per course, 2 Gy per day, 5 days per week; ALT, 70 patients) or to partly accelerated radiotherapy with final concomitant boost technique (75 Gy/40 fractions in 6 weeks; partly accelerated radiotherapy [PA-RT], 66 patients). RESULTS At the median follow-up of 60 months (range, 30–102 months), no statistical differences were observed in overall survival, progression free survival, or locoregional control between the 2 treatments. Actuarial 3-year overall survival and progression free survival were 37% and 35%, respectively, in the ALT group and 29% and 27%, respectively, in PA-RT group. The median overall survival and progression free survival were 24 and 15 months, respectively, in the ALT arm and 18 and 11 months, respectively, in PA-RT arm. Actuarial 3-year locoregional control rates were 32% in the ALT group and 27% in the PA-RT group. At multivariate analysis, tumor classification was the only factor that emerged as a significant independent variable affecting overall survival. Patients treated in the PA-RT arm experienced higher Grade 3+ (World Health Organization) acute skin and mucosal reactions than patients in the ALT arm. Moreover, local late mucosal and skin toxicities occurred more often in patients treated with PA-RT. CONCLUSIONS This trial failed to disclose statistically significant differences in the outcome of patients treated with either ALT or PA-RT. Therefore, definitive conclusions could not be made. However, acute skin effects and late mucosal and skin toxicities above the clavicles appeared to be significantly lower with chemoradiotherapy. Cancer 2001;92:2856–67. © 2001 American Cancer Society.

Purpose: To investigate the impact of pretreatment and treatment-related factors on local-regional control and overall survival rates in advanced (III and IV stage) head and neck cancer patients treated with alternating chemoradiotherapy, a selected group of 115 patients who had PS ≤ 1 and received a total dose of radiotherapy (RT) within ± 5% of that planned, was analyzed. Methods and Materials: Patients were planned to receive 4 cycles of chemotherapy (cisplatin and 5-fluorouracil) alternated with radiotherapy (60 Gy/30 fractions). However, mainly due to systemic toxicity, about 30% of the patients received less than 90% of the planned combined chemotherapy total dose (CCTD). Based on differences in treatment planning and delivery, patients were divided into two groups. For living patients, median follow-up is 34 months (range: 24–111 months). Results: At multivariate analysis, RT technique ( p = 0.008), N stage ( p = 0.010) and CCTD ( p = 0.027) were independent predictors of LRC. Compared to each favorable subset (RR = 1), the relative risks of LRC failure were 2.18 (95% CI: 1.21–3.91), 2.23 (95% CI: 1.11–4.50) and 2.23 (95% CI: 1.15–4.31) for patients without improved dose distribution and treatment delivery, with bilateral nodes or nodes greater than 6 cm, and with a CCTD lower than 90%, respectively. Regarding overall survival, only RT treatment was found to be an independent predictor ( p = 0.037), with an RR of 1.61 (95% CI: 1.02–2.53) for patients without improved dose distribution and treatment delivery. Conclusion: Optimal delivery of RT dose is crucial in patients with advanced head and neck tumors, even if they receive chemotherapy as part of their treatment. This study also suggests that chemotherapy total dose may play a role in patient outcome, but this must be confirmed prospectively.

6022Background: The impact of centre expertise on outcome of head and neck cancer (HNC) patients (pts) treated with chemotherapy (CT) +/- radiotherapy (RT) has been sparsely evaluated. Pts selectio...

To date, the specific role of "in-field" crusting exudation on pain and on activity of daily living (ADL) in head and neck cancer (HNSCC) patients undergoing treatment with cetuximab and radiochemotherapy has been neglected. The purpose of the study was to evaluate the role of crusting exudation on the severity of pain and ADL METHODS: Thirty-seven of the 45 HNSCC patients enrolled in the alternating radiotherapy, chemotherapy, and cetuximab trial were evaluated in this study. The main radiodermatitis signs (the intensity of erythema, the extension of dry, and moist desquamation and of necrosis)--including crusting exudation severity--pain, ADL, and radiodermatitis scores were registered at least weekly during and after treatment. The correlation between crusting exudation and pain or ADL was evaluated.The "in-field" crusting exudation score seemed to have the strongest correlation with pain (Spearman's rho = 0.897; p0.001) and the most intense influence on it (Co-B = 0.715; 95% C.I. = 0.643-0.787). However, it seemed to have a weaker correlation with ADL than the other clinical radiodermatitis signs.Crusts have the strongest correlation with pain in patients with Cetuximab-related radiation dermatitis. Moreover, the presence of crusts can lead operators to misclassify dermatitis as score 4, causing unnecessary delays or interruptions in treatment.

BACKGROUND The administration of granulocyte-monocyte colony stimulating factor (GM-CSF) should allow an increase in the doses of chemotherapy for patients with advanced cancers of the head and neck. PATIENTS AND METHODS Eleven patients with histologically proven relapsed squamous cell carcinoma of the head and neck entered this Phase I study based on the combination of cisplatin (20 mg/m2/day for 5 days), escalating doses of 5-fluorouracil, both given by intravenous injection from day 1 to 5, and GM-CSF, 5 micrograms/kg from day 8 to day 19. RESULTS The maximum tolerated 5-fluorouracil dosage was 300 mg/m2 i.v. bolus for 5 consecutive days q. 3 weeks. Thrombocytopenia was the limiting factor to further increase of 5-fluorouracil dosage. Moderate to severe stomatitis were quite rare despite the increased dose of the antimetabolite. GM-CSF was well tolerated: no significant local or systemic side effects attributable to this drug were recorded. CONCLUSIONS Adding GM-CSF to the combination of cisplatin and 5-fluorouracil allowed to increase 5-fluorouracil dose up to 50% over the conventional dosage. Further increase of the dose was precluded by the development of severe thrombocytopenia.

Background Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab. Patients and methods Eligible patients had stage III–IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m2/day × 5 days) and fluorouracil (200 mg/m2/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS). Results Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3–4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients. Conclusions The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.

Background The addition of gemcitabine may be a reasonable way to enhance the activity of the alternating cisplatin/5-fluorouracil and radiation regimen considered the referring approach for patients with advanced squamous cell carcinoma (SCC) of the head and neck at the National Institute for Cancer Research of Genoa. Methods Three courses of cisplatin, 20mg/m 2 /day and 5-fluorouracil, 200mg/m 2 /day, days 1–5 (weeks 1, 4, and 7) alternated to 3 courses of radiotherapy at standard fractionation (weeks 2–3, 5–6, 8–9) up to 60Gy, and gemcitabine, 50mg/m 2 on monday of each week of radiation, were administered to 47 patients with stage IV (42 patients) or relapsed after surgery (5 patients), SCC of the oral cavity, pharynx or larynx. Results Eighty-five percent of the patients completed the planned treatment. Main grade 3–4 acute toxicities were: mucositis (40%), neutropenia (26%) and thrombocytopenia (30%). Twenty-seven patients reached a complete response (57%). Seven partial responders were rendered disease-free by surgery (final complete response rate: 72%). At a median follow-up of 37 months, 3-year overall survival, progression-free survival and loco-regional control are 50%, 43% and 54%, respectively. Conclusions The addition of gemcitabine at low dose to our referring alternating regimen is feasible and very active. It may improve the long-term outcomes despite an acceptable increase of acute mucoseal toxicity.

The aim of this multicenter trial was to test the feasibility and the activity of a three-drug combination where paclitaxel is added to cisplatin and 5-fluorouracil. Patients with metastatic or relapsed SCC-HN unsuitable for further loco-regional radical treatment, not previously treated with chemotherapy, were eligible to receive paclitaxel 160 mg/m2 (3-hr infusion) day 1, CDDP 25 mg/m2/day and 5-FU 250 mg/m2/day bolus on days 1, 2, 3 every three weeks up to a maximum of five courses. Fourty-seven patients were enrolled by five Institutions in Italy. Main grade III-IV toxicities were: neutropenia (48%), thrombocytopenia (6%), anemia (4%), diarrhea (2%), mucositis (2%). Six patients had a complete response (13.3%) and eight a partial response (17.8%). Median progression free survival and overall survival are 4.1 and 7.9 months. One-year progression free survival and overall survival are 16% and 29%. This three-drug regimen has an excellent safety profile. The activity in the palliation of recurrent SCC-HN, however, does not appear to be improved in comparison with cisplatin and 5-fluorouracil or cisplatin and paclitaxel regimens. Recent studies indicate a more promising role of taxanes including triplets in the induction therapy of previously untreated patients.

Aims and background Radiation-induced permanent xerostomia occurs frequently in patients affected by squamous cell carcinoma of the head and neck treated by parallel opposed lateral fields. An ipsilateral technique by using co-planar multiple-field arrangement was designed to restrict treatment to the primary tumor and neck on the same side for patients with selected lateralized squamous cell carcinoma of the head and neck. Methods From November 2001 till December 2002, 30 patients affected by squamous cell carcinoma of tonsillar fossa, retro-molar trigone, alveolar ridge and oropharyngeal lateral wall were included in this investigational trial and treated with an ipsilateral multiple field technique: in detail, oblique opposed two upper half fields were planned ipsilaterally to the squamous cell carcinoma site to cover PTV1 and PTV2, whereas an anterior-lower half field was planned to encompass the lower neck node area above clavicles. On CT scans, the contralateral parotid gland was outlined as organ at risk and the contralateral upper lymph node area was contoured as volume of interest. In selected cases, convergent oblique two wedge-pair half fields were added to opposed oblique two-field technique in order to cover only PTV2: generally, in these patients, PTV1 received 1.8 Gy per fraction and PTV2 2.2 Gy per fraction up to total doses of 54 Gy and 66 Gy, respectively. Results Ten patients received radical radiotherapy, 9 patients radical alternating chemo-radiotherapy, and 11 patients adjuvant radiotherapy. At the end of treatment, unilateral confluent mucositis was recorded in 13 (43%) patients and unilateral moist skin epidermolysis in 14 (46%) patients. Six months after the end of radiotherapy, grade 0 xerostomia was recorded in 20 (67%) patients. No patient experienced grade 2+ xerostomia. At a median follow-up of 12 months, 26 (86%) patients were alive and well; 2 patients (6%) developed contralateral neck node failure, both 4 months after the end of ipsilateral radiotherapy. Conclusions These results, although preliminary, suggest that by using an ipsilateral radiotherapy technique, symptomatic xerostomia may be avoided in selected patients with lateralized squamous cell carcinoma of the head and neck without an increased short-term risk of contralateral nodal failure.

Background To report local long-term morbidity after concomitant boost radiotherapy (AFRT) or alternating chemoradiotherapy (CTRT), we analyzed the toxicity data recorded in 168 patients with advanced head and neck squamous cell carcinoma treated at our institution within phase II-III studies. Patients and Methods All patients enrolled in three consecutive phase II-III studies and followed for a minimum of three months after the end of treatment were included in the present analysis. Local late reactions were scored prospectively. The actuarial incidence of grade 2 or more (2-4) late local toxicity according to RTOG/EORTC was taken as endpoint. The median follow-up is 32.0 months (range, 3.3-138.1 months). For living patients the minimum and median follow-up are 12.1 and 69.3 months, respectively. Results The five-year actuarial incidence of grade 2+ and grade 3+ toxicity are 56.7 ± 5% and 21 ± 4%, respectively. At multivariate analysis, acute mucositis grade, complementary surgery, primary site and performance status proved to be independent predictive factors of grade 2+ late toxicity with P values of Conclusions A substantial proportion of surviving patients develops late complications, although severe irreversible reactions occur in a minority of patients. Acute local toxicity can be used to predict local late toxicity that arises within five years of the end of treatment.

1048 Background: Oral chemotherapy (CT) is an attractive treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by a hormone therapy. In our phase II study, we evaluated the role of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. In this abstract, first safety results of this trial are presented. Methods: Main eligibility criteria included: age ≥18 years, documented bone involvement previously untreated by CT, hormone receptor positive disease previously treated by at least one hormone therapy, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment. Results: Main pts characteristics in the full population were (n=70): median age: 60.6 years (34% ≥65 years); media...

In locally advanced undifferentiated nasopharyngeal carcinoma (UNPC), concomitant chemo-radiotherapy is the only strategy that gave better results over radiation alone in a phase III trial. Adding effective chemotherapy to a concomitant chemo-radiotherapy programme may be a way to improve the results further. 30 patients with previously untreated T4 and/or N2–3 undifferentiated nasopharyngeal carcinoma were consecutively enrolled and initially treated with 3 courses of epidoxorubicin, 90 mg/m2, day 1 and cisplatin, 40 mg/m2, days 1 and 2, every 3 weeks. After a radiological and clinical response assessment patients underwent 3 courses of cisplatin, 20 mg/m2/day, days 1–4 and fluorouracil, 200 mg/m2/day, days 1–4, i.v. bolus, (weeks 1, 4, 7) alternated to 3 courses of radiation (week 2–3, 5–6, 8–9–10), with a single daily fractionation, up to 70 Gy. WHO histology was type 2 in 30% and type 3 in 70% of the patients. 57% had T4 and 77% N2–3 disease. All the patients are evaluable for toxicity and response. All but one received 3 courses of induction chemotherapy. Toxicity was mild to moderate in any case. At the end of the induction phase 10% of CRs, 83.3% of PRs and 6.7% of SD were recorded. All the patients but one had the planned number of chemotherapy courses in the alternating phase and all received the planned radiation dose. One patient out of 3 developed grade III–IV mucositis. Haematological toxicity was generally mild to moderate. At the final response evaluation 86.7% of CRs and 13.3% of PRs were observed. At a median follow-up of 31 months, 13.3% of patients had a loco-regional progression and 20% developed distant metastases. The 3-year actuarial progression-free survival and overall survival rates were 64% and 83%. Induction chemotherapy followed by alternating chemo-radiotherapy is feasible and patients' compliance optimal. This approach showed a very promising activity on locally advanced UNPC and merits to be investigated in phase III studies. © 2000 Cancer Research Campaign http://www.bjcancer.com

Purpose: The aim of this study was to investigate the potential clinical relevance of cell kinetics parameters to the locoregional control (LRC) and overall survival of patients affected by head and neck squamous cell carcinoma (HN-SCC) treated by conventional radiotherapy, partly accelerated radiotherapy, or alternating chemoradiotherapy. Methods and Materials: Between January 1993 and June 1996,115 patients with HN-SCC at Stage III and IV entered the study. Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine (BrdUrd), an analogue of thymidine that is incorporated in DNA-synthesizing cells. In vivo S-phase fraction labeling index (LI), duration of S-phase (Ts), and potential doubling time (Tpot) were obtained by analysis of the flow cytometric content of BrdUrd and DNA. Eighty-two patients were randomly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy, whereas 33 other matching patients received conventional radiotherapy. Results: Univariate LRC analysis showed that LI value was a prognostically significant factor, independent of type of therapy. Multivariate analysis failed to show cell kinetics parameters as statistically significant factors affecting LRC probability and overall survival. However, subgroup analysis showed that LRC probability at 4 years for fast proliferating tumors characterized by a LI ≥ 8% was significantly better for patients treated either with alternating chemoradiotherapy or partly accelerated radiotherapy than it was for those treated with conventional radiotherapy. Conversely, LRC probability for slow proliferating tumors (LI < 8%) treated with the three treatment modalities was similar. Conclusions: These results showed that, independent of type of treatment, pretreatment cell kinetics provided only a weak prognostic role of outcome in HN-SCC. However, this report raises the hypothesis that fast growing HN-SCC may be more likely to benefit from intensified therapy, as given in this series. Cell kinetics parameters studied by the in vivo BrdUrd/flow cytometry method might be considered predictive factors of response, providing information on which type of treatment may be selected according to tumor proliferation rate.

Enhanced activity of some anticancer agents by the addition of interferons has been reported in murine tumours (Chirigos & Pearson 1973). More recent data show that interferon a-2b (lFNa-2b), even at low doses, can increase the activity of cyclophosphamide and cisplatin in human non-small cell lung cancer xenografts (Carmichael et a1. 1986), So far several clinical studies have reported the association between recombinant (r) IFNa-2b and chemotherapy in different human tumours, for example colorectal carcinoma (Wadler et a1. 1989) and ovarian cancer (Nardi et a1. 1990), but no clinical data concerning this association in head and neck cancer are available. Thus a phase I study was undertaken to evaluate the maximum tolerable dose of rIFNa-2b in combination with cisplatin in patients with relapsed squamous cell carcinoma of the head and neck.

To investigate neck control probability and the value of nodal response at completion of alternating chemoradiotherapy, a group of 43 patients was reviewed.Patients were treated with 60 Gy alternated with four cycles of cisplatin and fluorouracil. All patients had lymph nodes positive for squamous cell carcinoma from various primary sites, underwent computed tomography (CT) for staging and evaluation of response, and were treated at a single institution. Patients with bilateral lymph nodes (N2c) were further staged according to the side of dominant neck disease.After chemoradiotherapy alone, 2-year neck control probabilities (NCP) are 86+/-13%, 58+/-10%, and 0 for N1, N2a/b, and N3 neck stages, respectively (p = .038). Two-year NCP for 25 complete responders is 85+/-8%, whereas, at the same time interval, it is 17+/-9% for 18 partial responses (p.0001). Within patients with N1-2a/b neck disease, 21 complete responders had a 2-year NCP of 92+/-8%. Five (11%) heminecks in four patients developed severe (Radiation Therapy Oncology Group [RTOG] grade2) subcutaneous late reactions.For patients with N1-2a/b neck disease, response at the end of treatment as evaluated by both physical exam and CT is a reliable criterion to select patients for complementary surgery even after chemoradiotherapy. For N3 disease, planned neck dissection regardless of response seems warranted.

A previous phase I study showed that in a 5-day combination of cisplatin (CDDP) 20 mg/m2/day and 5-fluorouracil (5-FU) intravenous bolus, the maximum tolerable dose of 5-FU is 200 mg/m2/day without the use of growth factors and 300 mg/m2/day with recombinant human granulocyte-monocyte colony-stimulating factor (rhGM-CSF) support. In the present phase II study, 26 patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated with CDDP, 20 mg/m2/day, and 5-FU, 300 mg/m2/day intravenous bolus, for 5 consecutive days every 3 weeks. Granulocyte-macrophage colony-stimulating factor, 5 mg/kg/day subcutaneously, was administered from days 8 to 19. All patients had previously undergone surgery and/or radiation treatment. None had previously received chemotherapy. Mucositis (19% of the patients) and thrombocytopenia (42%) were the most frequent, but generally mild, toxicities. Relevant, GM-CSF-related side effects were detected in 12% of the patients. The median number of cycles delivered was four. Three complete and five partial responses were recorded (31% overall response rate). Further investigation of this regimen is unwarranted because of both its lack of improvement in antitumoral activity and the high costs incurred with the use of growth factors.

Summary Purpose: The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III—IV, inoperable, squamous cell carcinoma of the head and neck (SCC-HN). Patients and methods: Between August 1983 and December 1990, 273 patients with stage III—IV, previously untreated, unresectable SCC of the oral cavity, pharynx and larynx, were included into two consecutive randomized multi-institutional trials (HN-7 and HN-8 protocols) coordinated by the National Institute for Cancer Research (NICR) of Genoa. The HN-7 protocol compared neo-adjuvant chemotherapy (four cycles of vinblastine, 6 mg/m2 i.v. followed by bleomycin, 30 IU i.m. six hours later, day 1; methotrexate, 200 mg i.v., day 2; leucovorin, 45 mg orally, day 3) (VBM) followed by standard radiotherapy (70-75 Gy in 7-8 weeks) (55 patients) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation, 20 Gy each (61 patients). In the HN-8 protocol standard radiotherapy (77 patients) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin, 20 mg/m2/day and fluorouracil, 200 mg/m2/day, bolus, both given for five consecutive days (CF) instead of VBM (80 patients). A single database was created with the patients on the two protocols. Age at diagnosis, gender, site of the primary tumor, size of the primary, nodal involvement, performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method. The analyses were repeated including the treating institutions as a covariate (coordinating center versus others). Results: The multiple logistic regression analysis indicates that treatment (alternating more so than others, regardless of the chemotherapy regimen used) (P = 0.0001) is more likely to be associated with complete response. In addition, size of the primary tumor (P = 0.004), nodal involvement (P = 0.02) and performance status (P = 0.009) are prognostic variables affecting the probability of achieving a complete response. The Cox regression analysis indicates that treatment, performance status, size of the primary tumor, nodal involvement and, marginally, site of the primary tumor, are independent prognostic variables affecting the risk of death. When the radiationalone therapy is adopted as the reference treatment, the relative risk of death is 0.58 (95% confidence interval (CI) 0.400.84) for alternating CFand radiation, 0.79 (95% CI 0.53-1.16) for alternating VBM and radiation and 1.30 (95% CI 0.89-1.92) for sequential VBM and radiation. When the treating institution is included in the model, a 34% increased risk of death (P - 0.04) is observed for patients treated outside the coordinating center. Conclusion: In our series of patients with advanced, unresectable SCC-HN, treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis. The role of the treating institution in the modulation of the treatment outcomes was also relevant.

Background : In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. Purpose : After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. Methods : One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m 2 ] and fluorouracil [200 mg/m 2 ], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. Results : As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group ; P =.037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P =.008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P =.038, logrank test). Conclusions and Implications : The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.

For patients with advanced, unresectable squamous-cell carcinoma of the head and neck, radiotherapy is the standard treatment but has poor results. We therefore designed a randomized trial to determine whether alternating chemotherapy with radiotherapy would improve the survival of such patients.Patients in the trial had biopsy-confirmed unresectable, previously untreated Stage III or IV, squamous-cell carcinoma of the oral cavity, pharynx, or larynx. They were randomly assigned to chemotherapy consisting of four cycles of intravenous cisplatin (20 mg per square meter of body-surface area per day for five consecutive days) and fluorouracil (200 mg per square meter per day for five consecutive days) alternating with radiotherapy in three two-week courses (20 Gy per course; 2 Gy per day, five days per week), or to radiotherapy alone (up to 70 Gy; 2 Gy per day, five days per week).The 80 patients given chemotherapy alternating with radiotherapy and the 77 given radiotherapy alone were comparable in terms of age, sex, performance status, disease stage, and site of the primary tumor. Complete responses were obtained in 42 percent of the patients in the combined-therapy group and 22 percent of those in the radiotherapy group (P = 0.037). The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group (P less than 0.05); the 3-year survival was 41 percent and 23 percent, respectively. Severe mucositis occurred in 19 percent of the patients in the combined-therapy group and 18 percent of those in the radiotherapy group.In patients with advanced unresectable squamous-cell carcinoma of the head and neck, chemotherapy alternating with radiotherapy increases the median survival and doubles the probability of survival for three years as compared with radiotherapy alone. However, since local disease cannot be controlled in over half the patients who receive the combined treatment and since almost two thirds die within three years, further improvements in management are necessary.

Experimental and clinical data support the concomitant use of 5-fluorouracil (5-FU) and high-dose folinic acid (HDFA). To verify the role of such a combination in far advanced head and neck cancer, we performed a phase II study employing weekly HDFA, 500 mg/m2 in 2-h infusions, and 5-FU, 600 mg/m2 bolus injection. Twenty-seven evaluable patients with recurrent disease entered the study. One complete response, seven partial responses, 10 stable disease, and nine progressions were observed: the overall response rate was 29.6%. Oral mucositis and diarrhea were major side effects; five patients discontinued the treatment due to toxicity; no deaths correlated to the treatment were detected. Considering the characteristics of our patients, the 5-FU/HDFA combination has shown a satisfactory antitumoral activity, but toxicity was similar to other chemotherapy regimens.

From January 1987 to May 1988, 16 patients with advanced squamous cell carcinoma of the head and neck received combined treatment, based on an alternating schedule of chemotherapy and multiple fractions per day (MFD)-radiotherapy. The chemotherapy regimen consisted of cisplatin, 20 mg/m2, followed by 5-fluorouracil (5-FU), 200 mg/m2 i.v. push, from days 1 to 5 during weeks 1, 5, and 9. Radiotherapy was administered in two courses of 32 Gy each (total dose, 64 Gy) during weeks 2 and 3 and 6 and 7. Each course was given in two fractions per day, 5 days per week. The 16 patients were evaluated for toxicity and response. We observed 7 complete responders, 6 partial responders, and 3 nonresponders. The overall response rate was 81%. Toxicity was heavy: 44% of the patients developed grade III-IV mucositis. Our results suggest that cisplatin and 5-fluorouracil alternating with MFD-radiotherapy is effective; however, a new less toxic scheduling must be determinated.

15508 Background: Concomitant chemo-radiotherapy is the standard treatment for advanced UNPC. Induction chemotherapy may improve the results further by enhancing both locoregional and distant control. Methods: Fifty patients with previously untreated, locoregionally advanced UNPC were initially treated with 3 courses of epidoxorubicin, 90 mg/mq, day 1 and cisplatin, 40 mg/mq, days 1 and 2, every 3 weeks. After a radiological and clinical response assessment patients underwent 3 courses of cisplatin, 20 mg/mq/day, days 1–4 and fluorouracil, 200 mg/mq/day, days 1–4, i.v. bolus, (weeks 1,4,7) alternated to 3 splits of radiation (week 2–3, 5–6, 8–9-10), with a standard fractionation, up to 70 Gy. Histology was WHO type 1 in 1 pt (2%), WHO type 2 in 10 pt (20%), WHO type 3 in 39 pts (78%). All patients had stage IV disease (UICC 1992). Results: All the patients are evaluable for toxicity and response. All but one received 3 cycles of induction chemotherapy. Toxicities from induction chemoyherapy were: 2% grade 3 or 4 mucositis, 22% grade 3 or 4 nausea/vomiting, 6% grade 3 or 4 haematological toxicity and one episode of febrile neutropenia. At the end of induction phase 12% of CRs, 84% of PRs and 4% of SD were recorded. All patients but two had the planned number of chemotherapy courses in the alternating phase and all but one received the planned radiation dose. Toxicities from alternating chemo-radiotherapy were: 28% grade 3 or 4 mucositis, 8% grade 3 or 4 nausea/vomiting, 24% grade 3 or 4 haematological toxicity with no episodes of febrile neutropenia. At the final response evaluation 86% of CRs and 14% of PRs were observed. At a median follow up of 39 months, 14% of patients had locoregional failure, 20% had distant failure and 2% both. The 4-year actuarial progression free survival and overall survival rates were 71% and 81%. Conclusions: Treatment of locoregionally advanced UNPC with induction chemotherapy followed by alternating chemo-radiotherapy is feasible and patients’ compliance is optimal. 4-year outcomes seems better than those reported with concomitant chemo-radiotherapy alone. No significant financial relationships to disclose.

Thirty-four patients with advanced (stage IV) or relapsing squamous cell carcinoma of the head and neck (SCC-HN) were treated alternately with chemotherapy (CT) and radiotherapy (RT). Patients' characteristics were as follows: male: female ratio, 27:7; median age, 55 (34-76), median P.S., 1 (ECOG scale) (range 0-2). Patients studied had no renal, hepatic, or cardiac impairments, a life expectancy of greater than or equal to 3 months, and no previous treatment with RT or CT. Seventeen patients were previously untreated, and 17 had a relapse after radical surgery. The CT regimen consisted of 20 mg/m2 cisplatin, with 2 h forced diuresis, from day 1 to 5, and 200 mg/m2 i.v., from day 1 to 5, every 3 weeks, administered four times. The RT was performed after the first, second, and third CT course, and consisted of three courses of 20 Gy each, 2 Gy daily, 5 days per week. Weekend intervals were planned between CT and RT treatments. The 17 previously untreated patients showed an overall response rate of 88.2% [eight complete response (CR), seven partial response (PR), one stable disease (SD), one progression disease (PD)]; the 17 patients treated at relapse after radical surgery reached an overall response rate of 64.7% (six CR, five PR, six PD). Actuarial median survival is 47 weeks: 51 weeks in untreated patients, and 42 weeks in previously treated patients. Toxicity was mild, and only 10 patients suffered from grade III (WHO scale) gastrointestinal (2 patients), hematological (5 patients), mucosal (2 patients), and neurological (1 patient) toxicity. Neither grade IV toxicity nor treatment-related deaths have been observed. In our study, cisplatin and 5-FU alternating with RT has shown an interesting antitumor activity and moderate side effects.

Purpose To assess whether a radiotherapy time factor exists also for patients affected by head and neck squamous cell carcinoma and receiving combined chemoradiotherapy. Methods and materials From 1989 to 1997, of 121 patients affected by stage III or IV head and neck squamous cell carcinoma who underwent alternating chemotherapy and radiotherapy according to the Merlano regimen at our institution, 59 were selected for time factor analysis. Until 1995, if chemotherapy had to be delayed because of bone marrow toxicity, radiotherapy was also delayed accordingly. Since January 1996 in order to avoid treatment-free gaps, radiotherapy was delivered continuously until it was possible to resume chemotherapy. Potential predictive factors of local-regional control were included in univariate and multivariate models. The median follow-up is 26 months (5-121 months). Results As a result of change in treatment policy, mean radiotherapy duration was shorter for 25 patients treated after 1995 (group A, 8.4 weeks) than for those treated during 1995 or before (group B, 9.4 weeks) (t test, P = 0.0012). In contrast, as expected, mean chemotherapy duration remained relatively unchanged through the years (10.9 vs 10.7 weeks for groups B and A, respectively, t test, P = 0.77). At 2 years, the actuarial local-regional control rate was 53 ± 7% for the whole population. The estimated rates of local-regional control at 2 years were 49 ± 10% and 56 ± 9% for patients belonging to groups A and B, respectively. At univariate and multivariate analyses, treatment group was not predictive of local-regional control. Conclusions Our attempt to prospectively limit radiotherapy overall treatment time failed to improve outcome. The data, although obtained on a relatively limited number of patients, suggest that tumor cell repopulation during radiotherapy may not be clinically relevant when chemotherapy is part of the treatment for advanced head and neck squamous cell carcinoma.

Aims and background Several strategies combining radiotherapy and chemotherapy have been developed for the cure of squamous cell carcinoma of the head and neck (SCC-HN) in an attempt to improve loco-regional control and survival. This overview aims to summarize clinical results of reported randomized trials and to discuss the biological mechanisms underlying the interactive and non-interactive processes promoted when chemotherapy is added to radiotherapy. Methods The clinical goals of combined modality therapy and exploitable associations of chemotherapy and radiotherapy that may lead to a therapeutic gain in comparison with radiotherapy alone are reported and reviewed. Clinical applications of the four main ways of combining chemotherapy with radiotherapy (neoadjuvant, concomitant, alternating and adjuvant) are briefly re-analyzed and discussed. Results and Conclusions Published evidence suggests that induction chemotherapy (neo-adjuvant) should not be routinely recommended; however, induction chemotherapy increases the likelihood of larynx preservation in patients with laryngeal and hypopharyngeal cancer and should be offered as a treatment option as an alternative to surgery. Positive results of several randomized studies and a recent meta-analysis show that concomitant use of chemotherapy and radiotherapy in unresectable SCCHN is beneficial and should be considered as a potential standard treatment. A complementary biological staging of SCCHN, by evaluating new predictive factors of tumor response, is presently under investigation to better interpretate clinical randomized trials exploring chemo-radiotherapy.