Difficulties in conducting pure academic research, obstacles in data collection and quality of informations: The example of the INTERCEPTOR study.

PURPOSE/OBJECTIVE: On September 2009: We started a randomized multicenter phase III study comparing chemoradiation (CRT) (Aldestein RTOG regimen) versus induction chemotherapy followed by Cetuximab radiation (IBRT). The main study's aim was comparison of overall survival but no formal analyses have been made between the two arms because of low accrual and high amount of missing data. The goal of this paper is to identify the reasons of difference in accrual and quality of data among participating centers. MATERIAL/METHODS: Statistic: We correlated data collection quality with relevance of the centers, accrual and number of scientific papers (both specific on HNC and other topics) of each PI. We created an HNC publishing score dividing the number of HNC specific papers for the overall number of published papers. RESULTS: We observed a strong difference in the accrual of pts as well as in the quality of data among the participating centers. The accrual was independent from the quality of data since some centers with low accrual produced high quality data with an excellent follow up. We found a correlation among both number of published papers of each PI and HNC publishing score with the quality of data. CONCLUSION: The study demonstrated that expertise in HNC is important not only to ensure a better outcomes but also to provide high quality data in phase III trials.

Microwave assisted liver resection: clinical feasibility study and preliminary results.

AIM: The main goal of liver resection for malignant tumors is nowadays represented by properly parenchymal transection and careful control of hemostasis. Applying the concept of precoagulation of liver transection line we developed a new technique that provides the pre coagulation of the resection line using microwaves technologies. The purpose of this study is to evaluate the feasibility of this new liver transection technique demonstrating the high performance of this procedure, the accuracy in terms of squeeze effect on veins and portal branch and in terms of reducing the intra operative blood loss. METHODS: From December 2010 to January 2012 a total of ten patients (6 men and 4 women) affected by liver metastatic disease from colon rectal cancer and primitive liver cancer were treated (five patients with metastatic colorectal cancer disease and five patient with hepatocellular carcinoma respectively): patients requiring major liver resection were excluded from the present study focusing attention on minor liver resection. RESULTS: The technique used for the parenchyma transection is similar to those previously described by our group for hepatic radiofrequency assisted liver resection. There was no need for vascular occlusive clamping while during each surgical procedure the underpass of the hepatic hilum was done for safety control of any kind of hepatic bleeding. There was no need for ties and clips excluding the main vascular an bile pedicles that were sutured between ties. CONCLUSION: In conclusion this study with a small group of patients suggest surgical advantages in terms of statement for best practice in oncologic resection of liver malignancy. It allows a complete resection obtaining a negative pathologic margin, no blood loss and need for blood transfusions factors predicting post operative morbidity and survival, and consistently reducing time of procedure and avoidance of parenchymal ischemia. Further studies should confirm this preliminary data extending surgical indication to major hepatic resection.

Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study.

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/m(2)/day × 5 days) and fluorouracil (200 mg/m(2)/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.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study.

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.

Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck.

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.

Alternating gemcitabine and cisplatin with gemcitabine and radiation in stage IV squamous cell carcinoma of the head and neck.

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/m(2) on day 1 and cisplatin 20 mg/m(2) 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/m(2) 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.

Impact of the treating institution on the survival of patients with head and neck cancer treated with concomitant alternating chemotherapy and radiation.

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.

Alternating chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck: results from a phase III randomized trial.

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/m(2) of body surface area per day for 5 consecutive days) and 5-fluorouracil (200 mg/m(2) 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.

Lack of a time-factor in alternating chemoradiotherapy for advanced head and neck squamous cell carcinoma.

PURPOSE: To assess wheiher 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.

New chemoradiotherapy combinations in head and neck cancer.

Head and neck squamous cell cancer is the sixth most common cancer worldwide. Surgical management is effective as a single modality only for early-stage cancers (30% of patients). Making progress in this cancer is of vital interest. The standard treatment for advanced disease is chemoradiotherapy, with the goal of palliation of symptoms and prolongation of life. Response rates to even the best of regimens are approximately 30-40%, with the median survival period of approximately 6 months. Various approaches to treatment of recurrent disease are under investigation, including new drugs or combinations of drugs, with radiotherapy.

Gemcitabine, cisplatin, and radiation in advanced, unresectable squamous cell carcinoma of the head and neck: a feasibility study.

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.

Chemo-radiotherapy in locally advanced squamous cell carcinoma of the head and neck: factors affecting toxicity patterns.

Radiation and chemotherapy in the treatment of locally advanced squamous carcinoma of the head and neck can be used according to different strategies: concomitant, alternation, consecutive. The limiting acute toxicity is local with the radiosensitizing capacity of the drug and type of radiation fractionation being the predominant factors. Regimens providing more that 50% of complete responses are usually associate with a more than 40% incidence of severelocal reaction. More information is needed on late toxicity that influences the quality of life for these patients.

Induction chemotherapy followed by alternating chemo-radiotherapy in stage IV undifferentiated nasopharyngeal carcinoma.

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.

Evidence of cell kinetics as predictive factor of response to radiotherapy alone or chemoradiotherapy in patients with advanced head and neck cancer.

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.

Chemotherapy alternated with radiotherapy in the treatment of advanced head and neck carcinoma: predictive factors of outcome.

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 < or = 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.

Management of the neck after alternating chemoradiotherapy for advanced head and neck cancer.

BACKGROUND: To investigate neck control probability and the value of nodal response at completion of alternating chemoradiotherapy, a group of 43 patients was reviewed. METHODS: 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. RESULTS: 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] grade > 2) subcutaneous late reactions. CONCLUSIONS: 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.

Hydration regimen and hematological toxicity of a cisplatin-based chemotherapy regimen. Clinical observations and pharmacokinetic analysis.

The administration of 100 mg/m2 Cisplatin (CDDP) in five 20 mg/m2 daily infusions together with bolus 5-Fluorouracil (5FU) allows patients with advanced head and neck cancer (HNC) to be treated with a rapidly alternating chemoradiotherapy regimen in an out-patient setting. Due to the extremely low rate of acute renal failure, the induction of forced diuresis is not mandatory, although hydration is usually performed at every CDDP administration. In this retrospective analysis of 73 homogenously treated HNC patients, the influence of hydration on hematological toxicity was studied. A lower incidence of grade II to IV acute myelosuppression (57% vs 92%; p < 0.005), together with a lower rate of anemia lasting two weeks or more (13% vs 46%; p < 0.009), were seen in the group of patients treated with CDDP along with a forced hydration scheme (2000 ml normal saline and 20 mg furosemide before the CDDP infusion) when compared to patients on a non-forced diuresis regimen (no furosemide and 1500 ml normal saline). The lower hematological toxicity translated into a better compliance to treatment. No differences in terms of other toxicities or response rate were evident between the two groups. A pharmacokinetic study with a cross over design was performed on 7 patients, and suggests that the first day Pt kinetics are not affected by the hydration scheme used, although a significantly lower Pt urinary concentration was found in the forced diuresis group. A further kinetic analysis performed on one additional patient over the entire five-day period of two consecutive cycles showed a marked increase in the AUC of filterable Pt and in the unbound Pt fraction (fu) from the second to the fifth day in the forced hydration course, while this was not the case in the non-forced hydration course. Results from this kinetic study support the hypothesis of a lowering of Pt reactive species after repeated CDDP-furosemide treatments and an influence of furosemide-induced diuresis on Pt binding to plasma proteins.

Biological and clinical implications for multimodality treatment in patients affected by squamous cell carcinoma of the head and neck.

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 SCC-HN is beneficial and should be considered as a potential standard treatment. A complementary biological staging of SCC-HN, by evaluating new predictive factors of tumor response, is presently under investigation to better interpret clinical randomized trials exploring chemo-radiotherapy.

5-Fluorouracil dose intensification and granulocyte-macrophage colony-stimulating factor in cisplatin-based chemotherapy for relapsed squamous cell carcinoma of the head and neck: a phase II study.

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.

Treatment with cisplatin and fluorouracil alternating with radiation favourably affects prognosis of inoperable squamous cell carcinoma of the head and neck: results of a multivariate analysis on 273 patients.

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 radiation-alone therapy is adopted as the reference treatment, the relative risk of death is 0.58 (95% confidence interval (CI) 0.40-0.84) for alternating CF and 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.