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.

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.

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.

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.

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.

Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.

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/m2] and fluorouracil [200 mg/m2], 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.

Sequential versus alternating chemotherapy and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study.

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).

Chemoradiotherapy as an alternative to radiotherapy alone in fast proliferating head and neck squamous cell carcinomas.

The aim of this pilot study was to explore the prognostic relevance of cell kinetics parameters on the local control of patients affected by head and neck squamous cell carcinoma (HN-SCC), randomly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy. Between 1992 and 1995, 40 patients with HN-SCC at stages III and IV entered the study. Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine, 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 bromodeoxyuridine and DNA. Twenty patients were treated by alternating chemotherapy and conventional radiotherapy (arm A), whereas 20 other matching patients received partly accelerated radiotherapy alone (arm B). Univariate local control analysis showed that LI, TS, and Tpot were not prognostically significant in either arm. However, local control probability at 2 years for fast growing tumors, characterized by a LI of 9%, was higher for patients treated with alternating chemoradiotherapy than it was for those treated with partly accelerated radiotherapy alone (68 versus 39%). Conversely, local control probabilities for slow proliferating tumors (LI, <9%) treated in the two arms were similar. These results suggest a potential role for alternating chemotherapy and radiotherapy in HN-SCC patients with fast growing tumors.

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.

Chemotherapy for relapsed head and neck cancer: paclitaxel, cisplatin, and 5-fluorouracil in chemotherapy-naive patients. A dose-finding study.

The aim of this trial was to identify the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered via a 3-hour infusion day 1, together with cisplatin 20 mg/m2/d days 1 to 3 and 5-fluorouracil 200 mg/m2/d bolus days 1 to 3 every 21 days. The prophylactic administration of colony-stimulating factors was not allowed. Twenty-three patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck previously treated with surgery and/or radiotherapy were accrued. None had received chemotherapy previously. No grade 3/4 hematologic toxicity at nadir or other limiting toxicities were recorded with paclitaxel at 100 to 135 mg/m2 (six patients, 26 courses). Seven patients (six evaluable, 22 courses) were treated with 160 mg/m2. Grade 4 neutropenia at nadir with fever lasting 3 days was observed in one patient. Nonhematologic toxicities, including temporary peripheral neuropathy, asthenia, myalgias, vomiting, and mucositis were generally mild. Three patients were treated with 180 mg/m2 (eight courses). Grade 4 neutropenia at nadir was recorded in all patients and was febrile in two. Seven patients (six evaluable, 23 courses) were treated with paclitaxel 160 mg/m2, cisplatin 25 mg/m2/d, and 5-fluorouracil 250 mg/m2/d. Grade 4 febrile neutropenia at nadir was recorded in one patient. One episode of grade 4 mucositis and two episodes of grade 3 diarrhea were also recorded. Overall, eight responses (38%) were observed. In conclusion, the combination of paclitaxel 160 mg/m2, cisplatin 25 mg/m2/d, and 5-fluorouracil 250 mg/m2/d for 3 consecutive days can be administered safely without growth factor support. This regimen merits further investigation in a phase II trial.

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.

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.

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.

Concomitant administration of two standard regimens of chemotherapy and radiotherapy in advanced squamous carcinoma of the head and neck: a feasibility study.

BACKGROUND: In advanced squamous cell carcinoma of the head and neck, the superiority of a chemo-radiotherapy combination over radiotherapy alone has been strongly suggested. However, the best modality to combine the two treatments has still to be determinated. A pilot study was designed, testing a combination of two standard chemo- and radiotherapy regimens concomitantly administered. MATERIALS AND METHODS: 26 patients, with unresectable squamous cell carcinoma of the head and neck, were treated with three cycles of chemotherapy (cisplatin 20 mg/m2/day and fluorouracil 200 mg/m2/day as an intravenous bolus, for 5 consecutive days, every 21) simultaneously delivered with radiation (66-70 Gy/33-35 fractions/7 weeks). In order to reduce the mucoseal toxicity. observed in the first 15 patients, 1 week of pause was inserted after the third week of treatment in the subsequent 11 patients. RESULTS: Grade III-IV mucositis was detected in 40% of patients treated without pause after the third week of treatment and in 9% of those treated with. Complete responses were obtained in 13/26 patients (50%) and partial responses in 8/26 (31%). 1 stable disease, 3 early deaths (1 because of toxicity) and 1 lost before being evaluated were considered as treatment failures (19%). CONCLUSIONS: This concomitant chemo-radiotherapy approach showed a good antitumour activity but mucoseal toxicity is too high if no pause is planned during the treatment.

Randomized comparison of two chemotherapy, radiotherapy schemes for stage III and IV unresectable squamous cell carcinoma of the head and neck.

Between August 1983 and December 1986, 116 previously untreated patients with squamous cell carcinoma of the head and neck were randomized to receive induction chemotherapy followed by radiotherapy given in conventional fractions (55 patients, arm A) or an alternating chemotherapy and radiotherapy (3 courses of 20 Gy, 10 daily fractions each; 61 patients, arm B). The same chemotherapy was used in both arms: 6 mg/m2 vinblastine sulfate, hour 0; 30 mg bleomycin, hour 6; 200 mg methotrexate, hours 24 to 26; 45 mg leucovorin, hour 48. Forty-five patients had stage III disease and 71 had stage IV disease. All patients were evaluated for survival, 112 for toxicity, and 105 for analyses of response and time from the start of treatment until progression of disease. At the end of the combined treatment, we observed an overall response rate of 52% in arm A and an overall response rate of 64.9% in arm B. The incidence of mucositis was more relevant in arm B compared to arm A (P less than .00004). The difference in complete response, progression-free survival, and survival was statistically significant, with an advantage for arm B (P less than .03, P less than .02, and P less than .03, respectively). The analysis at a median follow-up of 36 months (range = 19 to 59) demonstrates a higher effectiveness for the alternating program.

Intensified chemotherapy with granulocyte-monocyte colony stimulating factor protection in advanced, relapsed squamous cell carcinoma of the head and neck. A phase I study.

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.

Concomitant alpha-interferon and chemotherapy in advanced squamous cell carcinoma of the head and neck.

The combination of chemotherapy and interferons has been tested in several human tumors but, until now, no clinical data have been reported in head and neck cancer. At the Istituto Nazionale per la Ricerca sul Cancro of Genoa, 14 patients with previously treated SCC-HN underwent the following regimen: cisplatin, 20 mg/m2/day, 5-fluorouracil, 200 mg/m2/day i.v. bolus and recombinant interferon-alpha-2b (r-IFN-alpha-2b) (Intron-A, Shering-Plough), 3 MIU/day i.m., for 5 consecutive days. Recombinant IFN-alpha-2b was also administered, at the same dosage, 3 times per week during the 2 weeks interval among cycles. Grade III-IV hematological toxicity was recorded in 43% of patients. Increasing fatigue, anorexia, and flu-like symptoms were experienced by most patients. For these reasons 9 of 14 patients needed a chemotherapy delay and a r-IFN-alpha-2b discontinuation. Therefore, due to the heavy toxicity observed, accural was terminated early. The overall response rate was 54% (31% CR, 23% PR). Among the 5 patients who never delayed chemotherapy and discontinued r-IFN-alpha-2b, all but one responded. In conclusion, a synergistic activity between chemotherapy and r-IFN-alpha-2b in head and neck cancer cannot be excluded, but, in our opinion, further investigations should consider less aggressive regimens and/or more selected patients.

Alternating cisplatin-5-fluorouracil and radiotherapy in head and neck cancer.

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.

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.