Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin's lymphoma.

There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1.2-3.2, and OR = 1.6, 95% CI = 1.1-2.4 respectively]. CTLA4-318C:49A:(AT)(82) was the most represented haplotype in the studied population and was associated with NHL (P = 0.0029, OR = 1.76, 95% CI = 1.2-2.5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a 'common' haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients.

Assessment of the efficacy of two dosages and schedules of human recombinant erythropoietin in the prevention and correction of cisplatin-induced anemia in cancer patients.

Despite the numerous studies demonstrating the effectiveness of epoetin á (human recombinant erythropoietin) versus placebo in cisplatin-induced anemia of cancer patients, data are lacking on the most effective doses and schedules of administration of epoetin á in this setting. The aim of the present study was to assess the best dose and schedule of administration of epoetin á in cancer patients with cisplatin-induced anemia. This was an open, randomized, single-institution phase II study comparing the ability of two doses and schedules of epoetin á of preventing and/or correcting anemia, measured as the increase in hemoglobin level and decrease in transfusion requirements, in 20 chemotherapy-naive patients with advanced stage head and neck, esophageal, and lung cancer, treated with cisplatin at doses 80 mg/m2. The secondary endpoint of the study was to assess the serum levels of certain cytokines involved in cancer anorexia/cachexia syndrome. The eligible patients were randomly assigned to treatment with either: a) subcutaneous epoetin á 150 U/kg three times a week for up to 12 consecutive weeks (Group A); b) subcutaneous epoetin á 50 U/kg daily for up to 12 consecutive weeks (Group B). The following laboratory parameters were assessed before the study entry and during the study: hemoglobin (weekly); serum iron, transferrin and ferritin (before entry). The following immunological parameters were assessed before and after study end: Interleukin (IL)-1á, IL-1 , IL-6 and Tumor Necrosis Factor (TNF) á. Twenty patients were enrolled, data were available for 17. Nine patients were assigned to Group A and 8 to Group B. No statistically significant difference of hemoglobin level was found between the 2 groups at baseline, at month 1, 2 and 3, neither in the comparison of the change from baseline between the two groups. In Group A fewer transfusions were administered per patient per month after the first month of epoetin á therapy, compared to Group B. No significant difference was found as for transfusion requirements at month 1, 2 and 3 between Group A and B. The epoetin á dose administered was slightly higher than that projected. Epoetin á was well-tolerated. There was no statistically significant correlation between change in hemoglobin level and tumor response for either group, neither between change in hemoglobin level and change in ECOG score from baseline to final was observed. The changes from baseline of IL-1á and IL-1 , IL-6 and TNFá were not remarkable nor univocal in either group, there was not correlation between hemoglobin change and serum cytokine changes from baseline, except for IL-6 in Group A.

Prevention of nausea and vomiting (N&V) in cancer patients receiving high-dose cisplatin. Assessment of the potential antiemetic activity of transdermal fentanyl (TTS-F) compared to standard antiemetic treatment in acute and delayed N&V: first clinical report.

UNLABELLED: A single-institution, prospective, open crossover study was performed to compare the effectiveness and tolerability of transdermal fentanyl (TTS-F) vs intravenous (i.v.) ondansetron (OND), both combined with i.v. DEX, in the prevention of acute nausea and vomiting (N&V), and TTS-F vs metoclopramide (M), both combined with intramuscular (i.m.) DEX, in the prevention of delayed N&V in patients with advanced stage head and neck squamous cell carcinoma receiving high-dose (> or = 100 mg/m2) cisplatin. This is the first report on the clinical use of TTS-F in this setting. PATIENTS AND METHODS: All patients were adequately informed of the study characteristics and gave their written informed consent before study entry. The antiemetic treatment for acute N&V consisted of A) OND 8 mg plus DEX 20 mg (i.v.) or B) TTS-F 75 micrograms/h plus DEX 20 mg i.v. For prevention of delayed N&V, patients receiving TTS-F for acute N&V were given TTS-F at the same dosage (75 micrograms/h) on days 2-5, whereas patients receiving OND for acute N&V were treated with M 20 mg orally every 6 h on days 2-5, starting 24 h after CDDP. All patients received DEX 8 mg i.m. every 12 h on days 2 and 3, 4 mg i.m. every 12 h on days 4 and 5, starting 24 h after CDDP. From November 1997 to April 1998, 15 consecutive patients entered the study and were assigned to one of the two alternative treatments for acute N&V. All of them were evaluable. Twelve patients were evaluable for delayed N&V. Seven patients were assigned to Group 1 starting with treatment A (OND + DEX) and 8 patients were assigned to Group 2 starting with treatment B (TTS-F + DEX). In the prevention of acute N&V, the overall efficacy of OND + DEX was statistically significantly higher than that of TTS-F + DEX in achieving Complete Response (CR) and Major Efficacy (ME = CR + Major Response, MaR). As for delayed N&V, the overall efficacy of M + DEX, both in achieving CR and ME, although higher, was statistically not significantly different from that of TTS-F + DEX. Unfortunately, due to the small number of patients included in the study, the sophisticated criteria for evaluating response in antiemetic research, such as the persistence of efficacy, the response after crossing-over, did not make it possible for us to draw additional conclusions, although the trend was in favor of "standard" treatments, particularly in acute N&V. The 'response to treatment A (OND + DEX) in the prevention of acute N&V was in the same range as the response to treatment A (M + DEX) for delayed N&V. The response to treatment B (TTS-F) for acute N&V was lower than the response to the same treatment for delayed N&V. The TTS-F treatment was well-tolerated with no significant side-effects including the well-known opioid-related symptoms. Our study confirms that the currently available standard antiemetic treatments both for acute and delayed N&V must be considered by far the most effective ones for clinical use.

Neo-adjuvant chemo-(immuno-)therapy of advanced squamous-cell head and neck carcinoma: a multicenter, phase III, randomized study comparing cisplatin + 5-fluorouracil (5-FU) with cisplatin + 5-FU + recombinant interleukin 2.

We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m2 cisplatin i.v. on day 1 plus 1000 mg m(-2) day(-1) 5-FU on days 1-5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8-12 and 15-19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and I from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved.

Clinical evaluation of two dosages and schedules of ifosfamide in combination with cisplatin in neo-adjuvant chemotherapy of patients with advanced (stage III-IV) head and neck squamous cell carcinoma: a phase II randomized study.

The aims of the present open, randomized, single-blind (patient), single institution, phase II study were: i) to compare the therapeutic effectiveness and toxicity of two dosages and schedules of ifosfamide (IFO) in combination with cisplatin (CDDP) mainly in the neo-adjuvant setting of patients (pts) with locally advanced (stage III-IV) head and neck squamous cell cancer (HNSCC) (primary endpoint); ii) to assess the quality of life (QL) of pts included in the study before and after treatment (secondary endpoint). From July 1996 to June 1997, 28 pts, all males (mean age 56.79 years, range 37-72), hospitalized in the Department of Medical Oncology, University of Cagliari, were enrolled in the study. Twenty pts (M/F 20/0, mean age 53.6, range 37-71 years; stage III 1 pt, stage IV 19 pts) were evaluable for response and all 28 pts enrolled were evaluable for toxicity. Arm A: IFO 2.2 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 2 cycles. Fifteen pts (11 of whom were evaluable) were enrolled in this Arm. Arm B: IFO 1.5 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 3 cycles. Thirteen pts (9 of whom were evaluable) were enrolled in this Arm. The two Arms were well-balanced for sex, age, site of primary, ECOG PS and clinical stage. After completion of 2 (Arm A) or 3 (Arm B) cycles of chemotherapy, the pts were assessed for response. All evaluable pts received treatment as planned. Six pts (54.5%) of Arm A and 4 pts (44.5%) of Arm B had partial response (PR) with an overall response rate (ORR) of 54.5% and 44.5%, respectively: it is worth noting that all (100%) pts who had PR in Arm B achieved a high-grade PR, i.e. >/=70%, whereas only one pt (16.7%) who had PR in Arm A achieved a high-grade PR. Three pts (27.3%) in Arm A and 2 pts (22.2%) in Arm B had stable disease (SD); 2 pts (18.2%) in Arm A and 3 pts (33.3%) in Arm B had progressive disease (PD). The actual dose intensity was over 80% of the projected dose intensity for both drugs and for both Arms. Over a total of 59 cycles administered, the total number of episodes of toxicity was 24 for Arm A and 17 for Arm B. Three pts out of 28 evaluable for toxicity (10.8%) died for Grade 5 hematological toxicity: all pts were included in Arm A. In Arm A, 2 pts (13.3%) experienced hematological Grade 3 toxicity and 2 pts (13.3%) hematological Grade 4 toxicity. In Arm B no pt experienced Grade 3-4 hematological toxicity. No Grade 3-4 toxicity of any other type was found in either Arm. The QL evaluation, using the Cella's FACT-G scale supplemented with disease-specific scale (FACT-H&N scale), did not show significant beneficial effect of neo-adjuvant chemotherapy treatment.

Comparison of oral 5-HT3-receptor antagonists and low-dose oral metoclopramide plus i.m. dexamethasone for the prevention of delayed emesis in head and neck cancer patients receiving high-dose cisplatin.

A phase III, single-institution, open, prospective, randomized, parallel study was carried out on head and neck cancer patients to compare a combination of low-dose (20 mg q.i.d.) oral metoclopramide (M) + i.m. Dexamethasone (D) with an oral 5-HT3-Receptor Antagonist (5-HT3-RA) alone in the prevention of high-dose (HD > or = 80 mg/m2) cisplatin-induced delayed emesis. 51 consecutive patients, all but two with advanced stage of disease, were treated for a total of 198 chemotherapic cycles: 23 patients entered Group A (5-HT3-RA) receiving a total of 108 cycles, 28 patients entered Group B (M + D) receiving a total of 90 cycles. The treatment groups were well matched for age, sex (almost all patients were males), ECOG PSR, stage of disease and alcohol intake. The efficacy of M + D was significantly higher than that of 5-HT3-RA in achieving complete protection (CR 88.9% vs 72.2%, chi2 9.9, p = 0.002) and major efficacy (ME: CR + MR) (94.5% vs 85.2%, chi2 5.6, p = 0.02). Generally, for both treatments (5-HT3-RA and M + D) a good control of delayed emesis was achieved in patients who had complete protection on acute emesis. A good control of acute emesis had a highly positive predictive value of delayed emesis for both treatments without significant difference between them (CR 85% for M + D and 82% for 5-HT3-RA; ME 88% for M + D and 92% for 5-HT3-RA). The failure (F) on acute emesis had a significantly higher negative predictive value of delayed emesis for M + D (98%) than 5-HT3-RA (67%). Our study is, to our knowledge, the first comparing M + D vs one 5-HT3-RA alone in the prevention of HD cisplatin-induced delayed emesis in a properly designed clinical trial. Our results show that M + D are more effective than 5-HT3-RA alone in the prevention of HD cisplatin induced delayed emesis, whereas 5-HT3-RA may be the treatment of choice in patients who had acute vomiting. Our study demonstrated not only the persistence of antiemetic efficacy but also increasing efficacy, during subsequent courses. Our results confirm that protection from acute emesis plays a major role in the appearance and control of delayed emesis.

Vinorelbine, cisplatin, and 5-fluorouracil as initial treatment for previously untreated, unresectable squamous cell carcinoma of the head and neck: results of a phase II multicenter study.

BACKGROUND: The combination of vinorelbine (VNR), cisplatin (CDDP), and 5-fluorouracil (5-FU) has previously been shown to be active in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCHNC). This multicenter Phase II study was carried out with the aim of evaluating the effectiveness of this combination in patients with previously untreated, unresectable locally advanced SCHNC. METHODS: Sixty patients with previously untreated, unresectable SCHNC were treated with CDDP 80 mg/m2 on Days 1, 5-FU 600 mg/m2 as a 4-hour infusion on Days 2-5, and VNR 25 mg/m2 i.v. bolus on Days 2 and 8. There were 15 patients with laryngeal carcinoma, 19 patients with oropharyngeal carcinoma, 15 with carcinoma in the oral cavity, 5 with carcinoma in the hypopharynx, and 4 with carcinoma in the maxillary sinus. Most patients (78%) had Stage IV disease. After achievement of the best possible objective response, patients were subjected to definitive locoregional treatment, i.e., radiotherapy and/or surgery, as appropriate. RESULTS: All patients completed the induction chemotherapy. After a mean of 3.86 cycles per patient, the overall response rate was 88% (95% confidence interval [CI], 82-94%), with a complete response rate of 23% (95% CI, 14-26%). Complete responses were more frequently seen in patients with N0-1 disease than in those with N2-3 disease (P = 0.037). No other statistically significant correlation between type of response and extent of disease was noted. Toxicity consisted mainly of myelosuppression and gastrointestinal side effects. After definitive locoregional treatment, 58% of patients were clinically free of disease. These patients included those who had complete response after induction chemotherapy, 19 of 39 patients who had partial response, and 2 with stable disease. Median disease free survival was 16 months, and median overall survival was 23 months. CONCLUSIONS: The combination regimen of CDDP, 5-FU, and VNR was very active in previously untreated SCHNC. It was well tolerated in most cases, and neurotoxicity was not a major side effect. This regimen, which does not require hospitalization, should be compared with standard chemotherapy, such as the combination of CDDP and continuous-infusion 5-FU.

Clinical and immunological evaluation of schizophyllan (SPG) in combination with standard chemotherapy in patients with head and neck squamous cell carcinoma.

A phase II randomized controlled trial was carried out to evaluate the clinical efficacy and tolerability of Schizophyllan (SPG) used in combination with standard chemotherapy in the neoadjuvant setting in patients with locally advanced head and neck squamous cell carcinoma. Several immunological parameters were considered to assess the immunoregulatory activity of SPG in the: same patients. The clinical and immunological evaluations were performed both before and at the end of the study (4 months later). All patients received standard chemotherapy for head and neck squamous cell carcinoma according to one of the following treatment regimens: 1) cisplatin 100 mg/m(2) i.v, day 1, 5-FU 1,000 mg/m(2) i.v. continuous infusion days 1 to 5; 2) cisplatin 80 mg/m(2) i.v, day 1, 5-FU 600 mg/m(2) i.v. over 4 h days 2 to 5, vinorelbine 20 mg/m(2) i.v. days 2 and 8. Antineoplastic regimens were repeated every 28 days x 4 cycles for approximately 4 months. SPG was administered weekly at a single dose of 40 mg intramuscularly for 4 months in addition to standard chemotherapy. Twenty-six patients were enrolled in the study, 22 of whom were evaluable. Thirteen patients were assigned to Arm A (treatment with SPG associated with chemotherapy, regimen 1 or 2) and 9 patients to Arm B (treatment with chemotherapy, regimen 1 or 2, alone). The overall response rate was not significantly different between the two Arms (92.3% in Arm A vs. 100% in Arm B), although a higher number of complete responses (CR) (3 = 23.1%) was registered in Arm A. Overall, the SPG treatment does not seem to have induced significant changes of the immunological parameters of our patients: this may be due to both the advanced cancer stage and the effect of chemotherapy, which are both well known causes of immunodepression. The significant differences between the two Arms were only: the CD8(+) lymphocytes were decreased in the patients treated with SPG and increased in controls; serum levels of IL-1 alpha was lower in patients treated with SPG than in the control group; the production in culture of IL-1 alpha was higher in Arm A than in Arm B and IL-6 was higher in Arm B than in Arm A. Treatment with SPG was proven safe and was well-toleratedby all patients.

Chemo-immunotherapy for advanced-stage malignancies and its impact on quality of life: multidimensional evaluation in ten cancer patients.

The aim of our study was to compare the impact of chemotherapy alone with that of chemotherapy plus immunotherapy on the quality of life (QL) of patients affected by advanced-stage malignancies (eight head and neck squamous-cell carcinomas, two melanomas). Ten patients receiving chemotherapy and immunotherapy sequentially were evaluated. The impact on QL was assessed by both objective and subjective scales. Evaluation was performed before the first cycle of therapy, at the end of chemotherapy, and after immunotherapy. The analysis of our data showed that the association of chemotherapy and immunotherapy did not significantly worsen the QL of patients as compared to chemotherapy alone.

Comparison of granisetron, ondansetron, and tropisetron in the prophylaxis of acute nausea and vomiting induced by cisplatin for the treatment of head and neck cancer: a randomized controlled trial.

BACKGROUND: A single-institution, prospective, randomized, open controlled trial was carried out on head and neck cancer patients to compare granisetron (GRA), ondansetron (OND), and tropisetron (TRO) in the prevention of cisplatin-induced acute nausea and vomiting. All patients were chemotherapy-naive and treated with cisplatin on Day 1 (80 to 100 mg/m2). METHODS: One hundred seventeen patients were treated for a total of 463 cycles of cisplatin-based chemotherapy and randomized to receive 24 mg of OND intravenously (i.v.), 3 mg of GRA i.v., or 5 mg of TRO i.v. for the control of acute nausea and emesis. RESULTS: In the GRA group, complete response (CR) was obtained in 119 of 165 cycles (72.1%), major response (MR) in 32 cycles (19.4%), minor response (MiR) in 5 cycles (3%), and a failure (F) in 9 cycles (5.5%). In the OND group, CR was obtained in 110 of 150 cycles (73.3%), MR in 31 cycles (20.7%), MiR in 2 cycles (1.3%), and F in 7 cycles (4.7%). In the TRO group, CR was obtained in 100 of 148 cycles (67.6%), MR in 26 cycles (17.6%), MiR in 15 cycles (10.1%), and F in 7 cycles (4.7%). Major efficacy (CR + MR) was obtained in 151 of 165 cycles (91.5%) for GRA, in 141 of 150 cycles (94.0%) for OND, and in 126 of 148 cycles (85.2%) for TRO. The difference in major efficacy between OND and TRO was statistically significant. When comparing MiR, both GRA and OND were more effective than TRO. No other significant differences were observed among the three antiemetic agents. CONCLUSIONS: Although our results were achieved in an open trial, they show that GRA and OND are equally effective antiemetic agents in the prevention of cisplatin induced acute nausea and vomiting. TRO provides almost the same protection but is not as effective as OND for major efficacy. All three antiemetics can be administered safely to patients undergoing chemotherapy with cisplatin at doses of 80 mg/m2 or more.

Evaluation by multidimensional instruments of health-related quality of life of elderly cancer patients undergoing three different "psychosocial" treatment approaches. A randomized clinical trial.

Our study belongs to the clinical trials in which the health-related quality of life (HQL) evaluation constitutes the primary endpoint. It was carried out with the aim of comparing the impact of three different types of psychological intervention, namely a psychopharmacological treatment alone, the same treatment plus social support carried out by volunteers (SSV) and a third treatment modality including "structured psychotherapy" (autogenous training), on improving the HQL of elderly cancer patients undergoing antineoplastic therapy with symptoms of anxiety and/or depression related to their disease. The eight questionnaires used for HQL evaluation were generally self-rated and multidimensional but unidimensional models were also employed. Seventy-four patients aged over 65 years with either solid tumors in different sites or hematological malignancies, generally in advanced stages (III-IV), were enrolled in the study. Of these patients, 72 (42 men and 30 women, mean age 70.68 years, range 66-85) were evaluable. Our study highlighted the usefulness of the pharmacological therapy (alprazolam + sulpiride) and of other specific ancillary treatments in reducing the incidence of the main HQL-related side-effects of antineoplastic therapy and the superiority of an "integrated" strategy, based both on psychopharmacology and psychosocial interventions, such as SSV with or without structured psychotherapy. The one-way analysis of variance carried out by us did not allow us to draw definitive conclusions about which of the two integrated treatments was to be considered the treatment of choice, as they proved to be almost equally effective.

Neo-adjuvant organ-preserving chemotherapy in the management of locally advanced oral cavity and oropharynx cancer.

We designed an open, non-randomized clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neo-adjuvant chemotherapy (NAG) in oral cavity and oropharynx cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. Moreover, an attempt was made to scale the extent of surgery by means of an Arbitrary Scale assigning different percentages to the different extents of surgical resection. Twenty-five patients with primary oral cavity and oropharynx cancer (stage III-TV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (1) (n=15) or to a regimen (2) consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2-5 and vinorelbine 20 mg/m(2) on days 2 and 8 (n=10). The 25 patients were all evaluable for response to NAC and 20 of them were evaluable for organ preservation. The overall response (OR) rate was 86.6% (13/15 patients) for regimen 1 (cisplatin + 5-FU) and 80% (8/10 patients) for regimen 2 (cisplatin + 5-FU + vinorelbine). The median follow-up duration was 20.6 months. 5/20 (25%) patients completely avoided surgery, 5/20 (25%) patients had a reduced extent of surgical resection, while: 10/20 (50%) patients received the previously planned surgical resection. Altogether, 10/20 (50%) patients treated with NAC either avoided or achieved a reduction in the previously planned surgical resection. Moreover, organ function was evaluated to support the assessment of treatment outcome in our patients. For this purpose we selected the Performance Status Scale for Head and Neck Cancer Patients: as expected, no significant impairment was detected in the area of comprehensibility of speech, but we were rather surprised that no significant impairment was found in the two areas of eating in public and normalcy of diet. NAG-associated toxicity was moderate and similar in the two chemotherapy regimens. The most relevant contributions offered by our study are represented by i) a Scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) an attempt to support the results with an assessment of treatment outcome.

Neo-adjuvant (primary) organ-preserving chemotherapy in the management of locally advanced laryngeal carcinoma.

We designed an open, non-randomized, phase II clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neoadjuvant chemotherapy (NAC) laryngeal cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. 32 patients with primary laryngeal cancer (stage III-IV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (20 patients) or to a regimen consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2-5 and vinorelbine 20 mg/m(2) on days 2 and 8 (12 patients). The patients were divided into 2 groups: A) those requiring total laryngectomy (TL) and B) those not requiring TL, i.e. patients eligible for conservative for conservative surgery. The 32 patients were all evaluable for response to NAC and 31 were evaluable for The complete remission rate was 50% (16/32) and the partial remission rate was 46.9% (15/32) with an overall response rate of 96.9%. The median follow-up duration was 20.2 months. Overall, 23 patients required TL (group A) and 8 patients a conservative laryngectomy (group B). 7/23 (30.5%) patients of group A did not undergo surgery (score 4) and 6/23 (26%) achieved a partial larynx preservation (3/23 score 3, 1/23 score 2, 2/23 score 1), while 10/23 (43.5%) received the previously planned TL (score 0). 5/8 (62.5%) patients of group B did not undergo surgery, whereas 3/8 (37.5%) received the previously planned surgery (score 0). Therefore, 12/31 patients (38.7%) completely avoided surgery and 6/31 (19.4%) achieved a reduction in the extent of planned surgical resection, that is 18/31 patients (58.1%) achieved a reduction in the extent of previously planned surgery attributable to NAG. Moreover, 3/31 patients underwent the previously planned conservative surgery consisting of H-SGL/HG. Altogether 21/31 (67.7%) patients preserved function. The most relevant contributions offered by our study are represented by i) a scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) by an attempt to support the results with an assessment of patients treatment outcome. Although the scale provided by us is an arbitrary one, it must be emphasized that our goal was to address the issue of quality of life in cancer patients by a more precise quantification of organ/function preservation.

[The immunological assessment of a combined therapeutic approach (chemo- + radiotherapy +/- surgery) including immunotherapy in neoplasms of the head and neck area at an advanced stage]. / Valutazione immunologica di un approccio terapeutico combinato (chemio + radioterapia +/- chirurgia) includente l'immunoterapia nelle neoplasie del distretto cervico-facciale in stadio avanzato.

Fourty-eight patients entered the study, 37 of whom were evaluable, who underwent a nonrandomized combined modality approach plus a randomized immunotherapy treatment assigning the patients to one of the three arms: 1) thymostimulin, 2) beta IFN, 3) thymostimulin + beta IFN. The patients enrollment started in May 1991 and was closed in February 1993: the final evaluation was in February 1994. An immunological evaluation was made for all patients enrolled. The immunological assessment confirms some previous reports, such as the defective proliferative response of PBMC, the high serum level and the low production in culture of soluble IL 2 receptor (s IL 2 R), the low serum level and the low production of IL 2, and moreover shows new data. It is noteworthy that the significant increases--especially for cytokines and s IL 2 R, except for IL 1 alpha which has decreased, both for serum levels and for culture production--are induced by treatment with beta IFN (or with thymostimulin + beta IFN), suggesting that beta IFn is the immunologically effective moiety.

Megestrol acetate in neoplastic anorexia/cachexia: clinical evaluation and comparison with cytokine levels in patients with head and neck carcinoma treated with neoadjuvant chemotherapy.

The aim of our study (clinical phase II open pilot study) was to evaluate the toxicity of megestrol acetate and its ability to increase appetite and body weight in patients with advanced-stage (III-IV) primary head and neck squamous cell carcinoma treated with neoadjuvant (primary) chemotherapy. Serum levels of interleukin-1 alpha and beta, interleukin-2 and 6, tumor necrosis factor-alpha, and the soluble receptor for interleukin-2 were evaluated before and after megestrol acetate treatment. The same cytokines and soluble interleukin-2 receptor were also measured in culture medium of peripheral blood lymphocytes from the same patients after stimulation with phytohemagglutinin. From April 1993 to February 1994, 11 male patients were enrolled in our study: their mean age was 57.8 years (range 43-69 years). Megestrol acetate was administered at a dose of 320 mg/day in the interval between chemotherapeutic cycles for a total of three consecutive cycles; 9 of the 11 patients could be evaluated (81.8%). Except for the performance status according to Karnofsky, all parameters were increased after megestrol acetate treatment. The average weight increased by 6.3 kg (13.2%), appetite by a score of 2.4 (38.6%) and the Spitzer's quality of life index by a score of 2.4 (36.2%). The performance status according to Karnofsky decreased in only 1 patient, remained the same in most patients, and in 2 patients was slightly improved. No significant side effects were observed during treatment. Serum levels of interleukin-1 alpha and beta, interleukin-2 and 6, tumor necrosis factor-alpha, and soluble interleukin-2 receptor were significantly higher than in normal subjects, prior to treatment with megestrol acetate. These levels dropped after megestrol acetate treatment with a statistically significant decrease for interleukin-1 alpha and beta and tumor necrosis factor-alpha. There were no significant differences in the production of cytokines by peripheral blood lymphocytes stimulated with phytohemagglutinin from patients before megestrol acetate treatment and normal subjects, with the exception of interleukin-6 (higher in patients) and of soluble interleukin-2 receptor (lower in patients). There was no significant difference in the cytokines and soluble interleukin-2 receptor produced in culture before and after megestrol acetate treatment, except for interleukin-6 which decreased after treatment.

Neo-adjuvant chemotherapy +/- immunotherapy with s.c. IL 2 in advanced squamous cell carcinoma of the head and neck: a pilot study.

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2-5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III-IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo-plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our "pilot" study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.

Ultrastructural, immunologic and clinical follow-up of five patients with HCL treated with interferon (IFN) for more than three years.

BACKGROUND: Treatment results in HCl have been improved by the use of alpha-IFN, which is now the standard first-line therapy for this disease, but the mechanism of IFN action is still unclear. It is known, however, that IFN is able to induce hematologic, immunological and phenotype membrane changes which parallel the patients' (pts) clinical response. The aim of our study was to correlate the clinical response to IFN treatment with ultrastructural and phenotype membrane changes in hairy cells (HCs), in order to elucidate the mechanism of IFN action at the cell level. METHODS: We assessed the phenotype membrane and ultrastructural changes induced in HCs by long-term alpha-IFN treatment in five pts with HCL; membrane-bound Il 2-R on PHA-stimulated PBL, the release of IL 2-R by PHA-stimulated PBL and the serum levels of s-IL 2-R were also determined in one pt. RESULTS: The surface immunological phenotype, mainly the HCL-related surface antigen CD25, changed after IFN treatment, dropping from abnormally high to normal values. Furthermore, IFN treatment induced ultrastructural changes in HCs, consisting mainly of a sharp reduction in, up to the almost complete disappearance of, the hairy projections: very few, if any, short, thick villi persisted. The ultrastructural changes in HCs paralleled clinical and hematologic response to IFN treatment in such a way that IFN alone may be considered the cause of these changes. As far as detection of the membrane-bound IL 2-R p55 chain on PHA-stimulated PBL is concerned, the expression of p55 is very high on the membrane of HCs; a high level of serum s-IL 2-R was also found in the HCL pt studied before IFN treatment, whereas the release of IL 2-R by PHA-stimulated PBL was higher than normal, but not significantly. Two of our pts, who did not respond or responded very poorly clinically to IFN treatment, should probably be considered cases of HCL "variants". CONCLUSIONS: The phenotype membrane and the ultrastructural changes in HCs very closely paralleled the patients' clinical responses to IFN, suggesting that both the immunologic and the morphologic changes induced in HCs by in vivo IFN treatment are a direct counterpart of its biologic effect.