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Background. In a group of patients with head and neck cancers (H&NC), the expansion of the population of CD3−,CD16+ natural killer (NK) cells in the peripheral blood was studied. Methods. Cytofluorimetric analysis of the expression of killer Ig-like receptors (KIR, namely p58.1, p58.2, p58.3, p70, and p140) and CD94-NKG2a was performed. Cytolytic activities were studied using 51Cr release assay. T and NK cell cloning was performed using limiting dilution culture conditions. Cytokine production was analyzed using commercial enzyme immunoassays. Results. Phenotypic analysis showed that the expanded populations were heterogeneous. Even in the presence of a large number of circulating NK cells, “nonspecific” cytolytic capacities were heavily reduced, whereas cytolytic capacity related to T cells was virtually normal. Unlike NK cell clones derived from healthy donors, most NK cells derived from H&NC patients expressed surface “activating” NK cell receptors (KAR) for HLA, detected by use of a redirected cytolytic assay. Analysis of the CD4+ subpopulation at the clonal level demonstrated that they had a severe proliferative defect. Conclusion. These experimental data indicated that H&NC patients have a polyclonal expansion of functionally deficient NK cells expressing KAR. In addition, the proliferative capacity of patients' “helper” cells was strongly inhibited, thus accounting for a severe impairment of cytolytic activity of the expanded NK cells. © 2003 Wiley Periodicals, Inc. Head Neck 25: 297–305, 2003

Current treatment of nasopharyngeal carcinomas includes radiation therapy (RT) alone or combined with chemotherapy and neck dissection. Consequently all patients with nasopharyngeal carcinomas are treated with RT. To evaluate the CT and MRI appearance of nasopharyngeal carcinomas treated with RT and the ability of CT and MRI to differentiate persistent or residual tumour from radio-induced changes of head and neck tissues. Post-treatment CT and MRI examinations of 28 patients with primary nasopharyngeal cancers treated with RT (6000–7500 cGy) were retrospectively evaluated. We divided the patients in three groups on the basis of the differences in the CT and MRI appearance of the primary tumours treated with RT 1. Responders (9 patients): complete resolution of tumour or reduction in tumour size = or > 75%; 2. Non-Responders (8 patients): persistent tumour or residual mass with reduction in tumour size = or < 50%; 3. Partial Responders: (11 patients) persistent residual mass with reduction in tumour size from 50% to 75% or persistent asymmetry of the mucosal surface. There are some points to analyse in the interpretation of CT and MRI imaging of post-treated nasopharynx: Transient changes of irradiated soft tissues are more prominent during the first three months after RT (increased en-hancement of the pharyngeal mucosa and thickening of the pharyngeal walls). Persis-tent changes are subgrouped in 1. Soft tissue changes: a. Glandular (major salivary glands scialoadenitis and fatty degeneration); b. Deep (reticulation and fibrous degeneration of pre- and post-styloid parapharyngeal fat; c. Visceral (retraction of the pharyngeal wall and distorsion of lateral recess); d. Nervous (radio-induced damage of the CNS such myelopathy and radionecrosis. 2. Bone tissue changes: a. Fatty degeneration of bone marrow of the skull base; b. Sclerosis of the cortical bone of the basisphenoid. 3. Sinonasal changes: Reactive chronic sinusitis. Perineural-perivascular spread and skull base erosion is indicative of a poor outcome. The patients of the third group may also be followed with seriated CT because they have a significant percentage of recurrence.

The aim of this study is to evaluate the impact of CT and MRI staging on the RT plan analyzing the patterns of spread of nasopharyngeal tumours. Pre-treatment CT and MRI examinations of 28 patients (28–65 years old, mean age 42; 16 men, 12 women) with primary nasopharyngeal cancer were retrospectively evaluated. CT and MRI in clinically known or suspected nasopharyngeal cancer showed in all cases the extent and spread of the pathologic tissue; consequently the Americal Joint Committee on Cancer (AJCC) staging system for primary nasopharyngeal tumours was strictly respected. Imaging permitted in all cases a good evaluation of neck nodes; retropharyngeal, junctional, jugulo-digastric and accessory spinal lymph nodes were correctly staged on the basis of size, density-intensity, shape and contrast enhancement. The impact of non- and minimally-invasive diagnostic imaging techniques on head and neck diseases is well known. Clinical evaluation of the nasopharynx and nearby deep fascial planes is hard and fiberoptic examination detects only mucosal surfaces of the organ. Consequently prognosis and therapy of nasopharyngeal carcinomas depend on CT and MR staging both of the primary site and neck nodes. The RT beam and portals are focused on the basis of imaging and the results of the therapy may be correctly investigated only by the comparative analysis of the first follow-up examination with pre-treatment morphological data.

Scopo del lavoro è quello di delineare le indicazioni generali alla radioterapia, definitiva o in associazione alla chirurgia, nei pazienti affetti da carcinoma del distretto testa-collo, anche sulla base delle informazioni TC ed RM, e di descrivere le alterazioni morfologiche radiologiche che emergono, differenziando quelle suggestive di persistenza o recidiva neoplastica, da quelle indotte dalla radioterapia. Sono stati selezionati 95 pazienti che hanno praticato radioterapia come unico trattamento o in associazione alla chirurgia. Il primo controllo radiologico è stato effettuato di norma in un periodo di tempo compreso tra i 3 e i 4, 5 mesi dal termine della radioterapia. I pazienti sono stati seguiti nel tempo con esami seriati rispettivamente a 6, 9 e 12 mesi a distanza dal termine della radioterapia, a seconda dei rilievi emersi al primo controllo a ciclo terapeutico ultimato. Per quanto concerne la valutazione della risposta del tumore primitivo alla radioterapia sono stati distinti tre gruppi di pazienti. Il primo gruppo comprende soggetti nei quali il tumore primitivo, valutato alla TC e/o RM prima del trattamento radioterapico, ha dimostrato una regressione volumetrica superiore al 75% nei controlli tra i 3 ed i 12 mesi dalla fine del ciclo terapeutico (31 pazienti). Il secondo gruppo comprende soggetti nei quali il volume tissutale residuo dopo radioterapia, nei controlli a tre mesi, ha dimostrato una regressione inferiore al 50%, una persistenza o addirittura una progressione (44 pazienti). Un terzo gruppo è costituito da soggetti nei quali la regressione volumetrica del tessuto neoplastico nel controllo a tre mesi dal termine del ciclo terapeutico radioterapico è compresa tra il 50 ed il 75%. Quest'ultimo gruppo è quello che pone i maggiori problemi diagnostici e che viene seguito con controlli seriati ogni tre mesi, anche in presenza di negatività degli esami clinici ed endoscopici (20 pazienti). Le alterazioni tissutali post-radioterapiche sono state distinte in transitorie e permanenti. Quelle transitorie hanno raggiunto il massimo della loro espressività al termine del ciclo di trattamento, con visualizzazione di una massa conglomerata più estesa del tumore primitivo. Quelle permanenti si sono verificate a carico dei tessuti superficiali (ispessimenti della cute e del platisma, addensamenti nel tessuto adiposo sottocutaneo), nei piani fasciali profondi periviscerali (fibrosi del connettivo lasso adiposo parafaringeo, cervicale anteriore e posteriore, pericarotideo), nelle logge salivari (scialoadenite reattiva e degenerazione grassa), a livello degli spazi mucosi profondi (ispessimento simmetrico e infiltrazione delle pliche ariepiglottiche e delle corde vocali false, obliterazione dei piani adiposi pre- e paraglottici). La difficoltà di interpretazione delle immagini, con particolare riguardo ai possibili falsi positivi e falsi negativi, rappresenta soltanto una delle diverse facce della complessa problematica in corso di carcinoma del distretto testa-collo. Infatti i quesiti da risolvere coinvolgono anche il clinico, il chirurgo, il radioterapista oltre che il radiologo, il cui sforzo comune deve essere quello di garantire al paziente la migliore terapia possibile a fronte di una qualità di vita accettabile.

The authors report their experience on six male patients and one female patient (age range: 58–76 years, median: 67) with facial tumours involving the anterior skull base, undergoing craniofacial resection between January 1992 and May 1994 at the Division of Surgical Oncology in the Tumor Institute, Genoa. Three patients had squamous carcinom and adenocarcinoma of the nasal fossa; two patients had squamous carcinoma rT4NO and adenocarcinoma rT4NO 1 of the maxillary sinus; one patient had squamous carcinoma of the eyelid, and another had squamous carcinoma of the internal chantus. Four patients had had previous radiotherapy, another underwent pre-operative chemoradiotherapy, and only two patients had not been treated before. A proper craniofacial tumour resection was performed in three patients; one patient had a left maxillectomy with ethmoidectomy and orbital exenteration; one patient underwent maxillectomy, resection of the medial and inferior wall of the orbit, ethmoidectomy, and orbital exenteration; one patient underwent maxillectomy, ethmoidectomy, and mucosectomy of the sphenoidal sinus, and one patient had total ethmoidectomy. As for reconstruction procedures of the anterior skull base, lyophilized dura with galeal pericranial flap was commonly used. A myocutaneous flap transposition (transverse rectus abdominis and latissimus dorsi myocutaneous flap) was used in two patients for the reconstruction of the resected tissues and bones of maxillary and orbital regions. Post-operative complications included intraoperative liquorrhea in one patient; one case of early and serious pneumocephalus; flap necrosis occurred following transposition of latissimus dorsi. Median hospital stay was 34 days. After a median follow-up of 18 months (range: 3 to 34 months) five of seven patients (71.4%) are alive and disease-free at 15, 17, 18, 30 and 34 months from surgery.

La patologia neoplastica maligna del distretto-testa collo presenta un notevole polimorfismo istologico, in rapporto ai diversi tessuti fisiologicamente presenti. La grande maggioranza concerne comunque i carcinomi e tra questi prevale il carcinoma a cellule squamose. Nella prognosi e nella scelta e pianificazione del trattamento assumono una importanza decisiva l'estensione del tumore primitivo e l'eventuale presenza ed entità del coinvolgimento linfonodale. In base al quesito clinico sono stati preliminarmente distinte diverse categorie di esami TC e RM. Le immagini ottenute sono state interpretate sulla base di un criterio anatomo-topografico che separa diversi spazi fasciali nell'ambito delle regioni sopra- e sottoioidea del distretto testa- collo. È stata quindi effettuata una valutazione comparativa delle informazioni ottenute dagli esami clinico-endoscopici e dalla diagnostica per immagini. TC e RM consentono una stadiazione completa dei carcinomi sia su T, perchè sono in grado di documentare lo sviluppo profondo sottomucoso e nell'ambito degli spazi fasciali limitrofi, nonchè la diffusione perineurale, perivascolare e le erosioni osteocartilaginee, parametri non analizzabili dall'endoscopia, sia su N, perchè svelano linfoadenopatie che per dimensioni e soprattutto per sede sono occulte all'esame clinico. Al contrario lesioni non rilevate mucose superficiali possono risultare del tutto mute alla diagnostica per immagini, così come è pressochè impossibile formulare una corretta caratterizzazione tissutale delle ipertrofie anche spiccate degli spazi mucosi rino- ed orofaringeo, informazioni che sono esaustivamente ottenibili dagli esami endoscopico-bioptici. Pertanto TC e RM hanno un notevole impatto nella stadiazione dei carcinomi del distretto testa-collo, ma il loro utilizzo va effettuato sempre complementariamente e successivamente ad esame clinico specialistico del paziente ed indagine endoscopica delle vie aerodigestive superiori.

PURPOSE To determine whether pretherapy cell kinetics can predict local control for patients affected by head and neck squamous cell carcinomas (HN-SCCs) to be treated by primary radiotherapy and, moreover, guide to a choice between conventional and accelerated radiotherapy. PATIENTS AND METHODS Between 1989 and 1993, 83 patients with stage II to IV HN-SCC entered the study. Multiple primary tumor biopsies were obtained 6 hours after in vivo infusion of bromodeoxyuridine (BrdUrd). In vivo S-phase fraction labeling index (LI), duration of S phase (Ts), and potential doubling time (Tpot) were obtained by analysis of multivariate flow-cytometric data. Between April 1989 and January 1991, 49 patients were treated by conventional radiotherapy (70 Gy in 35 fractions over 7 weeks), whereas, afterwards, 34 patients entered an accelerated radiotherapy regimen with the concomitant boost technique (75 Gy in 40 fractions over 6 weeks). RESULTS Univariate analysis showed that, among patients treated by conventional radiotherapy, local control probability was affected by tumor stage (P = .02), Tpot (P < .001), and LI (P = .04). Similarly, among patients treated with accelerated radiotherapy, we found that local control probability was related to tumor stage (P = .03) and primary tumor site (P = .05). For the subgroup of patients with tumors characterized by fast growth (Tpot < or = 5 days), accelerated radiotherapy gave a better local control rate than conventional radiotherapy (P = .02). Cox multivariate analysis of the total number of patients showed that the only significant independent prognostic factors related to local control were tumor stage (P = .002) and Tpot (P = .004). Moreover, when the Cox analysis was restricted to the subgroup of patients treated with conventional radiotherapy, Tpot was the most significant factor to predict local outcome (P < .01). CONCLUSION Pretreatment tumor Tpot appears to be an important independent prognostic factor for local control of HN-SCC treated by primary radiotherapy.

The efficacy of ten daily injections of 500 or 500,000 U of recombinant interleukin 2 (IL-2) day-1 given 1.5 cm from the insertion of the sternocleidomastoid muscle on the mastoid was evaluated in 31 patients with recurrent head and neck squamous cell carcinoma. No toxic effects were noted. One complete response (CR) and three partial responses (PRs) were observed in the 16 patients who received 500 U of IL-2, whereas the higher dose was not effective. The CR was recorded in one of the seven patients with a oropharyngeal recurrence. Partial responses were obtained in 1/5 patients with hypopharyngeal recurrences, in 1/5 patients with oral cavity recurrences and 1/7 patients with laryngeal recurrences. The duration of the responses was 3-5 months and additional courses of ten injections of IL-2 had no further effect. Images Figure 1 Figure 2

Patients with advanced head and neck squamous cell carcinoma (HNSCC) are severely immunocompromised. In virtually all such patients who have been studied, reduced numbers of circulating CD3+ T-cell-receptor (TCR)α/β + T lymphocytes, a reduction of natural killer (NK) activity, and a poor induction of lymphokine-activated killer (LAK) cell activity (following in vitro treatment with recombinant interleukin-2 [rIL-2]) have been detected. Recently, however, it has been demonstrated that perilymphatic injections of low doses of rIL-2 may induce a local reduction of tumor masses in these patients. The present study, a cooperative pilot effort on the clinical effects of this route of administration, showed an activation of the lytic machinery in lymphocytes belonging to the T-cell lineage, as well as a potentiation of NK activity in the peripheral blood. These findings demonstrated that the severe immunodeficiency of HNSCC patients may be at least partially corrected by in vivo administration of rIL-2.

Between 1983 and 1986, the National Institute for Cancer Research in Genoa and affiliated institutions conducted a randomized study to compare two different ways of combining chemotherapy (CT) and radiation therapy (RT). One hundred sixteen patients were randomized to receive neoadjuvant CT followed by definitive RT (treatment arm A) or alternating CT and RT. In treatment arm A, RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction, five fractions per week. In treatment arm B, RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each, 2 Gy/fraction, ten fractions/2 weeks alternated with four courses of CT. CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly, day 1; methotrexate 200 mg intravenously, day 2; leucovorin rescue, day 3. CT was repeated every 2 weeks up to four courses. The same CT was used in both treatment arms of the study. Fifty-five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B, respectively (P less than 0.03). Four-year progression-free survival was 4% in treatment arm A and 12% in treatment arm B (P less than 0.02), and four-year survival was 10% in A and 22% in B (P less than 0.02). Mucosal tolerance was significantly worse in treatment arm B (P less than 0.00004). The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics.

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

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients.

16 patients with oral leukoplakia were treated with oral 13-cis-retinoic acid. The initial dose, given for 3 months, was 0.2 mg/kg/day, increasing by a further 0.2 mg/kg/day in successive 3 month cycles. The maximum dosage reached at 1.0 mg/kg/day, was given to only 2 patients (who received a total of 15 months treatment). However, 10 patients completed the cycle at 0.8 mg/kg/day (12 months treatment in total), but treatment could not continue due to toxicity (grade I and II), which was cutaneous, mucosal, and haematological (hypertriglyceridemia and hypercholesterolemia). There was grade III toxicity in the skin and mucosa in only 1 case, a patient treated at a dose of 1.0 mg/kg/day. The toxicity was reversible in all cases. 14 of the patients completed the trial. In 4 there were improvements graded as partial responses (PR) obtained at 0.2 mg/kg/day (3PR) and 0.6 (1PR) and there was one complete response (CR) obtained at 0.4 mg/kg/day. Overall there was thus an objective response rate of 36% who showed 50% or more reduction in lesion size. After the retinoic acid treatment was stopped, patients were followed-up for 12 months; 2 patients showed regression of the responses obtained after 6 and 9 months. This study shows that oral treatment with 13-cis-retinoic acid at low dosages is efficacious and with minimal toxicity. It also shows that it is not feasible to treat these patients at doses above 0.8 mg/kg/day for long periods--mainly due to poor compliance.

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.

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

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

Radiotherapy is the standard approach to the treatment of advanced, unresectable squamous cell carcinoma of the head and neck. With radiotherapy alone the expected five-year survival is about 25 % , but it may be 1–2 %o in the patients with very advanced disease (T4 and/or N3 disease). Experimental and clinical data suggest a possible advantage by integrating chemotherapy and radiotherapy in such a tumors even if the true impact of combined modalities over radiotherapy alone remain unclear. Therefore we designed a randomized trial to compare standard radiation (Arm B) to alternating chemotherapy and radiation (Arm A), in patients with advanced, inoperable and previously untreated SCC-HN.

Bleeding and lymphorrhea are very frequent side effects in breast cancer (BC) and in head and neck cancer (HNC). They are related to wide muscular resection and/or lymphatic dissection which can delay wound healing in tissue repair. In order to reduce such side effects, between January 1989 and February 1992 two separate groups of patients with BC and HNC underwent intraoperative topical fibrin glue application. In both groups, a reduction in lymphorrhea, wound infection, and, consequently, length of hospitalization was observed as compared to previous experience.

Purpose: The aim of the study was to determine preliminarily whether cell kinetic parameters evaluated using in vivo infusion of bromodeoxyuridine (BrdUrd) and flow cytometry, play a role as prognostic factors of loco-regional control in squamous cell head and neck carcinoma treated with radiotherapy. Methods and Materials: Between April 1989 and December 1991, 42 patients with unresectable Stage II–IV squamous cell carcinoma of the oral cavity, pharynx or larynx were given an infusion of BrdUrd solution prior to primary tumor biopsy sampling at 4–6 hr later. The simultaneous labeling S-phase fraction (LI) and duration (Ts) as well as the estimated potential doubling time (Tpot) were measured using flow cytometric analysis of BrdUrd and DNA content. Twenty-six patients received standard radiotherapy (70 Gy/35 fractions/7 weeks) whereas 15 patients were treated with the concomitant boost technique (75 Gy/40 fractions/6 weeks). Results: A complete set of flow cytometric data was available for 31 patients. The median value of LI, Ts, and Tpot were 9%, 9 hr and 5 days, respectively. Univariate analysis among the patients treated homogeneously by standard radiotherapy, indicated that local control was affected by Tpot value ( p = 0.02). When the same analysis was performed for the patients treated with either standard radiotherapy or concomitant boost regimen, we found a p = 0.04. Thus, patients with a tumor Tpot value ⩽ 5 days had a significantly lower three-year local control than patients with Tpot > 5 days. Log-rank test univariate analysis showed, in addition, that nodal status was the strongest prognostic factor of local control ( p = 0.005). Age, tumor stage, tumor site, performance status, grading, radiotherapy regimen, DNA ploidy and LI value were, instead, not significantly related to loco-regional control. Finally, when comparing the type of radiotherapy for tumors with Tpot ⩽ 5 days, we found a trend toward a better local control after concomitant boost regimen, with respect to standard regimen ( p = 0.06). Conclusion: The present preliminary results suggest that Tpot could play a role as additional prognostic factor influencing the disease outcome in head and neck carcinoma treated by radiotherapy

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

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

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).

In a patient with recurrent head and neck squamous cell carcinoma, reconstruction of the floor of the mouth was carried out by transposition of a pectoralis major myocutaneous flap after composite resection. Twelve months after surgery, a chest wall metastasis corresponding to the site of the vascular pedicle was observed. It appears that the lymphatic and hematogenous tumor spread can occur along the vascular pathways of a transposed myocutaneous flap.

Endocrine cancer therapy began its development only after the availability of synthetic steroids made bilateral adrenalectomy and hypophysectomy possible.

Background The increasing complexity of management strategies for patients with head and neck squamous cell carcinoma (HN-SCC) calls for the investigation of new objective prognostic parameters to subdivide patients according to the tumor's biological aggressiveness. Methods We evaluated in 35 HN-SCC patients the pretreatment cell kinetics parameters and DNA ploidy after in vivo infusion of bromodeoxyuridine and flow cytometric analysis. Patients were treated with radical surgery followed by conventional radiation therapy. Locoregional control data are available for follow-up times above five years. Results We found that the likelihood of locoregional control for patients with rapidly proliferating HN-SCC characterized by a short potential doubling time (Tpot 5 days). Moreover, when patients were stratified according to DNA ploidy and Tpot value, we found that the locoregional failure rate for rapidly proliferating tumors was significantly higher for diploid HN-SCCs than for aneuploid HN-SCCs. Conclusion The present data suggest that patients with resectable HN-SCC characterized by fast growth might have a worse prognosis after surgery and adjuvant conventional radiotherapy and might benefit from more aggressive radiother-apeutic modalities.