Cryosurgery plus adjuvant systemic alpha2-interferon for HPV-associated lesions.

OBJECTIVE: The authors report their experience in patients with adjuvant systemic 2-interferon with the aim of defining the effectiveness, side-effects, indications and limitations of this treatment. MATERIALS AND METHODS: From January 1989 to December 1996, 123 patients with genital, anorectal and perineal HPV lesions were treated with cryosurgery; adjuvant systemic a2-interferon was administered to 38 of them. There were 76 female and 47 male patients (median age of 29 years, range; 15-56 years). Clinical examinations included: digital rectal examination, head and neck examination, urethral meatus inspection and, in female patients, gynaecological examination; they underwent colposcopylurethroscopy, proctosigmoidoscopy, cystoscopy (in advanced disease); scraping for cytology and PCR analysis, and biopsy for histology. Twenty-three percent of patients had more than one site involved; upper digestive tract involvement was observed in 6.6% and 47% had lesions larger than 6 sqcm. Twenty-five females with genital lesions had esocervical lesions only; ten of them had SIL1, while seven a SIL3. RESULTS: Ninety-eight out of 123 patients (79.7%) were recurrence-free after a median follow-up of 32 months. A recurrence was observed in 25 patients: in univariate analysis, recurrence of disease occurred more frequently in females (p = 0.04), in patients with longer duration of symptoms (p = 0.0002),with wider lesions (p = 0.00015), with head and neck involvement (p < 0.01), and in HIV-positive patients (p = 0.03). In multivariate analysis, duration of symptoms (p = 0.005), head and neck involvement (p = 0.01), and width of lesion > 3 sq cm (p = 0.025) were associated with increased risk CONCLUSION: Our findings confirm the value of cryosurgery in the treatment HPV lesions; it is less traumatic, and gives good aesthetic and functional results; moreover, large lesions may be treated and the depth of cryonecrosis is more suitably adapted. Patients amenable to adjuvant treatment with a2-interferon should have multiorgan involvement, HPV type 16 or 18, lesions >3 sqcm, long lasting symptoms (>6 months) and presence of SIL.

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

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

Cell kinetics analysis in patients affected by squamous cell carcinoma of the head and neck treated with primary surgery and adjuvant radiotherapy.

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) was significantly smaller than for HN-SCC patients with slow tumor proliferation (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 radiotherapeutic modalities.

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.

Micronucleus frequencies in exfoliated buccal cells in normal mucosa, precancerous lesions and squamous cell carcinoma.

OBJECTIVE: To assess the value of micronuclei in the characterization of precancerous lesions of the oral cavity with reference to their likelihood of progressing to malignant lesions. STUDY DESIGN: The frequency of micronuclei was determined in exfoliated cells from normal oral mucosa, a preneoplastic condition (leukoplakia) and precancerous lesions with and without dysplasia, squamous cell carcinomas and sites of previous carcinomas that had been removed. RESULTS: Average micronucleus frequencies were increased in precancerous lesions as compared to normal mucosa and further increased in carcinomas, suggesting that micronuclei are a biomarker of neoplastic progression in this type of cancer. With all samples, micronucleus frequencies were systematically higher when cells were collected by vigorous than by light scraping, suggesting a decreasing gradient from basal to superficial layers of mucosa. The micronucleus frequency did not vary with the sex or age of patients, while it did vary with the anatomic site of the lesions. CONCLUSION: Although the gradual increase in micronucleus counts from normal mucosa to precancerous lesions to carcinomas suggests a link of this biomarker with neoplastic progression, the large overlapping of data prevents its use as a predictor of progression of precancerous lesions to malignancy in individual patients.

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

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

[Diagnostic protocol of thyroid nodules used in a surgical case series (409 cases)]. / Protocollo diagnostico dei noduli tiroidei utilizzato in una casistica chirurgica (409 casi).

BACKGROUND: The introduction of ultrasonography and fine needle biopsy (FNB) has changed the approach towards thyroid pathology. At the Division of Surgical Oncology of the National Institute for Cancer Research in Genoa we use a complex diagnostic system for the selection of patients affected by thyroid pathologies. Our aim is to analyze this methodology and find the best diagnostic procedure for the individual patient. METHODS: Between January 1982 and June 1997, 2500 patients (pts) were found to be affected by thyroid pathologies. The diagnostic procedures for thyroid pathologies are: physical examination and anamnesis, scintigraphy, ultrasonography, fine needle biopsy, blood dosages, radiography of trachea and aesophagus; some cases require Computerized Tomography of the neck and Magnetic Nuclear Resonance. At the end of the examinations 409 pts underwent surgery; we will be evaluating the diagnostic system of these patients. RESULTS: We found from our data, that the group with the highest incidence of malignant tumors is characterized by a large number of instrumental examinations. In fact, 55/73 pts underwent all the instrumental exams, and in 21.1% a malignant tumor was found. These data are interesting, but more important is that only 409 patients out of 2500 underwent surgery 16.3%. CONCLUSIONS: We believe that one single instrumental examination is not enough to detect the characteristic of a thyroid nodule; the three most important examinations, scintigraphy, ultrasonography and cytology, would make it possible to select those cases which need a surgical approach. We believe that the 20% incidence in these cases can be considered good result, considering that the incidence of malignant tumors in thyroid pathologies is about 5% and that in these cases although the tumors were not malignant, they were operated on for functional or mechanical disorder.

[Precancerous lesions of the oral cavity: review of the literature and an analysis of cases]. / Lesioni precancerose del cavo orale: revisione della letteratura ed analisi di una casistica.

146 patients with precancerous lesions of the oral cavity were observed in our institute between 1988 and 1995. Out of a total of 188 lesions, 110 were single and 36 were multifocal. Histologically 164 lesions were classified as keratosis, 14 as dysplasia, and 10 as lichen ruber planus. 76 patients were treated by cryosurgery, 20 received medical treatment and 3 underwent surgery. Only 47 patients eliminated such risk factors as smoking and alcohol consumption from their daily life-styles. Complete response was 99%, 20.8% and 29.8%, respectively, for cryosurgery, medical treatment and preventive measures. Only 2 patients (1.4%) developed squamous cell carcinoma of the oral cavity. Of these, 1 had had keratosis of the tongue, treated with cryosurgery, while the other had had a medically treated dysplasia of the floor of the mouth. There were 8 precancerous lesion recurrences after cryosurgery and 2 after medical treatment. After cryosurgery 18 new lesions appeared in a site other than the primary site, 4 occurred after medical treatment, 1 after surgery and 2 in patients who had eliminated tobacco and alcohol consumption. Since precancerous lesions constitute a general apparatus disease, a systemic treatment is required which can stimulate cell differentiation and/or suppress the mechanisms inducing carcinogenesis. This may prevent the occurrence of new lesions. For this reason the authors believe that the initial treatment for patients with precancerous lesions should be medical. Loco-regional therapy should be reserved for those cases which do not respond to medical treatment.

In vivo cell kinetics in elderly patients affected by squamous cell carcinoma of the head and neck.

The purpose of the study was to determine whether pretreatment tumor cell kinetics can predict local control in elderly patients affected by squamous cell carcinoma of the head and neck (SCC-HN) and help guide different therapeutic modalities. Over a 6-year period, 52 patients with stage II to IV SCC-HN and aged more than 70 years were given an infusion of bromodeoxyuridine (BrdUrd) 6 hours prior to tumor biopsy sampling. The simultaneous labeling S phase fraction (LI) and duration (Ts) as well as potential doubling time (Tpot) were measured with flow cytometric analysis of BrdUrd and DNA content. Patients were then treated as follows: 14 with conventional radiotherapy; 13 with partly accelerated radiotherapy; 11 with chemoradiotherapy; 14 with surgery plus adjuvant radiotherapy. Univariate analysis showed that, independently of treatment type, patients with fast growing SCCs-HN characterized by Tpot value < or = 5 days had a lower three-year local control than patients with slow growing tumors with Tpot value > 5 days. Our results also demonstrated that surgery or chemoradiotherapy were effective treatments for fast growing tumors. Radiotherapy alone, instead, was more effective for slow growing tumors. Our data suggest that in vivo cell kinetics may play a role as additional prognostic factor for elderly patients with SCC-HN and predict the outcome of different treatments.

Staining of micronuclei in squamous epithelial cells of human oral mucosa.

OBJECTIVE: To evaluate the influence of methodologic variables, staining method and sampling, on the frequency of micronuclei scored in squamous epithelial cells of oral mucosa. Micronuclei were used as biomarkers of structural and numerical chromosome damage. STUDY DESIGN: Feulgen and Giemsa stain and fluorescent dyes Hoechst 33258 and propidium iodide were used for micronucleus staining. Cells were collected by either light or vigorous scraping of oral mucosa. RESULTS: Staining of micronuclei by Hoechst 33258 proved more handly, less time consuming and at least equally reliable to the more widely used Feulgen staining. Results with Giemsa stain and propidium iodide were unsatisfactory. Micronuclei were less frequent in superficial layers of the oral mucosa. CONCLUSION: Hoechst 33258 can be recommended for micronucleus staining in squamous epithelial cells of oral mucosa. Differences in scraping may affect the measurement of micronucleus frequency; scraping should therefore be carefully standardized in each laboratory.

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.

Combined craniofacial approach to facial tumours involving the anterior skull base.

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 carcinoma and adenocarcinoma of the nasal fossa; two patients had squamous carcinoma rT4NO and adenocarcinoma rT4NO1 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.

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.

[Early stages of laryngeal cancer (I-II stage) and therapeutic options: case report and review of literature]. / Tumori della laringe I-II stadio; opzioni terapeutiche, presentazione di una casistica e revisione della letteratura.

Between 1987 and 1993, 36 patients with early squamous cell carcinoma of the larynx (I-II stage) were treated with radiotherapy, at the National Institute for Cancer Research of Genoa; 25 patients were stage I (5 T1N0 of supraglottic larynx, 15 T1aN0 and 5 T1bN0 of glottic larynx) and 11 patients stage II (7 T2N0 of supraglottic larynx and 4 T2N0 of glottic larynx); there were 32 males (89%) and 4 females (11%), ages ranging from 34 to 83 years (mean age 61 years). The radiotherapy was performed utilizing the X-ray of a 6 MV linear accelerator, with a daily conventional fractionation and a dose of 66-70 Gy/33-35 fr./7 weeks, with co-axial latero-lateral beams including cervical lymph-nodes, except for T1N0 glottic cancer. The median follow-up was 51 months (range 8-84 months). The local control rate of all the patients was 80.5% at 51 months. According to the stage and tumor subsite, it was 80% for stage I a-b of the glottic site, 60% for the stage I of supraglottic site, 91% for stage II of supraglottic and glottic site. Only 6 patients (18%) underwent the salvage surgery and in all the patients the illness was under control. The overall survival rate was 83.3% at 51 months (4 patients died of a second tumor (11%) and 2 from heart disease (5.5%)). The only complication we observed was a glottic edema. The analysis of our results demonstrates that radiotherapy seems to be more appropriate in the T1a-b glottic cancer. These results are in agreement with those obtained by other studies. On the contrary, the results obtained with radiotherapy, in the T2N0 glottic cancer, are not satisfactory, with regard to local control, as those obtained with surgery, but offers best functional results. In most T2N0 tumors, after the failure of radiotherapy, a reconstructive laryngectomy is still possible. We also obtained good results with the supraglottic lesions. The small number of cases we treated does not allow us to achieve final conclusions and other studies are necessary to confirm our results.

In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

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.

[Non-toxic nodular goiter: treatment and follow-up]. / Trattamento e follow-up del gozzo non tossico uni o multinodulare.

Between 1982 and 1993, 224 patients (196 females and 28 males) with benign lesion of the thyroid underwent surgery. This group included: 1) 210 pts with p multinodular goiter or solitary nodule with normal serum levels of T3, T4, FT3, FT4, TSH (Thyroid stimulating hormone; 2) 14 pts with a hyper-functioning goiter; 3) 12 pts with recurrent nodules following surgery which had been carried out in another hospital. In this study only those pts with solid cold (hypofunctioning) nodules which had not been treated previously were evaluated. The minimal follow-up was 18 months. It consisted of serologic studies (86 cases), ultrasonography (70 cases) and ultrasonography and scintigraphy (5 cases). We performed isthmusectomy in 2 cases, total lobectomy in 42 cases and subtotal thyroidectomy in 42 cases. Out of the 86 pts evaluated, 70 (81.3%) were treated with post-surgical hormone suppressive therapy (Levothyroxin 100 gamma daily). The endogenous thyroid stimulating hormone (TSH) was suppressed in 50 cases (71%), while 20 pts (28.5%) remained within the norm. Thyroid ultrasonography demonstrated recurrent nodules in 14 out of the 86 evaluated (16.2%). All these pts received thyroxine therapy. Among the 50 pts who had been treated with an adequate dose of thyroid hormone, 5 had recurrences (10%), as compared to 3 out of the 20 cases (15%) who had been administered thyroxine dosage not high enough to suppress THS and to 6 pts out of the 16 (33.5%) who had not been administered thyroid hormone. One out of the 20 pts (5%) who had undergone total lobectomy and post-surgical suppressive hormone therapy developed recurrence as compared to 6 out of the 24 pts (25%) who had under gone lobectomy and had been administered a hormone dosage which was not high enough to suppress TSH. Four out of the cases (13.3%) who had under gone subtotal thyroidectomy and post-surgical suppressive hormone therapy had recurrence as compared to 3 out of the 12 (25%) who had undergone subtotal thyroidectomy without TSH suppression. We conclude that treatment with thyroid hormone decreases the risk of benign recurrences only when undergone a long thyroxine therapy in doses high enough to suppress endogenous TSH.

Temporary regression of recurrent squamous cell carcinoma of the head and neck is achieved with a low but not with a high dose of recombinant interleukin 2 injected perilymphatically.

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.

Potential doubling time in head and neck tumors treated by primary radiotherapy: preliminary evidence for a prognostic significance in local control.

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 < or = 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 < or = 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.

Mandible reconstruction with metallic endoprosthesis following Commando's operation for advanced head and neck cancer. Personal experience.

Invasion of the mandible is found in 22% to 29% of advanced (Stage III-IV) head and neck cancers; only an aggressive surgical technique, such as Commando's operation with subsequent reconstruction of tissue defects, can give a chance of cure to these patients. The reconstruction is feasible both by means of microsurgical free-tissue transfers or with alloplastic materials and myocutaneous flaps. Between 1982 and 1991, 34 patients in Stage III (n = 6; 17.7%) and IV (n = 28; 82.3%) head and neck cancers underwent Commando's operation with different types of reconstruction in 30 patients: pectoralis myocutaneous flap (n = 9), osteo-myocutaneous flap with the underlying segment of the fifth rib (n = 2), myocutaneous flap plus prosthesis (n = 17), or prosthesis alone (n = 2). Two different prostheses were implanted: the linear A-O mandibular reconstruction plate (n = 13), and the Dumbach titanium cage (n = 6). In the group of patients in which the linear A-O mandibular reconstruction plate was used there were four cases of prosthesis dislodgement and major exposure and one case of prosthesis breakage while in patients who were given the Dumbach titanium cage there were four cases of major exposure. Prosthesis removal was required in five and two patients with linear A-O and Dumbach titanium cage prosthesis, respectively. Median survival was 14 months with 28% five-year survival. In our experience, metallic prostheses with a shape and arrangement that allow a distribution of traction forces on a wider surface, with screws drilled in nonaligned points of the mandible, seem to be more reliable as they reduce the risk of dislodgement and breakage.