Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors.

BACKGROUND: The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors. PATIENTS AND METHODS: Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab. RESULTS: A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival. CONCLUSIONS: Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery.

BACKGROUND: Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. There is also evidence that many of the pathophysiological mechanisms which are involved in delirium are involved in sarcopenia too. This article describes the protocol of a pilot study to evaluate the feasibility of a larger one that will explore the pathophysiological mechanisms correlating POD with sarcopenia. We will analyse whether various biomarkers reflecting neuroinflammation, ROS, neuroendocrine disorders, and microvasculature lesions will be simultaneously expressed in in the blood, cerebrospinal fluid (CSF), and muscles of patients developing POD. METHODS: Two centres will be involved in this study, each recruiting a convenient sample of ten older patients with hip fracture. All of them will undergo a baseline Comprehensive Geriatric Assessment, which will be used to construct a Rockwood-based Frailty Index (FI). Blood samples will be collected for each patient on the day of surgery and 1 day before. Additionally, CSF and muscle fragments will be taken and given to a biologist for subsequent analyses. The presence of POD will be assessed in each patient every morning until hospital discharge using the 4AT. Delirium subtypes and severity will be assessed using the Delirium Motor Subtype Scale-4 and the Delirium-O-Meter, respectively. We will also evaluate the patient's functional status at discharge, using the Cumulated Ambulation Score. DISCUSSION: This study will be the first to correlate biomarkers of blood, CSF, and muscle in older patients with hip fracture.

A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck - the RESGEX study.

BACKGROUND: The aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment. PATIENTS AND METHODS: In this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival. RESULTS: Median progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02). CONCLUSIONS: The glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.

Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia.

Some cytokines have been involved in the pathogenesis of late onset Alzheimer's disease (LOAD). A possible increase in plasma cytokines levels has been reported in LOAD and vascular dementia (VD), but the results of previous studies are conflicting. We evaluated the plasma levels of IL-6, TNF-alpha, IL-1beta, and IL-10 in four groups of older individuals: 60 patients with LOAD, 80 patients with VD, 40 subjects with cerebrovascular disease but without dementia (CDND), and 42 controls (C). By analysis of covariance (adjustment for age, gender, coronary heart disease, diabetes, hypertension, smoking, and alcohol consumption) we found that: *IL-1beta was higher in VD, LOAD, and CDND compared with controls (p<0.005). *TNF-alpha was higher in VD and LOAD compared to C (p<0.05), and in VD compared to LOAD (p<0.03). *IL-6 was higher in VD compared with LOAD (p<0.03). No differences in IL-10 values were found (Kruskal-Wallis, Asymp. Sig. 0.14). By logistic regression analysis, we demonstrated that high levels (defined as above the median) of IL-1beta and TNF-alpha, but not of IL-6, were associated with increased likelihood of having VD and LOAD compared to C, while high IL-6 levels were associated with a increased probability of having VD, compared with LOAD. Our study support the notion of a low-grade systemic inflammation in older patients with LOAD or VD, characterized by an increase in plasma IL-1beta and TNF-alpha levels. The high IL-6 levels found in VD might be not a specific finding, as it might come from several conditions including atherosclerosis and related vascular risk factors, comorbidity, and frailty.

High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia.

In older individuals, inflammatory mechanisms have been linked to the pathogenesis of both dementia and functional impairment. In this cross-sectional study we have investigated the possible association between some markers of systemic inflammation and functional status, in a sample of one hundred and forty older demented patients including 60 patients with late onset Alzheimer's disease (LOAD) and 80 with vascular dementia (VD). Functional status was evaluated by Barthel Index (BI); the total score ranged from 0 (total dependency) to 20 (total autonomy). Interleukin-1beta, Tumor Necrosis Factor-alpha, Interleukin- 6, Interleukin- 8, and Transforming Grow Factor beta were quantified by ELISA. Among the cytokines evaluated, only IL-6 was correlated with the BI (r: -0.32, p < 0.001). The mean levels of IL-6 progressively decreased from I (9.50 pg/mL), to II (6.40 pg/mL), to III BI tertile (4.80 pg/mL) (p < 0.02). At multiple regression analysis, IL-6 was associated with BI in the whole sample and in VD, but not in LOAD, independent of age, gender, smoking, alcohol consumption, hypertension, diabetes, coronary heart disease, previous stroke, and mini mental state examination score. Our study suggests the existence of an independent and negative relationship between IL-6 plasma levels and functional status in older individuals with vascular dementia. This finding might contribute to explain the 'excess of disability' phenomenon described in older demented patients.

Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer.

Satraplatin is a novel oral platinum (IV) complex that shows activity against hormone-refractory prostate cancer (HRPC) in cisplatin-resistant human tumor lines in phase I and phase II trials. A randomized multicenter phase III trial with a target sample size of 380 patients was initiated in men with HRPC. After 50 randomized patients, the trial was closed to further accrual by the sponsoring company. An ad hoc analysis of all available data is reported here. Eligibility criteria included pathological proof of prostate cancer, documented progression despite prior hormonal manipulation, WHO PS 0-2, and no daily intake of narcotic analgesics. Patients were randomized between satraplatin 100 mg/m(2) for 5 days plus prednisone 10 mg orally BID or prednisone alone. Compliance was excellent. 48/50 patients have progressed and 42 have died, mostly due to prostate cancer. Median overall survival was 14.9 months (95% CI: 13.7-28.4) on the satraplatin plus prednisone arm and 11.9 months (95% CI: 8.4-23.1) on prednisone alone (hazard ratio, HR = 0.84, 95% CI: 0.46-1.55). A >50% decrease in prostrate specific antigen (PSA) was seen in 9/27 (33.3%) in the satraplatin plus prednisone arm vs. 2/23 (8.7%) on the prednisone alone arm. Progression-free survival was 5.2 months (95% CI: 2.8-13.7) on the satraplatin plus prednisone arm as compared to 2.5 months (95% CI: 2.1- 4.7) on the prednisone alone arm (HR = 0.50, 95% CI: 0.28-0.92). This difference is statistically significant (p = 0.023). Toxicity was generally minimal in both arms. This randomized comparison of a combination of satraplatin and prednisone versus prednisone alone supports the antitumor activity of the combination. Its role in the treatment of HPRC remains to be elucidated in an appropriate phase III setting.

Acute toxicity of conventional radiation therapy for high-risk prostate cancer in EORTC trial 22863.

OBJECTIVES: We analysed the acute toxicity observed in the European Organisation for Research and Treatment of Cancer (EORTC) randomised trial 22863 comparing conventional external irradiation with or without an agonist analogue of gonadotropin-releasing hormone in high-risk prostate cancer patients. METHODS: Four hundred five patients that received a dose of at least 30 Gy were considered evaluable for acute toxicity assessment. Toxicity was grouped in a few categories: general, genito-urinary, and lower gastro-intestinal. Univariate and multivariate analyses were performed using the World Health Organisation (WHO) toxicity score and grouping together toxicity scores in different bimodal and trimodal groups. RESULTS: Overall, our data show that age, previous surgery and irradiation dose are important predictive factors for acute toxicity, but not the use of combined hormone therapy. Fifteen percent of patients suffered of moderate to severe acute toxicity (WHO G3-G4). Life threatening toxicity was observed in six cases (1.5%). CONCLUSIONS: The assessment of toxicity combining in different groups the original five scores scale produced conflicting results similar to those commonly reported in literature. Interpretation of the role of pre-treatment factors with uneven distribution in the study requires careful evaluation. These data obtained with conventional curative irradiation of high-risk prostate cancer patients are proposed for comparison with results achieved using modern state-of-the-art irradiation techniques.

The EORTC Boron Neutron Capture Therapy (BNCT) Group: achievements and future projects.

Boron Neutron Capture Therapy (BNCT) is an experimental treatment modality that takes place in a nuclear research reactor. To progress from preclinical studies to patient treatment is a challenge requiring strict quality management and special solutions to licensing, liability, insurance, responsibility and logistics. The European Organisation for the Research and Treatment of Cancer (EORTC) BNCT group has started the first European clinical trial of BNCT for glioblastoma patients at the European High Flux Reactor (HFR) in Petten, The Netherlands, conducted by the Department of Radiotherapy of the University of Essen, Germany. A very strict quality management had to be installed following the European rules on safety and quality assurance for nuclear research reactors, for radioprotection, for radiotherapy and for clinical trials. The EORTC BNCT Group has created a virtual European-wide hospital to handle the complex management of patients treated with BNCT. New clinical trials are currently under development.

The EORTC Genito-Urinary Tract Cancer Group: 25 years of achievements and future strategies.

The European Organisation for Research and Treatment of Cancer (EORTC) Genito-Urinary (GU) Tract Cancer Group celebrates 25 years of activity in 2001. The Group has developed an intense research activity carrying out phase II and phase III clinical trials in prostate, bladder, renal, penile and testicular cancers. It is one of the most active groups within the EORTC, entering more than 1200 new patients in its trials in 2001. In its trials, the EORTC GU Group also focuses on quality control, quality of life and uro-pathology. Besides collaboration with other EORTC groups, the GU Group is very actively collaborating with international organisations. Currently, several large phase III studies are conducted in collaboration with European and North American organisations. For the next few years, the Group is committed to develop projects aimed at testing new drugs and therapeutic strategies and increasing the collaboration between basic science and clinical practice.

EORTC Radiotherapy Group: achievements and future projects. European Organisation for Research and Treatment of Cancer.

The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy (RT) Group will celebrate 27 years of activity in 2002. During its long history, the Radiotherapy Group has conducted a large number of studies which have provided valuable information on the radiation treatment of several disease sites. Group efforts have been concentrated on dose-effect studies, optimal fractionation schemes, combinations with other treatment modalities, and new radiotherapy techniques. The EORTC RT Group was the first in Europe to develop and introduce methodologies of Quality Assurance in radiotherapy. The RT Group actively collaborates with other EORTC Groups and international organisations. Currently, several phase III studies are being conducted in collaboration with European, North American and Australian organisations. The collaboration with RTOG led to the setting up of common systems for scoring late normal tissue effects. In the years to come, the Group will keep pioneering pivotal trials in radiotherapy and radio-chemotherapy. It will also explore combinations with novel therapies in phase I trials and implement innovative translational research programmes.

Addressing the challenge of intergroup studies in oncology: the EORTC experience. European Organisation for Research and Treatment of Cancer.

Intergroup studies are conducted by more than one clinical research group. There are several difficulties that hamper in practice the possibility of conducting such trials, as all interested parties will have to address unusual and complex issues. These are mainly related to differences in size, interests, motivations and means among different research organisations. The EORTC recognises the importance to promote intergroup collaboration providing to all interested groups the necessary expertise and organisational support to conduct intergroup studies. The role of the EORTC evolved from the spontaneous organisations of intergroup trials to the definition of a basic set of principles and criteria that groups have to fulfil to participate in intergroup trials. Recently, a specific EORTC Intergroup Office started its activity devoted to solve the issues related to the intergroup co-operation. This office will have an increasing role to promote and help in conducting intergroup studies.

Prognostic significance of cervical lymph nodes density evaluated by contrasted computer tomography in head and neck squamous cell carcinoma treated with hyperthermia and radiotherapy.

INTRODUCTION: A correlation between node hypodensity assessed by means of computer tomography (CT) and resistance to both chemotherapy and radiation therapy (XRT) in advanced head and neck tumours has been suggested in the literature. The outcome of a retrospective series of 50 patients with head and neck squamous cell carcinoma (SCC) and cervical nodes metastases treated with combined hyperthermia (HT) and definitive XRT was reviewed to investigate if node density confirmed its prognostic value. MATERIALS AND METHOD: For all patients, a pre-treatment contrasted CT scan performed at the Institution between 1987-1993 was available. The density of the largest node (> 2cm) was compared to that of adjacent nuchal muscles. Nodes with hypodense areas present in more than one third of the total volume were considered necrotic nodes. RESULTS: The patients were divided in two groups (with and without nodal necrosis), well balanced in terms of potential prognostic factors. No significant difference in overall nodal response rate, local control and survival was found in the two groups of patients. CONCLUSION: Nodal density assessed by contrasted CT scan in the series did not result in a significant prognostic factor in patients with SCC node metastases treated with HT and XRT. It is suggested that HT could act as a radiosensitizer in the treatment of hypodense (at CT scan) metastatic nodes overcoming the radioresistance of necrotic, presumably hypoxic nodal metastases.

The role of proton therapy in the treatment of large irradiation volumes: a comparative planning study of pancreatic and biliary tumors.

PURPOSE: The purpose of this study was to examine the potential benefit of proton therapy for abdominal tumors. Extensive comparative planning was conducted investigating the most up-to-date photon and proton irradiation technologies. METHODS AND MATERIALS: A number of rival plans were generated for four patients: two inoperable pancreatic tumors, one inoperable and one postoperative biliary duct tumor. The dose prescription goal for these large targets was 50 Gy, followed by a boost dose up to 20 Gy to a smaller planning target volume (PTV). Photon plans were developed using "forward" planning of coplanar and noncoplanar conformal fields and "inverse" planning of intensity-modulated (IM) fields. Proton planning was simulated as administered using the so called spot-scanning technique. Plans were evaluated on the basis of normal tissues' dose-volume constraints (Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1990;21:109-122) and coverage of treatment volumes with prescribed doses. RESULTS: For all cases, none of the forward calculated photon plans was able to deliver 50 Gy to large PTVs at the same time respecting the dose-volume constraints on all critical organs. Nine evenly spaced IM fields achieved or nearly achieved all maximum dose constraints to critical structures for two out of three inoperable patients. IM plans also obtained good results for the postoperative patient, even though the dose to the liver was very close to the maximum allowed. In all cases, photon irradiation of large PTV1s to 50 Gy followed by a 20 Gy boost entailed a risk very close to or higher than 5% for serious complications to the kidneys, liver, or bowel. Simple arrangements of 2, 3, and 4 proton fields obtained better dose conformation to the target, allowing the delivery of planned doses including the boost to all patients, without excessive risk of morbidity. Dose homogeneity inside the targets was also superior with protons. CONCLUSION: For the irradiation of large PTVs located in the abdominal cavity, where multiple, parallel structured organs surround the target volumes, proton therapy, delivered with a sophisticated isocentric technique, has the potential to achieve superior dose distributions compared with state-of-the-art photon irradiation techniques. IM photon plans obtain better results in the postoperative case, because the reduced volume lessens the effect of the unavoidable increase of integral dose to surrounding tissues.

Long-term results of 60 patients with pathologic stage I & IIA Hodgkin's disease treated with exclusive mantle radiation therapy.

Between January 1972 and December 1982 60 patients with pathological stage IA and IIA Hodgkin's disease (HD) were submitted to Mantle irradiation only. Twenty-five were in stage I (32.1%) and 35 in stage II (67.9%). All patients were submitted to staging laparotomy. Cases with large mediastinal mass were excluded from this series. Delivered doses were 44 Gy in involved areas, 40 Gy on the mediastinum and 36 Gy on uninvolved sites. Twenty-four patients in stage I (96%) and 33 in stage II (94.2%) obtained complete remission. Actuarial 10- and 20-yr overall (OS) rates were 86% and 79.1%, respectively. Event-free (EFS) and relapse-free (RFS) survival rates at 10 and 20 yr were 67.5% and 62.1%, respectively. The occurrence of disease relapse resulted in the only statistical significant prognostic factor for OS in both univariate and multivariate analysis. Distant and extranodal recurrences were significantly (P<0.01) related to a reduced OS. On multivariate analysis stage was the only determinant factor for increased RFS. Extended field RT proved to be an effective curative modality for stage I HD patients, whereas 15 out of 33 patients in stage II relapsed requiring salvage therapy. Long-term analysis of survival and treatment-related morbidity rates will improve our knowledge and assist the physicians to choose the therapeutic option to offer to HD patients.

Hypofractionated radiation therapy for inoperable advanced stage non-small cell lung cancer.

AIMS AND BACKGROUND: Inoperable advanced stage lung cancer is usually treated by radiation therapy. Although a minority of patients may achieve prolonged survival with aggressive therapeutic approaches, most patients present with adverse prognostic factors that do not allow curative treatment. For these cases palliation of symptoms becomes the main treatment purpose, and short treatment schedules are commonly employed. METHODS: Fifty-two inoperable patients with stage IIIB or IV non-small cell lung cancer (NSCLC) were treated with a hypofractionated schedule of radiotherapy. Initially all patients received 20 Gy in five fractions, and approximately one month after irradiation completion patients underwent clinical and radiological evaluation. Those that achieved a >50% reduction in tumor load and respiratory symptoms were submitted to a second similar short course of radiotherapy. RESULTS: Thirty-three (63%) patients received only one course of radiotherapy. After the first evaluation, 19 patients (37%), all stage IIIB, fulfilled the criteria to receive a total dose of 40 Gy. Survival rates at one and two years were 33% and 0%, respectively, in the group of patients that received 20 Gy, and 52% and 21% respectively, in the group treated with 40 Gy. Two-year survival rates were 10% for stage IIIB and 0% for stage IV patients. Among the patients that were irradiated with a dose of 20 Gy, a subjective reduction of dyspnea and cough and remission of hemoptysis were observed in 97%, 82% and 80% cases, respectively. Complete remission of dyspnea and coughing was observed in 17 (89%) and 14 (74%) patients treated with two irradiation courses. Only mild toxicity was recorded. CONCLUSIONS: Our treatment schedule achieved symptom control in the majority of patients. Early evaluation after 20 Gy allowed selection of responsive patients that could benefit from more prolonged treatment.

Orbital pseudotumor: case report and literature review.

The term orbital pseudotumor refers to a broad category of non-specific idiopathic inflammations of the orbit. This disease, which may affect any orbital structure, is one of the commonest causes of exophtalmus, occurring with a similar incidence in both sexes. The diagnosis is based on a combination of clinical, radiological and histopathological findings, after careful exclusion of specific systemic and local diseases. Many classification systems have been proposed and a range of therapeutic modalities, including surgery, steroids, immunosuppressive agents, and radiation therapy, have been employed by various authors in heterogeneous series of patients. This slowly proliferating disease, which usually presents with a long clinical history and high variability in clinical manifestations and prognosis, is difficult to manage with any of the available therapeutic options. The difficulties and controversies regarding the diagnostic and therapeutic management of these patients are addressed in an updated review of the literature and exemplified in our case report.

Brachytherapy for squamous cell carcinoma of the lip. The experience of the Institute of Radiology of the University of Rome "La Sapienza".

AIMS AND BACKGROUND: Cancer of the lip is the most common malignancy occurring in the oral cavity. The aim of our retrospective study was to review the results of patients with lower lip squamous cell carcinoma who were treated with radiotherapy. METHODS & STUDY DESIGN: From 1970 to 1992, 57 patients with squamous cell carcinoma of the lower lip were treated at the Institute of Radiology of the University of Rome "La Sapienza" with low-dose rate interstitial brachytherapy. According to the UICC 1992 TNM classification, the disease stage was T1 in 27 (47%) cases, T2 in 20 (35%) and T3 in 10 (18%); 8 patients (14%) were cN+. The median tumor dose was 62 Gy (range, 44-96): 10 patients (18%) received a total dose < 50 Gy, 28 (49%) between 50 and 70 Gy, and 19 (33%) > 70 Gy. The cN+ cases were irradiated to total doses of 65-70 Gy on the involved station. All patients obtained complete remission. RESULTS: The actuarial overall survival rates at 3, 5 and 10 years were 95%, 76% and 53%; actuarial disease-free survival at 3, 5 and 10 years was 84%, 81%, and 81%, respectively. Actuarial cause-specific survival was 98%, 88% and 84% at 3, 5 and 10 years, respectively. Actuarial local control rate was 90% at 3 and 5 years, rising to 94% with salvage surgery. Local-regional control was obtained in 90% and 86% of patients at 3 and 5 years, and in 93% and 89% of cases, respectively, following surgery. Five of 11 deaths were due to local-regional or distant disease recurrence. CONCLUSIONS: Tumor stage and positivity of regional nodes were the only predictive factors of survival and disease control. Radiation-induced morbidity was very low, and all patients considered their cosmetic outcome at least satisfactory.