Survival after biochemical failure in prostate cancer treated with radiotherapy: Spanish Registry of Prostate Cancer (RECAP) database outcomes.

INTRODUCTION: The clinical course in patients with prostate cancer (PCa) after biochemical failure (BF) has received limited attention. This study analyzes survival time from recurrence, patterns of progression, and the efficacy of salvage therapies in patients treated with radical or postoperative radiotherapy (RT). METHODS: This is a multicenter retrospective comparative study of 1135 patients diagnosed with BF and treated with either radical (882) or postoperative (253) RT. Data correspond to the RECAP database. Clinical, tumor, and therapeutic characteristics were collected. Descriptive statistics, survival estimates, and comparisons of survival rates were calculated. RESULTS: Time to BF from initial treatment (RT or surgery) was higher in irradiated patients (51 vs 37 months). At a median follow-up of 102 months (14-254), the 8-year cause-specific survival (CSS) was 80.5%, without significant differences between the radical (80.1%) and postoperative (83.4%) RT groups. The 8-year metastasis-free survival rate was 57%. 173 patients (15%) died of PCa and 29 (2.5%) of a second cancer. No salvage therapy was given in 15% of pts. Only 5.5% of pts who underwent radical RT had local salvage treatment and 71% received androgen deprivation (AD) ± chemotherapy. The worst outcomes were in patients who developed metastases after BF (302 pts; 26.5%) and in cases with a Gleason > 7. CONCLUSIONS: In PCa treated with radiotherapy, median survival after BF is relatively long. In this sample, no differences in survival rates at 8-years have been found, regardless of the time of radiotherapy administered. AD was the most common treatment after BF. Metastases and high Gleason score are adverse variables. To our knowledge, this is the first study to compare outcomes after BF among patients treated with primary RT vs. those treated with postoperative RT and to evaluate recurrence patterns, treatments administered, and causes of death. The results allow avoiding overtreatment, improving quality of life, without negatively affecting survival.

Outcomes and prognostic factors in intermediate-risk prostate cancer: multi-institutional analysis of the Spanish RECAP database.

PURPOSE: To retrospectively assess outcomes and to identify prognostic factors in patients diagnosed with intermediate-risk (IR) prostate cancer (PCa) treated with primary external beam radiotherapy (EBRT). MATERIALS AND METHODS: Data were obtained from the multi-institutional Spanish RECAP database, a population-based prostate cancer registry in Spain. All IR patients (NCCN criteria) who underwent primary EBRT were included. The following variables were assessed: age; prostate-specific antigen (PSA); Gleason score; clinical T stage; percentage of positive biopsy cores (PPBC); androgen deprivation therapy (ADT); and radiotherapy dose. The patients were stratified into one of three risk subcategories: (1) favourable IR (FIR; GS 6, ≤ T2b or GS 3 + 4, ≤ T1c), (2) marginal IR (MIR; GS 3 + 4, T2a-b), and (3) unfavourable IR (UIR; GS 4 + 3 or T2c). Biochemical relapse-free survival (BRFS), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were assessed. RESULTS: A total of 1754 patients from the RECAP database were included and stratified by risk group: FIR, n = 781 (44.5%); MIR, n = 252 (14.4%); and UIR, n = 721 (41.1%). Mean age was 71 years (range 47-86). Mean PSA was 10.4 ng/ml (range 6-20). The median radiotherapy dose was 74 Gy, with mean doses of 72.5 Gy (FIR), 73.4 Gy (MIR), and 72.8 Gy (UIR). Most patients (88%) received ADT for a median of 7.1 months. By risk group (FIR, MIR, UIR), ADT rates were, respectively, 88.9, 86.5, and 86.9%. Only patients with ≥ 24 months of follow-up post-EBRT were included in the survival analysis (n = 1294). At a median follow-up of 52 months (range 24-173), respective 5- and 10-year outcomes were: OS 93.6% and 79%; BRFS 88.9% and 71.4%; DFS 96.1% and 89%; CSS 98.9% and 94.6%. Complication rates (≥ grade 3) were: acute genitourinary (GU) 2%; late GU 1%; acute gastrointestinal (GI) 2%; late GI 1%. There was no significant association between risk group and BRFS or OS. However, patients with favourable-risk disease had significantly better 5- and 10-year DFS than patients with UIR: 98.7% vs. 92.4% and 92% vs. 85.8% (p = 0.0005). CSS was significantly higher (p = 0.0057) in the FIR group at 5 (99.7% vs. 97.3%) and 10 years (96.1% vs. 93.4%). On the multivariate analyses, the following were significant predictors of survival: ADT (BRFS and DFS); dose ≥ 74 Gy (BRFS); age (OS). CONCLUSIONS: This is the first nationwide study in Spain to report long-term outcomes of patients with intermediate-risk PCa treated with EBRT. Survival outcomes were good, with a low incidence of both acute and late toxicity. Patients with unfavourable risk characteristics had significantly lower 5- and 10-year disease-free survival rates. ADT and radiotherapy dose ≥ 74 Gy were both significant predictors of treatment outcomes.

Influence of different treatment techniques and clinical factors over the intrafraction variation on lung stereotactic body radiotherapy.

PURPOSE: In the present study we compared three different Stereotactic body radiation therapy (SBRT) treatment delivery techniques in terms of treatment time (TT) and their relation with intrafraction variation (IFV). Besides that, we analyzed if different clinical factors could have an influence on IFV. Finally, we appreciated the soundness of our margins. MATERIALS AND METHODS: Forty-five patients undergoing SBRT for stage I lung cancer or lung metastases up to 5 cm were included in the study. All underwent 4DCT scan to create an internal target volume (ITV) and a 5 mm margin was added to establish the planning target volume (PTV). Cone-beam CTs (CBCTs) were acquired before and after each treatment to quantify the IFV. Three different treatment delivery techniques were employed: fixed fields (FF), dynamically collimated arcs (AA) or a combination of both (FA). We studied if TT was different among these modalities of SBRT and whether TT and IFV were correlated. Clinical data related to patients and tumors were recorded as potential influential factors over the IFV. RESULTS: A total of 52 lesions and 147 fractions were analyzed. Mean IFV for x-, y- and z-axis were 1 ± 1.16 mm, 1.29 ± 1.38 mm and 1.17 ± 1.08 mm, respectively. Displacements were encompassed by the 5 mm margin in 96.1 % of fractions. TT was significantly longer in FF therapy (24.76 ± 5.4 min), when compared with AA (15.30 ± 3.68 min) or FA (17.79 ± 3.52 min) (p < 0.001). Unexpectedly, IFV did not change significantly between them (p = 0.471). Age (p = 0.003) and left vs. right location (p = 0.005) were related to 3D shift ≥2 mm. In the multivariate analysis only age showed a significant impact on the IFV (OR = 1.07, p = 0.007). CONCLUSIONS: The choice of AA, FF or FA does not impact on IFV although FF treatment takes significantly longer treatment time. Our immobilization device offers enough accuracy and the 5 mm margin may be considered acceptable as it accounts for more than 95 % of tumor shifts. Age is the only clinical factor that influenced IFV significantly in our analysis.

[Clinical impact of image guided radiotherapy]. / Radioterapia guiada por imagen. Impacto clínico.

Image guided radiotherapy (IGR) is a concept that encompasses the most modern way of administering radiotherapy treatment. The aim is to maximise the dose deposited in the target volume, minimising the dose in healthy organs. This would not be possible without the continuous development of technology and software, above all in the following areas: deformable image registration, replanning new treatments, real time image and calculation of accumulated dose. While the clinical impact is evident, little is said about the impact on the reorganisation of the Radiotherapy Oncology services. IGR supposes training all team members involved, with a training and a starting period. With the experience acquired, the time dedicated to each patient (in all stages of treatment: simulation, planning, starting out, systems for verifying position, on-line, off-line corrections, replanning, periodic clinical controls) is far higher than that required in conventional radiotherapy, which gives rise to new responsibilities and roles.

[Radiotherapy of mobile tumors]. / Radioterapia en tumores móviles.

In this article we detail some questions related to managing the treatment of mobile tumors, that is, those tumors that shift with respiratory movements, integrating movement into the plan of treatment. This fact complicates the administration of high doses of radiotherapy since, in such cases, the radiation margin must be wider than that required by the tumor itself, representing a greater risk to surrounding healthy tissue. However, the new technologies offer an alternative in these cases, such as tracking and respiratory gating in radiotherapy (RT), that is, the synchronization of treatment with respiratory movement. In gating we capture the tumor and other organs at risk at a specific moment in the breathing cycle, while in tracking we trace the tumor and the organs at risk throughout the breathing cycle. It is therefore essential to obtain good images and to correlate them with each phase of the breathing cycle. The tumors with which these strategies have been most employed are those of the lung, breast and lymphomas, and less frequently with some abdominal tumors such as pancreas, liver and prostate.

[Image-guided brachytherapy]. / Braquiterapia guiada por imagen.

Brachytherapy consists in the administration of radiation in intimate contact with the tumour, with a low exposure of neighbouring healthy tissues. Its use began in the early XX century and it has developed since then: different radioisotopes, systems of remote treatment, computer programs making individual dose calculation possible. In recent years there have been changes affecting two aspects of brachytherapy. In the first place, the incorporation of imaging techniques such as echography, computerised tomography (CT) and magnetic resonance (MR), indispensable for diagnosis and tumoural staging. Their use when the implant is being done helps in guiding and carrying out the operation with greater precision. In the second place, the use of CT, MR and echography makes better coverage of the tumour possible, or reduces the dose to healthy organs. They are used in inverse planning systems, which carry out dose calculation on the basis of the doses to be administered to the tumour and healthy organs. In these planning programs it is possible to make calculations more rapidly, taking account of the placement of the source at each moment in time. This technique, called real-time planning, is starting to show advantages in the treatment of prostate cancer. Incorporation of imaging techniques and improvements in calculation systems mean that brachytherapy is currently playing an important role in treating cancer of the prostate, cervix, breast, head and neck tumours, bronchial tubes or oesophagus.

The EORTC Quality of Life Questionnaire for patients with prostate cancer: EORTC QLQ-PR25. Validation study for Spanish patients.

OBJECTIVES: The EORTC Quality of Life (QL) Group has developed a questionnaire, the EORTC QLQ-PR25, for evaluating QL in prostate cancer. The aim of this study is to assess the psychometric properties of the EORTC QLQPR25 when applied to a sample of Spanish patients. MATERIALS AND METHODS: One hundred and thirty-seven prostate cancer patients with localised disease who started radiotherapy with radical intention combined with or without hormonotherapy prospectively completed the EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires three times: on the first and last day of radiotherapy and in the follow-up period. Psychometric evaluation of the questionnaires' structure, reliability and validity was conducted. RESULTS: Multitrait scaling analysis showed that many of the item-scale correlation coefficients met the standards of convergent and discriminant validity. Exceptions appeared mainly in the scales for bowel symptoms and for hormonal- treatment-related symptoms. Cronbach's coefficients of the scales were good (0.72-0.86) for the urinary symptoms and sexual function scales but they were lower (<0.70) for the bowel and hormonal treatment scales. Most scales of the EORTC QLQ-PR25 had low to moderate intercorrelations. Correlations between the scales of the QLQ-C30 and the module were generally low. Group comparison analyses showed better QL in patients with higher Performance Status. Changes in QL appeared throughout the measurements. These were in line with the treatment process. CONCLUSIONS: The EORTC QLQ-PR25 was a reliable and valid instrument when applied to a sample of Spanish prostate cancer patients. These results are in line with those of the EORTC validation study.

[Neutropenia and fever in the patient with cancer]. / Neutropenia y fiebre en el paciente con cáncer.

Infection in the immunocompromised host is a serious clinical situation due to its high morbi-mortality and is one of the most frequent complications in the patient with cancer. In patients treated with chemotherapy, the risk of infection basically depends on the duration and intensity of the neutropenia. It is essential to evaluate, the most probable pathogen involved to initiate, a priori, the most suitable treatment, and also to evaluate the general clinical situation of the patient, because from the very beginning the treatment is quite aggressive. Outpatient care is possible for patients at "low risk" of complications. By evaluating the antecedents and clinical history of the patient, through physical exploration and from the data of laboratory and radiological explorations these points can be acknowledged. The early start of broad spectrum antibiotherapy is crucial, and in this chapter we review the most recent therapeutical recommendations.

[Malign obstruction of the superior vena cava]. / Obstrucción maligna de la vena cava superior.

The present paper offers a review of the malign syndromes of the superior vena cava, their clinical expressions related to the anatomical characteristics of the compartment where the superior vena cava runs, the diagnostic requirements for realising treatment under the best conditions and the ensemble of measures that must be adopted in dealing with this.

[Acute dysphagia of oncological origin. Therapeutic management]. / Disfagia aguda de causa oncológica. Manejo terapéutico.

Dysphagia is one of the most frequent syndromes in patients with tumours of the head and neck, and the oesophagus. This can be the initial symptom or, more frequently, related to the oncological treatment. We review the most important therapeutic and physio-pathological aspects of acute dysphagia of oncological origin. Deglutition is a complex process in which numerous muscular-skeletal structures intervene under the neurological control of different cranial nerves. The complex neuro-muscular coordination needed for a correct deglutition can be affected by numerous situations, both from the effect of the tumours and from their treatment, basically surgery or radiotherapy. In conclusion, it can be affirmed that for a suitable treatment of oncological dysphagia, a correct initial evaluation and an active treatment are required, since not only the patient's quality of life but, on numerous occasions, the possibility of continuing the treatment and thus maintaining the possibilities of a cure depend on control of the dysphagia.

[Metastatic bone disease. Diagnosis and treatment]. / Enfermedad metastásica ósea. Diagnóstico y tratamiento.

The high incidence of bone metastasis secondary to carcinomas and its serious functional repercussion are motives for constant study and advance in the methods of evaluation, diagnosis and treatment. Pain is the most frequently shown symptom, although at times the start is a pathological fracture. The classic tests of detection and evaluation of the spread of the metastatic disease, simple radiology and gammagraphy, are today complemented by others such as computerised tomography (CT) and magnetic resonance (MR), improving the information on the characteristics of the lesion both inside and outside the bone. On the other hand, positron emission tomography (PET) is showing a far higher sensitivity than gammagraphy and will probably be the test of the future for the early detection of metastasis and of silent primary tumours. The possibilities of treatment of bone metastasis are based on the use of bone regenerators, radiotherapy and surgery. The former two are indicated in lesions already detected in radiography, whether symptomatic or not, if there is no foreseeable risk of fracture. Surgery is indicated in situations of poor or null response to those treatments, when the risk of fracture is high or a pathological fracture has been produced. Before any therapeutic planning, a detailed evaluation of the patient must be carried out, both at a local level (size, site, extension of the metastasis) and general (type of primary tumour, phase of treatment and response, estimated survival).

[Medullar compression]. / Compresión medular.

Medullar compression is an oncological and neurological emergency, whose diagnosis and early treatment are key factors for avoiding severe and irreversible neurological damage. Paralysis, loss of consciousness and alteration in control of the sphincters are the final consequence of the process, and represent an important source of morbidity of the oncology patient, besides being related to a shorter time of survival. The invasion of the vertebral body by haematogenous dissemination is the most frequent cause of medullar compression. On occasions it can create mechanical vertebral instability which represents a real orthopaedic emergency. Pain is the earliest and most frequent symptom. The signs and symptoms appear to the degree that the process advances, passing through motor weakness, alterations in consciousness until paralysis and incontinence of the sphincters are reached, as a result of complete neurological damage. Clinical history and physical exploration should lead to suspicion about the level at which medullar compression is developing, and the most important complementary exploration is MR of the entire spine, which should be requested immediately in order to decide on starting treatment. Treatment is individualised and must be started early. In general, corticoids in combination with radiotherapeutic oncological treatment and/or surgery are the therapeutic weapons to employ.

[Emergency treatment of urological complications in cancer patients]. / Manejo urgente de las complicaciones urológicas en el paciente tumoral.

Patients affected by neoplastic diseases frequently come for consultation to the emergency services of our hospitals. A large part of these consultations occur due to complications of an urological type, whatever the origin of the tumour that the patient presents. The pathology can be secondary to the neoplasy or to the means used in its treatment, although they are often complications that appear independently of the course of the disease. We offer an outline of the most frequent causes of emergency consultation due to urological problems in the patient affected by neoplastic diseases, whether they are in the urogential apparatus or not. We comment especially on the initial study and treatment by the emergency doctor or by the oncologist.

[Effect of PSA nadir and the time to nadir in the disease-free period in localized prostatic carcinoma treated with radical radiation]. / Influencia del nadir de PSA y el tiempo a nadir en el periodo libre de enfermedad (PLE) del carcinoma prostático localizado tratado con irradiación radical.

OBJECTIVE: To evaluate the prognostic significance of PSA nadir (nPSA) and the time to nadir in disease free of recurrence (DFR) in localized carcinoma of prostate treated with radical radiotherapy (RTR). MATERIAL AND METHODS: From October 1984 to December 1998, 86 patients have been treated with prostate carcinoma. It was considered of Low risk those patients with PSA < or = 10 ng/ml, Gleason = 6 or stage T1-T2. Moderate risk: those with one elevated of the three parameters. High risk: two or more parameters. The treatment was carried out in a lineal accelerator using photons of 15 MV, with standard technique and frationation, administering a median dose of 66 Gy (58-75 Gy). It was defined disease free of recurrence (DFR), the time to clinical PSA or biochemical failure. This one was defined as the time starting from the date of nadir PSA to the second consecutive increase of PSA value after three separate serial measurements separated for at least one month. RESULTS: The median of initial PSA value was of 16 ng/ml (1-270), initial clinical stage T1-T2 (70p), stages T3-T4 (14p), and unknown in 2p. The median of Gleason score was 6 (2-10). According to the group of risk they were classified as: low risk in 16 patients (19%), moderated risk in 22 patients (26%), high risk in 21 patients (24%), and unknown in 27 patients (31%). Median nPSA value was 0.8 ng/ml (limits: 0-139) and the median time elapsed between the initial PSA and nPSA has been of 11 months (limits: 0-72 months). The actuarial DFR projected to five years in those patients with nPSA = 1 ng/ml was of 67% vs. 47% in patient with nPSA figures > 1 ng/ml (p = 0.0018). The PFD in patients with time to nadir (t nadir) < 12 months it was of 20% vs. 80% in patients with t nadir > 12 months (p < 0.0001). Multivariate analysis demonstrated that time to nadir (H.R: 0.11 p = 0.001), group of risk (H.R: 28.72 p = 0.020), and grade of differentiation (HR: 28.72 p = 0.010), were determinant to DFR. CONCLUSIONS: nPSA is an important factor to determine the objective response to radiotherapy. nPSA and time to nadir are prognostic factors that influences significantly on the DFR. The indication of adjuvant treatment in those patients with unfavorable prognostic factors such us those who do not reach nadir PSA < or = 1 ng/ml and time to nadir < or = 12 months, deserves the realization of a prospective study.

Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer.

PURPOSE: Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS: Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS: Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION: This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.

[Conservative treatment of microcytic carcinoma of the bladder; report of a new case]. / Tratamiento conservador en carcinoma microcítico de vejiga; aportación de un nuevo caso.

OBJECTIVE: To report an additional case of small cell carcinoma treated conservatively. METHODS: Herein we describe a case of small cell carcinoma of the bladder that had been treated conservatively because of the age of the patient. The specific characteristics of the case are described and the clinical and pathological aspects of the disease are briefly reviewed. RESULTS/CONCLUSION: Although treatment of this disease is primarily by cystectomy followed by chemo and radiotherapy, organ-sparing neoadjuvant chemo and radiotherapy as an alternative to surgery could be attempted to obtain complete remission in selected patients.

[Quality of Life of cancer patients: studies by the Oncology Department of the Hospital of Navarra in the Quality of Life Group of the EORTC]. / La Calidad de Vida en el paciente oncológico: estudios del Servicio de Oncología del Hospital de Navarra en el Grupo de Calidad de Vida de la EORTC.

The Quality of Life of cancer patients and its assessment are of great important nowadays. They are useful in offering a treatment that is better adapted to the characteristics of the patient and the development of his/her illness. Patients have to evaluate their Quality of Life through measurement instruments. The European Organisation of Research and Treatment of Cancer-EORTC is an international body devoted to research in cancer treatment. One of its divisions is working on the study of the Quality of Life. They have developed a core questionnaire for Quality of Life measurement and modules for different types of tumour and treatment to complement this. The Oncology Department of the Hospital of Navarra has been collaborating in this group since 1992. The Department has participated in the creation or validation of the core questionnaire and different modules. It is measuring the Quality of Life in different clinical studies. All members of the department are collaborating in these studies.

Radical chemoradiotherapy for elderly patients with bladder carcinoma invading muscle.

BACKGROUND: Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with bladder carcinoma invading muscle. In 1988, the authors began a protocol with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC regimen) and radiotherapy for these patients. Traditionally, age has been considered a determinant factor thereby excluding the older patients from the oncologic protocols that are considered to be more aggressive. The authors analyzed 20 patients (age > 70 years) who were treated during this period with the same protocol as the authors' other patients. METHODS: The study included 20 patients (age range, 70-78 years; median age, 74 years) including 4 patients with T2 disease, 9 with T3 disease, and 7 with T4 disease. All patients had a Karnofsky performance status of > 60. Treatment protocol included cytoreductive transurethral resection, 2 cycles of M-VAC chemotherapy, and radiotherapy (45 grays [Gy] on pelvic volume) with concurrent cisplatin (20 mg/m2 on Days 1-5. Response was determined by cystoscopic evaluation. If there was a complete response, radiotherapy continued until a total dose of 65 Gy; if there was not a complete response, cystectomy was performed. RESULTS: Tumor response after a dose of 45 Gy included 11 complete responses (55%), 5 partial responses (25%), and 4 nonresponses (20%). Overall survival was 75%, 34%, and 27% in the 2nd, 3rd, and 5th years of follow-up, respectively. Cause specific survival was 79%, 54%, and 38%, respectively. Survival for patients with complete response was 100%, 60%, and 48%, respectively. Severe toxicity was uncommon, with the most frequent toxicities being leukopenia and cystitis. No treatment-related death occurred with either treatment protocol. CONCLUSIONS: The age of the individual must not become a strict exclusion criterion for the radical treatment of old patients with invasive bladder carcinoma.

Inhibition of Ras/Raf interaction by anti-oncogenic mutants of neurofibromin, the neurofibromatosis type 1 (NF1) gene product, in cell-free systems.

The neurofibromatosis type 1 (NF1) gene encodes a protein, neurofibromin, containing GTPase-activating protein-related domain (GRD) that stimulates intrinsic GTPase activity of Ras protein. By screening a randomly mutagenized NF1-GRD library in Saccharomyces cerevisiae, we isolated two NF1-GRD mutants (NF201 and NF204) with single amino acid substitutions, which suppress the heat shock-sensitive phenotype of the RAS2(G19V) mutant. The NF1-GRD mutants also suppress the oncogenic Ras-induced transformation of NIH 3T3 mouse fibroblasts (Nakafuku, M., Nagamine, M., Ohtoshi, A., Tanaka, K., Toh-e, A., and Kaziro, Y. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 6706-6710). In this paper, we investigated the molecular mechanism of inhibition of the transforming Ras-specific function by the NF1-GRD mutants in mammalian cells. In human embryonic kidney (HEK) 293 cells, the mutant NF1-GRDs attenuated the stimulation of mitogen-activated protein kinase by Ras(G12V), but not by platelet-derived growth factor. In cell-free systems, purified recombinant NF1-GRD mutants showed an inhibitory effect on the association of Ras.guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) with Raf at several times lower concentrations than the wild type. Furthermore, it was revealed that the binding affinity of the mutant NF1-GRDs toward Ras.GTP gamma S is approximately 5-10 times higher than the wild type. These results suggest that the mutant NF1-GRDs tightly bind to an oncogenic Ras in its GTP-bound active conformation and block the interaction between Ras and its effector, Raf.

Split hyperfractionated accelerated radiation therapy and concomitant cisplatin for locally advanced head and neck carcinomas: a preliminary report.

PURPOSE: The feasibility and activity of an intensive chemoradiotherapeutic scheme for patients with locally advanced squamous cell head and neck cancers were tested in a single institution Phase II pilot study. METHODS AND MATERIALS: Between January 1990 and February 1992, 40 patients were entered into this trial. The treatment protocol consisted of split hyperfractionated accelerated radiation therapy (SHART), 1.6 Gy per fraction given twice per day to a total dose of 64-67.2 Gy for a total of 6 weeks with a 2-week gap, and cisplatin (20 mg/sqm/Days 1 to 5, in continuous perfusion) concomitantly. RESULTS: All of the 40 patients are evaluable for response and survival. Toxicity was significant, but tolerable. A complete tumor response to this treatment was achieved by 37 patients (92.5%). With a minimal follow-up of 22 months (median 30 months) there have been 16 local relapses and 19 patients have died, 2 without tumor. The projected 2- and 3-year overall survival rates are 64% (confidence interval (CI) 95%, 49-79%) and 47%, respectively. The 2-year local control probability has been 56% (CI 95%, 39-73%). CONCLUSION: This treatment obtains a high rate of complete responses with increased acute toxicity but tolerable late effects. Preliminary results are encouraging for laryngeal neoplasms. A longer follow-up is needed to evaluate the impact of this treatment on patient survival.