Vassilis Kouloulias

Oral squamous cell cancer: early detection and the role of alcohol and smoking

ObjectiveOral squamous cell carcinoma has a remarkable incidence worldwide and a fairly onerous prognosis, encouraging further research on factors that might modify disease outcome.Data sourcesA web-based search for all types of articles published was initiated using Medline/Pub Med, with the key words such as oral cancer, alcohol consumption, genetic polymorphisms, tobacco smoking and prevention. The search was restricted to articles published in English, with no publication date restriction (last update 2010).Review MethodsIn this review article, we approach the factors for a cytologic diagnosis during OSCC development and the markers used in modern diagnostic technologies as well. We also reviewed available studies of the combined effects of alcohol drinking and genetic polymorphisms on alcohol-related cancer risk.ResultsThe interaction of smoking and alcohol significantly increases the risk for aero-digestive cancers. The interaction between smoking and alcohol consumption seems to be responsible for a significant amount of disease.ConclusionPublished scientific data show promising pathways for the future development of more effective prognosis. There is a clear need for new prognostic indicators, which could be used in diagnostics and, therefore a better selection of the most effective treatment can be achieved.

Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors

The aim of this study was to evaluate the effectiveness and possible toxicity of the combination of temozolomide (TMZ) with whole-brain irradiation (WBI) in the treatment of brain metastases from solid tumors. Patients and Methods: 33 patients with brain metastases were included in the study and treated with TMZ 60 mg/m2/day (days 1-16) concomitantly with WBI (36 Gy/12 fractions given in 16 days). One month after the end of radiotherapy, 6 cycles of TMZ were administered as adjuvant treatment (200 mg/m2/day for 5 consecutive days every 28 days). Results: Responses were assessed using computed tomography at the end of the 3rd and 6th cycle of chemotherapy. The objective response rate was 54.5% and 57.6% after the 3rd and the 6th cycle, respectively. The median overall survival was 12 months. In patients with metastases from lung cancer the objective response rate was 11/14 (78.6%) after both the 3rd and the 6th cycle of treatment. The most common side effects were anemia (24.2%), thrombocytopenia (18.2%), as well as nausea and vomiting (18.2%). The high incidence of hepatotoxicity (45.5%) might be related to concomitantly administered antiepileptic drugs and not to TMZ. Conclusion: WBI combined with TMZ as concomitant and adjuvant treatment is effective in treating brain metastases, with acceptable mild side effects.

Amifostine as radioprotective agent for the rectal mucosa during irradiation of pelvic tumors: A phase II randomized study using various toxicity scales and rectosigmoidoscopy

Aim: To evaluate the cytoprotective effect of amifostine against radiation-induced acute toxicity to the rectal mucosa. Patients and Methods: 36 patients irradiated for prostate or gynecologic cancer were randomized to receive amifostine (n = 18, group A) or not (n = 18, group B). The radiation-induced acute rectal toxicity was evaluated by using three different toxicity scales: WHO scale, EORTC/RTOG toxicity criteria, and a modified toxicity scale based on the LENT-SOMA grading scale and the endoscopic terminology of the World Organization for Digestive Endoscopy. The objective measurements were coming from flexible rectosigmoidoscopy performed at baseline and 1–2 days after completion of the radiotherapy schedule. Anterior-posterior fields were used in the gynecologic patients while 3-D conformal 4-field technique was applied in the prostate cancer patients. The area under the curve (AUC) for dose-volume histograms (DVHs) of the rectum was also assessed during a 3-D treatment planning schedule, and no significant differences were assessed between the two groups, indicating a homogeneous dose-volume effect. Results: Amifostine was well tolerated. No grade 2 or higher WHO and EORTC/RTOG acute toxicity was noted in group A, while acute rectal toxicity (≥ grade 1) was observed in 16/18 patients of group B versus 2/18 of group A (p < 0.001). The onset as well as the duration of acute rectal toxicity were significantly improved in group A (p = 0.002). Rectosigmoidoscopy revealed more severe rectal mucositis in noncytoprotected patients (group B), and modified LENT-SOMA overall mucositis grading score was significantly lower in group A (p = 0.003). Conclusion: Amifostine seems to have a significant cytoprotective efficacy in acute radiation-induced rectal mucositis in terms of symptomatic and objective endpoints.Ziel: Auswertung der zytoprotektiven Wirkung von Amifostin hinsichtlich der strahlungsinduzierten akuten Toxizität auf die Rektumschleimhaut. Patienten und Methodik: 36 aufgrund eines Prostata- oder gynäkologischen Karzinoms bestrahlte Patienten nahmen an einer randomisierten Studie teil. Die eine Hälfte (n = 18, Gruppe A) erhielt Amifostin, die andere Hälfte (n = 18, Gruppe B) nicht. Die strahlungsinduzierte akute Toxizität auf die Rektumschleimhaut wurde mit Hilfe von drei verschiedenen Toxizitätsskalen ausgewertet: der WHO-Skala, den Toxizitätskriterien der EORTC/RTOG und einer modifizierten Toxizitätsskala, die sowohl auf der LENTSOMA-Skala als auch auf der endoskopischen Terminologie der Weltorganisation für intestinale Endoskopie beruht. Zu Beginn und 1-2 Tage nach Beendigung der Strahlentherapie wurden mit Hilfe der flexiblen Rektosigmoidoskopie objektive Messungen vorgenommen. Für die gynäkologischen Patienten wurden ventrodorsale Felder benutzt, wohingegen bei den Patienten mit Prostatakarzinom eine 3-D konformale 4-Felder-Technik appliziert wurde. Während des 3-D-Therapieplans wurde auch die Fläche unter der Kurve (AUC) für die Auswertung in rektalen Dosis-Volumen-Histogrammen (DVH) bestimmt. Zwischen den beiden Gruppen war jedoch kein signifikanter Unterschied festzustellen, was auf eine homogene Dosis-Volumen-Wirkung hindeutet. Ergebnisse: Amifostin war gut verträglich. In Gruppe A wurde der Toxizitätsgrad 2 nach WHO und EORTC/RTOG weder erreicht noch überschritten. In Gruppe A wurde in 16 von 18 Fällen eine akute rektale Toxizität ≥ Grad 1 festgestellt, in Gruppe B dagegen nur in zwei von 18 Fällen (p < 0.001). Bei Gruppe A war hinsichtlich der Zeit bis zum Auftreten der Proktitis sowie deren Dauer eine deutliche Überlegenheit zu verzeichnen (p = 0.002). In der Kontrollgruppe (Gruppe B) deckte die Rektosigmoidoskopie eine wesentlich schwerere Rektumschleimhautentzündung auf, während dir Toxizität entsprechend der modifizierten LENT-SOMA-Skala in der Amifostingruppe bedeutend niedriger war (p = 0.003). Schlussfolgerung: Amifostin scheint in Anbetracht der beobachteten Symptome, gemessen an objektiven Endpunkten, bei akuter strahlungsinduzierter Proktitis eine zytoprotektive Wirkung zu haben

Radiotherapy in conjunction with intravenous infusion of 180 mg of disodium pamidronate in management of osteolytic metastases from breast cancer: Clinical evaluation, biochemical markers, quality of life, and monitoring of recalcification using assessments of gray-level histogram in plain radiographs

PURPOSE To evaluate the clinical improvement and radiographically monitor the effect of local radiotherapy in conjunction with disodium pamidronate (DP) on metastatic osteolytic disease. METHODS AND MATERIALS Thirty-three patients with osteolytic metastasis from advanced breast cancer received radiotherapy with a 6-MV linear accelerator up to a dose of 30 Gy (3 Gy/fraction, 5 d/wk) combined with 24 monthly sessions of a 180-mg DP infusion. Conventional X-rays were obtained during the first six sessions of DP treatment, retaining the same settings for each exposure. The analysis of the image attributes was based on measuring the first-order statistics of the mean value and energy of gray-level histograms in the osteolytic region. RESULTS The 6-month measurements compared with baseline showed statistically significant differences (p < 0.01, Wilcoxon test) in energy of gray-level histogram (-10.8%), mean value of gray-level histogram (+9.5%), pain score (-5.8 points), Eastern Cooperative Oncology Group status (-2.4 points), urine hydroxyproline/creatinine ratio (-41.7%), urine calcium/creatinine ratio (-58.8%), and bone alkaline phosphatase (-42.4%). Quality of life as determined by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (version 3) also improved. During follow-up, 88% of patients had complete and 12% partial responses (International Union Against Cancer radiologic criteria). On multivariate analysis, greater changes in the mean value of the gray-level histogram and negative nodal status were predictors for a reduction in the number of skeletal complications after therapy. Flu-like syndrome occurred in 13 patients (39%) and was well managed with mild antipyretics. CONCLUSION Image-processing in plain radiographs offers an objective way to assess recalcification. The image-processing indexes, along with the measurements of performance status, quality of life, and biochemical markers, improved significantly. Local radiotherapy combined with long-term high-dose DP up to 180 mg is tolerable and has a high therapeutic response.

Role of radiotherapy in the management of hepatocellular carcinoma: A systematic review.

Many patients with hepatocellular carcinoma (HCC) present with advanced disease, not amenable to curative therapies such as surgery, transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization (TACE) and radiation therapy. Especially TACE, delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy, has given favorable results on local control and survival. Radiotherapy, as a therapeutic modality of internal radiation therapy with radioisotopes, has also achieved efficacious tumor control in advanced disease. On the contrary, the role of external beam radiotherapy for HCC has been limited in the past, due to the low tolerance of surrounding normal liver parenchyma. However, technological innovations in the field of radiotherapy treatment planning and delivery, have provided the means of delivering radical doses to the tumor, while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy, evaluated for efficacy and safety for HCC, report encouraging results. In this review, we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.

Amifostine as Radioprotective Agent for the Rectal Mucosa during Irradiation of Pelvic Tumors

Aim: To evaluate the cytoprotective effect of amifostine against radiation-induced acute toxicity to the rectal mucosa. Patients and Methods: 36 patients irradiated for prostate or gynecologic cancer were randomized to receive amifostine (n = 18, group A) or not (n = 18, group B). The radiation-induced acute rectal toxicity was evaluated by using three different toxicity scales: WHO scale, EORTC/RTOG toxicity criteria, and a modified toxicity scale based on the LENT-SOMA grading scale and the endoscopic terminology of the World Organization for Digestive Endoscopy. The objective measurements were coming from flexible rectosigmoidoscopy performed at baseline and 1–2 days after completion of the radiotherapy schedule. Anterior-posterior fields were used in the gynecologic patients while 3-D conformal 4-field technique was applied in the prostate cancer patients. The area under the curve (AUC) for dose-volume histograms (DVHs) of the rectum was also assessed during a 3-D treatment planning schedule, and no significant differences were assessed between the two groups, indicating a homogeneous dose-volume effect. Results: Amifostine was well tolerated. No grade 2 or higher WHO and EORTC/RTOG acute toxicity was noted in group A, while acute rectal toxicity (≥ grade 1) was observed in 16/18 patients of group B versus 2/18 of group A (p < 0.001). The onset as well as the duration of acute rectal toxicity were significantly improved in group A (p = 0.002). Rectosigmoidoscopy revealed more severe rectal mucositis in noncytoprotected patients (group B), and modified LENT-SOMA overall mucositis grading score was significantly lower in group A (p = 0.003). Conclusion: Amifostine seems to have a significant cytoprotective efficacy in acute radiation-induced rectal mucositis in terms of symptomatic and objective endpoints.Ziel: Auswertung der zytoprotektiven Wirkung von Amifostin hinsichtlich der strahlungsinduzierten akuten Toxizität auf die Rektumschleimhaut. Patienten und Methodik: 36 aufgrund eines Prostata- oder gynäkologischen Karzinoms bestrahlte Patienten nahmen an einer randomisierten Studie teil. Die eine Hälfte (n = 18, Gruppe A) erhielt Amifostin, die andere Hälfte (n = 18, Gruppe B) nicht. Die strahlungsinduzierte akute Toxizität auf die Rektumschleimhaut wurde mit Hilfe von drei verschiedenen Toxizitätsskalen ausgewertet: der WHO-Skala, den Toxizitätskriterien der EORTC/RTOG und einer modifizierten Toxizitätsskala, die sowohl auf der LENTSOMA-Skala als auch auf der endoskopischen Terminologie der Weltorganisation für intestinale Endoskopie beruht. Zu Beginn und 1-2 Tage nach Beendigung der Strahlentherapie wurden mit Hilfe der flexiblen Rektosigmoidoskopie objektive Messungen vorgenommen. Für die gynäkologischen Patienten wurden ventrodorsale Felder benutzt, wohingegen bei den Patienten mit Prostatakarzinom eine 3-D konformale 4-Felder-Technik appliziert wurde. Während des 3-D-Therapieplans wurde auch die Fläche unter der Kurve (AUC) für die Auswertung in rektalen Dosis-Volumen-Histogrammen (DVH) bestimmt. Zwischen den beiden Gruppen war jedoch kein signifikanter Unterschied festzustellen, was auf eine homogene Dosis-Volumen-Wirkung hindeutet. Ergebnisse: Amifostin war gut verträglich. In Gruppe A wurde der Toxizitätsgrad 2 nach WHO und EORTC/RTOG weder erreicht noch überschritten. In Gruppe A wurde in 16 von 18 Fällen eine akute rektale Toxizität ≥ Grad 1 festgestellt, in Gruppe B dagegen nur in zwei von 18 Fällen (p < 0.001). Bei Gruppe A war hinsichtlich der Zeit bis zum Auftreten der Proktitis sowie deren Dauer eine deutliche Überlegenheit zu verzeichnen (p = 0.002). In der Kontrollgruppe (Gruppe B) deckte die Rektosigmoidoskopie eine wesentlich schwerere Rektumschleimhautentzündung auf, während dir Toxizität entsprechend der modifizierten LENT-SOMA-Skala in der Amifostingruppe bedeutend niedriger war (p = 0.003). Schlussfolgerung: Amifostin scheint in Anbetracht der beobachteten Symptome, gemessen an objektiven Endpunkten, bei akuter strahlungsinduzierter Proktitis eine zytoprotektive Wirkung zu haben

Apoptotic and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy : preliminary report

Goal of workThe aim of this study was to investigate the expression of pro-apoptotic protein p53 and anti-apoptotic proteins BCl-2 and MCl-1, as well as the expression of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1beta (IL-1β) in patients developing mucositis during radiotherapy for head and neck cancer.Materials and methodsThirty-five patients receiving radiotherapy for head/neck cancer were included in this study. Patients were examined before radiotherapy. Oral mucositis was recorded weekly during radiotherapy. Cytologic smears from the oral cavity were taken with a brush. Immunocytochemical staining was performed by the use of p53, BCl-2, MCl-1 TNF and IL-1β monoclonal antibodies.Main resultsP53 was expressed in 1 of 15 smears before the initiation of radiotherapy (6.5%) compared to 3 of 7 smears from patients with grade III mucositis (43%) during radiotherapy. BCl-2 was expressed in 15 of 15 smears before radiotherapy (100%) and in three of seven patients with grade III mucositis (43%) during radiotherapy. MCl-1 was expressed in 10 of 14 samples before radiotherapy (71.5%) and in two of seven patients with grade III (28.5%) mucositis during radiotherapy. TNF was expressed in 9 of 14 patients before radiotherapy (64%) and in six of seven patients with grade III mucositis during radiotherapy (86%). IL-1β was detected in 7 of 14 patients before radiotherapy (50%) compared to 6 of 7 patients with grade III mucositis during radiotherapy (86%).ConclusionOur preliminary results indicate an induction of apoptosis and inflammation in the oral mucosa in patients developing mucositis during radiotherapy for head/neck cancer.

A Phase II Randomized Study of Topical Intrarectal Administration of Amifostine for the Prevention of Acute Radiation-Induced Rectal Toxicity

Purpose:To investigate the cytoprotective effect of intrarectal amifostine administration on acute radiation-induced rectal toxicity.Patients and Methods:67 patients with T1b–2 N0 M0 prostate cancer were randomized to receive amifostine intrarectally (group A, n = 33) or not (group B, n = 34) before irradiation. Therapy was delivered using a four-field technique with three-dimensional conformal planning. In group A, 1,500 mg amifostine was administered intrarectally as an aqueous solution in a 40-ml enema. Two different toxicity scales were used: EORTC/RTOG rectal and urologic toxicity criteria along with a Subjective-RectoSigmoid (S-RS) scale based on the endoscopic terminology of the World Organization for Digestive Endoscopy. Objective measurements with rectosigmoidoscopy were performed at baseline and 1–2 days after the completion of radiotherapy. The area under curve for the time course of mucositis (RTOG criteria) during irradiation represented the mucositis index (MI).Results:Intrarectal amifostine was feasible and well tolerated without any systemic or local side effects. According to the RTOG toxicity scale, five out of 33 patients showed grade 1 mucositis in group A versus 15 out of 34 patients with grade 1/2 in group B (p = 0.026). Mean rectal MI was 0.3 ± 0.1 in group A versus 2.2 ± 0.4 in group B (p < 0.001), while S-RS score was 3.9 ± 0.5 in group A versus 6.3 ± 0.7 in group B (p < 0.001). The incidence of urinary toxicity was the same in both groups.Conclusion:Intrarectal administration of amifostine seems to have a cytoprotective efficacy in acute radiation-induced rectal mucositis. Further randomized studies are needed for definitive therapeutic decisions.Ziel:Untersuchung des zytoprotektiven Effekts von intrarektal verabreichtem Amifostin zur Verhinderung akuter rektaler Strahlentoxizität.Patienten und Methodik:67 Patienten mit einem Prostatakarzinom im Stadium T1b–2 N0 M0 wurden randomisiert zwei Gruppen zugeteilt: Gruppe A (n = 33) mit und Gruppe B (n = 34) ohne intrarektale Verabreichung von Amifostin vor der Bestrahlung. Zur Behandlung wurde eine Vier-Felder-Technik mit dreidimensionaler konformaler Bestrahlungsplanung eingesetzt. Die Patienten in Gruppe A erhielten 1 500 mg Amifostin intrarektal als wässrige Lösung in einem 40-ml-Klysma. Zwei verschiedene Toxizitätsskalen wurden verwendet, die rektalen und urologischen Toxizitätskriterien der EORTC/RTOG und die auf der endoskopischen Terminologie der WODE (World Organization for Digestive Endoscopy) basierende S-RS-Skala („Subjective-RectoSigmoid scale“). Mittels Rektosigmoidoskopie wurden objektive Messungen vor und 1–2 Tage nach der Beendigung der Strahlentherapie durchgeführt. Der Bereich unter der Kurve (AUC) für den zeitlichen Verlauf einer Mukositis (RTOG-Kriterien) während der Bestrahlung stellte den Mukositis-Index (MI) dar.Ergebnisse:Die intrarektale Verabreichung von Amifostin erwies sich als einfach und gut verträglich und führte zu keinen systemischen oder lokalen Nebenwirkungen. Gemäß der RTOG-Toxizitätsskala zeigten fünf von 33 Patienten der Gruppe A eine Mukositis Grad 1 und 15 von 34 Patienten der Gruppe B eine Mukositis Grad 1/2 (p = 0,026). Der mittlere rektale MI betrug in Gruppe A 0,3 ± 0,1 gegenüber 2,2 ± 0,4 in Gruppe B (p < 0,001), während der S-RS-Score in Gruppe A bei 3,9 ± 0,5 gegenüber 6,3 ± 0,7 in Gruppe B lag (p < 0,001). Toxische Wirkungen an den Harnwegen traten in beiden Gruppen gleich häufig auf.Schlussfolgerung:Die intrarektale Verabreichung von Amifostin scheint bei akuter strahleninduzierter Entzündung der Rektumschleimhaut zytoprotektiv zu wirken. Weitere randomisierte Studien sind erforderlich, um definitive Therapieentscheidungen treffen zu können.

A short radiotherapy course for locally advanced non-small cell lung cancer (NSCLC). Effective palliation and patients’ convenience

In order to facilitate patients with symptomatic locally advanced NSCLC, especially those coming from remote areas we have employed two palliative RT schedules. The first (S1) is the well known from Medical Research Council (MRC) randomized studies 2 x 8.5 Gy one week apart and the second (S2) is a two-day RT schedule: three fractions of 4.25 Gy are given on the first day and two fractions of 4.25 Gy on the second day. The records of 92 patients were reviewed (48 for S1 and 44 for S2). Patients, disease characteristics and results were similar for both groups; rates of symptom disappearance were for S1 and S2, respectively: cough 24 and 20%, hemoptysis 60 and 67%, chest pain 57 and 64% and dyspnoea 55 and 45% The overall condition improved in 39 and 36%, respectively. The median palliation time in days was in S1 and S2, respectively: cough 70 and 66, haemoptysis 133 and 139, chest pain 68 and 62 and dyspnoea 74 and 69 days. The median survival was 25 weeks in both S1 and S2 groups (P=0.89 log-rank test). At 52 weeks (one year), ten (21%) and seven (16%) of the patients were alive in S1 and S2 groups, respectively. At 104 weeks, the corresponding figures were two (4%) and two (4.7%) for S1 and S2. Our results are in accordance to those reported in literature regarding the safety and efficacy of palliative hypofractionated radiotherapy schemes. Their use in selected patients could be cost-effective and convenient for patients especially those coming from remote areas.

Relative output factor measurements of a 5 mm diameter radiosurgical photon beam using polymer gel dosimetry

Besides the fine spatial resolution inherent in polymer gel-magnetic resonance imaging (MRI) dosimetry, the method also features the potential for multiple measurements of varying sensitive volume in a single experiment by integrating results in MRI voxels of finite dimensions (i.e., in plane resolution by slice thickness). This work exploits this feature of polymer gel dosimetry to propose an experimental technique for relative output factor (OF) measurements of small radiosurgical beams. Two gel vials were irradiated with a 5 and 30 mm diameter 6 MV radiosurgery beam and MR scanned with the same slice thickness and three different in plane resolutions. Using this experimental data set, 5 mm OF measurements with the PinPoint ion chamber are simulated by integrating results over a sensitive volume equal to that of the chamber. Results are found in agreement within experimental uncertainties with actual PinPoint measurements verifying the validity of the proposed experimental procedure. The polymer gel data set is subsequently utilized for OF measurements of the 5 mm beam with varying sensitive volume to discuss the magnitude of detector volume averaging effects. Seeking to correct for volume averaging, results are extrapolated to zero sensitive volume yielding a 5 mm OF measurement of (0.66±5%). This result compares reasonably with corresponding ionometric and radiographic film measurements of this work and corresponding, limited, data in the literature. Overall, results suggest that polymer gel dosimetry coupled with the proposed experimental procedure helps overcome not only tissue-equivalence and beam perturbation implications but also volume averaging and positioning uncertainties which constitute the main drawback in small radiosurgical beam dosimetry.