John Kouvaris

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.

Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review.

Capecitabine (Xeloda®) was developed as a pro-drug of fluorouracil (FU), with the aim of improving tolerability and intratumor drug concentrations through its tumor-specific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing on its clinical effectiveness against various carcinomas. Identification of all eligible English trails was made by searching the PubMed and Cochrane databases from 1980 to 2007. Search terms included capecitabine, Xeloda and cancer treatment. Nowadays, FDA has approved the use of capecitabine as a first line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine is preferred. The drug is also approved for use as a single agent in metastatic breast cancer patients who are resistant to both anthracycline and paclitaxel-based regimens or when further anthracycline treatment is contraindicated. It is also approved in combination with docetaxel after failure of prior anthracycline-based chemotherapy. In patients with prostate, pancreatic, renal cell and ovarian carcinomas, capecitabine as a single-agent or in combination with other drugs has also shown benefits. Improved tolerability and comparable efficacy, compared with the intravenous FU/LV combination, in addition to its oral administration, make capecitabine an attractive option for the treatment of several types of carcinomas.

Granulosa Cell Tumor of the Ovary: Tumor Review

Granulosa cell tumors of the ovary are rare neoplasms that originate from sex-cord stromal cells. The long natural history of granulosa cell tumors and their tendency to recur years after the initial diagnosis are the most prominent of their characteristics. The secretion of estradiol is the reason for signs at presentation such as vaginal bleeding and precocious puberty. Abdominal pain and hemoperitoneum, which occasionally can occur, are attributable to tumor rupture. The most common finding in pelvic examination is a tumor mass, which is subsequently confirmed with imaging techniques. Surgery is the mainstay of initial management for histological diagnosis, appropriate staging, and debulking. A more conservative unilateral salpingo-oophorectomy is indicated in patients with stage I disease and patients of reproductive age. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment for postmenopausal women and those with more advanced disease. The stage of disease is the most important prognostic factor associated with the risk of relapse. There are no clear conclusions regarding the role of postoperative chemotherapy or radiotherapy in stage I disease and in those with completely resected tumor. The use of adjuvant chemotherapy or radiotherapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy is the treatment of choice for patients with advanced, recurrent, or metastatic disease, and BEP (bleomycin, etoposide, and cisplatin) is the preferred regimen. Although the overall rate of response to treatment is high, the impact of treatment on disease-free or overall survival is unknown. Prolonged surveillance is mandatory because tumors tend to recur years after the initial diagnosis.

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.

Temozolomide with Radiation Therapy in High Grade Brain Gliomas: Pharmaceuticals Considerations and Efficacy; A Review Article

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5–8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiaton therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide’s characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.

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.