John Daniilidis

Concomitant Radiochemotherapy vs Radiotherapy Alone in Patients with Head and Neck Cancer

The primary objective of the present randomized phase III trial was to compare the 3-yr survival rate of patients treated with standard fractionated radiotherapy (RT) alone or with the same RT concomitantly with cisplatin (DDP) or carboplatin (Cb). From January 1995 until July 1999, 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer (HNC) were randomized to receive either RT monotherapy (70Gy, Group A) or the same RT concomitantly with DDP (100 mg/m2 on d 2, 22, 42, Group B) or Cb (7 AUC on d 2, 22, 42, Group C). There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy. However, median time to progression (TTP) and overall survival (OS) were significantly longer in patients treated with concomitant chemoradiotherapy. Thus, median TTP was 6.3, 45.2, and 17.7 mo in groups A, B, and C respectively (p=0.0002). Similarly, median OS was 12.2, 48.6, and 24.5 mo, respectively (p=0.0003). At 3 yr follow-up, 17.5% of patients in group A were alive compared to 52% in group B and 42% in group C (p<0.001). Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity. Also, severe nausea/vomiting was more pronounced in group B, as expected. The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone.

Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A Hellenic Cooperative Oncology Group phase II study.

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

RADIATION THERAPY AND CONCURRENT CISPLATIN ADMINISTRATION IN LOCALLY ADVANCED HEAD AND NECK CANCER A Hellenic co-operative oncology group study

In an attempt to improve local control of locally advanced head and neck cancer, radiation therapy was combined with cisplatin. Forty-eight patients entered into this study. All patients were irradiated with a 60Co unit and according to the protocol they should receive 70 Gy in the tumor area and 45 Gy in the rest of neck. Cisplatin was administered at a dose of 100 mg/m2 on days 2, 22 and 42. Thirty-seven (80%) patients received the total radiation dose as initially planned. Thirty-four (72%) patients achieved complete and 5 (10%) partial response. Grade 3-4 toxicities included vomiting (14%), stomatitis (4%), diarrhea (2%), myelotoxicity (14%), hoarseness (4%), dysphagia (30%), weight loss (32%), nephrotoxicity (4%) and dermatitis (2%). After a median follow-up of 26 (range, 18-33) months, 16 patients have died. Among the 35 complete responders 6 later on relapsed. Median relapse-free survival has not yet been reached. Combined radiation therapy and cisplatin appears to be a highly active treatment in patients with advanced head and neck cancer as far as primary locoregional response is concerned.

Paclitaxel and gemcitabine in advanced non-nasopharyngeal head and neck cancer: A phase II study conducted by the Hellenic Cooperative Oncology Group

BACKGROUND Paclitaxel as monotherapy or in combination with other drugs has demonstrated significant activity in patients with squamous cell carcinoma of the head and neck region (SCCHN). Preclinical studies have shown gemcitabine to be highly active in SCCHN cell lines. PURPOSE OF THE STUDY To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and gemcitabine as first-line chemotherapy in patients with recurrent and/or metastatic head and neck cancer (HNC). PATIENTS AND METHODS From September 1996 until May 1998, 44 patients with non-nasopharyngeal recurrent and/or metastatic HNC entered the study. There were 37 men and seven women with a median age of 61 years (range 35-79) and a median performance status of 1 (range 0-2). The location of the primary tumor in the majority of them was either the larynx or the oral cavity. Treatment consisted of six cycles of gemcitabine 1100 mg/m2 over 30 min on days 1 and 8 immediately followed on day 1 by paclitaxel 200 mg/m2 by three-hour infusion. The treatment was repeated every three weeks. RESULTS Twenty-four (55%) patients completed all six cycles of treatment. A total of 205 cycles were administered, 165 (81%) of them at full dose. The median relative dose intensity (DI) of gemcitabine was 0.93 and of paclitaxel 0.95. Except for alopecia, which was universal, grade 3-4 toxicities included neutropenia (21%), thrombocytopenia (5%), anemia (5%), infection (5%), flu-like syndrome (5%) and peripheral neuropathy (2%). Five (11%) patients achieved complete and 13 (30%) partial responses, for an overall response rate of 41%. After a median follow-up of 13 months, the median time to progression was four months and median survival nine months. CONCLUSIONS The combination of paclitaxel and gemcitabine is active and well tolerated in patients with recurrent and/or metastatic HNC-randomized studies comparing this combination with other regimens are warranted.

Induction Chemotherapy with Cisplatin, Epirubicin, and Paclitaxel (CEP), Followed by Concomitant Radiotherapy and Weekly Paclitaxel for the Management of Locally Advanced Nasopharyngeal Carcinoma

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

PLATINUM-BASED CHEMOTHERAPY FOLLOWED BY RADIATION THERAPY OF LOCALLY ADVANCED NASOPHARYNGEAL CANCER A retrospective analysis of 39 cases

A retrospective analysis was performed of 39 patients with locally advanced nasopharyngeal cancer treated with combined chemotherapy and radiation therapy during the last five years at our departments. There were 26 men and 13 women with median age 55 (24-75) years. Histology was squamous cell carcinoma in 6 patients and undifferentiated carcinoma in the remaining 33 patients. Induction chemotherapy consisted of either regimen A (cisplatin 100 mg/m2 day 1, 5-FU 1,000 mg/m2 days 2-6 as continuous infusion, bleomycin 15 mg days 15 and 29 i.m., mitomycin 4 mg/m2 day 22 and hydroxyurea 1,000 mg/m2 daily days 23-27) or regimen B (carboplatin 300 mg/m2 day 1, 5-FU 1,000 mg/m2 days 1-5 as continuous infusion and methotrexate 1.2 g/m2 day 14 with leucovorin rescue). After completion of induction chemotherapy 13 patients (33%) had complete remission (CR) and 19 (49%) partial remission (PR). The CR rate was increased after radiation therapy to 72%. Survival rates were 88% at 12 and 78% at 24 months. Median time to progression was 29.5 months. In conclusion, induction chemotherapy with a platinum-based regimen followed by radiation therapy achieved a high rate of local control. If the treatment also prolongs survival must, however, be studied by randomized trials.

Haplotypes of human leukocyte antigens among patients with nasopharyngeal cancer in Greece

The concept that the major histocompatibility complex (MHC) plays an important role in the pathogenesis of nasopharyngeal cancer (NPC) in several ethnic groups has gained increased attention during the last 15 years. Earlier studies have suggested that an increased risk of NPC is associated with specific phenotypes of human leukocyte antigens (HLA). The present study was performed to examine the association of HLA specificities and haplotypes with NPC in a Greek population. In a genotypical study of 53 patients, a significant association between the haplotype HLA-B5DR11 and NPC was found, mainly in patients > 45 years. Also, the above haplotype was significantly associated with longer disease-free interval. HLA-B5 and HLA-B5DR11 were more often seen among patients with squamous cell histology than among those with the undifferentiated type. These results suggest that MHC loci are probably implicated in the pathogenesis and outcome of NPC in Greek patients.

Kombinierte Radiochemotherapie bei lokal fortgeschrittenem Nasopharynxkarzinom

ZusammenfassungHintergrund. Das Nasopharynxkarzinom (NPK) ist ein epithelialer Tumor, dessen biologisches Verhalten sich völlig von den übrigen Karzinomen der Kopf-Hals-Region unterscheidet. Patienten/Methodik. Die Krankheitsverläufe von 93 Patienten mit lokal fortgeschrittenem NPK wurden retrospektiv ausgewertet, die entweder mit Induktionschemotherapie und nachfolgender Radiotherapie (79 Patienten) oder mit simultaner Chemoradiotherapie (14 Fälle) behandelt wurden. Ergebnisse. Insgesamt erreichten 66 Patienten (71%) eine Vollremission (VR). Innerhalb von 5,5 Jahren wurde bei 28 dieser 66 Patienten ein Rezidiv beobachtet, in 25 Fällen lokoregionär. Im Mittel betrug die Zeit bis zur Progression 22,5 Monate, das Gesamtüberleben 45 Monate, die 5-Jahresüberlebensrate 41,5%. Alter, T- und N-Stadium, histologischer Tumortyp und Therapieschema waren unabhängige signifikante Einflussfaktoren für das Gesamtüberleben. Schlussfolgerungen. Mittels kombinierter Radiochemotherapie lassen sich bei fortgeschrittenem NPK hohe VR-Raten erzielen. Das Hauptproblem besteht in lokoregionären Rezidiven. Zukünftige Studien müssen das optimale Behandlungsprotokoll für die kombinierte Radiochemotherapie definieren.AbstractBackground. Nasopharyngeal cancer (NPC) is a tumor of epidermoid origin with an entirely different biological behavior than other carcinoma of the head and neck region. Patients/methods. A retrospective analysis was performed in 93 cases with locally advanced NPC treated with induction chemotherapy followed by radiation therapy (RT; 79 patients) or concomitant RT and chemotherapy. Results. Totally 66 patients (71%) achieved a complete response (CR), 68% of the patients treated with induction chemotherapy followed by RT, 86% with concomitant chemoradiotherapy. After a median follow-up of 5.5 years 28 out of these 66 relapsed, 25 of them locoregionally. Median time to progression was 22.5 months, median overall survival (OS) 45 months, 5-year actuarial survival was 41.5%. Age, T and N classification, histological type and type of chemotherapy were independent significant factors for OS. Conclusions. Combined chemotherapy and RT in patients with locally advanced NPC result in a high CR rate. The main problem remains the locoregional control. Randomized studies are needed in order to define the optimal use of chemotherapy in combination with RT.

Vertical partial laryngectomy: our results after treating 81 cases of T2 and T3 laryngeal carcinomas

From 1976 to 1989, 81 patients with T2 and T3 laryngeal carcinomas were treated with vertical patrial laryngectomy at the University ENT Department of Thessaloniki, Greece. All patients were male with a median age of 56 years (33-71 years). Four patients had N1 lymph nodes. Ten patients received post-operative radiotherapy. Seventeen patients developed local recurrences or distant metastases. Mean follow-up was more than seven years. Absolute three-year survival was 94.6 per cent for 74 patients and absolute five-year survival was 89.6 per cent for 58 patients. Actuarial five-year survival of the whole group of 81 patients was 91 per cent calculated with the Kaplan-Meier method. Recurrence rate and survival of stage II and III patients are also discussed and compared using the log-rank test. We conclude that vertical partial laryngectomy is a very successful treatment selection for T2 glottic and false vocal cord carcinomas and for some selected T3 glottic lesions.

Squamous cell carcinoma antigen, circulating immune complexes, and immunoglobulins in monitoring squamous cell carcinoma of head and neck: a study of the hellenic co-operative oncology group (HeCOG).

This study investigates the clinical utility of squamous cell carcinoma antigen (SCC-Ag), circulating immune complexes (CIC), and immunoglobulins (IgA, IgG, IgM) in the diagnosis, monitoring, and prognosis of 117 squamous cell carcinoma of the head and neck (SCC-HN) patients having local and/or systemic treatment. Serum marker levels were measured in a prospective study. SCC-Ag was positive in 28.2% of patients, the CIC in 63.2%, the IgA in 11.1%, the IgG in 15.4%, and the IgM in 9.44%. Statistically significant correlation was found between the initial SCC-Ag levels and tumor localization, whereas the CIC levels were increasing significantly with progressing disease stages. It was also found that the significant decrease of SCC-Ag, IgA, and CIC levels at the end of treatment was correlated with an increased incidence of disease-free status. The initial values of IgG and the disease stage were significantly correlated with a favorable treatment outcome. The pretreatment elevated SCC-Ag and IgM serum values showed a significant trend to predict a disease progression. Using a Cox proportional hazards model the IgG serum values, the primary site, and the disease stage were significant predictors for time to progression. The significant decrease of SCC-Ag, IgA, and CIC values at the completion of treatment was correlated with an increased incidence of disease-free status. This study indicates that only the estimation of SCC-Ag and in some degree the IgM and/or IgG is a potential tool for monitoring the efficacy of treatment or disease recurrence in SCC-HN.