Anna Kalogera-Fountzila

Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation

BACKGROUND Concomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial. PATIENTS AND METHODS Totally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m(2), epirubicin 75 mg/m(2) and paclitaxel (Taxol) 175 mg/m(2) (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m(2) (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients). RESULTS Sixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT. CONCLUSION IC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone.

Phase II Study of Neoadjuvant Imatinib in Glioblastoma: Evaluation of Clinical and Molecular Effects of the Treatment

Purpose: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. Experimental Design: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. Results: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. Conclusions: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients. (Clin Cancer Res 2009;15(19):6258–66)

Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer A Hellenic Cooperative Oncology Group phase II study*

AIM To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). BACKGROUND Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. PATIENTS AND METHODS From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. RESULTS Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached CONCLUSIONS The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.

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.

Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a Hellenic Cooperative Oncology Group Phase II study.

Abstract A phase II study was conducted to evaluate the activity and toxicity profile of the combination of docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer (ABC). Thirty-nine eligible patients with a median performance status of I (range, 0–2) were enrolled in the study. Treatment consisted of docetaxel 75 mg/m2 in a 1-hr infusion on day 1 preceded by gemcitabine 1000 mg/m2 over 30 min on days 1 and 8. One hundred eighty-one treatment cycles were administered, 113 (62.4%) of them at full dose. Relative dose intensity of gemcitabine and of docetaxel was 0.73 and 0.85, respectively. More common grade 3–4 toxicities included neutropenia (49%), anemia (10%), fatigue (10%), nausea/vomiting (8%), and alopecia (77%). Seven patients were hospitalized for febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was required in 90% of patients. Overall, 14 patients (36%) responded, 3 (7.5%) of them completely. Median duration of response was 10.3 months (range, 4.6–17.5+). Median time to progression was 7 months (range, 0.2–17.5+) and median survival 12.7 months (range, 2-–20.5+). In conclusion, the combination of docetaxel and gemcitabine, as used in the present study, has moderate activity in anthracycline-resistant ABC. Future studies should incorporate prophylactic administration of G-CSF to reduce the incidence of febrile neutropenia and maintain dose intensity.

Usefulness of Tumor Volumetry as a Prognostic Factor of Survival in Head and Neck Cancer

Background: The TNM classification system of tumor stage does not always reflect the actual tumor mass present at diagnosis. This study aimed at evaluating the prognostic value of volumetric data regarding survival in head and neck cancer patients being treated with either cisplatin or carboplatin administered concomitantly with radiotherapy. Patients and Methods: We retrospectively analyzed 107 patients suffering from squamous cell carcinoma of the head and neck in a Greek-German cooperational study (see Table 1). All patients were treated by radiotherapy and concomitant chemotherapy. 65 patients received chemotherapy with carboplatin and 42 with cisplatin. More than 6,200 CT scans were analyzed by digitalization of contours which subsequently led to the computation of the tumor volume (primary and macroscopic lymph node metastases). Results: Median follow-up was 43 months and median survival 30 months. Median initial tumor volume was 32.5 ml (range 2.1–220.1 ml) in the carboplatin and 44.4 ml (range 3.2–202.5 ml) in the cisplatin group (see Figure 1). After treatment, tumor volumes did not differ significantly (median of 3.1 ml [range 0.0–167.1 ml] and 3.5 ml [range 0.0–166.0 ml], respectively). 41 patients (63.1%) died in the carboplatin group and 22 patients (52.4%) in the cisplatin group (see Figure 2). Pretherapeutic tumor volume was prognostic with respect to survival while TNM classification and age were not. Pretherapeutic tumor volume was negatively and percent decrease in tumor volume positively associated with survival (see Tables 2 and 3). Conclusion: Knowledge of the initial tumor volume adds valuable information in terms of prognosis. Initial tumor volume should be included in all future clinical trials regarding head and neck cancer patients.Hintergrund: Das TNM-Tumorklassifikationssystem repräsentiert nicht immer die tatsächliche Tumormasse bei Diagnose. Diese Studie hatte die Überprüfung der prognostischen Wertigkeit volumetrischer Analysen bezüglich des Überlebens bei Patienten mit Kopf-Hals-Tumoren, die radiotherapeutisch und mit begleitender Chemotherapie (Cisplatin oder Carboplatin) behandelt wurden, zur Zielsetzung. Patienten und Methodik: Wir analysierten retrospektiv 107 Patienten mit Kopf-Hals-Tumoren im Rahmen einer griechisch-deutschen Kooperationsstudie (s. Tabelle 1). Alle Patienten erhielten eine Radiotherapie, 65 Patienten zusätzlich eine Carboplatin-, 42 Patienten eine Cisplatin-Chemotherapie. Mehr als 6 200 CT-Bilder wurden mittels Digitalisierung der Konturen bearbeitet, sodass daraus das Tumorvolumen (Primarius inkl. makroskopischer Lymphknotenmetastasen) berechnet werden konnte. Ergebnisse: Das mediane Follow-up betrug 43 Monate, das mediane Überleben 30 Monate. Das mediane initiale Tumorvolumen betrug 32,5 ml (2,1–220,1 ml) in der Carboplatin- und 44,4 ml (3,2–202,5 ml) in der Cisplatin-Gruppe (s. Abbildung 1). Nach Beendigung der Therapie unterschieden sich die Tumorvolumina nicht signifikant (Median von 3,1 ml [0,0–167,1 ml] bzw. 3,5 ml [0,0–166,0 ml]). In der Carboplatin-Gruppe starben 41 (63,1%) der Patienten, in der Cisplatin-Gruppe 22 (52,4%) (s. Abbildung 2). Das prätherapeutische Tumorvolumen war im Gegensatz zur TNM-Klassifikation prognostisch bezüglich des Überlebens. Das prätherapeutische Tumorvolumen war negativ, die prozentuale Abnahme des Tumorvolumens positiv mit dem Überleben assoziiert (s. Tabellen 2 und 3). Schlussfolgerung: Das initiale Tumorvolumen ist ein wichtiger Prognostikator des Überlebens und sollte in alle zukünftigen Studien bezüglich Kopf-Hals-Tumoren inkludiert werden.

Gemcitabine Combined with Gefitinib in Patients with Inoperable or Metastatic Pancreatic Cancer: A Phase II Study of the Hellenic Cooperative Oncology Group with Biomarker Evaluation

The combination of gemcitabine and gefitinib was evaluated in advanced pancreatic cancer. Totally, 53 patients were treated with a 7 week cycle of gemcitabine (1,000 mg/m2 given weekly) followed by six 4 week cycles of gemcitabine given on days 1, 8 and 15. Gefitinib 250 mg was administered daily. Responses were seen in 6, and stabilization of the disease in 12 patients. The main toxicity was myelotoxicity (92%). The 6-month progression-free survival (PFS) was 30%. Median PFS was 4.1 months and median survival 7.3 months with a 1 year survival rate of 27%. The above combination demonstrated promising activity in advanced pancreatic cancer.

Reirradiation for Recurrent Neck Metastases of Head-and-Neck Tumors Using CT-Guided Interstitial 192Ir HDR Brachytherapy

Purpose:To report the therapeutic results obtained with CT-guided interstitial high-dose-rate brachytherapy (HDR-BRT) as exclusive treatment for recurrent neck metastases of head-and-neck tumors.Patients and Methods:Between 1995 and 1999, 49 patients with prior radiation therapy (RT) with or without surgery for primary head-and-neck tumors were treated for recurrent neck metastases located within previously irradiated volumes. All patients had fixed lymphadenopathy with a mean tumor volume of 96 cm3 (range, 15–452 cm3). There were 38 males and eleven females with a mean age of 60 years (range, 28–79 years). All patients had previously received RT as primary or adjuvant treatment with a mean dose of 54 Gy (range, 45–80 Gy). 36 patients (73%) underwent surgery, and 26 (53%) received adjuvant or palliative chemotherapy. The accelerated hyperfractionated interstitial HDR-BRT (2 × 3.0 Gy/day) delivered 30 Gy in 37/49 (75%) and 36 Gy in 12/49 implants (25%).Results:At a minimum 6-week follow-up, the response rate was 83% (41/49) with complete remission in 20% (10/49) and partial remission in 63% (31/49) of the implanted tumor sites. 8/49 patients (17%) did not respond to the treatment. After 19 months of median follow-up, the local control rate was 69% and a total of 15/49 patients (30%) experienced local disease progression. Of these, nine (18%) had locoregional progression and six (12%) progression within the treated volume. The median post-BRT survival was 14 months. The overall survival rate was 52% at 1 year, 31% at 2 years, and 6% at 3 years.Conclusion:In patients with recurrent cervical lymphadenopathy of head-and-neck tumors, exclusive interstitial HDR-BRT can provide palliation and tumor control.Ziel:Vorstellung der CT-gestützten interstitiellen High-Dose-Rate-Brachytherapie (HDR-BRT) als ausschließliches Therapieverfahren in der Behandlung zervikaler Lymphknotenrezidive von Kopf-Hals-Tumoren.Patienten und Methodik:Zwischen 1995 und 1999 wurden insgesamt 49 Patienten mit zervikalen Lymphknotenrezidiven behandelt. Alle 49 Patienten (38 männlich, elf weiblich, Durchschnittsalter 60 Jahre [28–79 Jahre]) waren mit einer durchschnittlichen Zielvolumendosis von 54 Gy (45–80 Gy) vorbestrahlt, und 36 (73%) waren voroperiert. Eine adjuvante oder palliative Chemotherapie war bei 26 Patienten (53%) durchgeführt worden. Alle Patienten erhielten eine akzeleriert-hyperfraktionierte BRT (2 × 3 Gy/Tag) bis zu einer Gesamtdosis von 30 Gy in 37/49 (75%) und 36 Gy in 12/49 Implantaten (25%). Das durchschnittliche Tumorvolumen betrug 96 cm3 (15–452 cm3).Ergebnisse:Die Ansprechrate nach 6 Wochen betrug 83%. Bei 10/49 Patienten (20%) wurde eine komplette Remission, bei 31/49 (63%) eine partielle Remission erzielt. 8/49 (17%) zeigten kein Ansprechen bzw. eine lokale Progredienz. Nach einer medianen Nachbeobachtungszeit von 19 Monaten betrug die lokale Kontrollrate 69%, bei 15/49 Patienten (30%) lag ein Tumorprogress vor. Dabei zeigten 9/15 (60%) eine lokoregionäre Progression. Lediglich bei 6/15 (40%) handelte es sich um echte In-loco-Rezidive, die innerhalb des BRT-Volumens gelegen waren. Das mediane Überleben betrug 14 Monate, die Gesamtüberlebensrate nach 1 Jahr 52%, nach 2 Jahren 31% und nach 3 Jahren 6%.Schlussfolgerung:Die CT-gestützte interstitielle HDR-BRT ist ein wertvolles Instrument für die palliative Behandlung von Patienten mit Halslymphknotenrezidiven bei Kopf-Hals-Tumoren.

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck

BACKGROUND Paclitaxel has been demonstrated to have significant activity in recurrent or metastatic head and neck cancer (HNC). In addition, the combination of paclitaxel and cisplatin is active in untreated patients with inoperable HNC. Substitution of carboplatin for cisplatin allows the treatment to be delivered on an outpatient basis. PURPOSE OF THE STUDY To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and carboplatin as first-line chemotherapy in patients with recurrent or metastatic HNC. PATIENTS AND METHODS From March 1994 until August 1996, 49 patients with recurrent or metastatic HNC were treated with paclitaxel (200 mg/m2, by three-hour infusion) followed by carboplatin at an AUC of 7 mg.min/ml, every four weeks. G-CSF was administered prophylactically on days 2 to 12 of each cycle. There were 41 men and 8 women with a median age of 57 years (range 23-73). The majority of the patients were symptomatic and they had recurrent disease locoregionally. Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cell cancers of other areas of the head and neck region (non-NPC). RESULTS At the completion of treatment, two patients with NPC demonstrated complete and six partial responses for an overall response rate of 57% (95% CI 29%-82%). Among patients with non-NPC, the response rate was 23% (95% CI 9%-37%). After a median follow up period of 15 months, the median time to progression was 4.3 months in the non-NPC group and 16.5 months in the NPC group. At the time of the analysis, median survival had not been reached in NPC while it was 7.3 months in non-NPC patients. Grade 3-4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting and diarrhea (4% each). CONCLUSIONS The combination of paclitaxel and carboplatin appears to be well tolerated but only moderately active in patients with advanced non-NPC of the head and neck region. However, its activity appears promising in NPC and deserves further investigation.

Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group.

SummaryPaclitaxel (TaxolR) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m2 over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35–77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in ≥5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27kipl positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27kipl. The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.