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Outcome and Prognostic Factors in Olfactory Neuroblastoma: A Multicenter Rare Cancer Network Study
Proceedings of the 47th Annual ASTRO Meeting
2213
Prediction of Outcome by Cisplatin DNA-adduct Formation in Patients with Stage III/IV Head and Neck Squamous Cell Carcinoma, Treated by Concurrent Cisplatin-Chemoradiation (RADPLAT)
F. Hoebers,1 D. Pluim,2 A. Balm,3 H. Bartelink,1 A. Begg,2 J. Schellens,4 M. Verheij1 Radiotherapy, Netherlands Cancer Institute, Amsterdam, Netherlands, 2Experimental Therapy, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Head and Neck Oncology and Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands, 4Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands 1
Purpose/Objective: Cisplatin-DNA adduct formation in normal tissue has been shown to correlate with outcome in patients with NSCLC treated with chemoradiation and in advanced stage solid tumors treated with chemotherapy. The purpose of the present study was to explore relationships between adduct levels in tumor and normal tissue in patients with head and neck squamous cell carcinoma (HNSCC), treated with cisplatin-based chemoradiation and investigate relationships with treatment outcome. Materials/Methods: Patients with stage III/IV HNSCC were treated within a randomized phase III trial, investigating the optimal route of cisplatin administration, concurrently with standard fractionated radiation (70 Gy in 35 fractions, 7 weeks)(RADPLAT). Mode of cisplatin administration was either high dose intra-arterially (IA, 150 mg/m2, with systemic rescue by sodium-thiosulphate, on days 2,9,16 and 23) or standard dose intravenously (IV, 100 mg/m2, on days 1,22,43). In a subgroup of patients, adduct levels were assessed in white blood cells (WBC) and primary tumor before and 23 hours after 1st RADPLAT treatment. 32P-postlabeling technique was used to quantify selectively the major forms of cisplatin-DNA adducts (i.e. intrastrand GG and AG adducts). Levels of adducts were correlated with locoregional tumor control. Results: 35 patients have been included; 21 received standard IV and 14 received high-dose IA cisplatin infusion. At a median follow-up of 21 months (range 5–38) for patients alive at last follow-up, the estimated locoregional (LR) tumor control rates were 74% at 1 year and 69% at 2 years, with no differences between 2 treatment schedules applied. WBC were obtained from all patients, primary tumor from 12 with lesions, accessible for biopsy. The table presents results of adduct-levels in normal and tumor tissue. Adduct levels in primary tumor were 3– 4 fold higher than in WBC for both IA and IV treatment (p⫽0.01). Systemic adduct levels (in WBC) were higher in IV treated patients compared to selective IA infusion (p⫽0.04). Adduct levels in primary tumors after IA infusion were comparable to levels after IV treatment, despite the use of higher cisplatin doses and selective tumor-directed infusion. Intrastrand GG adduct levels were 10-fold higher than AG-adducts, both in WBC and in primary tumor. Analysis of LR control of all patients by the level of adduct formation in primary tumor (presented as ⱕ median and ⬎ median) showed that patients with higher GG adduct levels had a significant better LR control (p⫽0.049). Similar results were found for AG adducts, although not significantly different. Levels of adducts in WBC were not predictive for LR control. Conclusions: Cisplatin-DNA adduct levels in primary tumor appear to be predictive for LR control. No differences were observed in intra-tumoral adduct levels between IA or IV treatments, despite selective infusion of high-dose cisplatin with the IA procedure. However, systemic adduct levels in WBC from IV treated patients were higher than in IA patients, consistent with less systemic exposure after IA administration.
2214
Outcome and Prognostic Factors in Olfactory Neuroblastoma: A Multicenter Rare Cancer Network Study
M. Ozsahin,1 O. Olszyk,2 O. Karakoyun-Celik,3 B. Pehlivan,4 D. Azria,5 M. Roelandts,6 M. Kaanders,7 M. Cengiz,8 M. Krengli,9 A. Zouhair1 1 Radiation Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2Radiation Oncology, Centre Oscar Lambret, Lille, France, 3Radiation Oncology, Massachusetts General Hospital, Boston, MA, 4Radiation Oncology, Institut Gustave Roussy, Villejuif, France, 5Radiation Oncology, CRLC Val d’Aurelle, Montpellier, France, 6 Radiation Oncology, Institut Jules Bordet, Brussels, Belgium, 7Radiation Oncology, UMC St Radboud, Nijmegen, Netherlands, 8Radiation Oncology, Hacettepe University Medical School, Ankara, Turkey, 9Radiation Oncology, Universita Degli Studi Del Piemonte Orientale, Novara, Italy Purpose/Objective: To define outcome, prognostic factors, and patterns of failure in olfactory neuroblastoma, which is a rare tumor arising from the olfactory neuroepithelium. Materials/Methods: A series of 56 adult patients treated for non-metastatic olfactory neuroblastoma in 13 European and American centers between 1971 and 2004 were included in this retrospective study. Median age was 50 years (range: 15–79), and male-to-female ratio was 29/27. Histopathologic diagnosis was obtained in all patients. Diagnostic work-up included computed tomography in 51 (91%), and magnetic resonance imaging in 28 (50%) patients. According to Kadish classification, there were 7 patients (12%) with stage A, 24 (43%) with stage B, and 25 (45%) with stage C. UICC classification included 5 patients (9%) with T1, 20 (36%) with T2, 9 (16%) with T3, 13 (23%) with T4a, and 9 (16%) with T4b tumors. Forty-eight patients presented with N0 (86%) disease. Most of the patients (n ⫽ 46) benefited from surgery (S). Treatment consisted of a combination of S, radiation therapy (RT), and chemotherapy (CT) in 12 patients (21%), S⫹RT in 29 (52%), S alone in 5 (9%), RT⫹CT in 6 (11%), and RT alone in 4 (7%) patients. Total excision was possible in 40 out of 46 operated patients (R0 in 28,
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I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
R1 in 12, and R2 in 6). All but 5 patients benefited from RT with a median dose of 60 Gy in median 2 Gy/fr (range: 1.6 –2.5) during median 42 days (range: 21–77). RT was delivered using 2D-RT in 27 patients (48%), 3D-RT in 22 (39%), and intensity modulated RT (IMRT) in 2 (3%). Planning treatment volume included the tumor bed in 44 (86%), and tumor bed and involved lymph nodes in 7 (14%) patients. Median 4 cycles (range: 2–12) of chemotherapy were given in 18 patients (32%) using several combinations including platinum or doxorubicin. Median follow-up period was 74 months (range: 7- 314). Results: Median time to locoregional progression was 27 months (range: 0 –309). Local progression was observed in 23 patients (41%), regional in 16 (29%), and distant metastases in 10 (18%) patients. Causes of death included disease progression in 25, postoperative complications in 3, and intercurrent disease in 2 patients. The 5-year overall survival, disease-free survival (DFS), and locoregional control was 60%, 43%, and 53%; respectively. In univariate analyses (logrank test), factors favorably influencing the DFS were T1, T2, or T3 disease vs. T4 (p ⫽ 0.06), no nodal (N0) disease (p ⫽ 0.0007), RT dose 54 Gy or more (p ⫽ 0.006), treatment with surgery (p ⫽ 0.01), and total resection (p ⫽ 0.009) or R0/R1 resection (p ⫽ 0.01) in operated patients. Multivariate analysis (Cox model) revealed that the best independent factors predicting the outcome were T1-T3 disease (relative risk [RR] ⫽ 0.69; p ⫽ 0.05), no nodal (N0) involvement (RR ⫽ 0.60; p ⫽ 0.05), R0 or R1 resection (RR ⫽ 0.33; p ⫽ 0.008), and RT dose 54 Gy or more (RR ⫽ 0.30; p ⫽ 0.007). Conclusions: In this multicenter retrospective study, olfactory neuroblastoma was found to have the best outcome especially treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT. Novel therapies including concomitant chemotherapy and/or higher dose IMRT should be prospectively investigated in this rare disease.
2215
Carbon Ion Radiotherapy for Mucosal Malignant Melanoma of the Head and Neck
K. Kagawa,1 H. Mayahara,1,2 Y. Oda,1 A. Kawaguchi,1 M. Murakami,1,2 Y. Hishikawa,1,2 M. Abe1 1
Radiology, Hyogo Ion Beam Medical Center, Ibo-gun, Hyogo, Japan, 2Medical Imaging and Ion Beam Therapy, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
Purpose/Objective: To evaluate the efficiency and toxicity of carbon ion radiotherapy (RT) for mucosal malignant melanoma of the head and neck. Materials/Methods: Between February and July in 2002, eight patients with mucosal malignant melanoma of the head and neck were treated by carbon ion RT. Total tumor dose was 57.6 GyE/16 fractions/4 weeks. Primary tumor sites and corresponding T-stages were as follows: nasal cavity/ethmoid sinus/hard palate ⫽ 5/2/1, T1/T2/T3/T4 ⫽ 1/2/2/3. Pretreatment FDG-PET showed no distant metastasis in all patients. The patients were followed for a median period of 24 months (range 5–31 months). Results: All patients completed intended treatment. Eight patients (100%) reached ⬎50% tumor regression within 3 months. The 2-year local control rate was 100%. Within 8 months, 6 patients (75%) developed distant metastases. The 2-year disease-free and overall survival rates were 25% and 50%, respectively. Most recurrent diseases were multiple metastases and became fatal. Acute toxicities classified by the NCI-CTC 2.0 were Grade 2 in the skin (n ⫽ 4), Grade 3 in the oral mucosa (n ⫽ 5), and Grade 2 in the nasal mucosa (n ⫽ 5), which were all tolerable and healed within 2 months. All patients continued oral feeding during the treatment course. Late toxicities classified by the RTOG/EORTC scoring system were Grade 1 in the skin (n ⫽ 3) and Grade 1 in the nasal mucosa (n ⫽ 5). Conclusions: Carbon ion RT is very effective for local control of mucosal malignant melanoma of the head and neck. As for distant metastasis, however, even early cases developed multiple metastases after local control of the primary tumor sites. The current multidrug chemotherapy has limited effects on disseminated diseases.
2213
Prediction of Outcome by Cisplatin DNA-adduct Formation in Patients with Stage III/IV Head and Neck Squamous Cell Carcinoma, Treated by Concurrent Cisplatin-Chemoradiation (RADPLAT)
F. Hoebers,1 D. Pluim,2 A. Balm,3 H. Bartelink,1 A. Begg,2 J. Schellens,4 M. Verheij1 Radiotherapy, Netherlands Cancer Institute, Amsterdam, Netherlands, 2Experimental Therapy, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Head and Neck Oncology and Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands, 4Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands 1
Purpose/Objective: Cisplatin-DNA adduct formation in normal tissue has been shown to correlate with outcome in patients with NSCLC treated with chemoradiation and in advanced stage solid tumors treated with chemotherapy. The purpose of the present study was to explore relationships between adduct levels in tumor and normal tissue in patients with head and neck squamous cell carcinoma (HNSCC), treated with cisplatin-based chemoradiation and investigate relationships with treatment outcome. Materials/Methods: Patients with stage III/IV HNSCC were treated within a randomized phase III trial, investigating the optimal route of cisplatin administration, concurrently with standard fractionated radiation (70 Gy in 35 fractions, 7 weeks)(RADPLAT). Mode of cisplatin administration was either high dose intra-arterially (IA, 150 mg/m2, with systemic rescue by sodium-thiosulphate, on days 2,9,16 and 23) or standard dose intravenously (IV, 100 mg/m2, on days 1,22,43). In a subgroup of patients, adduct levels were assessed in white blood cells (WBC) and primary tumor before and 23 hours after 1st RADPLAT treatment. 32P-postlabeling technique was used to quantify selectively the major forms of cisplatin-DNA adducts (i.e. intrastrand GG and AG adducts). Levels of adducts were correlated with locoregional tumor control. Results: 35 patients have been included; 21 received standard IV and 14 received high-dose IA cisplatin infusion. At a median follow-up of 21 months (range 5–38) for patients alive at last follow-up, the estimated locoregional (LR) tumor control rates were 74% at 1 year and 69% at 2 years, with no differences between 2 treatment schedules applied. WBC were obtained from all patients, primary tumor from 12 with lesions, accessible for biopsy. The table presents results of adduct-levels in normal and tumor tissue. Adduct levels in primary tumor were 3– 4 fold higher than in WBC for both IA and IV treatment (p⫽0.01). Systemic adduct levels (in WBC) were higher in IV treated patients compared to selective IA infusion (p⫽0.04). Adduct levels in primary tumors after IA infusion were comparable to levels after IV treatment, despite the use of higher cisplatin doses and selective tumor-directed infusion. Intrastrand GG adduct levels were 10-fold higher than AG-adducts, both in WBC and in primary tumor. Analysis of LR control of all patients by the level of adduct formation in primary tumor (presented as ⱕ median and ⬎ median) showed that patients with higher GG adduct levels had a significant better LR control (p⫽0.049). Similar results were found for AG adducts, although not significantly different. Levels of adducts in WBC were not predictive for LR control. Conclusions: Cisplatin-DNA adduct levels in primary tumor appear to be predictive for LR control. No differences were observed in intra-tumoral adduct levels between IA or IV treatments, despite selective infusion of high-dose cisplatin with the IA procedure. However, systemic adduct levels in WBC from IV treated patients were higher than in IA patients, consistent with less systemic exposure after IA administration.
2214
Outcome and Prognostic Factors in Olfactory Neuroblastoma: A Multicenter Rare Cancer Network Study
M. Ozsahin,1 O. Olszyk,2 O. Karakoyun-Celik,3 B. Pehlivan,4 D. Azria,5 M. Roelandts,6 M. Kaanders,7 M. Cengiz,8 M. Krengli,9 A. Zouhair1 1 Radiation Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2Radiation Oncology, Centre Oscar Lambret, Lille, France, 3Radiation Oncology, Massachusetts General Hospital, Boston, MA, 4Radiation Oncology, Institut Gustave Roussy, Villejuif, France, 5Radiation Oncology, CRLC Val d’Aurelle, Montpellier, France, 6 Radiation Oncology, Institut Jules Bordet, Brussels, Belgium, 7Radiation Oncology, UMC St Radboud, Nijmegen, Netherlands, 8Radiation Oncology, Hacettepe University Medical School, Ankara, Turkey, 9Radiation Oncology, Universita Degli Studi Del Piemonte Orientale, Novara, Italy Purpose/Objective: To define outcome, prognostic factors, and patterns of failure in olfactory neuroblastoma, which is a rare tumor arising from the olfactory neuroepithelium. Materials/Methods: A series of 56 adult patients treated for non-metastatic olfactory neuroblastoma in 13 European and American centers between 1971 and 2004 were included in this retrospective study. Median age was 50 years (range: 15–79), and male-to-female ratio was 29/27. Histopathologic diagnosis was obtained in all patients. Diagnostic work-up included computed tomography in 51 (91%), and magnetic resonance imaging in 28 (50%) patients. According to Kadish classification, there were 7 patients (12%) with stage A, 24 (43%) with stage B, and 25 (45%) with stage C. UICC classification included 5 patients (9%) with T1, 20 (36%) with T2, 9 (16%) with T3, 13 (23%) with T4a, and 9 (16%) with T4b tumors. Forty-eight patients presented with N0 (86%) disease. Most of the patients (n ⫽ 46) benefited from surgery (S). Treatment consisted of a combination of S, radiation therapy (RT), and chemotherapy (CT) in 12 patients (21%), S⫹RT in 29 (52%), S alone in 5 (9%), RT⫹CT in 6 (11%), and RT alone in 4 (7%) patients. Total excision was possible in 40 out of 46 operated patients (R0 in 28,
S355
S356
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
R1 in 12, and R2 in 6). All but 5 patients benefited from RT with a median dose of 60 Gy in median 2 Gy/fr (range: 1.6 –2.5) during median 42 days (range: 21–77). RT was delivered using 2D-RT in 27 patients (48%), 3D-RT in 22 (39%), and intensity modulated RT (IMRT) in 2 (3%). Planning treatment volume included the tumor bed in 44 (86%), and tumor bed and involved lymph nodes in 7 (14%) patients. Median 4 cycles (range: 2–12) of chemotherapy were given in 18 patients (32%) using several combinations including platinum or doxorubicin. Median follow-up period was 74 months (range: 7- 314). Results: Median time to locoregional progression was 27 months (range: 0 –309). Local progression was observed in 23 patients (41%), regional in 16 (29%), and distant metastases in 10 (18%) patients. Causes of death included disease progression in 25, postoperative complications in 3, and intercurrent disease in 2 patients. The 5-year overall survival, disease-free survival (DFS), and locoregional control was 60%, 43%, and 53%; respectively. In univariate analyses (logrank test), factors favorably influencing the DFS were T1, T2, or T3 disease vs. T4 (p ⫽ 0.06), no nodal (N0) disease (p ⫽ 0.0007), RT dose 54 Gy or more (p ⫽ 0.006), treatment with surgery (p ⫽ 0.01), and total resection (p ⫽ 0.009) or R0/R1 resection (p ⫽ 0.01) in operated patients. Multivariate analysis (Cox model) revealed that the best independent factors predicting the outcome were T1-T3 disease (relative risk [RR] ⫽ 0.69; p ⫽ 0.05), no nodal (N0) involvement (RR ⫽ 0.60; p ⫽ 0.05), R0 or R1 resection (RR ⫽ 0.33; p ⫽ 0.008), and RT dose 54 Gy or more (RR ⫽ 0.30; p ⫽ 0.007). Conclusions: In this multicenter retrospective study, olfactory neuroblastoma was found to have the best outcome especially treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT. Novel therapies including concomitant chemotherapy and/or higher dose IMRT should be prospectively investigated in this rare disease.
2215
Carbon Ion Radiotherapy for Mucosal Malignant Melanoma of the Head and Neck
K. Kagawa,1 H. Mayahara,1,2 Y. Oda,1 A. Kawaguchi,1 M. Murakami,1,2 Y. Hishikawa,1,2 M. Abe1 1
Radiology, Hyogo Ion Beam Medical Center, Ibo-gun, Hyogo, Japan, 2Medical Imaging and Ion Beam Therapy, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
Purpose/Objective: To evaluate the efficiency and toxicity of carbon ion radiotherapy (RT) for mucosal malignant melanoma of the head and neck. Materials/Methods: Between February and July in 2002, eight patients with mucosal malignant melanoma of the head and neck were treated by carbon ion RT. Total tumor dose was 57.6 GyE/16 fractions/4 weeks. Primary tumor sites and corresponding T-stages were as follows: nasal cavity/ethmoid sinus/hard palate ⫽ 5/2/1, T1/T2/T3/T4 ⫽ 1/2/2/3. Pretreatment FDG-PET showed no distant metastasis in all patients. The patients were followed for a median period of 24 months (range 5–31 months). Results: All patients completed intended treatment. Eight patients (100%) reached ⬎50% tumor regression within 3 months. The 2-year local control rate was 100%. Within 8 months, 6 patients (75%) developed distant metastases. The 2-year disease-free and overall survival rates were 25% and 50%, respectively. Most recurrent diseases were multiple metastases and became fatal. Acute toxicities classified by the NCI-CTC 2.0 were Grade 2 in the skin (n ⫽ 4), Grade 3 in the oral mucosa (n ⫽ 5), and Grade 2 in the nasal mucosa (n ⫽ 5), which were all tolerable and healed within 2 months. All patients continued oral feeding during the treatment course. Late toxicities classified by the RTOG/EORTC scoring system were Grade 1 in the skin (n ⫽ 3) and Grade 1 in the nasal mucosa (n ⫽ 5). Conclusions: Carbon ion RT is very effective for local control of mucosal malignant melanoma of the head and neck. As for distant metastasis, however, even early cases developed multiple metastases after local control of the primary tumor sites. The current multidrug chemotherapy has limited effects on disseminated diseases.