- Email: [email protected]
A NEW FUNCTION FOR HEAD & NECK ACCELERATED REPOPULATION
OPTlMlSlNG MULTIDISCIPLINARY TREATMENT (SURGERY, RADIOTHERAPY, CHEMOTHERAPY)
64 poster INDUCTION CHEMOTHERAPY FOLLOWED BY CONCURRENT CETUXIMAB WITH EXTERNAL BEAM RADIOTHERAPY FOR RECURRENT NASOPHARYNGEAL CARCINOMA T. T. D. Chua', V. Lee' HONGKONGSANATORIUM& HOSPITAL, Cancer Centre, Happy Valley, Hong Kong (SAR) China QUEENMARYHOSPITAL, Hong Kong, Hong Kong (SAR) China
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Purpose: Locally recurrent nasopharyngeal carcinoma (NPC) not amenable to surgical salvage or brachytherapy carries a poor prognosis. External beam radiotherapy (ERT) with or without chemotherapy is commonly employed but treatment results are unsatisfactory. Over-expression of epidermal growth factor receptor is common in NPC and combining cetuximab with ERT may improve outcome. Materials: Nineteen patients with advanced loco-regional recurrence of NPC not amenable to surgery or brachytherapy were enrolled into the study. All patients had prior chemo-radiotherapy as definitive treatment prior to recurrence. One patient had rT1 disease, 5 had rT2,5 had rT3, and 8 had rT4. Six patients also had cervical nodal recurrence. Treatment consisted of induction chemotherapy with gemcitabine and platinum for 3 cycles followed by ERT using intensity-modulated radiotherapy or helical tomotherapy. Median dose to target was 54 Gy (range 60-66Gy). Cetuximab was administered using a loading dose of 400mg/m2 1 week before ERT followed by weekly dose of 250mglm' during treatment. Results: All patients completed ERT and the median number of cycles of cetuximab was 6 (range: 2-7). Treatment was generally well tolerated, with grade 3 mucositis in 10.5% and grade 3 rash in 10.5%. After a median follow-up of 29 months, 11 patients had progression of loco-regional disease. Progression-free survival rate was 41.3% at 1-year and 35.4% at 2year. Overall survival rate was 81.9% at 1-year and 75.6% at 2-year. Late complications included carotid hemorrhage in 2, brain necrosis in 2 and osteoradionecrosis in 1. One patient died of hemorrahage from carotid pseudoaneurysym. Conclusions: Our study shows that combining cetuximab with chemoradiotherapy in recurrent NPC is feasible and well tolerated, and suggests a role of cetuximab in this setting. Addition of cetuximab to chemo-radiotherapy is a reasonable approach in recurrent NPC, and should be tested in randomized trial. 65 poster UPA, UPAR AND MASPIN EXPRESSION AS A BIOMARKER IN INVASIVE ORAL SQUAMOUS CELL CARCINOMA K. Yoshizawa', S. Kawashiri', H. Kitahara', K. Kato', N. Noguchi', E. Yamamoto' KANAZAWA UNIVERSITY,Oral and Maxillofacial Surgery, Kanazawa-shi, Japan
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Purpose: Objectives: The aim of this study was to investigate the association between uPA, uPAR, maspin and various invasive oral squamous carcinomas. The binding of urokinase plasminogen activator (uPA) to its receptor (uPAR) has been implicated in cancer invasion and metastasis. This activity is known to be regulated by several inhibitors such as the mammary serine protease inhibitor (maspin) which is known to have a tumor-suppressor function that is manifested by blocking UPNUPARcomplex. On other hand however, the association between these levels of expression, prognoses and invasion has not been demonstrated in human oral squamous cell cancer (OSCC). Further understanding of UPNUPARand maspin expression in OSCC will enable the development of more accurate and useful prognostic markers and thus more effective treatments. Materials: Methods:Sections of 54 specimens of primary oral squamous cell carcinoma (OSCC) were immunostained to assess the expression and localization of markers in cancer cells at the invasive front that were distinguished by mode of cancer invasion as described by Yamamoto et al. We also compared the clinicopathological features of OSCC cases with these expression levels. We further examined UPNUPAR,maspin protein and mRNA expression in a series of 8 oral squamous cell lines with different invasive phenotypes, grade 3, 4C and 4D using reverse transcriptase polymerase chain reaction and Western blotting analysis. Results: Results: Expression of maspin was significantly lower in highly invasive OSCC than in lower invasive OSCC. Of significance, we found that cytoplasmic subcellular localization of maspin in OSCC was associated with a poor prognosis, whereas nuclear maspin localization was indicative of less aggression. In contrast, the expression of uPA, uPAR was significantly higher in highly invasive OSCC than in lower invasive OSCC. Conclusions: Conclusions: These results suggest that the status of uPA, uPAR maspin expression may be a useful prognostic marker for OSCC.
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Optimising multidisciplinary treatment (Surgery, radiotherapy, chemotherapy) 66 poster 3D-OPTIMISED IMAGE-GUIDED IR-192 HDR BRACHYTHERAPY IN ORAL CANCER MULTIMODAL TREATMENT V. Titova', V. Petrovsky', J. Kreynina'
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RUSSIANSCIENTIFICCENTEROF ROENTGENOLOGY, Department of Brachytherapy, Moscow, Russian Federation
Purpose: lnspite of oral cancer can be considered an ideal indication for brachytherapy as a function - preserve method, the results of HDR brachytherapy are contradictory and depend on tumor localization in mouth cavity, stage, local spread, prognostic factors and treatment schemes. To evaluate if image-guided 3D-optimisation of Ir-192 HDR brachytherapy improves the results of multimodal treatment and life quality in oral cancer patients. Materials: From February 2008 till June 2010 Ir-192 HDR brachytherapy (Microselectron HDRQ, Nucletron) was performed as a part of multimodal treatment in 46 oral cancer pts. 35-73 y . ~ . [mean age 58,l y.~.], men 64,3%, women-34,7%. Tongue tumor 21(45,7%) pts., mouth floor 14(30,4%), inferior lip 8 (17,4%), buccal mucosa 3 (6,5%). TlNoMo 14(30,4%), T2NoMo 19(41,3%), T2-3No-2Mo 4 (8,7%), T4No-1Mo 9 (19,6%), in toto T1-2NoMo 71,7% pts. 34 (73,9%) pts. received radiotherapy (RT) alone, in 12(26%) pts. chemoradiation (ChRT) was conducted with PFu and TP as neoadjuvant chemotherapy in standard schedule. EBRT TD 24-46Gy was a first step of RT [mean total dose 38,7Gy, tongue cancer 42,2Gy, buccal mucosa 33,3Gy, mouth floor 41,1Gy, inferior lip 38,IGyI. After a planned break [23,8-27,4, mean - 25,2 days] CT-based 3D-optimized brachytherapy with 4-6 flexible catheters was performed, 3Gy/fraction for DlOO twice a day in 4 hours, TD 26-41Gy [mean TD 31,3Gy: tongue 31,3Gy, buccal mucosa 29Gy, mouth floor 30,3Gy, inferior lip 34,7Gy]. Results: In 6-8 weeks we had reached CR in 39(84,8%) pts., PR in 5 (10,9%), no progression during the treatment. In 12 month DFS 80,4%, local control - 87%, all cases of progression were registered in T3-4N1-2Mo pts. No acute side effects grade Ill-IV RTOG had been observed. Conclusions: 3D-optimised lr-192 HDR brachytherapy is effective and safe for oral cancer multimodal treatment programs. 67 poster A NEW FUNCTION FOR HEAD & NECK ACCELERATED REPOPULATION M. A. Carrasco Herrera', S. Velhzquez Miranda', J. Pachbn Ibafiez', M. Herrador C6rdoba' HOSPITALVIRGEN DEL Rocio, Department of Medical Physics and Radiation Safety, Sevilla, Spain HOSPITALVIRGEN DEL ROCiO, Radiotherapy, Sevilla, Spain
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Purpose: Develop a model that can explain the repopulation accelerated in head and neck tumors and use it to calculate the probability of tumour control (TCP) for patients with cancer of the larynx, using Monte Carlo simulation techniques. Materials: Software has been developed with an algorithm based on Monte Carlo simulation with the following main assumptions techniques: - Tumor cells growth function is a simple exponential model with a doubling time equal to potential duplication time TD, i.e., cells always grow at same rate. - Cell loss factor (CLF) indicates the percentage of new cells that die due to different causes: hypoxia, lack of nutrients, etc. This factor (1) is not constant, so while the tumor becomes larger, it increases to reach a saturation value (CLFsat). - The effect of radiation is given by the factor of survival, which follows the linear-cuadratic model. These expressions have been introduced in the algorithm, whereas the probability of growth, cell loss factor and the fraction of survival remain binomial probability distributions. It has been assumed that doubling time, beta and alpha radiobiological settings remain normal distributions, whereas the standard deviation is the 20% difference from the value of the parameter. A number of 10 tumors have been considered in each simulation. Model has been tested either to standard as to altered fractionation with T1NOMO glottic cancer patients. We used its histograms dose-volume (HDV) and a constant clonogens' density.
C L F = CLF,,t
(1 - e C a N )
Results: Our time-independent model for accelerated repopulation predicts properly clinical outcomes for standard, accelerated fractionation regimens and hyperfractionation schedules, being remarkable that it predicts the accelerated repopulation for postoperative patients, with effective doubling times less than the non-operated effective doubling times. Conclusions: The developed algorithm gets good results in the clinic, even in postoperative, allowing reliable designs of schedules.
64 poster INDUCTION CHEMOTHERAPY FOLLOWED BY CONCURRENT CETUXIMAB WITH EXTERNAL BEAM RADIOTHERAPY FOR RECURRENT NASOPHARYNGEAL CARCINOMA T. T. D. Chua', V. Lee' HONGKONGSANATORIUM& HOSPITAL, Cancer Centre, Happy Valley, Hong Kong (SAR) China QUEENMARYHOSPITAL, Hong Kong, Hong Kong (SAR) China
'
Purpose: Locally recurrent nasopharyngeal carcinoma (NPC) not amenable to surgical salvage or brachytherapy carries a poor prognosis. External beam radiotherapy (ERT) with or without chemotherapy is commonly employed but treatment results are unsatisfactory. Over-expression of epidermal growth factor receptor is common in NPC and combining cetuximab with ERT may improve outcome. Materials: Nineteen patients with advanced loco-regional recurrence of NPC not amenable to surgery or brachytherapy were enrolled into the study. All patients had prior chemo-radiotherapy as definitive treatment prior to recurrence. One patient had rT1 disease, 5 had rT2,5 had rT3, and 8 had rT4. Six patients also had cervical nodal recurrence. Treatment consisted of induction chemotherapy with gemcitabine and platinum for 3 cycles followed by ERT using intensity-modulated radiotherapy or helical tomotherapy. Median dose to target was 54 Gy (range 60-66Gy). Cetuximab was administered using a loading dose of 400mg/m2 1 week before ERT followed by weekly dose of 250mglm' during treatment. Results: All patients completed ERT and the median number of cycles of cetuximab was 6 (range: 2-7). Treatment was generally well tolerated, with grade 3 mucositis in 10.5% and grade 3 rash in 10.5%. After a median follow-up of 29 months, 11 patients had progression of loco-regional disease. Progression-free survival rate was 41.3% at 1-year and 35.4% at 2year. Overall survival rate was 81.9% at 1-year and 75.6% at 2-year. Late complications included carotid hemorrhage in 2, brain necrosis in 2 and osteoradionecrosis in 1. One patient died of hemorrahage from carotid pseudoaneurysym. Conclusions: Our study shows that combining cetuximab with chemoradiotherapy in recurrent NPC is feasible and well tolerated, and suggests a role of cetuximab in this setting. Addition of cetuximab to chemo-radiotherapy is a reasonable approach in recurrent NPC, and should be tested in randomized trial. 65 poster UPA, UPAR AND MASPIN EXPRESSION AS A BIOMARKER IN INVASIVE ORAL SQUAMOUS CELL CARCINOMA K. Yoshizawa', S. Kawashiri', H. Kitahara', K. Kato', N. Noguchi', E. Yamamoto' KANAZAWA UNIVERSITY,Oral and Maxillofacial Surgery, Kanazawa-shi, Japan
'
Purpose: Objectives: The aim of this study was to investigate the association between uPA, uPAR, maspin and various invasive oral squamous carcinomas. The binding of urokinase plasminogen activator (uPA) to its receptor (uPAR) has been implicated in cancer invasion and metastasis. This activity is known to be regulated by several inhibitors such as the mammary serine protease inhibitor (maspin) which is known to have a tumor-suppressor function that is manifested by blocking UPNUPARcomplex. On other hand however, the association between these levels of expression, prognoses and invasion has not been demonstrated in human oral squamous cell cancer (OSCC). Further understanding of UPNUPARand maspin expression in OSCC will enable the development of more accurate and useful prognostic markers and thus more effective treatments. Materials: Methods:Sections of 54 specimens of primary oral squamous cell carcinoma (OSCC) were immunostained to assess the expression and localization of markers in cancer cells at the invasive front that were distinguished by mode of cancer invasion as described by Yamamoto et al. We also compared the clinicopathological features of OSCC cases with these expression levels. We further examined UPNUPAR,maspin protein and mRNA expression in a series of 8 oral squamous cell lines with different invasive phenotypes, grade 3, 4C and 4D using reverse transcriptase polymerase chain reaction and Western blotting analysis. Results: Results: Expression of maspin was significantly lower in highly invasive OSCC than in lower invasive OSCC. Of significance, we found that cytoplasmic subcellular localization of maspin in OSCC was associated with a poor prognosis, whereas nuclear maspin localization was indicative of less aggression. In contrast, the expression of uPA, uPAR was significantly higher in highly invasive OSCC than in lower invasive OSCC. Conclusions: Conclusions: These results suggest that the status of uPA, uPAR maspin expression may be a useful prognostic marker for OSCC.
S 27
Optimising multidisciplinary treatment (Surgery, radiotherapy, chemotherapy) 66 poster 3D-OPTIMISED IMAGE-GUIDED IR-192 HDR BRACHYTHERAPY IN ORAL CANCER MULTIMODAL TREATMENT V. Titova', V. Petrovsky', J. Kreynina'
'
RUSSIANSCIENTIFICCENTEROF ROENTGENOLOGY, Department of Brachytherapy, Moscow, Russian Federation
Purpose: lnspite of oral cancer can be considered an ideal indication for brachytherapy as a function - preserve method, the results of HDR brachytherapy are contradictory and depend on tumor localization in mouth cavity, stage, local spread, prognostic factors and treatment schemes. To evaluate if image-guided 3D-optimisation of Ir-192 HDR brachytherapy improves the results of multimodal treatment and life quality in oral cancer patients. Materials: From February 2008 till June 2010 Ir-192 HDR brachytherapy (Microselectron HDRQ, Nucletron) was performed as a part of multimodal treatment in 46 oral cancer pts. 35-73 y . ~ . [mean age 58,l y.~.], men 64,3%, women-34,7%. Tongue tumor 21(45,7%) pts., mouth floor 14(30,4%), inferior lip 8 (17,4%), buccal mucosa 3 (6,5%). TlNoMo 14(30,4%), T2NoMo 19(41,3%), T2-3No-2Mo 4 (8,7%), T4No-1Mo 9 (19,6%), in toto T1-2NoMo 71,7% pts. 34 (73,9%) pts. received radiotherapy (RT) alone, in 12(26%) pts. chemoradiation (ChRT) was conducted with PFu and TP as neoadjuvant chemotherapy in standard schedule. EBRT TD 24-46Gy was a first step of RT [mean total dose 38,7Gy, tongue cancer 42,2Gy, buccal mucosa 33,3Gy, mouth floor 41,1Gy, inferior lip 38,IGyI. After a planned break [23,8-27,4, mean - 25,2 days] CT-based 3D-optimized brachytherapy with 4-6 flexible catheters was performed, 3Gy/fraction for DlOO twice a day in 4 hours, TD 26-41Gy [mean TD 31,3Gy: tongue 31,3Gy, buccal mucosa 29Gy, mouth floor 30,3Gy, inferior lip 34,7Gy]. Results: In 6-8 weeks we had reached CR in 39(84,8%) pts., PR in 5 (10,9%), no progression during the treatment. In 12 month DFS 80,4%, local control - 87%, all cases of progression were registered in T3-4N1-2Mo pts. No acute side effects grade Ill-IV RTOG had been observed. Conclusions: 3D-optimised lr-192 HDR brachytherapy is effective and safe for oral cancer multimodal treatment programs. 67 poster A NEW FUNCTION FOR HEAD & NECK ACCELERATED REPOPULATION M. A. Carrasco Herrera', S. Velhzquez Miranda', J. Pachbn Ibafiez', M. Herrador C6rdoba' HOSPITALVIRGEN DEL Rocio, Department of Medical Physics and Radiation Safety, Sevilla, Spain HOSPITALVIRGEN DEL ROCiO, Radiotherapy, Sevilla, Spain
' '
Purpose: Develop a model that can explain the repopulation accelerated in head and neck tumors and use it to calculate the probability of tumour control (TCP) for patients with cancer of the larynx, using Monte Carlo simulation techniques. Materials: Software has been developed with an algorithm based on Monte Carlo simulation with the following main assumptions techniques: - Tumor cells growth function is a simple exponential model with a doubling time equal to potential duplication time TD, i.e., cells always grow at same rate. - Cell loss factor (CLF) indicates the percentage of new cells that die due to different causes: hypoxia, lack of nutrients, etc. This factor (1) is not constant, so while the tumor becomes larger, it increases to reach a saturation value (CLFsat). - The effect of radiation is given by the factor of survival, which follows the linear-cuadratic model. These expressions have been introduced in the algorithm, whereas the probability of growth, cell loss factor and the fraction of survival remain binomial probability distributions. It has been assumed that doubling time, beta and alpha radiobiological settings remain normal distributions, whereas the standard deviation is the 20% difference from the value of the parameter. A number of 10 tumors have been considered in each simulation. Model has been tested either to standard as to altered fractionation with T1NOMO glottic cancer patients. We used its histograms dose-volume (HDV) and a constant clonogens' density.
C L F = CLF,,t
(1 - e C a N )
Results: Our time-independent model for accelerated repopulation predicts properly clinical outcomes for standard, accelerated fractionation regimens and hyperfractionation schedules, being remarkable that it predicts the accelerated repopulation for postoperative patients, with effective doubling times less than the non-operated effective doubling times. Conclusions: The developed algorithm gets good results in the clinic, even in postoperative, allowing reliable designs of schedules.