- Email: [email protected]
Local Chemotherapy and Laser for Palliation of Recurrent Cancer
Otolaryngology– Head and Neck Surgery Volume 133 Number 2
R568 FGF-Targeted TK Gene Therapy for Head and Neck Squamous Cell Carcinoma Daqing Li, MD; Bert W O’Malley, Jr, MD (presenter) Philadelphia PA; Philadelphia PA
Problem: To improve the specificity in targeting the tumor cells and circumvent the deficiency of adenoviral receptor in adenovirus-mediated gene therapy, an emerging strategy is to redirect adenovirus towards specific receptors that are highly expressed in tumor tissue of head and neck squamous cell carcinoma (HNSCC). The unique feature of human HNSCC is the overexpression of fibroblast growth factor (FGF) receptor. FGF-targeted adenovirus-mediated thymidine kinase (Ad-tk) gene transfer against HNSCC was attempted. Methods: Randomized, controlled studies in the murine orthotopic model of HNSCC. The intervention groups consisted of Ad-tk, FGF-targeted Ad-tk and controls. FGF receptor ligand, recombinant FGF2 was used for the present study. Tumor sizes were measured before and after treatment. Statistic analysis was performed for each of the groups. Results: By using a bifunctional conjugate-FGF2 consisting of a blocking anti-adenoviral knob Fab linked to basic FGF, Ad-tk gene transduction of HNSCC cells was significantly enhanced. Targeted Ad-tk gene transfer resulted in
highly significant anti-tumor effect in the treatment of human HNSCC in our mouse model. Conclusion: The FGF2-targeted Ad-tk gene transfer significantly improves the specificity in targeting the tumor cells of HNSCC and therefore significantly improves the therapeutic outcome of Ad-tk gene therapy. Significance: The results of FGF-targeted Ad-tk gene therapy demonstrate that clinically effective in vivo treatment of human HNSCC can be achieved. The clear benefit of this strategy supports further clinical studies for the treatment of HNSCC.T R569 Neck Surgery in Patients with Head and Neck Carcinoma after Definitive Chemoradiotherapy: Analysis of Residual and Regional Failure Carlos M Martin, MD (presenter) Santiago Spain
Problem: Neck surgery in patients with head and neck carcinoma after definitive chemoradiotherapy: An analysis of residual and regional failure. Martin C., Dios C., Cabanas E. and labella T. Organ preservation treatment with chemoradiotherapy is accepted as an alternative to extensive surgery. Whereas several studies have proven achieves primary tumor control, the uncertainty of neck response to organ preservation treatment favors early surgical control of regional disease. Methods: We examined retrospectively 38 patients with head and neck carcinoma that were treated through an organ preservation protocol and salvage neck dissection. Results: There were 2 women and 36 men ( ratio 15:1), and the age range was 32 to 75 years ( median, 53,2). The distribution of stage tumor was: IV, 29 patients (78%); III, 8 patients ( 21%), and II, one patient. Overall, 18 patients had regional failure and 20 patients residual pathologic or clinical tumor. Conclusion: The data from this analysis support that the patients with residual pathologic or clinical tumor after chemoradiotherapy and salvage neck dissection had significantly improved rates of disease-free and overall survival compared with patients with regional failure. In this group the distant metastasis are more frequently. Significance: This study demonstrates that is necessary an early surgical control of the regional disease after chemoradiotherapy. R570 Local Chemotherapy and Laser for Palliation of Recurrent Cancer Marcos B Paiva, MD PhD (presenter); Michael Bublik, MD; Luis Paul Kowalski, MD PhD; Joel A Sercarz, MD Los Angeles CA; Los Angeles CA; Los Angeles CA; Los Angeles CA
Problem: Laser induced thermal therapy (LITT) with the neodymium:yttrium-aluminum-garnet (Nd:YAG) (1064 nm)
POSTERS
B7-H4 in ACC and examined the relationship between B7-H4 expression by ACC cells and tumor-associated T cell infiltration. Methods: Immunohistochemical localization of B7-H4, CD3, and CD8 was performed on archival sections of 23 ACCs. B7-H4 staining intensity was graded on a scale of 0 to 4⫹ and the proportion of positive tumor cells was estimated based on evaluation of the entire section. The proportion of CD3 and CD8 positive T lymphocytes was scored as 0, 1⫹, 2⫹, or 3⫹ (⬍1, 10-20, 21-100, or 100 lymphocytes/200x field). Results: Intense (3⫹ to 4⫹) cytoplasmic and cell surface B7-H4 staining was detected in 90% of tumor cells in 20/23 specimens. B7-H4 staining clearly delineated the extent of the tumor, including foci of perineural invasion. There was an inverse correlation between B7-H4 and tumor-associated T cells; most cases with high levels of B7-H4 expression had only few (0 to 1⫹) CD3 and CD8 lymphocytes. By contrast, 2/3 cases with low B7-H4 scores had the increased CD3 and CD8 lymphocytes. Conclusion: This study is the first to demonstrate the expression of B7-H4 in ACC. The high level of expression in most cases and the inverse association with tumor-associated CD3 and CD8 lymphocytes suggest that B7-H4 may play a role in the shielding tumor cells from T cell-mediated immune surveillance. Significance: This ability to evade immune surveillance may be a key virulence factor for ACCs and also raises possibilities for the development of novel targets for future therapeutics.
Research Posters P151
Research Posters
laser via fiberoptics is becoming a more precise, minimally invasive alternative for thermoablation of unresectable or recurrent head and neck neoplasms, but recurrence is often seen at the margin. Combining intratumor chemotherapy with interstitial laser should be most effective using drugs activated by thermal energy. The objective of the current study was to review safety and toxicity of cisplatin in a gel (CDDP/ gel) combined with LITT for treatment of recurrent cancer in 3 patients with advanced stage disease. Methods: The cisplatin dose used was 0.25mL gel/cm3 tumor volume every week for 3 sessions(mean cumulative dose per patient was 0.35 to 12.35mg cisplatin). A total of 5 tumors were treated with CDDP/gel and persistent disease treated by LITT (PD⫽2,200 J/cm2) a week after the chemotherapy session. Results: The average survival for these patients was 9.5 months, and no dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. All patients expired of progressive disease. Conclusion: In this study treatment of accessible solid tumors with CDDP/gel by intratumor administration followed by LITT proved to be safe and feasible. Based on preclinical evidence garnered at UCLA, and the results of this study we are encouraged to continue our pursuit of improving LITT combined with chemotherapy. Significance: In the lab, local chemotherapy has been shown to significantly improve laser thermal therapy. This is the first case report showing safety of this method and the potential for future tranlsational studies combining laser and chemotherapy for cancer treatment.”
R571 Radiotherapy Efficacy in Cervical Metastasis from Laryngeal and Hypopharyngeal Tumors Carla
Branco,
MD
(presenter);
Judite
Ramos;
Miguel
Magalhaes; Joao Manuel Andrade Olias, MD Sobreda Portugal; Lisboa Portugal; Lisoa Portugal; Cascais Portugal
Problem: Adjuvant radiotherapy plays nowadays an important role in the treatment of patients with laryngeal and hypopharyngeal squamous cell carcinoma. When used alone, radiotherapy has similar results as surgery in local control of tumours in early stages (I and II). The effectiveness of radiotherapy in the treatment of cervical ganglionar metastasis remains controversial and there is a conviction that these metastasis are more radioresistant than their primaries. Methods: Retrospective study with a population of 104 patients with squamous carcinoma of larynx and hypopharynx who also presented with nodal disease and underwent radiotherapy between 1990 and 1995, in the Instituto Portugueˆs de Oncologia de Lisboa – Portugal.
Results: The nodal disease control rate was 46,1%. The regional outcome was influenced by clinical features such as nodal size (p⬍0,01) and fixity (p⫽0,007), but not bynodal multiplicity, bilaterality or primary tumour characteristics. Conclusion: Results suggest that a planned neck dissection after radiotherapy could be beneficial if nodes larger than 3 cm or fixed are present. Significance: A planned neck dissection after radiotherapy could be beneficial if metastasis from laryngeal and hypopharyngeal tumours larger than 3 cm or fixed are present.
R572 A Phase Ib/II Clinical Study on Vascular Targeting Therapy of Head and Neck Carcinoma Marc Dellian, MD PhD (presenter); Sebastian Strieth, MD; Uwe Michaelis, MD; Kurt Naujoks, MD; Barbara Wollenberg, MD PhD Munich Germany; Munich Germany; Mastinsried Germany; Munich Germany; Luebeck Germany
Problem: Vascular targeting with cytotoxic drugs encapsulated into cationic lipid complexes is a new approach for therapy of solid tumors (Dellian et al., Laryngo-Rhino-Otol. 81:509, 2002). Cationic lipid complexes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Encapsulation of paclitaxel in cationic lipid complexes significantly increased the antitumoral efficacy of the drug in vivo. Following successful preclinical studies, we have initiated a phase Ib/II clinical study on vascular targeting therapy of recurrent head and neck squamous cell carcinoma with paclitaxel in cationic lipid complexes. Methods: It was the aim of the present study to evaluate safety and antitumoral efficacy of paclitaxel encapsulated in cationic lipid complexes (MBT0206/EndoTag1) in 7 patients with recurrent, therapy refractory head and neck squamouscell carcinoma. The drug was administered in two therapy schedules with increasing dose. Results: In all 7 patients, during and after injection no signs of acute or chronic toxicity were observed: Vital and lab safety parameters remained nearly constant. Laser Doppler flowmetry demonstrated a reduction of tumor perfusion in patients showing cutaneous tumor infiltration to 56% of baseline values. Conclusion: Our results indicate that the dose and schedule suggested from preclinical toxicology studies was well tolerated by the patients. Laser Doppler flowmetry confirmed the antivascular mechanism of action of the therapy. Significance: Targeting of the endothelium of head and neck squamous cell carcinoma with cationic liposomes is a new, promising approach for tumor therapy. At present, phase 2 clinical studies are in preparation.”
POSTERS
P152
Otolaryngology– Head and Neck Surgery August 2005
R568 FGF-Targeted TK Gene Therapy for Head and Neck Squamous Cell Carcinoma Daqing Li, MD; Bert W O’Malley, Jr, MD (presenter) Philadelphia PA; Philadelphia PA
Problem: To improve the specificity in targeting the tumor cells and circumvent the deficiency of adenoviral receptor in adenovirus-mediated gene therapy, an emerging strategy is to redirect adenovirus towards specific receptors that are highly expressed in tumor tissue of head and neck squamous cell carcinoma (HNSCC). The unique feature of human HNSCC is the overexpression of fibroblast growth factor (FGF) receptor. FGF-targeted adenovirus-mediated thymidine kinase (Ad-tk) gene transfer against HNSCC was attempted. Methods: Randomized, controlled studies in the murine orthotopic model of HNSCC. The intervention groups consisted of Ad-tk, FGF-targeted Ad-tk and controls. FGF receptor ligand, recombinant FGF2 was used for the present study. Tumor sizes were measured before and after treatment. Statistic analysis was performed for each of the groups. Results: By using a bifunctional conjugate-FGF2 consisting of a blocking anti-adenoviral knob Fab linked to basic FGF, Ad-tk gene transduction of HNSCC cells was significantly enhanced. Targeted Ad-tk gene transfer resulted in
highly significant anti-tumor effect in the treatment of human HNSCC in our mouse model. Conclusion: The FGF2-targeted Ad-tk gene transfer significantly improves the specificity in targeting the tumor cells of HNSCC and therefore significantly improves the therapeutic outcome of Ad-tk gene therapy. Significance: The results of FGF-targeted Ad-tk gene therapy demonstrate that clinically effective in vivo treatment of human HNSCC can be achieved. The clear benefit of this strategy supports further clinical studies for the treatment of HNSCC.T R569 Neck Surgery in Patients with Head and Neck Carcinoma after Definitive Chemoradiotherapy: Analysis of Residual and Regional Failure Carlos M Martin, MD (presenter) Santiago Spain
Problem: Neck surgery in patients with head and neck carcinoma after definitive chemoradiotherapy: An analysis of residual and regional failure. Martin C., Dios C., Cabanas E. and labella T. Organ preservation treatment with chemoradiotherapy is accepted as an alternative to extensive surgery. Whereas several studies have proven achieves primary tumor control, the uncertainty of neck response to organ preservation treatment favors early surgical control of regional disease. Methods: We examined retrospectively 38 patients with head and neck carcinoma that were treated through an organ preservation protocol and salvage neck dissection. Results: There were 2 women and 36 men ( ratio 15:1), and the age range was 32 to 75 years ( median, 53,2). The distribution of stage tumor was: IV, 29 patients (78%); III, 8 patients ( 21%), and II, one patient. Overall, 18 patients had regional failure and 20 patients residual pathologic or clinical tumor. Conclusion: The data from this analysis support that the patients with residual pathologic or clinical tumor after chemoradiotherapy and salvage neck dissection had significantly improved rates of disease-free and overall survival compared with patients with regional failure. In this group the distant metastasis are more frequently. Significance: This study demonstrates that is necessary an early surgical control of the regional disease after chemoradiotherapy. R570 Local Chemotherapy and Laser for Palliation of Recurrent Cancer Marcos B Paiva, MD PhD (presenter); Michael Bublik, MD; Luis Paul Kowalski, MD PhD; Joel A Sercarz, MD Los Angeles CA; Los Angeles CA; Los Angeles CA; Los Angeles CA
Problem: Laser induced thermal therapy (LITT) with the neodymium:yttrium-aluminum-garnet (Nd:YAG) (1064 nm)
POSTERS
B7-H4 in ACC and examined the relationship between B7-H4 expression by ACC cells and tumor-associated T cell infiltration. Methods: Immunohistochemical localization of B7-H4, CD3, and CD8 was performed on archival sections of 23 ACCs. B7-H4 staining intensity was graded on a scale of 0 to 4⫹ and the proportion of positive tumor cells was estimated based on evaluation of the entire section. The proportion of CD3 and CD8 positive T lymphocytes was scored as 0, 1⫹, 2⫹, or 3⫹ (⬍1, 10-20, 21-100, or 100 lymphocytes/200x field). Results: Intense (3⫹ to 4⫹) cytoplasmic and cell surface B7-H4 staining was detected in 90% of tumor cells in 20/23 specimens. B7-H4 staining clearly delineated the extent of the tumor, including foci of perineural invasion. There was an inverse correlation between B7-H4 and tumor-associated T cells; most cases with high levels of B7-H4 expression had only few (0 to 1⫹) CD3 and CD8 lymphocytes. By contrast, 2/3 cases with low B7-H4 scores had the increased CD3 and CD8 lymphocytes. Conclusion: This study is the first to demonstrate the expression of B7-H4 in ACC. The high level of expression in most cases and the inverse association with tumor-associated CD3 and CD8 lymphocytes suggest that B7-H4 may play a role in the shielding tumor cells from T cell-mediated immune surveillance. Significance: This ability to evade immune surveillance may be a key virulence factor for ACCs and also raises possibilities for the development of novel targets for future therapeutics.
Research Posters P151
Research Posters
laser via fiberoptics is becoming a more precise, minimally invasive alternative for thermoablation of unresectable or recurrent head and neck neoplasms, but recurrence is often seen at the margin. Combining intratumor chemotherapy with interstitial laser should be most effective using drugs activated by thermal energy. The objective of the current study was to review safety and toxicity of cisplatin in a gel (CDDP/ gel) combined with LITT for treatment of recurrent cancer in 3 patients with advanced stage disease. Methods: The cisplatin dose used was 0.25mL gel/cm3 tumor volume every week for 3 sessions(mean cumulative dose per patient was 0.35 to 12.35mg cisplatin). A total of 5 tumors were treated with CDDP/gel and persistent disease treated by LITT (PD⫽2,200 J/cm2) a week after the chemotherapy session. Results: The average survival for these patients was 9.5 months, and no dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. All patients expired of progressive disease. Conclusion: In this study treatment of accessible solid tumors with CDDP/gel by intratumor administration followed by LITT proved to be safe and feasible. Based on preclinical evidence garnered at UCLA, and the results of this study we are encouraged to continue our pursuit of improving LITT combined with chemotherapy. Significance: In the lab, local chemotherapy has been shown to significantly improve laser thermal therapy. This is the first case report showing safety of this method and the potential for future tranlsational studies combining laser and chemotherapy for cancer treatment.”
R571 Radiotherapy Efficacy in Cervical Metastasis from Laryngeal and Hypopharyngeal Tumors Carla
Branco,
MD
(presenter);
Judite
Ramos;
Miguel
Magalhaes; Joao Manuel Andrade Olias, MD Sobreda Portugal; Lisboa Portugal; Lisoa Portugal; Cascais Portugal
Problem: Adjuvant radiotherapy plays nowadays an important role in the treatment of patients with laryngeal and hypopharyngeal squamous cell carcinoma. When used alone, radiotherapy has similar results as surgery in local control of tumours in early stages (I and II). The effectiveness of radiotherapy in the treatment of cervical ganglionar metastasis remains controversial and there is a conviction that these metastasis are more radioresistant than their primaries. Methods: Retrospective study with a population of 104 patients with squamous carcinoma of larynx and hypopharynx who also presented with nodal disease and underwent radiotherapy between 1990 and 1995, in the Instituto Portugueˆs de Oncologia de Lisboa – Portugal.
Results: The nodal disease control rate was 46,1%. The regional outcome was influenced by clinical features such as nodal size (p⬍0,01) and fixity (p⫽0,007), but not bynodal multiplicity, bilaterality or primary tumour characteristics. Conclusion: Results suggest that a planned neck dissection after radiotherapy could be beneficial if nodes larger than 3 cm or fixed are present. Significance: A planned neck dissection after radiotherapy could be beneficial if metastasis from laryngeal and hypopharyngeal tumours larger than 3 cm or fixed are present.
R572 A Phase Ib/II Clinical Study on Vascular Targeting Therapy of Head and Neck Carcinoma Marc Dellian, MD PhD (presenter); Sebastian Strieth, MD; Uwe Michaelis, MD; Kurt Naujoks, MD; Barbara Wollenberg, MD PhD Munich Germany; Munich Germany; Mastinsried Germany; Munich Germany; Luebeck Germany
Problem: Vascular targeting with cytotoxic drugs encapsulated into cationic lipid complexes is a new approach for therapy of solid tumors (Dellian et al., Laryngo-Rhino-Otol. 81:509, 2002). Cationic lipid complexes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Encapsulation of paclitaxel in cationic lipid complexes significantly increased the antitumoral efficacy of the drug in vivo. Following successful preclinical studies, we have initiated a phase Ib/II clinical study on vascular targeting therapy of recurrent head and neck squamous cell carcinoma with paclitaxel in cationic lipid complexes. Methods: It was the aim of the present study to evaluate safety and antitumoral efficacy of paclitaxel encapsulated in cationic lipid complexes (MBT0206/EndoTag1) in 7 patients with recurrent, therapy refractory head and neck squamouscell carcinoma. The drug was administered in two therapy schedules with increasing dose. Results: In all 7 patients, during and after injection no signs of acute or chronic toxicity were observed: Vital and lab safety parameters remained nearly constant. Laser Doppler flowmetry demonstrated a reduction of tumor perfusion in patients showing cutaneous tumor infiltration to 56% of baseline values. Conclusion: Our results indicate that the dose and schedule suggested from preclinical toxicology studies was well tolerated by the patients. Laser Doppler flowmetry confirmed the antivascular mechanism of action of the therapy. Significance: Targeting of the endothelium of head and neck squamous cell carcinoma with cationic liposomes is a new, promising approach for tumor therapy. At present, phase 2 clinical studies are in preparation.”
POSTERS
P152
Otolaryngology– Head and Neck Surgery August 2005