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Cetuximab (C225) Plus Cisplatin (CDDP) Irinotecan (CPT11) and Thoracic Radiotherapy (TRT) Definitive Treatment for Locally-advanced, Clinically Unresectable Esophageal Cancer: A Southwest Oncology Group (SWOG) Phase II Trial with Molecular Correlates (S0414)
I. J. Radiation Oncology d Biology d Physics
S168
Volume 75, Number 3, Supplement, 2009
Results: A total of 164 patients had received preoperative radiochemotherapy (45 Gy with continuous 5-FU) and 52 patients postoperative radiochemotherapy (50.4 Gy with 5-FU continuously or bolus). The most prevalent fecal symptoms were: diarrhea (80%), flatulence (75%), and tenesmus (15%). In patients without a colostomy (n = 152), only 18% reported a perfect fecal continence. Incontinence involved mainly gas (73%) and liquid stool (66%) with 16% reporting incontinence for solid stool. A total of 46% of the non-colostomy patients reported to wear pads because of fecal incontinence and 49% were unable to delay defecation for more than 15 minutes. Patients with low lying tumors (p = 0.006) and those with reoperation because of anastomotic leakage (p = 0.041) experienced more incontinence. Global QOL (p = 0.041), physical functioning (p \ 0.001) and role functioning (p \ 0.001) were significantly lower in colostomy patients as compared to non-colostomy patients. Higher (above median) incontinence score values were associated with lower global QOL (p = 0.002) as well as lower role functioning (0.014), cognitive functioning (p\0.001) and social functioning (p\0.001). As compared to the age- and gender-adjusted German general population (Schwarz and Hinz; Eur J Cancer 2001) QOL was significantly compromised in younger patients (50–60-years-old) affecting in particular role functioning, emotional functioning, cognitive functioning, social functioning, and fatigue, while in older patients (.60-yearsold) QOL-reduction was less pronounced and involved mainly social functioning. Conclusions: Ano-rectal function after combined radiochemotherapy and sphincter-preserving surgery for locally-advanced rectal cancer is suboptimal especially in patients with low-lying tumors. Patients with compromised fecal continence report significantly lower QOL levels in particular for social functioning. Survivors after multimodality treatment of rectal cancer might benefit from prolonged physical and social rehabilitation especially those under the age of 60. Author Disclosure: H. Geinitz, None; A. Kamp, None; A. Seidl, None; R. Thamm, None; R. Rosenberg, None; F. Lordick, None; M. Fuchs, None; W. Heitland, None; F. Zimmermann, None; M. Molls, None.
1094
Cetuximab (C225) Plus Cisplatin (CDDP) Irinotecan (CPT11) and Thoracic Radiotherapy (TRT) Definitive Treatment for Locally-advanced, Clinically Unresectable Esophageal Cancer: A Southwest Oncology Group (SWOG) Phase II Trial with Molecular Correlates (S0414)
C. R. Thomas1, B. H. Goldman2, J. K. Benedetti2, H. J. Lenz3, T. A. Baker4, L. Hammond-Thelin5, V. K. Mehta6, C. M. FenoglioPreiser7, J. L. Abbruzzese8, C. D. Blanke9 1 OHSU Knight Cancer Institute, Portland, OR, 2Southwest Oncology Group Statistical Center, Seattle, WA, 3University of Southern California, Los Angeles, CA, 4Gulf Coast MBCCOP, Mobile, AL, 5San Antonio Cancer Institute, San Antonio, TX, 6 Swedish Cancer Institute, Seattle, WA, 7Southwest Oncology Group GI Committee, Ann Arbor, MI, 8M. D. Anderson Cancer Center, Houston, TX, 9University of British Columbia, Vancouver, BC, Canada Purpose/Objective(s): While RTOG-8501 established definitive concomitant chemoradiotherapy (CRT) as a standard of care for patients with locally-advanced EC in the United States, median overall survival (OS) for patients has changed little over the past 2 decades. Thus, new regimens are needed. Based on Phase I–II data of CDDP, CPT11, and TRT and separate Phase I–III data of cetuximab, SWOG GI Committee designed a Phase II trial (S0414) to test this novel combined-modality approach. Specific aims were to: (1) assess 2-year OS, (2) toxicity profile, (3) objective response rate (RR), (4) time-to-progression (TTP), and (5) association between gene expression levels and germ line polymorphisms involved in DNA repair, drug metabolism, the EGFR pathway, and clinical outcome. Materials/Methods: Eligibility: cT4M0 disease or medically unresectable, biopsy-proven, primary EC (squamous cell or adenocarcinoma), thoracic-GE junction location, with adequate major organ function. Cetuximab 400 mg/m2 was given Day 1 of cycle (C) 1, cetuximab 250 mg/m2 was given Day 8, and 15 of C1 and Day 1, 8, and 15 for subsequent C; CDDP 30 mg/m2 was given Day 1, and 8 each C; CPT11 65 mg/m2 was given Day 1, and 8 each C. the TRT started Day 1 C3 @ 1.8 Gy/d 28 fractions, 5 days/ week to a total dose of 50.4 Gy. Planned accrual was 75 adeno patients and 25 squamous cell patients, with the regimen considered of further interest if 2-year OS $43%. Results: The study was closed due to slow accrual, with 22 patients enrolled from May 2005–September 2007. One patient was ineligible (tumor\20 cm from incisors). Male/Female = 15/6, Zubrod P-Status 0–1 = 20, 2 = 1, Adeno/Squam = 10/11, white/Nonwhite = 15/6, median age 61 years. Two deaths were due to protocol treatment (sudden death and GI necrosis); 5 patients had multiple Grade 4 toxicities. A total of 48% and 29% of patients had Grade 3 and 4 toxicity, respectively, 52% hematologic, 24% fatigue, 19% nausea/emesis, 19% dehydration, and 19% anorexia. Seventeen patients could be evaluated for RECIST response, including 1 CR (6%), 1 PR (6%), and 3 Stable dx (18%). Median PFS = 6 months and OS = 11 months after 23 months of follow-up. Gene expression levels were available for 17 patients. Median (range) levels were COX2: 1.96 (0.25–17.09); EGFR: 3.22 (1.08–58.99); ERCC1: 1.66 (0.88–4.70); ERCC2: 1.54 (0.53–6.65); and GSTPpi: 5.03 (2.37–43.99). Conclusions: Concomitant cetuximab, CDDP, CPT11, and TRT for patients with EC were poorly tolerated in the first cooperative group trial with this regimen, as mortality approached 10%. Single-institution Phase II cetuximab-based CRT has yielded encouraging results in preliminary analysis. Hence, SWOG endorses enrollment on RTOG-0436 in order to further define the therapeutic ratio of cetuximab-based combined-modality Rx. Data on 2-year survival and correlation with molecular markers is forthcoming. Author Disclosure: C.R. Thomas, None; B.H. Goldman, None; J.K. Benedetti, None; H.J. Lenz, Response Genetics, E. Ownership Interest; T.A. Baker, None; L. Hammond-Thelin, None; V.K. Mehta, None; C.M. Fenoglio-Preiser, None; J.L. Abbruzzese, None; C.D. Blanke, None.
1095
Patterns of Failure in Patients with Anal Canal Carcinoma Treated with 3-D-based Radiotherapy using Conformal Therapy or Intensity Modulated Radiation Therapy in Combination with Chemotherapy
D. A. Cuthbert, T. Vuong, S. Devic, G. Artho, T. Alcindor, P. Charlebois, B. Stein McGill University, Montreal, QC, Canada Purpose/Objective(s): To analyze patterns of failure in patients with anal canal cancer treated with 3D based radiation therapy using either conformal therapy or intensity modulated radiation therapy (IMRT) combined with chemotherapy (CT). Materials/Methods: All patients treated with curative intent from 1998–2008 were analyzed. Treatment consisted of 3D-CRT (7 fields) from 1998–2005 or IMRT (5–7 fields) from 2005–2008. Clinical target volume (CTV) included the tumor bed, perirectal
S168
Volume 75, Number 3, Supplement, 2009
Results: A total of 164 patients had received preoperative radiochemotherapy (45 Gy with continuous 5-FU) and 52 patients postoperative radiochemotherapy (50.4 Gy with 5-FU continuously or bolus). The most prevalent fecal symptoms were: diarrhea (80%), flatulence (75%), and tenesmus (15%). In patients without a colostomy (n = 152), only 18% reported a perfect fecal continence. Incontinence involved mainly gas (73%) and liquid stool (66%) with 16% reporting incontinence for solid stool. A total of 46% of the non-colostomy patients reported to wear pads because of fecal incontinence and 49% were unable to delay defecation for more than 15 minutes. Patients with low lying tumors (p = 0.006) and those with reoperation because of anastomotic leakage (p = 0.041) experienced more incontinence. Global QOL (p = 0.041), physical functioning (p \ 0.001) and role functioning (p \ 0.001) were significantly lower in colostomy patients as compared to non-colostomy patients. Higher (above median) incontinence score values were associated with lower global QOL (p = 0.002) as well as lower role functioning (0.014), cognitive functioning (p\0.001) and social functioning (p\0.001). As compared to the age- and gender-adjusted German general population (Schwarz and Hinz; Eur J Cancer 2001) QOL was significantly compromised in younger patients (50–60-years-old) affecting in particular role functioning, emotional functioning, cognitive functioning, social functioning, and fatigue, while in older patients (.60-yearsold) QOL-reduction was less pronounced and involved mainly social functioning. Conclusions: Ano-rectal function after combined radiochemotherapy and sphincter-preserving surgery for locally-advanced rectal cancer is suboptimal especially in patients with low-lying tumors. Patients with compromised fecal continence report significantly lower QOL levels in particular for social functioning. Survivors after multimodality treatment of rectal cancer might benefit from prolonged physical and social rehabilitation especially those under the age of 60. Author Disclosure: H. Geinitz, None; A. Kamp, None; A. Seidl, None; R. Thamm, None; R. Rosenberg, None; F. Lordick, None; M. Fuchs, None; W. Heitland, None; F. Zimmermann, None; M. Molls, None.
1094
Cetuximab (C225) Plus Cisplatin (CDDP) Irinotecan (CPT11) and Thoracic Radiotherapy (TRT) Definitive Treatment for Locally-advanced, Clinically Unresectable Esophageal Cancer: A Southwest Oncology Group (SWOG) Phase II Trial with Molecular Correlates (S0414)
C. R. Thomas1, B. H. Goldman2, J. K. Benedetti2, H. J. Lenz3, T. A. Baker4, L. Hammond-Thelin5, V. K. Mehta6, C. M. FenoglioPreiser7, J. L. Abbruzzese8, C. D. Blanke9 1 OHSU Knight Cancer Institute, Portland, OR, 2Southwest Oncology Group Statistical Center, Seattle, WA, 3University of Southern California, Los Angeles, CA, 4Gulf Coast MBCCOP, Mobile, AL, 5San Antonio Cancer Institute, San Antonio, TX, 6 Swedish Cancer Institute, Seattle, WA, 7Southwest Oncology Group GI Committee, Ann Arbor, MI, 8M. D. Anderson Cancer Center, Houston, TX, 9University of British Columbia, Vancouver, BC, Canada Purpose/Objective(s): While RTOG-8501 established definitive concomitant chemoradiotherapy (CRT) as a standard of care for patients with locally-advanced EC in the United States, median overall survival (OS) for patients has changed little over the past 2 decades. Thus, new regimens are needed. Based on Phase I–II data of CDDP, CPT11, and TRT and separate Phase I–III data of cetuximab, SWOG GI Committee designed a Phase II trial (S0414) to test this novel combined-modality approach. Specific aims were to: (1) assess 2-year OS, (2) toxicity profile, (3) objective response rate (RR), (4) time-to-progression (TTP), and (5) association between gene expression levels and germ line polymorphisms involved in DNA repair, drug metabolism, the EGFR pathway, and clinical outcome. Materials/Methods: Eligibility: cT4M0 disease or medically unresectable, biopsy-proven, primary EC (squamous cell or adenocarcinoma), thoracic-GE junction location, with adequate major organ function. Cetuximab 400 mg/m2 was given Day 1 of cycle (C) 1, cetuximab 250 mg/m2 was given Day 8, and 15 of C1 and Day 1, 8, and 15 for subsequent C; CDDP 30 mg/m2 was given Day 1, and 8 each C; CPT11 65 mg/m2 was given Day 1, and 8 each C. the TRT started Day 1 C3 @ 1.8 Gy/d 28 fractions, 5 days/ week to a total dose of 50.4 Gy. Planned accrual was 75 adeno patients and 25 squamous cell patients, with the regimen considered of further interest if 2-year OS $43%. Results: The study was closed due to slow accrual, with 22 patients enrolled from May 2005–September 2007. One patient was ineligible (tumor\20 cm from incisors). Male/Female = 15/6, Zubrod P-Status 0–1 = 20, 2 = 1, Adeno/Squam = 10/11, white/Nonwhite = 15/6, median age 61 years. Two deaths were due to protocol treatment (sudden death and GI necrosis); 5 patients had multiple Grade 4 toxicities. A total of 48% and 29% of patients had Grade 3 and 4 toxicity, respectively, 52% hematologic, 24% fatigue, 19% nausea/emesis, 19% dehydration, and 19% anorexia. Seventeen patients could be evaluated for RECIST response, including 1 CR (6%), 1 PR (6%), and 3 Stable dx (18%). Median PFS = 6 months and OS = 11 months after 23 months of follow-up. Gene expression levels were available for 17 patients. Median (range) levels were COX2: 1.96 (0.25–17.09); EGFR: 3.22 (1.08–58.99); ERCC1: 1.66 (0.88–4.70); ERCC2: 1.54 (0.53–6.65); and GSTPpi: 5.03 (2.37–43.99). Conclusions: Concomitant cetuximab, CDDP, CPT11, and TRT for patients with EC were poorly tolerated in the first cooperative group trial with this regimen, as mortality approached 10%. Single-institution Phase II cetuximab-based CRT has yielded encouraging results in preliminary analysis. Hence, SWOG endorses enrollment on RTOG-0436 in order to further define the therapeutic ratio of cetuximab-based combined-modality Rx. Data on 2-year survival and correlation with molecular markers is forthcoming. Author Disclosure: C.R. Thomas, None; B.H. Goldman, None; J.K. Benedetti, None; H.J. Lenz, Response Genetics, E. Ownership Interest; T.A. Baker, None; L. Hammond-Thelin, None; V.K. Mehta, None; C.M. Fenoglio-Preiser, None; J.L. Abbruzzese, None; C.D. Blanke, None.
1095
Patterns of Failure in Patients with Anal Canal Carcinoma Treated with 3-D-based Radiotherapy using Conformal Therapy or Intensity Modulated Radiation Therapy in Combination with Chemotherapy
D. A. Cuthbert, T. Vuong, S. Devic, G. Artho, T. Alcindor, P. Charlebois, B. Stein McGill University, Montreal, QC, Canada Purpose/Objective(s): To analyze patterns of failure in patients with anal canal cancer treated with 3D based radiation therapy using either conformal therapy or intensity modulated radiation therapy (IMRT) combined with chemotherapy (CT). Materials/Methods: All patients treated with curative intent from 1998–2008 were analyzed. Treatment consisted of 3D-CRT (7 fields) from 1998–2005 or IMRT (5–7 fields) from 2005–2008. Clinical target volume (CTV) included the tumor bed, perirectal