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Adaptive Chemoradiation Therapy for Head and Neck Cancer Based on Multiparametric MRI: Interim Results of a Prospective Randomized Trial
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Volume 99 Number 2S Supplement 2017 had negative margins, and 37 had positive margins. When used, the median dose for adjuvant radiation was 60 Gy (range 48-70.4 Gy). Compared to negative margins, NAAE margins were associated with having a T3-4 stage, an N2-3 stage, ECE, PNI, a larger depth of invasion, and adjuvant radiation/chemoradiation. For patients with negative, NAAE, and positive margins, the 2-year estimates of LRR were 27%, 36%, and 47% (pZ0.06), and 2-year estimates of PFS were 65%, 50%, and 22% (p<0.001). On multivariate analysis, compared to NAAE margins, positive margins had a trend for worse LRR (HR 2.35, pZ0.13) and inferior PFS (HR 2.10, pZ0.0008); whereas outcomes were more favorable for negative margins but not statistically significant (LRR HR 0.83, pZ0.34; PFS HR 0.85, pZ0.32). Similar results were seen for patients with adverse risk features who received adjuvant radiation for negative compared to NAAE margins (LRR HR 0.70, pZ0.22; PFS HR 0.74, pZ0.20). Conclusion: Our institutional experience indicates that there may be a benefit to having negative margins of the initial specimen compared to margins that are NAAE. Positive margins for patients with OCSCC are associated with inferior outcomes. Author Disclosure: J.P. Harris: None. J.L. Shah: None. K.B. Schaberg: None. M.M. Chen: None. J.J. Chen: None. T.T. Bui: None. V. Divi: None. C.S. Kong: None. W. Hara: task force member; NCI Metastatic and Recurrent Head & Neck Task Forc.
2804 Adaptive Chemoradiation Therapy for Head and Neck Cancer Based on Multiparametric MRI: Interim Results of a Prospective Randomized Trial P.G. Hawkins,1 J.Y. Lee,1 C. Lee,1 M. Green,1 M.L. Mierzwa,2 M.P. Aryal,1 G.S. Arnould,1 F. Worden,1 P.L. Swiecicki,1 M.E. Spector,1 M. Schipper,1 Y. Cao,1 and A. Eisbruch1; 1University of Michigan, Ann Arbor, MI, 2Department of Radiation Oncology, University of Michigan, Ann Arbor, MI Purpose/Objective(s): Tumor regions characterized by hypo-perfusion (HP) with dynamic contrast-enhanced (DCE)-MRI and restricted diffusion (RD) with diffusion-weighted (DW)-MRI have been reported to harbor aggressive disease. We report interim results of a randomized trial assessing radiation boost to HP and RD sub-volumes in poor-prognosis head and neck cancer (HNC). Materials/Methods: Prospective randomized trial: Patients with either HPV (+), T4/N3 HNC and a heavy smoking history, or HPV (-), T3-4/N3 HNC undergo multiparametric MRI at baseline and 2 weeks mid-treatment. HP is defined as DCE-MRI-measured plasma volume <0.042cc/gr. RD is defined as DW-MRI-measured apparent diffusion coefficient <1.2x10-3mm2/sec. We characterize the HP and RD regions within the tumor prior to and after 2 weeks of chemo-radiation. Patients with spatially stable HP or RD sub-volumes at both baseline and 2 weeks are randomized to boost to these sub-volumes, to biologically equivalent 86 Gy, versus standard dose (70 Gy). Paired two-tailed t-tests were used to compare changes in sub-volumes, and univariate Cox-regression to correlate clinical and imaging variables with locoregional failure (LRF). Results: Thirty of planned 80 patients have been randomized to date: 15 to receive boost and 15 to standard therapy. Six additional patients did not retain high-risk sub-volumes at 2 weeks and were treated to the standard dose, yielding 36 patients with evaluable baseline and 2-week multiparametric MRI studies. The HP sub-volume comprised a mean of 23% of the primary tumor at baseline and 15% at 2 weeks (pZ0.042). The RD sub-volume comprised a mean of 41% of the primary tumor at baseline and 21% at 2 weeks (p<0.001). The average volume of overlap between the HP and RD sub-volumes comprised 8% of the primary tumor at baseline and 3% at 2 weeks (pZ0.036). The sub-volumes planned for boost, comprising both stable HP and RD, averaged 15% of the primary tumor at 2-weeks. At median follow-up 8.1 months, 33 patients were evaluable for clinical outcome: 15 treated with boost and 18 with standard dose. Of these, 2 (13%) and 4 (22%) patients experienced LRF in the boost and standard arms, respectively. All failures in the boost arm were HPV (-), while in the standard arm, 2 LRF occurred HPV (+) patients. No difference
in grade >Z 3 acute or late toxicities was observed between arms. Mean RD subvolume at 2 weeks emerged as a marginally significant factor for LRF. Conclusion: HP and RD sub-volumes are spatially distinct and only slightly overlap in advanced HNC, suggesting they represent different biological features of aggressive cancer and providing rationale for using both to direct radiation boost, as done in the current study. As this study continues, we will assess whether LRF arise preferentially in regions of HP or RD, and whether boosting these regions improves locoregional control. Author Disclosure: P.G. Hawkins: None. J.Y. Lee: None. C. Lee: None. M. Green: None. M.L. Mierzwa: None. M.P. Aryal: None. G.S. Arnould: None. F. Worden: Research Grant; Bristol Myers Squibb. Honoraria; Bristol Myers Squibb, Merck. Advisory Board; Bristol Myers Squibb, Genzyme, Merck. P.L. Swiecicki: None. M.E. Spector: None. M. Schipper: Consultant; Armune Bioscience and Hygieia Sciences. Y. Cao: Research Grant; Siemens, Epicentrix, Inc, NIH, Siemens. Honoraria; Siemens. Patent/License Fees/Copyright; US Patent 61/656,323. A. Eisbruch: Research Grant; NIH. Co-chair; NIH.
2805 Radiation Doses to All Salivary Glands Affect Patient-Reported Xerostomia and Quality of Life: A Longitudinal Study P.G. Hawkins,1 J.Y. Lee,1 Y. Mao,2 M. Green,1 F. Worden,1 P.L. Swiecicki,1 M.E. Spector,1 M. Schipper,1 P. Li,1 and A. Eisbruch1; 1 University of Michigan, Ann Arbor, MI, 2Cancer Center, Sun Yat-sen University, Guangzhou, China Purpose/Objective(s): Randomized studies comparing 2-dimensional (2D) radiotherapy (RT) and parotid-sparing intensity-modulated RT (IMRT) in patients with head and neck cancer (HNC) have demonstrated improvements in saliva output and observer-rated xerostomia with IMRT. However, patient-reported xerostomia (PRX) has either not differed (Kam MK et al., JCO, 2007) or been only marginally better with IMRT in the first year post-therapy (Nutting CM et al., Lancet Oncology, 2011). We hypothesized that doses to all salivary glands, including the mucin-producing submandibular and minor glands within the oral cavity, are important determinants of PRX. We sought to assess the effect of doses to these structures in patients with HNC receiving IMRT aiming to spare all glands. Materials/Methods: Patients with HNC receiving IMRT to the bilateral neck answered a validated xerostomia questionnaire (XQsum) consisting of 4 questions inquiring about oral dryness during eating and speaking (XQeat), and 4 about dryness at rest (XQrest), as well as a validated, multidomain HN quality of life questionnaire (HNQOL). The scale for XQ ranges from 0-100, with higher scores denoting worse xerostomia. PRX and HNQOL data were obtained at each follow-up visit through 48 months. Univariate and multivariate Cox-regression were used to correlate PRX and HNQOL scores with clinical factors, time since therapy, and mean RT doses to the parotid glands (PG), contralateral submandibular gland (SMG), and oral cavity (OC). These factors were combined into random effect models to account for within-person correlations arising from repeated measures. Results: Two-hundred and fifty-two HNC patients treated with IMRT completed a total of approximately 600 PRX and HNQOL questionnaires through 48 months post-RT. Median mean doses to both parotids, contralateral SMG, and OC, were 36 (range 3-64), 31 (6-57), and 37 (8-70) Gy, respectively. Mean OC doses correlated moderately with both mean PG (rZ0.42, p<0.001) and SMG (rZ0.34, p<0.001) doses, as did mean PG and SMG doses with each other (rZ0.33, p<0.001). Mean XQsum scores were 39 (standard deviation 21), 31 (22), 29 (22), and 27 (21) at 1, 12, 24, and 48 months post-RT, respectively. On univariate analysis, N stage, and mean PG, SMG, and OC doses statistically significantly correlated with XQsum, XQeat, XQrest, HNQOL Summary, and HNQOL Eating domain scores (all p<0.01). In all instances, higher mean doses were associated with higher (worse) scores. Scores improved significantly over time, with steeper improvement of XQsum at lower SMG dose. On
Volume 99 Number 2S Supplement 2017 had negative margins, and 37 had positive margins. When used, the median dose for adjuvant radiation was 60 Gy (range 48-70.4 Gy). Compared to negative margins, NAAE margins were associated with having a T3-4 stage, an N2-3 stage, ECE, PNI, a larger depth of invasion, and adjuvant radiation/chemoradiation. For patients with negative, NAAE, and positive margins, the 2-year estimates of LRR were 27%, 36%, and 47% (pZ0.06), and 2-year estimates of PFS were 65%, 50%, and 22% (p<0.001). On multivariate analysis, compared to NAAE margins, positive margins had a trend for worse LRR (HR 2.35, pZ0.13) and inferior PFS (HR 2.10, pZ0.0008); whereas outcomes were more favorable for negative margins but not statistically significant (LRR HR 0.83, pZ0.34; PFS HR 0.85, pZ0.32). Similar results were seen for patients with adverse risk features who received adjuvant radiation for negative compared to NAAE margins (LRR HR 0.70, pZ0.22; PFS HR 0.74, pZ0.20). Conclusion: Our institutional experience indicates that there may be a benefit to having negative margins of the initial specimen compared to margins that are NAAE. Positive margins for patients with OCSCC are associated with inferior outcomes. Author Disclosure: J.P. Harris: None. J.L. Shah: None. K.B. Schaberg: None. M.M. Chen: None. J.J. Chen: None. T.T. Bui: None. V. Divi: None. C.S. Kong: None. W. Hara: task force member; NCI Metastatic and Recurrent Head & Neck Task Forc.
2804 Adaptive Chemoradiation Therapy for Head and Neck Cancer Based on Multiparametric MRI: Interim Results of a Prospective Randomized Trial P.G. Hawkins,1 J.Y. Lee,1 C. Lee,1 M. Green,1 M.L. Mierzwa,2 M.P. Aryal,1 G.S. Arnould,1 F. Worden,1 P.L. Swiecicki,1 M.E. Spector,1 M. Schipper,1 Y. Cao,1 and A. Eisbruch1; 1University of Michigan, Ann Arbor, MI, 2Department of Radiation Oncology, University of Michigan, Ann Arbor, MI Purpose/Objective(s): Tumor regions characterized by hypo-perfusion (HP) with dynamic contrast-enhanced (DCE)-MRI and restricted diffusion (RD) with diffusion-weighted (DW)-MRI have been reported to harbor aggressive disease. We report interim results of a randomized trial assessing radiation boost to HP and RD sub-volumes in poor-prognosis head and neck cancer (HNC). Materials/Methods: Prospective randomized trial: Patients with either HPV (+), T4/N3 HNC and a heavy smoking history, or HPV (-), T3-4/N3 HNC undergo multiparametric MRI at baseline and 2 weeks mid-treatment. HP is defined as DCE-MRI-measured plasma volume <0.042cc/gr. RD is defined as DW-MRI-measured apparent diffusion coefficient <1.2x10-3mm2/sec. We characterize the HP and RD regions within the tumor prior to and after 2 weeks of chemo-radiation. Patients with spatially stable HP or RD sub-volumes at both baseline and 2 weeks are randomized to boost to these sub-volumes, to biologically equivalent 86 Gy, versus standard dose (70 Gy). Paired two-tailed t-tests were used to compare changes in sub-volumes, and univariate Cox-regression to correlate clinical and imaging variables with locoregional failure (LRF). Results: Thirty of planned 80 patients have been randomized to date: 15 to receive boost and 15 to standard therapy. Six additional patients did not retain high-risk sub-volumes at 2 weeks and were treated to the standard dose, yielding 36 patients with evaluable baseline and 2-week multiparametric MRI studies. The HP sub-volume comprised a mean of 23% of the primary tumor at baseline and 15% at 2 weeks (pZ0.042). The RD sub-volume comprised a mean of 41% of the primary tumor at baseline and 21% at 2 weeks (p<0.001). The average volume of overlap between the HP and RD sub-volumes comprised 8% of the primary tumor at baseline and 3% at 2 weeks (pZ0.036). The sub-volumes planned for boost, comprising both stable HP and RD, averaged 15% of the primary tumor at 2-weeks. At median follow-up 8.1 months, 33 patients were evaluable for clinical outcome: 15 treated with boost and 18 with standard dose. Of these, 2 (13%) and 4 (22%) patients experienced LRF in the boost and standard arms, respectively. All failures in the boost arm were HPV (-), while in the standard arm, 2 LRF occurred HPV (+) patients. No difference
in grade >Z 3 acute or late toxicities was observed between arms. Mean RD subvolume at 2 weeks emerged as a marginally significant factor for LRF. Conclusion: HP and RD sub-volumes are spatially distinct and only slightly overlap in advanced HNC, suggesting they represent different biological features of aggressive cancer and providing rationale for using both to direct radiation boost, as done in the current study. As this study continues, we will assess whether LRF arise preferentially in regions of HP or RD, and whether boosting these regions improves locoregional control. Author Disclosure: P.G. Hawkins: None. J.Y. Lee: None. C. Lee: None. M. Green: None. M.L. Mierzwa: None. M.P. Aryal: None. G.S. Arnould: None. F. Worden: Research Grant; Bristol Myers Squibb. Honoraria; Bristol Myers Squibb, Merck. Advisory Board; Bristol Myers Squibb, Genzyme, Merck. P.L. Swiecicki: None. M.E. Spector: None. M. Schipper: Consultant; Armune Bioscience and Hygieia Sciences. Y. Cao: Research Grant; Siemens, Epicentrix, Inc, NIH, Siemens. Honoraria; Siemens. Patent/License Fees/Copyright; US Patent 61/656,323. A. Eisbruch: Research Grant; NIH. Co-chair; NIH.
2805 Radiation Doses to All Salivary Glands Affect Patient-Reported Xerostomia and Quality of Life: A Longitudinal Study P.G. Hawkins,1 J.Y. Lee,1 Y. Mao,2 M. Green,1 F. Worden,1 P.L. Swiecicki,1 M.E. Spector,1 M. Schipper,1 P. Li,1 and A. Eisbruch1; 1 University of Michigan, Ann Arbor, MI, 2Cancer Center, Sun Yat-sen University, Guangzhou, China Purpose/Objective(s): Randomized studies comparing 2-dimensional (2D) radiotherapy (RT) and parotid-sparing intensity-modulated RT (IMRT) in patients with head and neck cancer (HNC) have demonstrated improvements in saliva output and observer-rated xerostomia with IMRT. However, patient-reported xerostomia (PRX) has either not differed (Kam MK et al., JCO, 2007) or been only marginally better with IMRT in the first year post-therapy (Nutting CM et al., Lancet Oncology, 2011). We hypothesized that doses to all salivary glands, including the mucin-producing submandibular and minor glands within the oral cavity, are important determinants of PRX. We sought to assess the effect of doses to these structures in patients with HNC receiving IMRT aiming to spare all glands. Materials/Methods: Patients with HNC receiving IMRT to the bilateral neck answered a validated xerostomia questionnaire (XQsum) consisting of 4 questions inquiring about oral dryness during eating and speaking (XQeat), and 4 about dryness at rest (XQrest), as well as a validated, multidomain HN quality of life questionnaire (HNQOL). The scale for XQ ranges from 0-100, with higher scores denoting worse xerostomia. PRX and HNQOL data were obtained at each follow-up visit through 48 months. Univariate and multivariate Cox-regression were used to correlate PRX and HNQOL scores with clinical factors, time since therapy, and mean RT doses to the parotid glands (PG), contralateral submandibular gland (SMG), and oral cavity (OC). These factors were combined into random effect models to account for within-person correlations arising from repeated measures. Results: Two-hundred and fifty-two HNC patients treated with IMRT completed a total of approximately 600 PRX and HNQOL questionnaires through 48 months post-RT. Median mean doses to both parotids, contralateral SMG, and OC, were 36 (range 3-64), 31 (6-57), and 37 (8-70) Gy, respectively. Mean OC doses correlated moderately with both mean PG (rZ0.42, p<0.001) and SMG (rZ0.34, p<0.001) doses, as did mean PG and SMG doses with each other (rZ0.33, p<0.001). Mean XQsum scores were 39 (standard deviation 21), 31 (22), 29 (22), and 27 (21) at 1, 12, 24, and 48 months post-RT, respectively. On univariate analysis, N stage, and mean PG, SMG, and OC doses statistically significantly correlated with XQsum, XQeat, XQrest, HNQOL Summary, and HNQOL Eating domain scores (all p<0.01). In all instances, higher mean doses were associated with higher (worse) scores. Scores improved significantly over time, with steeper improvement of XQsum at lower SMG dose. On