Pre- Versus Post-operative Radiotherapy

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1 Postoperative Radiation and Chemoradiation: Indications and Optimization of Practice Dislosures Clinical trial support from Genentech Inc. Sue S. Yom, MD, PhD Associate Professor UCSF Radiation Oncology Clinical Indicators of Increased Post- Operative Risk Tumor at or close to surgical margin Perineural Invasion Cartilage invasion Invasion of bone or soft tissues of the neck Emergent Tracheostomy Pre- Versus Post-operative Radiotherapy Lymph-vascular Invasion Multiple (> 2) lymph node metastasis Extra capsular extension RTOG 73-03! RT + Surgery for Head & Neck Carcinoma! Larynx! Hypopharynx! Stage II-IV! S! T! T! F! Y! Sex! T-Stage! N-Stage! OC & OP also had definitive RT arm (65-70 Gy) with surgery for residual cancer Pre-op RT (50 Gy)+ surgery Surgery + Post-op RT (60 Gy) Kramer, Head Neck Surg 1987;10:19-30 RTOG N=277, 10y followup Treatment Group!!LR Control!!Survival! Pre-op RT 58% 33% (N = 136) p = 0.04! p = 0.10! Post-op RT 70% 38% (N = 141) Surgery and RT complics similar in two groups Tupchong et al. IJROBP 20:21-28,1991" 1

2 Historical PORT results Locoregional control 69-72% 5-year survival 30-40% Radiation Dose MD Anderson randomized dose-finding study N=240 Stratification! Oral Cavity! Larynx! Hypopharynx! Larynx! Low risk -> no radiation Int Risk* High Risk Dose A 57 Gy/32 Fx Dose B 63 Gy/35 Fx Dose C 68.4 Gy/38 Fx Based on T- & N-stage, margin, PNI Raised midway from Gy/29-30 Fx MDA dose finding results <54 Gy had significantly higher failure rate ECE needed at least 63 Gy 2-3 negative factors increased LR recurrence risk: oral cavity close/pos margins perineural >2 involved nodes node >3 cm treatment delay >6 wks Zubrod performance status>2 4 negative factors à locoregional recurrence risk similar to ECE Radiation Timing Peters, IJROBP, 1993, 26:3-11 2

3 MD Anderson study on accelerated RT oral cavity, oropharynx, larynx, hypopharynx Last 2 wks CCB LRC & OS by package time (date of surgery to PORT completion) for high risk pts Pathologic T stage was T3 4 in 129 (61%) and N2 3 in 123 (58%) patients Ang KK, IJROBP 2001, 51:571 LRC and OS based on interval from surgery to PORT median = 31d Chemotherapy Rationale for chemoradiation To overcome radioresistance To increase local control To eradicate systemic micro mets Randomized trials of RT vs chemort: EORTC & RTOG 9501 To counteract accelerated repopulation after surgical cytoreduction NEJM 2004; 350: NEJM 2004: 350:

4 EORTC vs RTOG LRC 11-13% improvement EORTC RTOG EORTC vs RTOG OS 10-11% improvement EORTC RTOG NOT STATISTICALLY SIGNIFICANT EORTC & RTOG - Combined data 30% reduction in risk of death RTOG 9501: 10 year followup No overall benefit for LRC or OS from postop chemoradiation at 10 years LRC still better for ECE or pos margins Multiple nodes without ECE or pos margin: shows no LRC benefit from postop CRT Analysis of patients with up to 6 involved nodes Conclusion: Multiple nodes is not an indicator for postoperative chemoradiation Suggestion of unexplained non-cancer related deaths in patients who received chemo in absence of ECE/+marg Other ideas: Using Targeted Therapy RTOG 0920 for intermediate (NOT HIGH RISK) cancers OC, larynx, OPX p16+/- Intermediate risk factors: ct2-3, N0-2 (minimal T4a) Stage III-IVA PNI LVSI Close <5mm >5mm deep RT: 60 Gy in 30 fractions RT: 60 Gy in 30 fractions Cetuximab 400 mg/m2 loading, 250 mg/m2 x 10 cycles Open and accruing, goal is 700 pts 4

5 Postop chemoradiation + targeted therapy: phase II RTOG 0234 for high risk disease cetuximab cetuximab Historically based comparison: DFS for RT-Doc/cetuximab vs RTOG 9501 Disease-Free Survival (%) Patients at Risk RTOG 0234 RTOG Years after Registration / / / 0234 RT+Doc+Cet / / / // / /// /// / // / /// / / / // / / HR (95% CI) / / / / / 0.72 (0.50, 1.02) / 1-sided log-rank p= RT+CDDP Led to creation of RTOG 1216: open trial of cisplatin vs docetaxel vs doc+cetux Special case? Extracapsular extension in HPV resected dz Reporting of ECE in practice is not graded/detailed Clinical guidelines and randomized study data do not differentiate between different types of ECE Lewis et al, Modern Path 2011 For p16+ oropharynx cancer, ECE may not carry negative prognosis until it reaches the level of soft tissue metastasis i.e. obliteration of nodal architecture (Sinha 2011) Caveat: based on Washington University retrospective review in which half the patients received chemo-rt Conclusions Postoperative not preoperative radiation is standard. Accelerated fractionation may benefit patients with a delayed RT start. Total treatment package time is highly prognostic for high risk patients. Patients with 2 LN, ECE, +margins are at the highest risk for recurrence. 4+ clustered factors confer poor prognosis similar to ECE. Postop chemo-rt is beneficial for patients with involved margins or ECE or both. Postoperative therapy for HPV+ disease follows the standard of care for the moment but prognostic factors are being re-analyzed. Current trials incorporate targeted therapies; immunebased therapy is a future possibility. 5