Pre- Versus Post-operative Perineural Invasion Cartilage invasion - - PDF document

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Postoperative Radiation and Chemoradiation: Indications and Optimization of Practice

Sue S. Yom, MD, PhD Associate Professor UCSF Radiation Oncology

Dislosures

• Clinical trial support from Genentech Inc.

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
• Lymph-vascular Invasion
• Multiple (> 2) lymph node metastasis
• Extra capsular extension

Pre- Versus Post-operative Radiotherapy

RTOG 73-03 RT + Surgery for Head & Neck Carcinoma

Larynx Hypopharynx Stage II-IV

S

• T
• R
• A
• T
• I
• F
• Y
• Sex

T-Stage N-Stage

R

• A
• N
• D
• O
• M
• I
• Z
• E
• Pre-op RT (50 Gy)+

surgery Surgery + Post-op RT (60 Gy)

Kramer, Head Neck Surg 1987;10:19-30

OC & OP also had definitive RT arm (65-70 Gy) with surgery for residual cancer

RTOG 73-03

Pre-op RT 58% 33% (N = 136) Post-op RT 70% 38% (N = 141)

p = 0.04

Treatment Group LR Control Survival

Tupchong et al. IJROBP 20:21-28,1991

p = 0.10

Surgery and RT complics “similar” in two groups

N=277, 10y followup

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Historical PORT results

• Locoregional control 69-72%
• 5-year survival 30-40%

Radiation Dose

Stratification

• Oral Cavity
• Larynx
• Hypopharynx
• Larynx

R

• A
• N
• D
• O
• M
• I
• Z
• E
• Dose A 57 Gy/32 Fx

Dose B 63 Gy/35 Fx Dose C 68.4 Gy/38 Fx

Int Risk* High Risk

MD Anderson randomized dose-finding study

• Based on T- & N-stage, margin, PNI
• Raised midway from 52.2-54 Gy/29-30 Fx

N=240

Low risk -> no radiation

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 à locoregional recurrence risk similar to ECE

Peters, IJROBP, 1993, 26:3-11

Radiation Timing

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MD Anderson study on accelerated RT

Ang KK, IJROBP 2001, 51:571

• ral cavity,
• ropharynx,

larynx, hypopharynx Pathologic T stage was T3–4 in 129 (61%) and N2–3 in 123 (58%) patients

Last 2 wks CCB

LRC & OS by package time (date of surgery to PORT completion) – for high risk pts

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
• To counteract accelerated repopulation

after surgical cytoreduction

Randomized trials of RT vs chemoRT: EORTC 22931 & RTOG 9501

NEJM 2004; 350:1945-1952 NEJM 2004: 350:1937-1944

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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 R

• A
• N
• D
• O
• M
• I
• Z
• E
• 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

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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 (%) 25 50 75 100 Years after Registration 1 2 3 Disease-Free Survival (%) 25 50 75 100 Years after Registration 1 2 3 Patients at Risk RTOG 0234 RTOG 9501 106 202 82 131 56 109 14 90 HR (95% CI) 0.72 (0.50, 1.02) 1-sided log-rank p=0.031 0234 RT+Doc+Cet 9501 RT+CDDP

/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

Led to creation of RTOG 1216:

• pen trial of

cisplatin vs docetaxel vs doc+cetux

Special case? Extracapsular extension in HPV resected dz

• 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

• 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

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; immune-

based therapy is a future possibility.