Transcript Post-operative Radiotherapy for Esophageal Cancer Parag Sanghvi, M.D., M.S.P.H. Department of Radiation Medicine Esophageal Care Conference 3/26/2007

Post-operative
Radiotherapy for
Esophageal Cancer
Parag Sanghvi, M.D., M.S.P.H.
Department of Radiation Medicine
Esophageal Care Conference
3/26/2007
Background

5 year OS for locally advanced
esophageal cancers (T3 or above, N+) is
dismal
Preoperative ChemoRT vs. Postoperative ChemoRT

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This has not been studied in a randomized trial
head to head
Prefer pre-operative chemoRT
Allows for tumor downstaging  R0 resection
 Complete pathologic response improves survival
 Feasibility and Patient compliance
 ? Earlier control of micro-metastatic disease


Only 1 of 6 randomized trials have shown OS
benefit to neoadjuvant chemoRT (Walsh)
Preoperative ChemoRT trials
Post-operative RT+/Chemotherapy
Data is primarily from Asia and Europe
 Most randomized trials have looked at
Surgery + RT vs. Surgery alone
 No randomized trial has compared postoperative concurrent chemoRT to either
chemotherapy or RT alone

Indications for Post-operative RT
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Standard Indications
 Positive
Margins
 Gross Residual Disease

Less Clear

+ LN
 + ECE on adenopathy
Current NCCN Guidelines for
Post-operative Therapy
Randomized Trials
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Teniere et al Surg Gynecol Obstet. Aug 1991; 173(2):
123-30 (France)
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Fok et al Surgery. Feb 1993; 113(2) 138-47 (Hong
Kong)
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S + RT vs. S
Xiao et al The Annals of Thoracic Surgery Feb 2003;
75(2): 331-336 (China)
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S+ RT vs. S
LN +  S+ RT vs. S
Macdonald et al NEJM. Sept 2001; 345:725-730 (USA)

GE junction  S + CRT vs. S
French trial – Post-operative
Radiation for Esophageal SCCA
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221 patients treated with “curative” resection
Squamous cell histology; mid/distal location
Post-op RT 45-55 Gy vs. Observation
Post-op RT did not improve OS
5 y OS 19% (38% if node -; 7% if node +
Locoregional failure decreased after RT: 30 %  15%
Benefit significant in node negative patients: 35% LR
failure vs. 10%
Hong Kong Trial – Postoperative
RT for Esophageal cancer
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Single institution randomized trial, 130
patients
Curative Resection 60 patients  30 S+ RT
vs. 30 S
 Palliative Resection 70 patients  35 S + RT
vs. 35 S
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RT dose/technique unknown
Hong Kong Trial - Results
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Overall Median Survival, All patients
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Local Recurrence, Palliative Surgery patients
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S+RT 10% vs. S 13%
Complications
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S+ RT 20% vs. S 46 % (p=0.04)
Local Recurrence, Curative Surgery
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
S + RT 8.7 months vs. S 15.2 months (p=0.02)
S+RT 37% vs. S 6% (p<0.0001)
Intra-thoracic recurrence, All patients

S+RT 4 patients vs. S 13 patients (p=0.01)
Chinese trial – Post-operative
radiation for Esophageal SCCA
Randomized to post-operative RT vs.
observation; 495 patients  275 S, 220
S+ RT
 Most of mid thoracic esophagus (67%), T3
(69%) and 48% had + LN
 Margin status unknown
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Chinese Trial – RT parameters
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RT
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Extended Field RT
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Included bilateral SCV, mediastinal and peri-gastric
LN
60 Gy
Chinese Trial - Results
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5 y OS
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S+ RT 41.3 % vs. S 37.1 % (p=0.45)
LN –
 S+RT
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LN+
 S+RT
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29.2 % vs. S 14.7% (p=0.07)
Stage II
 S+
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52.8 % vs. S 51% (p=0.95)
RT 50.3 % vs. S 51.3 % (p=0.63)
Stage III OS
 S+
RT 35.1% vs. S 13.1 % (p=0.003)
Chinese trial - Results
Stage III
Chinese trial - Results
LN + patients
Chinese Trial - Sites of Failure
Conclusions
Post-operative RT improves OS in Stage
III and potentially LN + patients
 Post-operative RT decreases risk of intrathoracic LN recurrence and anastomotic
recurrence

Macdonald trial – Post-operative
chemoRT for GE junction/stomach
adenoCA
Randomized to post-operative
chemoradiation vs. observation
 556 patients; 20% GE junction tumors
 Stage IB – IV M0, negative margins
 Adenocarcinoma histology
 D2 dissection recommended
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 10%
D2; 36% D1; 54% D0
Macdonald Trial - Treatment
Schema
Chemotherapy  d 28 ChemoRT  2
cycles additional chemotherapy
 Chemotherapy
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 5FU
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+ Leucovorin
RT – 45 Gy/25 fx
 Tumor
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bed + Regional LN + 2 cm margin
64% completed chemoRT as planned
Macdonald Trial – Tumor
Characteristics
Macdonald Trial Results
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5 year Median Survival
 S+
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3 y OS
 S+
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CRT 36 months vs. S 27 months
CRT 50% vs. S 41% (p= 0.005)
3 y RFS
S
+ CRT 48% vs. S 31% (p <0.001)
Macdonald Trial – Overall Survival
Macdonald Trial – Relapse Free
Survival
Macdonald Trial – Sites of Relapse
Macdonald Trial - Conclusions

Add chemoRT for GE junction adenoCA

T3 or higher
 + LN
 + margins, + residual disease
 ? Selected T2 cases
Non Randomized Trials
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Liu HC et al. World J. Gastroenterology.
2005; 11(34): 5367-5372
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S+ CRT vs. S + RT
Bedard EL et al. Cancer Jun 2001;
91(12): 2423-2430
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N1 patients  S + CRT vs. S
Taiwan Study – Postoperative
ChemoRT vs. RT for esophageal
SCCA
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60 patients; 30 patients in each arm
T3/T4 N0/N1 M0 thoracic esophageal SCCA
Surgery included
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En-bloc esophagectomy – sub-total resection of esophagus with
bilateral 10 cm adjacent soft-tissue margin
followed by proximal gastrectomy/porta hepatis LN dissection
Cervical LN sampling
Prospectively enrolled into post-operative chemoRT vs.
RT alone
Taiwan study – RT parameters
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Treatment started within 3 weeks of surgery
RT
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40 Gy AP/PA followed by 15-20 Gy 3 D boost
 standard 1.8 Gy/fx
 Margins
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Sup / Inf 5 cm
Elsewhere 3 cm
Mean dose 58.32 Gy (50.4 – 59.4 Gy)
Taiwan study - Chemotherapy
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Chemotherapy
6
weekly cycles CDDP 30 mg/m2 during RT
 4 weeks after chemoRT, additional adjuvant
chemotherapy 4 cycles of CDDP 20mg/m2 +
5 FU 1000mg/m2 X 5 days bolus infusion
Taiwan study - Patient
Characteristics
Taiwan study - Patient
Characteristics
Taiwan Study - Results
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ChemoRT
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30/30 received planned dose RT
 15/30 received planned dose concurrent chemo; 10
received 4/6 weekly cycles; 5 received <4 cycles
 15/30 received adjuvant chemotherapy
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RT
 24/30
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received planned dose RT
Median follow-up 18 months
Taiwan Study - Results
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ChemoRT
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Mean survival 31.9 months
 3 y/o OS 70%
 3 y/o LRF 40%
 3 y/o DF 27%
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RT
 Mean
survival 20.7 months
 3 y/o OS 33.7%
 3 y/o LRF 60%
 3 y/o DF 57%

Treatment modality and tumor grade were
significant on multi-variate analysis
Taiwan Study - Results
Taiwan Study - Results
Taiwan Study - ChemoRT
complications
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Complications
 Anastomotic
Stricture 36%
 Chronic Aspiration 33%
 Pneumonia 20%
Taiwan Study - Conclusions
ChemoRT showed improved OS
compared to RT alone in T3 or higher
patients
 Improved overall survival compared to
historical data for surgery alone
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Canadian Study – Postoperative
chemoRT in patients with N+
esophageal cancer
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Retrospective review of N1 patients – chemo RT vs.
surgery alone; 70 patients
39 pts to chemoRT arm vs. 31 patients to surgery alone;
in final analysis 38 pts. ChemoRT & 28 pts. Surgery
alone
Thoracic & GE junction tumors
AdenoCA & Squamous histology
T1-T4, all N1
Transhiatal esophagectomy
Canadian Study - Treatment
Schema
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2 cycles of chemotherapy  RT with 3rd & 4th
cycle of chemotherapy
Chemotherapy
 CDDP
60 mg/m2
 Continuous infusion 5-FU
 Epirubicin 50 mg/m2 in last 6 patients

RT
 50
Gy (36 Gy AP/PA followed by 14 Gy 3D planning)
Canadian Study - Patient
Characteristics
Patient characteristics and tumor
characteristics well balanced between two
groups
 No data on # LN + or ECE status provided
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Canadian Study –Tumor
Characteristics
Canadian Study - Results
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Median follow-up 19 months
Surgery + ChemoRT
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Median DFS – 10.2 months
Local Recurrence 13%
Median Time to LR 22.2 months
Median OS 47.5 months
5 y OS 48%
Surgery
Median DFS – 10.6 months
Local Recurrence 35%
Median Time to LR 9.5 months
Median OS 14.1 months
 5 y OS 0%
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Canadian Study – Overall Survival
Canadian Trial - Conclusion
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Benefit of ChemoRT in node + patients
Additional abstracts
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Kurtzman SM et al. (ASTRO 1995)
 192
patients
 Esophageal adenoCA
 Post-op RT with 5FU/Leucovorin & γInterferon
 39% 3 y OS
Additional abstracts
Kang HJ et al (ASCO 1992)
 Phase 2 trial
 ChemoRT
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 40-50
Gy
 CDDP + 5 FU
47% 20 month survival rate
 93% LCR
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What about post-op chemotherapy
alone?
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2 randomized Japanese trials
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Ando N et al. J of Thoracic and Cardiovascular Surgery. 1997; 114;204-205
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Randomized study; 205 patients
S + C vs. S alone
Chemo – 2 cycles of Cisplatin (70 mg./m2) + Vindesine
5 y OS S + C 48.1 % vs. S 44.9% (p = NS)
Ando N et al. JCO. Dec 2003; 21(24): 4592-4596
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Randomized study; 242 patients
Thoracic SCCA
S+C vs. S alone
Chemo – 2 cycles of Cisplatin (80 mg/m2) + 5 FU (800mg/m2/5 day infusion)
5 y OS 61 vs. 52 % (p=0.13);5 y DFS 55% vs. 45% (p=0.04); 5 y DFS in N + patients
52% vs. 38% (p=0.04)
Significant nodal failure in S + C patients; role of RT??
Overall Conclusions
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Treatment decisions need to be individualized
Pre-operative chemoRT preferable when needed
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Recognize the morbidity of neoadjuvant chemoRT; consider
surgery first in resectable patients with marginal performance
status
Post-operative chemoRT for
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+ margins, residual gross disease
+ LN
locally advanced disease (T3 or higher) with – margins, - LN?
Acknowledgements
Dr. John Holland
 Dr. Charles Thomas
 Dr. Tasha Mcdonald
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