Post-operative Radiotherapy for Esophageal Cancer

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

Background
5 year OS for locally advanced esophageal cancers (T3 or above, N+) is dismal

Preoperative ChemoRT vs. Post-operative ChemoRT
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 post-operative concurrent chemoRT to either chemotherapy or RT alone

Indications for Post-operative RT
Standard Indications
Positive Margins
Gross Residual Disease
Less Clear
+ LN
+ ECE on adenopathy

Current NCCN Guidelines for Post-operative Therapy

Randomized Trials
Teniere et al Surg Gynecol Obstet . Aug 1991; 173(2): 123-30 ( France )
S+ RT vs. S
Fok et al Surgery . Feb 1993; 113(2) 138-47 ( Hong Kong )
S + RT vs. S
Xiao et al The Annals of Thoracic Surgery Feb 2003; 75(2): 331-336 ( China )
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
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
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
RT dose/technique unknown

Hong Kong Trial - Results
Overall Median Survival, All patients
S + RT 8.7 months vs. S 15.2 months (p=0.02)
Local Recurrence, Palliative Surgery patients
S+ RT 20% vs. S 46 % (p=0.04)
Local Recurrence, Curative Surgery
S+RT 10% vs. S 13%
Complications
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

Chinese Trial – RT parameters
RT
Extended Field RT
Included bilateral SCV, mediastinal and peri-gastric LN
60 Gy

Chinese Trial - Results
5 y OS
S+ RT 41.3 % vs. S 37.1 % (p=0.45)
LN –
S+RT 52.8 % vs. S 51% (p=0.95)
LN+
S+RT 29.2 % vs. S 14.7% (p=0.07)
Stage II
S+ 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 intra-thoracic 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
10% D2; 36% D1; 54% D0

Macdonald Trial - Treatment Schema
Chemotherapy  d 28 ChemoRT  2 cycles additional chemotherapy
Chemotherapy
5FU + Leucovorin
RT – 45 Gy/25 fx
Tumor bed + Regional LN + 2 cm margin
64% completed chemoRT as planned

Macdonald Trial – Tumor Characteristics

Macdonald Trial Results
5 year Median Survival
S+ CRT 36 months vs. S 27 months
3 y OS
S+ 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
Liu HC et al. World J. Gastroenterology . 2005; 11(34): 5367-5372
S+ CRT vs. S + RT
Bedard EL et al. Cancer Jun 2001; 91(12): 2423-2430
N1 patients  S + CRT vs. S

Taiwan Study – Postoperative ChemoRT vs. RT for esophageal SCCA
60 patients; 30 patients in each arm
T3/T4 N0/N1 M0 thoracic esophageal SCCA
Surgery included
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
Treatment started within 3 weeks of surgery
RT
40 Gy AP/PA followed by 15-20 Gy 3 D boost
standard 1.8 Gy/fx
Margins
Sup / Inf 5 cm
Elsewhere 3 cm
Mean dose 58.32 Gy (50.4 – 59.4 Gy)

Taiwan study - Chemotherapy
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 - Results
ChemoRT
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
RT
24/30 received planned dose RT
Median follow-up 18 months

ChemoRT
Mean survival 31.9 months
3 y/o OS 70%
3 y/o LRF 40%
3 y/o DF 27%
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 - ChemoRT complications
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

Canadian Study – Postoperative chemoRT in patients with N+ esophageal cancer
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
2 cycles of chemotherapy  RT with 3 rd & 4 th 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

Canadian Study –Tumor Characteristics

Canadian Study - Results
Median follow-up 19 months
Surgery + ChemoRT
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%

Canadian Study – Overall Survival

Canadian Trial - Conclusion
Benefit of ChemoRT in node + patients

Additional abstracts
Kurtzman SM et al. (ASTRO 1995)
192 patients
Esophageal adenoCA
Post-op RT with 5FU/Leucovorin & γ -Interferon
39% 3 y OS

Additional abstracts
Kang HJ et al (ASCO 1992)
Phase 2 trial
ChemoRT
40-50 Gy
CDDP + 5 FU
47% 20 month survival rate
93% LCR

What about post-op chemotherapy alone?
2 randomized Japanese trials
Ando N et al. J of Thoracic and Cardiovascular Surgery . 1997; 114;204-205
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
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
Treatment decisions need to be individualized
Pre-operative chemoRT preferable when needed
Recognize the morbidity of neoadjuvant chemoRT; consider surgery first in resectable patients with marginal performance status
Post-operative chemoRT for
+ margins, residual gross disease
+ LN
locally advanced disease (T3 or higher) with – margins, - LN?

Acknowledgements
Dr. John Holland
Dr. Charles Thomas
Dr. Tasha Mcdonald

Post-operative Radiotherapy for Esophageal Cancer

by fondas vak on Feb 01, 2010

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