Post-operative Radiotherapy for Esophageal CancerParag Sanghvi, M.D., M.S.P.H.Department of Radiation MedicineEsophageal Care Conference 3/26/2007

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 IndicationsPositive MarginsGross 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 SPalliative 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

Chemotherapy5FU + Leucovorin

RT – 45 Gy/25 fxTumor bed + Regional LN + 2 cm margin

64% completed chemoRT as planned

Macdonald Trial – Tumor Characteristics

Macdonald Trial Results

5 year Median SurvivalS+ CRT 36 months vs. S 27 months

3 y OSS+ CRT 50% vs. S 41% (p= 0.005)

3 y RFSS + 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

Chemotherapy6 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

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

Taiwan Study - Results 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 - Results

Taiwan Study - Results

Taiwan Study - ChemoRT complications

ComplicationsAnastomotic 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 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

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 patientsEsophageal adenoCAPost-op RT with 5FU/Leucovorin & γ-

Interferon39% 3 y OS

Additional abstracts

Kang HJ et al (ASCO 1992) Phase 2 trial ChemoRT

40-50 GyCDDP + 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