Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2012
Presenter: Thierry Conroy, MD
Presenter's Affiliation: Centre Alexis Vautrin, Vandoeuvre-lès-Nancy, France
- Definitive chemoradiotherapy (CRT) is currently the standard of care in patients with unresectable, locally advanced esophageal cancer (EC).
- Historically, studies have used chemotherapy with cisplatin/5FU with local failure rates of 60% (Stahl et al. JCO, 2005) and have demonstrated life threatening toxicity as high as 10% (RTOG 85-01, Herkovic et al., NEJM 1992)
- New combinations with various chemotherapy agents are under investigation to improve safety and survival.
- The authors previously reported on a randomized phase II study to assess the complete response (CR) rate of CRT with FOLFOX versus 5FU/cisplatin in 97 pts with localized EC (Conroy 2010). Chemoradiotherapy was completed in 74 vs. 66% of patients and the endoscopic complete response rate was 45 vs. 29%, for FOLFOX vs. 5FU/cisplatin, respectively.
- The current study is a phase III randomized trial assessing progression-free survival in patients treated with definitive chemoradiotherapy with FOLFOX versus 5FU/cisplatin.
Materials and Methods
- In this phase III randomized trial, stratification was performed centrally in a 1:1 ratio according to histological disease type, pretreatment weight loss in the prior 6 months (<10% vs ?10%), ECOG PS (0 vs 1 vs 2), and center.
- Inclusion criteria:
- Patients with technically unresectable esophageal cancer or those with surgical contraindications or who refused to undergo surgery
- Age >18 years
- ECOG performance status ? 2
- Previously untreated adenocarcinoma or squamous cell esophageal cancer (any T, N0 or N1, M0 or M1a)
- Adequate bone marrow reserve, normal renal and liver function and sufficient nutritional intake of >1000 kcal/day.
- Exclusion Criteria:
- Metastatic disease, multiple carcinomas of the esophagus, weight loss >20% of body weight, grade 1 peripheral neuropathy, symptomatic cardiac disease or invasion intro the tracheo-broncial tree or fistula
- The radiation dose was 50 Gy in 2 Gy daily fractions over 5 weeks.
- In Arm A (FOLFOX), patients received 6 bimonthly cycles:
- Oxaliplatin 85 mg/m2 d1, leucovorin 200 mg/m2 followed by 5-FU 400 mg/m2 bolus d1 then 1,600 mg/m2 46h continuous infusion
- The first 3 cycles were delivered concurrently with radiation therapy and the last 3 cycles were delivered adjuvantly.
- In Arm B (Cisplatin/5FU), patients received 4 cycles:
- Cisplatin 75 mg/m2 d1 followed by 5FU 1,000 mg/m2/d ci d1-4,
- The first 2 cycles were delivered concurrently with radiation therapy and the last 2 cycles were delivered adjuvantly
- The primary endpoint was progression-free survival (PFS).
- Main secondary endpoints were overall survival (OS), grade 3-4 toxicities, and quality of life.
- An intent-to-treat analysis was performed.
- 267 patients were enrolled between 10/2004 and 8/2011.
- Median follow-up was 25.3 months.
- There were no statistically significant differences in patient or tumor characteristics between the two groups. For the entire population, 81% were male, the median age was 61 years. Overall, 53% of patients had a performance status of 0. The majority of patients had squamous cell carcinoma (85.8%) and stage III disease (52%).
- Full treatment was delivered to 67.9% patients receiving FOLFOX and 72.2% receiving cisplatin/5FU (p=0.05). There was also no difference in treatment delay between the two arms.
- The FOLFOX arm had increased rates of peripheral neuropathy (18.3 vs. 0.8%, p<0.0001).
- The Cisplatin/5FU arm had increased rates of mucositis (32 vs. 26.7%, p=0.011), alopecia (9.4 vs. 1.5%, p=0.006), and renal toxicity (11.7 vs. 3.0%, p=0.036).
- Otherwise, grade 3/4 toxicities comparing FOLFOX vs. Cisplatin/5FU were not statistically significant:
- Hematologic: Neutropenia (29.0 vs. 28.9%), febrile neutropenia (5.3 vs. 7.0%), anemia 5.3 vs. 10.9%) and thrombocytopenia (6.9 vs. 7.8)
- GI-related: Esophagitis (6.9 vs. 12.5%), vomiting (3.8 vs. 2.4%) and diarrhea (1.5 vs. 0.7%)
- There was a trend toward more toxic deaths in the cisplatin/5FU arm (6.4 vs. 1.1%, p=0.06).
- The rate of 3 year PFS (18.2 vs.17.4%) was not statistically significantly different between the two arms. Additionally, the rate of complete response (41% vs. 41.3%), primary tumor failure (25.5 vs. 23.7 %), and median O (20.2 vs. 17.5 months) was not significantly different.
- Definitive chemoradiotherapy with FOLFOX does not improve progression-free survival in patients with unresectable localized esophageal cancer
- FOLFOX shows more grade 1-2 peripheral neuropathy, but less toxic deaths, mucositis, alopecia and renal toxicity, when compared to cisplatin/5FU.
- FOLFOX is a safer new options in patients with a contraindication to cisplatin.
- FOLFOX is convenient and leads to shorter chemotherapy (12 days vs. 16-20 days) given in an outpatient setting.
- While cisplatin/5FU has been the backbone of chemoradiotherapy in esophageal cancer, FOLFOX can also be used to treat patients with unresectable localized esophageal cancer.
- This regimen may be particularly promising for patients with renal disease.
- In light of the recent publication of the CROSS trial (Van Hagen, NEJM 2012), which evaluated carboplatin and paclitaxel in the neoadjuvant setting and found favorable outcomes and low toxicity rates, further studies may investigate the benefit of carboplatin and paclitaxel in the definitive chemoradiotherapy setting.
- Further investigation into regimens that may improve overall survival and response are still warranted, given dismal long-term survival rates after unresectable esophageal cancer.