Randomized Phase II Study of PET Response–Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial

Abstract

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

PET/CT-tailored treatment of locally advanced oesophago-gastric junction adenocarcinoma: a report on the feasibility of the multicenter GastroPET study

“…Similarly, in the CALBG 80803 trial, no significant difference in the rate of PET-response was seen between FOLFOX and carboplatin/paclitaxel (64.9% versus 56.1%). 13 This observation confirms that PET-response is a sustainable predictor of tumour chemosensitivity and to a large extent independent from variations in platinum-based chemotherapy regimens. Accordingly, Ott et al 7 reported that PET-response was the only independent factor predicting recurrence ( p = 0.018) in a group of completely resected (R0) patients with oesophago-gastric cancer.…”

“… 7 In the consecutive MUNICON I and II studies, the same group of investigators demonstrated that an early metabolic response-guided treatment algorithm identifies non-responding patients and allows for the adjustment of the perioperative treatment strategy. 8 , 9 Since then, several other groups developed response-guided treatment algorithms with some modifications in methodology, endpoints and trial designs 10 – 13 but implementation into clinical practice is still lagging behind.…”

Esophageal cancer: Is the CROSS strategy ready for history books?

“…Other positron emission tomography strategy (CALGB 80803) was recently published and will need further development. 15 Many studies have documented resistance to therapy (chemotherapy and or chemoradiation) in the presence of CSCs and enrichment of CSCs in the residual resistant cancer. 13,[16][17][18][19][20] Will we ever be able to customize approach for an individual patient?…”

Commentary: Crossing off CROSS for treatment of esophageal adenocarcinoma

“…Data from CALGB 80803 and my institution further confirm that carboplatin-paclitaxel is a suboptimal regimen to achieve micrometastatic control in EAC. 7,8 Radiation may improve local control in cases of lower-quality surgical resections (almost half of patients in the CROSS trial underwent transhiatal esophagectomy! ), but the prospect of preserving the esophagus through the use of chemoradiation-which the authors argue is possible-appears to be a mirage as elusive as the meaning Although CROSS retains a role for esophageal squamous cell carcinoma, better systemic options exist for adenocarcinoma, for which high-quality surgical resection remains a mainstay of treatment.…”