Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ.

The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence-and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in highvolume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC

Pretargeted radioimmunotherapy (RIT) increases the dose of radionuclide delivered to tumor sites while limiting radiation to normal tissues. The three components in Pretarget include a streptavidin-containing targeting molecule, a synthetic clearing agent (sCA), and (90)Y and/or (111)In-DOTA-biotin. This trial determined the feasibility and safety of using a genetically engineered fusion protein directed to TAG-72 as the targeting agent. Nine (9) patients with metastatic colorectal cancer (TAG-72+) received 160 mg/m(2) of CC49Fusion protein intravenously (i.v.), followed by the sCA, 45 mg/m(2) i.v. Twenty-four (24) hours later, patients received radiolabeled DOTA-biotin (either 0.65 or 1.3 mg/m(2)). All patients received 5 mCi of (111)In-DOTA-biotin for imaging and dosimetry purposes and patients 4-9 received 10 mCi/m2 of (90)Y-DOTA-biotin as well. The mean plasma T1/2 of CC49Fusion protein was 23 +/- 6 hours. Greater than 95% of the circulating CC49Fusion protein was eliminated from the circulation within 6 hours of sCA administration. The radiolabeled DOTA-biotin rapidly localized to tumor sites while the unbound fraction was rapidly excreted. The mean tumor-to-marrow radiation dose ratio was 139:1 and mean tumor: whole body was 56:1. No infusion-related, renal, hepatic, or hematologic toxicities were noted. CC49Fusion protein performs well in a pretargeted RIT schema, and further study with escalating doses of (90)Y should be pursued. This strategy has the potential to deliver effective radiation tumor doses to TAG- 72+ tumors.

Rationale Escalation of the Zevalin dose is limited by hematologic toxicity associated with marrow B-cells ± tumor cells. Rituxan treatment before Zevalin may reverse marrow infiltration with malignant and normal B-cells allowing an increase in the dosage of Zevalin with enhanced radiation delivery to lymphoma tumor sites. Since NHL is radiation sensitive, a substantial increase in radiation dose delivered should increase the ORR and CR rates. Design Low-grade follicular/transformed NHL patients receive 4 weekly dose of Rituxan (375mg/m2) before the corresponding Zevalin dose. Bilateral bone marrow biopsies/aspirates as well as biodistribution and dosimetry studies using 111In-2B8 were obtained before and after Rituxan. The trial was schedule to escalate the Zevalin dose (from 0.4 to 0.7 mCi/Kg). After completion of the 0.4 mCi/kg cohort an additional cohort of Rituxan sensitive patients using 0.3 mCi/kg was completed. Safety, pharmacokinetics, dosimetry and preliminary responses are presented. Results 5 pts were enrolled in the 0.4mCi/kg cohort and 6 pts in the 0.3 mCi/kg cohort. In the 10 Rituxan sensitive patients the plasma T ½ and the AUC of 111In-2B8 increased after the administration of Rituxan, with a reduction in the plasma clearance (T½ from 45 ± 4.5 hours to 54 ± 1.9 hours, AUC from 60 ± 10 hrs/μCi/ml to 85 ± 14 hrs/μCi/ml, and the clearance from 1.4 ± 0.3 ml/hrs/kg to 0.9 ± 0.2 ml/hrs/kg). Dosimetry showed no differences in the radiation-absorbed dose for major normal organs (whole body, liver, kidneys) except for the spleen in which a reduction was observed in 7 out of 10 patients. The radiation-absorbed dose to the marrow increased after Rituxan; from 3.6 rads/mCi to 4.28 rads/mCi. In the 0.4 mCi/kg cohort 3 out of 4 evaluable patients for response had a complete response, and 1 patient had progression documented at initial evaluation six weeks post-Zevalin (patient refractory to previous Rituxan). No non-hematological toxicity was observed. One patient had a grade 4 thrombocytopenia, 3 patients had grade 3 thrombocytopenia, and 4 patients had grade 4 WBC and ANC. All patients recovered within two weeks after the nadir. Two out of 6 patients treated in the 0.3 mCi/kg cohort had complete response by physical evaluation, and 4 had partial response; no early progressions were seen in this cohort. No non-hematological toxicity was observed. Only one patient had a grade 4 WBC and ANC, and 2 patients had a grade 3; 3 patients had grade 3 thrombocytopenia; all patients recovered. Conclusions The administration of high doses of Rituxan before Zevalin prolongs the circulation time of the radiolabeled antibody and increases the bone marrow exposure to the radioisotope. Additionally, the increased amount of the radiolabeled antibody available after Rituxan therapy with the prolonged circulation time may explain the unusual high complete response rate observed in this small number of patients despite extensive chemotherapy failures. Although this is very provocative data, the number of patients is very limited to generate a strong conclusion. The trial continues at this time.