1. Esophageal Cancer: A Critical Evaluation of Systemic Second-Line Therapy Christiane Maria Rosina Thallinger, Markus Raderer, and Michael Hejna J Clin Oncol 2011;29(35):4709-14. Prof. 정재헌 / R2 이민혜 Review Article

2. Introduction Esophageal cancer 7th leading cause of death Median survival : 24 months 5-year survival rate : ↓30% ≥2/3 of patients : unresectable or metastatic disease at time of diagnosis First-line chemotherapy : fluorouracil + cisplatin ± 3rd drug (such as epirubicin or a taxane)  response rates : 20% ~ 48%  5-year survival rates : 15% 40% of first-line treatment fails : second line therapy

3. Methods Computerized (MEDLINE) and manual searches : 1996 ~ 2011 25 published reports + 4 abstracts : on second-line chemotherapy Total of 678 patients with inoperable or metastatic esophageal cancer Second-line therapy : antineoplastic systemic therapy (including neoadjuvant therapy) → antineoplastic drug or combination of drugs (including targeted therapies) Exclusions : combinations of chemotherapy with radiotherapy, gastric cancer trials without any subgroup analyses of gastroesophageal cancers Responders : complete remission (CR) or partial remission (PR)

6. Single-Agent Chemotherapy

7. Irinotecan Weekly single-agent irinotecan 100mg/m2 on D1, D8, and D15, repeated on day 28 If toxicity was below WHO grade 3, the dose of irinotecan was increased in 20mg steps in subsequent cycles up to a maximum dose of 140mg/m2 PR : 2 patients (15%) SD : 3 patients(23%) Median time to progression : 2 months (1~8 months) Median survival : 5 months (2~16 months) Weekly single-agent irinotecan 100mg/m2 on D1, D8, and D15, repeated on day 28 If toxicity was below WHO grade 3, the dose of irinotecan was increased in 20mg steps in subsequent cycles up to a maximum dose of 140mg/m2 PR : 2 patients (15%) SD : 3 patients(23%) Median time to progression : 2 months (1~8 months) Median survival : 5 months (2~16 months)

8. Vinorelbine Vinorelbine 25mg/m2 weekly CR : 1 patient (6%), lasting for 31 weeks SD : 31% Vinorelbine 25mg/m2 weekly CR : 1 patient (6%), lasting for 31 weeks SD : 31%

9. Taxanes 23 patients were enrolled in a phase II study of either paclitaxel or docetaxel Paclitaxel 175mg/m2 (n=11) or docetaxel 100mg/m2 (n=12) Repeated every 3 weeks for a maximum of six courses of therapy SD : 30% No apparent differences were seen between the single agents 23 patients were enrolled in a phase II study of either paclitaxel or docetaxel Paclitaxel 175mg/m2 (n=11) or docetaxel 100mg/m2 (n=12) Repeated every 3 weeks for a maximum of six courses of therapy SD : 30% No apparent differences were seen between the single agents

10. Taxanes Paclitaxel 140 mg/m2, continuous infusion over 4 days, every 3 weeks no responses (n=13) Paclitaxel 140 mg/m2, continuous infusion over 4 days, every 3 weeks no responses (n=13)

11. Taxanes Docetaxel : various doses (ie, 100 mg/m2, 75 mg/m2, or 70 mg/m2, every 3 weeks) Response rates : poor at 28%, 0%, and 16%, respectively Overall survival : 8.1 months (range, 6.6 to 11.3 months) in one study Docetaxel : various doses (ie, 100 mg/m2, 75 mg/m2, or 70 mg/m2, every 3 weeks) Response rates : poor at 28%, 0%, and 16%, respectively Overall survival : 8.1 months (range, 6.6 to 11.3 months) in one study

12. Combination Chemotherapy

13. Taxane-based combination regimens 8 patients with advanced esophageal cancer Oral capecitabine 1,000mg/m2 twice daily on D1~14 + docetaxel 75mg/m2 on D1, every 3 weeks Overall response rate : 25% Severe neutropenia in almost half the patients 8 patients with advanced esophageal cancer Oral capecitabine 1,000mg/m2 twice daily on D1~14 + docetaxel 75mg/m2 on D1, every 3 weeks Overall response rate : 25% Severe neutropenia in almost half the patients

14. Taxane-based combination regimens Initial dose : docetaxel 65mg/m2 + irinotecan 160mg/m2, every 3 weeks -> Severe myelosuppression Docetaxel 25mg/m2 + irinotecan 55mg/m2 on D1, D8, D15, every 4 weeks Response rate : 12.5% Overall survival : 6 months Initial dose : docetaxel 65mg/m2 + irinotecan 160mg/m2, every 3 weeks -> Severe myelosuppression Docetaxel 25mg/m2 + irinotecan 55mg/m2 on D1, D8, D15, every 4 weeks Response rate : 12.5% Overall survival : 6 months Docetaxel 35mg/m2 + irinotecan 50mg/m2 on D1, D8, every 3 weeks Response rate : 20.0% Time to progression : 3.5 months Overall survival : 11.4 months Severe adverse effects : diarrhea, neutropenia, hyperglycemia Docetaxel 35mg/m2 + irinotecan 50mg/m2 on D1, D8, every 3 weeks Response rate : 20.0% Time to progression : 3.5 months Overall survival : 11.4 months Severe adverse effects : diarrhea, neutropenia, hyperglycemia

15. Taxane-based combination regimens Docetaxel 70mg/m2 + cisplatin 75mg/m2 on D1, every 3 weeks Overall response rate : 34.2% Progression-free survival : 4.5 months Overall survival : 7.4 months WHO grades 3 to 4 hematologic toxicities : half the patients Docetaxel 70mg/m2 + cisplatin 75mg/m2 on D1, every 3 weeks Overall response rate : 34.2% Progression-free survival : 4.5 months Overall survival : 7.4 months WHO grades 3 to 4 hematologic toxicities : half the patients

16. Taxane-based combination regimens Docetaxel + nedaplatin (plus fluorouracil in one series) All these trials, however, were performed in Asian patients Response rates : 11%~39% Docetaxel + fluorouracil + nedaplatin, response rate : 63% (small pilot study with only 8 patients with SCC) Hematologic toxicities were mostly mild and manageable. Progression-free survival : 1.8~6.5 months Docetaxel + nedaplatin (plus fluorouracil in one series) All these trials, however, were performed in Asian patients Response rates : 11%~39% Docetaxel + fluorouracil + nedaplatin, response rate : 63% (small pilot study with only 8 patients with SCC) Hematologic toxicities were mostly mild and manageable. Progression-free survival : 1.8~6.5 months

17. DCF-type regimens Docetaxel 70mg/m2 on D1 + cisplatin 80mg/m2 on D1 + fluorouracil 800 mg/m2 on D1-5, every 4 weeks Response rate : 50% Progression-free survival and overall survival were not stated by the authors Severe leucopenia : GCSF support was needed in 68% of patients Docetaxel 70mg/m2 on D1 + cisplatin 80mg/m2 on D1 + fluorouracil 800 mg/m2 on D1-5, every 4 weeks Response rate : 50% Progression-free survival and overall survival were not stated by the authors Severe leucopenia : GCSF support was needed in 68% of patients Docetaxel 60mg/m2 on D1 + cisplatin 10 mg/d on D1-5 + fluorouracil 500 mg/d D1-5, every 3 weeks Overall response rate : 35% Time to progression : 4 months Overall survival : 8 months Neutropenia WHO grades 3 to 4 occurred in 13 patients (65%) Docetaxel 60mg/m2 on D1 + cisplatin 10 mg/d on D1-5 + fluorouracil 500 mg/d D1-5, every 3 weeks Overall response rate : 35% Time to progression : 4 months Overall survival : 8 months Neutropenia WHO grades 3 to 4 occurred in 13 patients (65%)

18. Nontaxane–based combinations Mitomycin 6mg/m2 + ifosfamide 3g/m2 + cisplatin 50mg/m2 on D1 as an outpatient regimen, every 3 weeks Response rate : 12.5% WHO grades 3 to 4 neutropenia : 21% of patients Progression free survival : 2.0 months Overall survival : 5.2 months Mitomycin 6mg/m2 + ifosfamide 3g/m2 + cisplatin 50mg/m2 on D1 as an outpatient regimen, every 3 weeks Response rate : 12.5% WHO grades 3 to 4 neutropenia : 21% of patients Progression free survival : 2.0 months Overall survival : 5.2 months

19. Targeted therapies

20. Monoclonal antibodies Cetuximab 500mg/m2 on D1 + irinotecan 180mg/m2 on D1, every 2 weeks PR rate : 14% Progression-free survival : 3.3 months Overall survival : 5.5 months Cetuximab 500mg/m2 on D1 + irinotecan 180mg/m2 on D1, every 2 weeks PR rate : 14% Progression-free survival : 3.3 months Overall survival : 5.5 months Chimeric mouse/human monoclonal antibody, targeting epidermal growth factor receptor (EGFR) Cetuximab 400mg/m2 on week 1 and 250mg/m2 weekly thereafter Only one PR Progression-free survival : 1.8 Months Overall survival : 4.0 months Chimeric mouse/human monoclonal antibody, targeting epidermal growth factor receptor (EGFR) Cetuximab 400mg/m2 on week 1 and 250mg/m2 weekly thereafter Only one PR Progression-free survival : 1.8 Months Overall survival : 4.0 months

21. Tyrosine kinase inhibitors Gefitinib 250mg/d for a minimum of 8 weeks 3 patients (15%) have a PR and 3 patients have SD Gefitinib 250mg/d for a minimum of 8 weeks 3 patients (15%) have a PR and 3 patients have SD Orally active EGFR tyrosine kinase inhibitor : Gefitinib 500 mg/d 3 patients (9%) had PRs lasting for 154, 280, and 121 days, respectively Adverse effects were non-hematologic (12% to 58%) : diarrhea (58%), skin toxicity (42%), vomiting (12%), and elevated transaminases (12%) Orally active EGFR tyrosine kinase inhibitor : Gefitinib 500 mg/d 3 patients (9%) had PRs lasting for 154, 280, and 121 days, respectively Adverse effects were non-hematologic (12% to 58%) : diarrhea (58%), skin toxicity (42%), vomiting (12%), and elevated transaminases (12%) Progression-free survival : 4.6 months Overall survival : 5.5 months Gefitinib 500 mg/d, and response was evaluated every 8 weeks 1 patient (2.8%) achieved a PR 10 (27.8%) had SD Progression-free survival : 1.9 months Overall survival : 5.5 months Significantly better : female patients, high EGFR expression, SCC histology Gefitinib 500 mg/d, and response was evaluated every 8 weeks 1 patient (2.8%) achieved a PR 10 (27.8%) had SD Progression-free survival : 1.9 months Overall survival : 5.5 months Significantly better : female patients, high EGFR expression, SCC histology Erlotinib 150 mg/d 6 patients (20%) with EGFR-negative tumors 24 patients (80%) with EGFR overexpressing tumors Erlotinib 150 mg/d 6 patients (20%) with EGFR-negative tumors 24 patients (80%) with EGFR overexpressing tumors 2 PRs : EGFR-positive cohort (8%) No responses : EGFR-negative cohort Time to progression :3.3 months (SCC), 1.6 months(AC)

22. Ongoing Second-Line Trials

23. Conclusions Approximately 40% of patients who experience progressive disease after first-line chemotherapy are able to undergo second-line treatment. The response rates were generally low (between 0% and 39%), with only two small studies reporting objective responses of 50% and 63%, respectively. Time to progression ranged from 1.4 to 6.2 months, and the overall survival was disappointing at 4.0 to 11.4 months. No standard second-line therapy has emerged. Future research will need to focus on individual therapy strategies such as genetic receptor mutations to increase the therapeutic outcome.