Local Esophageal Cancer Summary Updated Apr 2017 by Dr. Jenny Ko (Medical Oncologist, Abbotsford Cancer Centre) Reviewed by Dr. Yoo-Joung Ko (Medical Oncologist, Sunnybrook Odette Cancer Centre, University of Toronto), Dr. Vincent Tam (Medical Oncologist, Tom Baker Cancer Centre, University of Calgary) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. Epidemiology Incidence: adenocarcinoma is increasing dramatically (?due to obesity), SCC decreasing over time. SCC comprises 90% of all esophageal cancers. - Incidence of superficial esophageal cancer is increasing, particularly in Asian countries where screening for upper digestive tract cancers is common - Similar trend in United States, attributed in part to routine endoscopic surveillance for malignancy and high-grade dysplasia in patients with Barrett's esophagus Risk factors Age Lifestyle - SCC: smoking, alcohol, betel nut chewing, N-nitroso containing foods - AdenoCA: obesity, smoking, N-nitroso foods Hereditary: Tylosis (hyperkaratosis palms and soles of feet) AD 17q25 for SCC Other - SCC: Achalasia, caustic stricture,?hpv, prior H&N SCC - AdenoCA: HP infection, Barrett s (GERD), obesity, Zollinger Ellison, prior cholecystectomy,?drugs that relax esophageal sphincter (nitrates, BDZ) Staging CT chest/abdomen/pelvis Endoscopy/EUS: biopsy, location, T staging PET: essential for pre-operative assessment Differences between squamous and adenocarcinoma in staging - In SCC, stages can change depending on grade and location Ø E.g. Poor grade, upper/middle location upgraded from 1Aà1B, 1Bà2A etc. - In adenocarcinoma, only TNM stages affect final stage. Upper (cervical) cancer, T4 generally difficult to resect and typically treated with chemoradiation. Multidisciplinary approach important Treatment Regional Lymphatic Drainage Upper (Cervical) scalene, internal jugular, upper and lower cervical, periesophageal, and supraclavicular Middle upper periesophageal (above the azygos vein), subcarinal, lower (Intrathoracic) periesophageal (below the azygos vein) Lower (GEJ) Lower esophageal (below the azygos vein), diaphragmatic, pericardial, left gastric, celiac Superficial Esophageal Cancer (up to 1A)
- Usually treated with surgery alone (esophagetomy); endoscopic mucosal resection is also an option, but not the preferred treatment Localized Esophageal Cancer chemoradiation therapy + surgery if resectable RT Alone - modern techniques (eg. 3D conformal [3D-CRT], IMRT) associated with more favorable toxicity profiles than those with lower energy units in earlier years - however, role of RT alone has been supplanted by combined chemort in the majority of pts despite a higher rate of treatment related toxicity Trimodality Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer (CROSS) (Van Hagen NEJM 2012) Primary Endpoint Inclusion/Exclusion Weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery vs Surgery alone OS 366 with esophageal or junctional cancer 75% had adenoca 23% SCC 2% large cell undifferentiated carcinoma Size (N) 366 Results pcr 29% in chemort/surgery group Complete resection with no tumor within 1mm of the resection margin (R0) in 92% vs 69%. mos 49.4 mo vs 24.0 mo HR 0.657, p=0.003 Most common major heme toxic effects in chemort-surgery: leukopenia, and neutropenia Most common non-heme: anorexia, fatigue Postop complication similar in both groups. In hospital mortality 4% in both Other Comments Preop chemort improved survival among pts w potentially curable esophageal or EGJ cancer. The regimen was associated w acceptable adverse event rates 91% received full treatment Phase III Trial of Trimodality Therapy With Cisplatin, Fluorouracil, Radiotherapy, and Surgery Compared With Surgery Alone for Esophageal Cancer: CALGB 9781 (Tepper JCO 2008) Esophagectomy with node dissection alone Vs Cisplatin/ 100mg/m2 fluorouracil 1000 mg/m2/d for 4 days on weeks 1 and 5 concurrent with RT (50.4Gy total: 1.8 Gy/fraction over 5.6 weeks) followed by esophagectomy with node dissection Inclusion/Exclusion Patients with nonmetastatic esophageal cancer Size (N) 475 Results mos 4.48 vs 1.79 years in favor of trimodality therapy (p=0.002) 5 year survival 39% vs 16% in favor of trimodality therapy The results from this trial reflect long term survival advantage with use of chemort followed by surgery in treatment of esophageal cancer, and support trimodality therapy as a standard of care for pts with this disease
Surgery Alone Versus Chemoradiotherapy Followed by Surgery for Stage I and II Esophageal Cancer: Final Analysis of Randomized Controlled Phase III Trial FFCD 9901 (Mariette JCO 2014) Surgery alone Vs NCRT followed by surgery (45Gy in 25 fractions over 5 weeks with 2 courses of concomitant chemo compared to 5FU 800mg/m2 and cisplatin 75mg/m2 mfu 93.6 mo Primary Endpoint OS Inclusion/Exclusion Patients with localized cancers of the esophagus (ie stage I or II) Size (N) 195 Results R0 resection rate 93.8 vs 92.1% (p=0.749) 3 years OS 47.5 vs 53.0, HR 0.99, p=0.94 Postop mortality rate 11.1% vs 3.4% (p=0.049) Because interim analysis of the 1ry endpoint revealed an improbability of showing the superiority of either treatment arm(hr 1.09, p=0.66), the trial was stopped for anticipated futility Compare w surgery alone, NCRT w cisplatin plus FU does not improve R0 resection rate or survival but enhances postop mortality in pts w stage I or II EC (take this with a grain of salt, however). Trial stopped early after prespecified interim analysis due to treatment futility Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer (Van Hagen NEJM 2012) Neoadjuvant chemort before surgery Primary Endpoint Inclusion/Exclusion 17 trials from previous meta-analysis and 7 further studies updated analysis has 4188 pts Size (N) Results HR for all-cause mortality for neoadjuvant chemort was 0.78, p<0.0001 HR for SCC only was 0.8 and for adenocarcinoma only was 0.75, p=0.02 HR for all-cause mortality for neoadjuvant chemo was 0.87, p=0.005 HR for SCC only was 0.92, p=0.18 and for adenoca only was 0.83, p=0.01) HR for overall indirect comparison of all-case mortality for neoadjuvant chemort vs neoadjuvant chemo was 0.88, p=0.07) This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemort or chemo over surgery alone in pts w esophageal carcinoma. A clear advantage of neoadjuvant chemort over neoadjuvant chemo has NOT been established Definitive chemoradiation therapy Chemoradiation With and Without Surgery in Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus (Stahl JCO 2005) Primary Endpoint Inclusion/Exclusion Induction chemo followed by chemort (40Gy) followed by surgery (arm A) Vs the same induction chemo followed by chemort (at least 65Gy) without surgery (Arm B) OS Patients with locally advanced SCC of the esophagus
Size (N) 172 Results Local PFS better in surgery group (2 year PFS 40.7%, HR B vs A 2.1, p=0.003) OS equivalent between the 2 treatment groups(log-rank test for equivalence, p<0.05) Cox regression analysis revealed clinical tumor response to induction chemo to be the single independent prognostic factor for OS (HR 0.30, p<0.0001) Treatment related morality sig increased in surgery group than in chemort group(12.8 vs 3.5%, p=0.03). Adding surgery to chemort improves local tumor control but does not increase survival of pts w locally advanced esophageal SCC. Tumor response to induction chemo identifies a favorable prognostic group within these high risk pts, regardless of the treatment group. Combined Chemotherapy and Radiotherapy Compared with Radiotherapy Alone in Patients with Cancer of the Esophagus (Herskovic NEJM 1992) 4 courses of combined FU (1000mg/m2 daily for 4 days) and cisplatin (75mg/m2 on d1) +5000cGy of RT vs 6400cGy of RT alone Primary Endpoint OS Inclusion/Exclusion SCC or adenoca of the thoracic esophagus Size (N) 121 Results Pts getting combined treatment had fewer local (p<0.02) and for distant (p<0.01) recurrences mos 8.9 mo in RT treated pts vs 12.5 mo in chemort arm 5Y OS 26 vs 0% Severe and life threating side effects occurred in 44% and 20% of the pts who received combined therapy, as compared w 25% and 3% of those treated w RT alone Concurrent therapy w cisplatin and FU and RT is superior to RT alone in pts w localized carcinoma of the esophagus, as measured to by control of local tumors, distant mets, and survival, but at the cost of increased side effects. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. (Minsky JCO 2002) 4 monthly cycles of 5FU (1000mg/m2/24hours for 4 days) and cisplatin 75mgm2 bolus day 1) with concurrent 64.8 Gy vs. same chemo schedule but with concurrent 50.4Gy Inclusion/Exclusion Clinical stage T1-T4, N0/1, M0 SCC or adenocarcinoma selected for a nonsurgical approach Size (N) 218 Results NO DIFFERENCE IN: mos (13.0 vs 18.1 mo), 2 year survival (31 vs 40%) or local/regional failure and local/regional persistence of disease (56 vs 52%) between the high dose and standard dose arms Although 11 treatment related deaths occurred in the high dose arm compared w two in the standard dose arm, 7 of the 11 deaths occurred
in the patients who had received 50.4 Gy or less The higher RT dose did NOT increase survival or local/regional control Although there was a higher treatment related mortality rate in the pts assigned to the high dose RT arm, it did not seem to be related to the higher RT dose The standard RT dose for pts treated w concurrent 5FU and cisplatin chemo is 50.4Gy Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer (Conroy NEJM 2012) 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 Primary Endpoint PFS Inclusion/Exclusion Patients with technically unresectable esophageal cancer or those with surgical contraindications or who refused to undergo surgery Size (N) 267 Results 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 OS (20.2 vs. 17.5 months) was not significantly different. 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). 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. Neoadjuvant chemotherapy followed by surgery Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. (Ando JCO 2003)
Surgery alone Vs surgery plus chemo, including 2 courses of cisplatin 80mg/m2 on d1) and FU 800mg/m2 x 5 days within 2 months after surgery Primary Endpoint Inclusion/Exclusion Size (N) 242 Results 5 year DFS 45% vs 55%, p=0.037 DFS Patients with localized SCC of thoracic esophagus, undergoing transthoracic esophagectomy w lymphadenectomy 5 year OS rate 52 vs 61%, p=0.13 (NONSIG) Grade 3 or 4 heme or nonheme toxicities were limited Postop adjuvant chemo w cisplatin and FU is better able to prevent relapse in pts w esophageal cancer than surgery alone Long-Term Results of a Randomized Trial of Surgery With or Without Preoperative Chemotherapy in Esophageal Cancer (MRC.OEO2) (Allum JCO 2009) Surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS) Primary Endpoint OS Inclusion/Exclusion Patients undergoing radical surgery for esophageal cancer Size (N) 802 Results The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P =.03) which in absolute terms is a 5- year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P <.001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%. Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. (Stahl JCO 2009)
Induction chemo (15 weeks) followed by surgery (arm A) Vs Chemotherapy (12 weeks) followed by chemort (3 weeks) followed by surgery (Arm B) Treatment in arm A consisted of induction chemotherapy with 2.5 courses of cisplatin, fluorouracil, leucovorin (PLF). One course comprised a 6-week schedule of weekly fluorouracil (2 g/m2, 24-hour infusion) and leucovorin (500 mg/m2, 2-hour infusion) as well as biweekly cisplatin (50 mg/m2, 1-hour infusion). Treatment of arm B consisted of 2.0 courses of the same induction chemotherapy. This was followed by 3 weeks of combined chemoradiotherapy. Surgery was performed 3 to 4 weeks after the end of chemotherapy (arm A) or chemoradiotherapy (arm B). Primary Endpoint OS Inclusion/Exclusion Patients with locally advanced (ut3-4nxm0) adenocarcinoma of the lower esophagus or gastric cardia Size (N) 126 Results Arm B had a sig higher probability of showing pcr (15.6 vs 2%) or tumor free lymph nodes (64.4 vs 37.7%) at resection. Preop RT improved 3 year survival rate from 27.7% to 47.4% (p=0.07, HR 0.67) mos 21 vs 31m (significant) Postop mortality was nonsig increased in chemort group (10.2 vs 3.8%, p=0.26) Although the study was closed early and statistical sig was not achieved, results point to a survival advantage for preop chemort compared w preop chemo in adenocarcinomas of the EGJ Other Comments Initial results of CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer. (Goodman GI ASCO 2017) Randomized to one of 2 induction CT arms: Modified FOLFOX-6 (oxaliplatin, leucovorin, 5-FU), days 1, 15, 29 or Carboplatin/Paclitaxel (CP), days 1, 8, 22, 29. Repeat PET was performed days 36-42; change in max standardized uptake value (SUV) from baseline was assessed. PET non-responders ( 35% decrease in SUV PET-NR) crossed over to alternative CT regimen during CRT (50.4Gy/28 fractions). PET responders (>35% decrease in SUV PET-R) continued on same CT during CRT. Primary Endpoint pcr in PET-NR who crossed over to alternative chemotherapy Inclusion/Exclusion patients (pts) with resectable esophageal and gastroesophageal junction (GEJ) adenocarcinomas. Size (N) 257 Results FOLFOX vs CP PET-R 57 vs 50% pcr 38 vs 10% PET-NR 30 vs 38% pcr 16 vs 15% For PET-NR who crossed over to alternative CT during CRT, pcr was 15.6%; 95% CI (0.08, 0.26). Other Comments Efficacy criteria were met for an improvement in pcr rates among pts who were PET-NR after induction CT and received alternative CT during CRT for esophageal and GEJ adenoca. Pts receiving induction and concurrent CP had an unexpectedly low pcr.
Adjuvant therapy GEJ adenocarcinoma treated similarly to gastric adenocarcinoma (e.g. MAGIC, MacDonald protocol, ARTIST); no evidence for adjuvant therapy in SCC or upper/middle esophageal cancer. Utility of post induction therapy PET scans - Post induction therapy FDG-PET provides info about metabolic response in the primary tumor that may be clinically useful for selection of subsequent therapy. - In particular some retrospective data suggest that post-chemo FDG-PET scan may serve to identify those pts for whom surgery might be avoided - However, others have failed to find a correlation between the postchemort SUV on PET and pathologic response - Thus, these data need to be confirmed and validated in a prospective trial before PETdirected therapy for esophageal cancer can be considered a standard approach - The main use of PET may be to recognize which pts are not responding to induction chemo. Surveillance strategy No RCTs to guide postop surveillance strategy and no data that shows improvement or quality of life or longevity from earlier detection of asymptomatic recurrences. NCCN guidelines suggest: - Hx/Px q3-6 months for 1-3 years, then every 6 months for year 4 and 5, then annually - CBC and chemistry profile, as clinically indicated - Radiologic imaging and upper GI endoscopy, as clinically indicated - dilation for anastomotic stenosis - nutritional counseling