# Radiation Oncology/Esophagus/Early Stage

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Early Stage (Resectable) Esophageal Cancer

## Overview

* Surgical resection alone has been the historical treatment modality for localized esophageal CA. Unfortunately, only 30-40% are resectable, and only 20% can undergo curative resection. Survival after surgery alone is not great; however, 5-year OS improved from 5% in the 1970s to ~20% now. Median OS is around 1 - 1.5 years
* Even with R0 resection, local, regional and distant failures are a problem
* Adjuvant radiation was evaluated in 2 randomized trials in the 1980's. There was no benefit
* Adjuvant chemoradiation was evaluated in patients with GE junction tumors and stomach tumors (INT 0116). There was a survival benefit, and is standard of care in stomach patients. It's not entirely clear whether GE junction patients are best served by this strategy vs the neoadjuvant chemo-RT-surgery strategy favored in esophageal cancer. Argument can be made for neoadjuvant treatment, since many failures are distant
* Neoadjuvant radiation has been evaluated in 5 randomized trials done in the 1970's and 1980's. Four showed no difference, one showed a benefit in 2x2 design with chemotherapy. A meta-analysis reveal trend (p=0.06) to benefit with pre-op RT, but estimated magnitude is only 3-4%
* Neoadjuvant chemotherapy has been evaluated in multiple randomized trials, and the historical results have been underwhelming. A large modern European trial (MRC) showed a survival benefit for neoadjuvant cisplatin/5-FU, while a comparable modern US trial (INT-0113) did not. As a result, neoadjuvant chemo is currently not recommended in the USA, while it is an option in Europe
* Neoadjuvant chemo-radiation was evaluated in 7 trials in 1990's, with various RT doses/fractionations, various chemo doses/fractionations, and various entry criteria. 3 meta-analyses were done on that data, two argue for survival benefit and better LR control to neoadjuvant CRT over surgery alone, while the third is non-committal. CALGB 9781 was a modern trial not included in the meta-analyses. It only accrued 56/475 patients, but showed a significant survival benefit for trimodality therapy. Many institutions in the US offer neoadjuvant CRT as an option
* The benefit of trimodality therapy vs definitive CRT was evaluated in two European randomized trials in locally advanced resectable patients; both defined primary chemo-RT as the standard group. Overall, there was no difference in survival with the addition of surgery compared with more intense primary chemo-RT. However, there may be patients subsets who nevertheless benefit from surgery. These are yet to be identified, but may include non-responders to initial chemo-RT
* A direct comparison between radical surgery alone and radical radiation alone was done in China. Report published in 2006 showed no difference in 5-year OS (35%) or PFS (23%). RT was given as 50 Gy standard fractionation, followed by BID boost to 68-71 Gy.
* There is no clearly established standard treatment; both surgery alone and concurrent chemo-RT (to 50.4 Gy in the US) are viable strategies; benefit of trimodality therapy remains unclear

## Surgery Alone

* Only 30-40% of patients present with resectable disease, and only ~20% undergo curative resection
* Techniques:
** Transthoracic (Ivor-Lewis): abdominal and right thoracic incision
** Transhiatal: abdominal and left cervical incision
** Minimally invasive esophagectomy: typically uses thoracoscopic approach
* Surgery alone outcomes:
** Median OS is only 14-16 months (but perhaps as high as 21 months in CALGB 9781). Please see control arms of trials below
** 3-year OS is ~35%; 5-year OS (and cure rate) is ~20%
* Rate of R0 resection (negative surgical margins) is only 50-60%
* Even with R0 resection, locoregional recurrences and metastatic disease is common
Technique
* Meta-analysis; 1999 (1986-1996) PMID 10075357 -- "Transhiatal versus Ivor-Lewis oesophagectomy: is there a difference?" (Rindani R, Aust N Z J Surg. 1999 Mar;69(3):187-94.)
** 44 series reviewed; 33 series with 2675 patients with transhiatal surgery, 29 series with 2808 patients with Ivor-Lewis surgery. Groups comparable
** Post-op mortality: comparable for respiratory, cardiovascular, wound healing, and chylothorax complications. Transhiatal worse for anastomotic leaks, anastomotic strictures, and recurrent laryngeal nerve injury
** 30-day mortality: transhiatal 6% vs. Ivor-Lewis 9%
** 5-year OS: transhiatal 24% vs. Ivor-Lewis 26% (NS)
** Conclusion: comparable; transhiatal somewhat higher post-op complication rate
* Michigan; 2007 (1976-2006) PMID 17717440 -- "Two Thousand Transhiatal Esophagectomies: Changing Trends, Lessons Learned." (Orringer MB, Ann Surg. 2007 Sep;246(3):363-374.)
** Retrospective. 2,007 surgeries (Group I: 1063 between 1976-1998; Group II: 944 between 1998-2006), 76% for cancer. Comparison of the groups
** Group I vs. Group II: Improvement in hospital mortality (4% vs. 1%), mean blood loss (677 ml vs. 368 ml), anastomotic leak (14% vs. 9%), discharge within 10 days (52% vs. 78%)
** Conclusion: Historical morbidity and mortality reduced with consistent technique and clinical pathway

## Surgery +/- Adjuvant RT

* 2 randomized trials in the 1980's, neither showed survival advantage for RT. In fact, a Hong Kong trial with 3.5 Gy/fx showed worse survival due to RT-related deaths
* Local control better with RT, leading to suggestion of post-op RT for patients with residual disease
* Hong Kong
** Randomized. 130 patients, squamous cell and adenoCA, treated with surgery (60 curative and 70 palliative; stratified). Arm 1) surgery alone vs. Arm 2) RT 49/14 in 3.5 Gy/fx
** 1993 PMID 8430362 -- "Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study." (Fok M, Surgery. 1993 Feb;113(2):138-47.)
*** Outcome: Median OS surgery 15 months vs. adjuvant RT 8 months (SS). If curative resection, no difference for LC or OS. If palliative resection, LR benefit (20% vs. 46%) but no impact on OS
*** Toxicity: stomach complications surgery 6% vs. RT 37% (SS), 5 deaths as result of bleeding
*** Conclusion: Worse survival with adjuvant RT due to RT-related deaths and early mets
** Comment: According to authors, high dose/fx due to heavy demand on RT facilities
* France (1987-?)
** Randomized. 221 patients with squamous cell in middle/lower third, stratified N0/N1/N2, treated with surgery. Arm 1) surgery alone vs. Arm 2) post-op RT (45-55 Gy).
** 1991 PMID 1925862 — "Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French University Association for Surgical Research." (Teniere P et al. Surg Gynecol Obstet. 1991 Aug;173(2):123-30.) Minimum F/U 3 years
*** Outcome: 3-year DFS 19%; No OS benefit for any subgroup. Decreased LR for RT (35% to 10%)
** Comment: It is interesting that this esophageal trial was published in a Gynecology and Obstetrics journal even though it's French.

## Surgery +/- Adjuvant Chemo-RT

* Intergroup - INT 0116 (1991-98)
** Randomized. 556 patients. Completely resected (negative margins) adenocarcinoma of the stomach or GE junction. Stage IB to IV(M0) [1988 staging; IB=T1N1 or T2N0]. Stratified by T stage and number of nodes. Compared surgery plus: Arm 1) observation vs. Arm 2) chemo -> concurrent chemo-RT. Bolus 5-FU (425 mg/m2/d) + LV (20mg/m2/d) x 5 days, followed by RT one month later. Chemotherapy given on first 4 and last 3 days of RT (dose 5-FU 425; LV 20). Adjuvant chemo one month following RT with two 5-day cycles of 5-FU/LV given one month apart. A D2 lymph node dissection was recommended, but most (54%) had a less than D1 dissection or a D1 dissection (31%).
** RT technique: 45 Gy to tumor bed, regional nodes, 2 cm beyond proximal and distal margins of resection. Defined tumor bed by pre-op CT. Lymph nodes included were: perigastric, celiac, local para-aortic, splenic, hepatoduodenal or hepatic-portal, and pancreaticoduodenal. Exclusion of the splenic nodes was allowed in patients with antral lesions if it was necessary to spare the left kidney. For tumors of GE junction, included paracardial and paraesophageal lymph nodes.
** 2001 PMID 11547741 — "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction." MacDonald JS et al. N Engl J Med. 2001 Sep 6;345(10):725-30.
*** Outcome: median OS surgery 2.2 years vs. surgery+CRT 3.0 years (SS). 3-year OS 41% vs. 50%; 3-year RFS 31% vs 48%, median RFS 1.6 years vs 2.5 years (SS); LR 29% vs 19%, regional relapse 72% vs 65% (largely abdominal carcinomatosis), DM higher 18% vs 33%. Regional failure included peritoneal spread or liver mets. Only 64% in chemo/RT arm completed therapy as planned.
*** Toxicity: Grade 3 or higher, hematologic 54%, GI 33%. 17% stopped treatment due to toxic effects. 32% of pts in chemo/RT group experience grade 4 toxic effects; 1% had treatment-related deaths.
*** Conclusion: Adjuvant CRT beneficial in GEJ tumors (T2N0, T1N1 and higher) after curative resection

## Neoadjuvant RT + Surgery vs Surgery Alone

* 5 randomized trials, latest published in 1992
* 4 trials showed no difference, one shows survival advantage but in a 2x2 design with chemo
* Meta-analysis showed no clear improvement in survival (p=0.06), with benefit for RT likely in the order of 3-4%
* Meta-analysis; 2005 PMID 16235286 -- "Preoperative radiotherapy for esophageal carcinoma." (Arnott SJ, Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001799.)
** 5 randomized trials. 1147 patients, mostly squamous cell. Median F/U 9 years
** Outcome: Pre-op RT trend to survival benefit (HR 0.89, p=0.06)
** Conclusion: No clear evidence of benefit; effect likely modest 3-4%
* 2nd Scandinavian trial (1983-1988)
** 1992 PMID 1455880 -- "Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer." (Nygaard K, World J Surg. 1992 Nov-Dec;16(6):1104-9; discussion 1110.)
** Randomized. 186 patients with squamous cell, 2x2 design: Arm 1) surgery alone, Arm 2) neoadjuvant cisplatin/bleomycin, Arm 3) neoadjuvant RT 35 Gy, and Arm 4) neoadjuvant chemotherapy and RT
** Outcome: 3-year OS significantly higher if receiving RT vs. no RT. No difference if receiving chemo vs. no chemo; Females significantly better survival
** Conclusion: neoadjuvant RT has benefit, neoadjuvant chemotherapy does not
* Scotland (1979-1983)
** Randomized. 176 patients, operable squamous cell or adenoCA of middle/lower third. Arm 1) preoperative RT 20/10 AP/PA vs. Arm 2) surgery alone.
** 1992 PMID 1496141 -- "Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial." (Arnott SJ, Radiother Oncol. 1992 Jun;24(2):108-13.)
*** Toxicity: None significant; no impact on operative complications
*** Outcome: median OS no difference; 5-year OS preop RT 9% vs. surgery 17% (NS)
*** Prognostic factors: LN+, high grade, male sex
** Conclusion: Low dose pre-op RT offers no advantage
* Beijing (1977-1985)
** 1989 PMID 2646253 -- "Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients." (Wang M, Int J Radiat Oncol Biol Phys. 1989 Feb;16(2):325-7.)
** Randomized. 206 patients, tumor <8cm, patients <65. Arm 1) preop RT AP/PA 40 Gy whole mediastinum and left gastroepiploic lymphatics
** Op stats: resection RT 93% vs. surgery alone 85%, mortality 5% vs. 6%, LN mets 27% vs. 35%
** Outcome: 5-year OS RT 35% vs. surgery alone 30%; patients with Grade III esophagitis survival 50%; LN failure 41% vs. 34%
** Conclusion: no difference
* EORTC (1976-1982)
** Randomized. 208 patients. Squamous cell only. Arm 1) preop RT 33/10 fractions, interval to surgery <8 days vs. Arm 2) surgery alone.
** 1987 PMID 3630187 (No abstract) — "The value of preoperative radiotherapy in esophageal cancer: results of a study of the EORTC." Gignoux M et al. World J Surg. 1987 Aug;11(4):426-32.
*** Op stats: Operability equal (RT 95%, no RT 100%); Resectability similar (RT 77%, no RT 82%), operative mortality slightly favoring surgery alone (RT 25%, no RT 18%),
*** Outcome: 5 year OS preop RT 10% vs. surgery 9% (NS). Survival for resected patients favored RT arm (RT 16% versus no RT 10%). Local failure preop RT 46% vs. surgery alone 67%
** Conclusion: No benefit for preop RT
* France (1973-1976)
** Randomized. 124 patients, squamous cell. Arm 1) 40 Gy Co-60 in 8 days (@ 5 Gy/fx?) vs. Arm 2) surgery alone
** 1981 PMID 6794167 -- "Preoperative radiotherapy for carcinoma of the esophagus." (Launois B, Surg Gynecol Obstet. 1981 Nov;153(5):690-2.)
*** Resection rate: RT 70% vs. surgery alone 58% (NS), operative mortality 23% both arms (NS)
*** Outcome: 5-year OS: RT 9% vs. surgery alone 11% (NS)
** Conclusion: No benefit for preop RT

## Neoadjuvant Chemotherapy + Surgery vs Surgery Alone

* Several small randomized trials were performed, but results were not overwhelming
* A Dutch trial showed significant benefit for cisplatin/etoposide, but it was never published as a manuscript
* Intergroup trial INT-0113 done in the US showed no benefit for cisplatin/5-FU
* In contrast, a British MRC trial showed a survival benefit in a very similar setting, with cisplatin/5-FU. Most patients were able to complete this schedule
* As a result, neoadjuvant chemo is accepted in Europe but not in the US
Meta-Analysis
* Sydney; 2007 PMID 17329193 -- "Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis." (Gebski V, Lancet Oncol. 2007 Mar;8(3):226-34.)
** Meta-analysis. 10 trials of neoadjuvant chemo-RT vs surgery alone, 1209 patients. 8 trials of neoadjuvant chemotherapy vs surgery alone, 1724 patients. Local operable esophageal cancer.
** Neoadjuvant chemo-RT: 2-year OS benefit 13% (20% vs 33%, but large variability between studies 7% - 59%). Effect favored chemo-RT in only 2 of 10 studies, but overall OS HR 0.81 (SS). By subtype, squamous cell HR 0.84 and adenoca 0.75.
** Neoadjuvant chemo: 2-year OS benefit 7%, HR 0.9 (p=0.05), no benefit in squamous cell (HR 1.03, NS), benefit in adenoCA (HR 0.78, SS)
** Conclusion: Significant survival benefit for preop chemo-RT, and to lesser extent chemo
* Sydney; 2011 PMID 21684205 -- "Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis." (Sjoquist KM, Lancet Oncol. 2011 Jul;12(7):681-92.)
** Meta-analysis. 12 trials of neoadjuvant chemo-RT vs surgery alone, (n=1854). 9 trials of neoadjuvant chemotherapy vs surgery alone, (n=1981). 2 trials of neoadjuvant chemoradiotherapy vs neoadjuvant chemotherapy, (n=194). 1 factorial trial included two comparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy (n=81). Resectable esophageal cancer.
** Neoadjuvant chemo-RT: HR for all-cause mortality: 0.78 (95% CI 0.70-0.88; p<0.0001)
*** HR for squamous-cell ca: 0.80 (0.68-0.93; p=0.004)
*** HR for adenoca: 0.75 (0.59-0.95; p=0.02)
** Neoadjuvant chemo: HR for all-cause mortality: 0.87 (0.79-0.96; p=0.005)
*** HR for squamous-cell ca: 0.92 (0.81-1.04; p=0.18)
*** HR for adenoca: 0.83 (0.71-0.95; p=0.01)
** HR for the overall indirect comparison of all-cause mortality for neoadjuvant chemo-RT vs chemo: 0.88 (0.76-1.01; p=0.07).
Randomized Evidence
* MRC Trial (1992-1998)
** 2002 PMID 12049861 -- "Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial." (MRC Oesophageal CWG, Lancet. 2002 May 18;359(9319):1727-33.)
** Randomized. 802 patients, any cell type, resectable. Arms 1) cisplatin 80 mg/m2 + 5-FU 1000 mg/m2 x2 cycles followed by surgery vs. 2) surgery alone. Preop RT could be given at discretion regardless of randomization.
*** Outcome: median OS chemo-S 17 months vs. S alone 13 months (SS); R0 in 60% vs. 54% (SS)
*** Toxicity: no difference
*** Conclusion: 2 cycles of neoadjuvant cisplatin/5-FU improve survival
** Comment: different outcome from US INT-0113 trial, despite similar design
* RTOG 89-11 (INT-0113) (1990 - 1995)
** Randomized. 443 patients with Stage I-III, excluding cervical esophagus and SCV LN+. Randomized to chemo then surgery vs surgery alone. Chemo consisted of 3 cycles of cisplatin/5-FU then 2 additional cycles. Post-op RT allowed for R1 or R2 resection
** 5-years; 1998 PMID 9869669 -- "Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer." (Kelsen DP, N Engl J Med. 1998 Dec 31;339(27):1979-84.) Median F/U 4.6 years
*** Outcome: median OS chemo-S 15 months vs. surgery 16 months (NS); no difference in LR control, or DM rate
*** Toxicity: tolerable; no increase in surgical morbidity/mortality
*** Conclusion: Preoperative cisplatin/5-FU does not improve outcome
** 9-years; 2007 PMID 17704421 -- "Long-Term Results of RTOG Trial 8911 (USA Intergroup 113): A Random Assignment Trial Comparison of Chemotherapy Followed by Surgery Compared With Surgery Alone for Esophageal Cancer." (Kelsen DP, J Clin Oncol. 2007 Aug 20;25(24):3719-25.) Median F/U 8.8 years
*** Outcome: Median OS 1.3 years both arms (NS), 5-year OS not given but both <25%
*** By resection: median OS R0 2.2 years vs. R1 1.0 years vs. R2 0.6 years vs. not resected 0.2 years (SS); 5-year OS R0 32% vs. R1 5%
** Conclusion: Neoadjuvant chemo no benefit. Need R0 resection for reasonable survival. For R1 resection, only CRT offers possibility of long-term DFS
* Netherlands, 1997 ASCO Abstract (1990-96) — "Neoadjuvant chemotherapy in operable esophageal squamous cell cancer: final report of a phase III multicenter randomized controlled trial." Kok TC et al. ASCO Abstract #984. Proc ASCO 1997; 16: 277.
** 160 pts. Randomized to neoadjuvant chemo before surgery vs surgery alone. Chemo: cisplatin + etoposide x 2 cycles, then assess response. If good response, continue for 2 more cycles; otherwise proceed with surgery.
** Increase in MS 19 m (chemo) vs 11 m (surgery).
** Comment: Never published in manuscript form
* 2nd Scandinavian trial (1983-1988)
** 1992 PMID 1455880 -- "Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer." (Nygaard K, World J Surg. 1992 Nov-Dec;16(6):1104-9; discussion 1110.)
** Randomized. 186 patients with squamous cell, 2x2 design: Arm 1) surgery alone, Arm 2) neoadjuvant cisplatin/bleomycin, Arm 3) neoadjuvant RT 35 Gy, and Arm 4) neoadjuvant chemotherapy and RT
** Outcome: 3-year OS significantly higher if receiving RT vs. no RT. No difference if receiving chemo vs. no chemo; Females significantly better survival
** Conclusion: neoadjuvant RT has benefit, neoadjuvant chemotherapy does not

## Neoadjuvant Chemo-RT + Surgery vs Surgery Alone

* 7 published trials, with various RT doses/fractionations, various chemo doses/fractionations, and various entry criteria
* Most recent meta-analysis (2007) shows a 2-year OS benefit of 13% for neoadjuvant chemo-RT over surgery alone, though only 2 of 10 trials were individually positive (Walsh, Tepper)
* As a result, many centers offer neoadjuvant CRT, typically cisplatin/5-FU (per PMID 17185197)
* Retrospective review from Duke suggests there is no benefit to paclitaxel-based neoadjuvant chemo-RT over cisplatin/5-FU
Meta-Analyses
* Sydney; 2007 PMID 17329193 -- "Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis." (Gebski V, Lancet Oncol. 2007 Mar;8(3):226-34.)
** Meta-analysis. 10 trials of neoadjuvant chemo-RT vs surgery alone, 1209 patients. 8 trials of neoadjuvant chemotherapy vs surgery alone, 1724 patients. Local operable esophageal cancer.
** Neoadjuvant chemo-RT: 2-year OS benefit 13% (20% vs 33%, but large variability between studies 7% - 59%). Effect favored chemo-RT in only 2 of 10 studies (Walsh, Tepper), but overall OS HR 0.81 (SS). By subtype, squamous cell HR 0.84 and adenoca 0.75.
** Neoadjuvant chemo: 2-year OS benefit 7%, HR 0.9 (p=0.05), no benefit in squamous cell (HR 1.03, NS), benefit in adenoCA (HR 0.78, SS)
** Conclusion: Significant survival benefit for preop chemo-RT, and to lesser extent chemo
* Meta-analysis; 2005 PMID 15674197 — "Neoadjuvant chemoradiotherapy for esophageal carcinoma: a meta-analysis." Greer SE et al. Surgery. 2005 Feb;137(2):172-7.
** 6 randomized trials, 738 patients
** Outcome: Small, non-significant trend toward improved long-term survival for the NCRT + surgery. RR = 0.86 (p=0.07)
** Conclusion: Whether benefit justified given expense and risk is not clear
* Meta-analysis; 2004 PMID 15194636 -- "Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis." (Fiorica F, Gut. 2004 Jul;53(7):925-30.)
** 6 published randomized trials and 764 patients. Males 78%-93%
** Outcome: 3-year trimodality better for mortality rate (OR 0.53, SS) but higher post-op mortality (OR 2.1, SS). Mortality attributed largely to EORTC trial with 3.7 Gy/fx, and difference was absent after excluding it
** Conclusion: Chemo-RT plus surgery significantly reduces 3 year mortality
** Comment: Significant variation in RT dose and technique, chemo doses and regimens, and surgical technique.
* Meta-analysis; 2003 PMID 12781882 -- "A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer." (Urschel JD, Am J Surg. 2003 Jun;185(6):538-43).
** 9 randomized trials including 1,116 patients.
** Outcome: 3-year trimodality better for OS (HR 0.66, SS); rate of complete resection (HR 0.53, SS); and LR control (0.38, SS). No difference for DM (data from only 3 trials).
** Best outcome when chemo-RT given concurrently (OR 0.45, SS) vs. sequentially (OR 0.8, NS)
** Conclusion: Neoadjuvant concurrent chemo-RT with surgery improved 3-year OS, and reduced LR recurrence
Randomized Evidence
* NEOCRTEC5010 (2007 - 2014) Vinorelbine/Cisplatin 40 Gy + Surgery vs. Surgery alone
** Randomized. 451 patients, esophageal squamous cell carcinoma, potentially resectable (T1-T4N1, T4N0). Arm 1) RT 40/20 using 3D (3 cm distal margin), with concurrent vinorelbine / cisplatin x 2 cycles, followed by esophagectomy vs 2) esophagectomy
** 2018 PMID 30089078 -- "Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial." (Yang H, J Clin Oncol. 2018 Sep 20;36(27):2796-2803. doi: 10.1200/JCO.2018.79.1483. Epub 2018 Aug 8.)
*** Outcome: Path CR in Arm 1 was 43%. R0 resection rate CRT 98% vs surgery 91% (SS). Median OS 8.3 years vs 5.5 years (SS). DFS 8.3 years vs 3.5 years (SS)
*** Toxicity: CRT had leukopenia (49%) and neutropenia (46%). Postop complications comparable, except arrhythmia (CRT 13% vs surgery 4%, SS). Peritreatment mortality CRT 2.2% vs surgery 0.45 (NS).
*** Conclusion: Neoadjuvant chemoRT followed by surgery improves survival over surgery alone, with acceptable adverse events
* FFCD 9901 (French Francophone de Cancerologie Digestive) (2000-2009) -- 5-FU/Cisplatin 45 Gy + Surgery vs. Surgery alone
** Multicenter. 195 pts, clinical Stages I-II. Randomized to surgery alone or neoadjuvant chemoradiotherapy (NCRT) followed by surgery. 45 Gy in 25 fractions; 5-FU and cisplatin x 2 cycles on weeks 1 and 5.
** Closed early after interim analysis due to futility.
** 2014 PMID 24982463 -- "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 C, JCO -- Online before print June 30, 2014) -- Median f/u 93.6 mo (7.8 yrs)
*** Pretreatment stage: 19% Stage I, 53% IIA, 27% IIB. Squamous 70%.
*** Similar R0 resection rate: 93.8% (NCRT) vs 92.1% (S), NS. 3-yr OS 47.5% vs 53.0%, NS; increase in postoperative mortality, 11.1% vs 3.4%, SS.
*** Improvement in local control: LRR 29% (NCRT) vs 15% (S), SS.
*** Conclusion: "Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC."
** 2014 (Editorial, Czito) PMID 24982460: Comparison with CROSS. Different histologic subtypes. French more early stage patients. Different chemo. Different post-op mortality rates (Dutch 4% both arms, French 11% NACT arm vs 3% surgery only arm).
* CROSS Study (2004-2008) -- Carbo/Taxol/RT 41.4 Gy + Surgery vs. Surgery alone
** Randomized. Study design: 368 pts with resectable (T1N1; T2-3 N0-1 M0) adeno (75%) or squamous ca (23%) of esophagus (75%) or GEJ (22%). Randomized to weekly paclitaxel 50 mg/m2 and carboplatin AUC = 2 x 5 weeks with concurrent RT (41.4 Gy in 23 fx). PTV = GTV + 4 cm prox/distally (3 cm distal if into stomach) & 1.5 cm radially followed by surgery versus surgery alone.
** 2010 ASCO Abstract "Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study." (Gaast et al., ASCO 2010 Abstract).
*** Outcome: MS 49 mo (CRT) vs. 26 mo (surgery alone) (p=0.011). 2 year OS 67% vs. 52%. R0 resections 92.3% vs. 64.9%. pCR rate 32.6% in CRT arm. Surgery performed in 90% of CRT arm vs. 86% of surgery alone arm.
*** Grade 3+ toxicities in CRT arm: Leukopenia 7%, nonhematological toxicities all < 5%. In-hospital mortality 3.8% CRT v. 3.7% surgery alone.
*** Conclusion: "Weekly administrations of carboplatin and paclitaxel with concurrent radiotherapy improves overall survival compared to surgery alone. Since toxicity was also acceptable (i.e. compared with cisplatin/5FU historical controls), this regimen can be considered the standard of care for patients with resectable esophageal or esophagogastric junction cancer."
** 2012 PMID 22646630: "Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer." (van Hagen et al.; NEJM 2012;366:2074-84).
*** Outcome: 91% got all chemo, 92% all RT. 94% in CRT got surgery, vs 99%. Post-op mortality 4% both arms, complications both arm higher than historically. MS 49.4 mo (CRT) vs 24.0 mo (surgery alone) (p=0.003). R0 resections 92% (CRT) vs 69%. pCR 29% in CRT arm.
*** Grade 3+ toxicity in CRT arm: Leukpenia 11%, anorexia 9%, all others <5%. One grade 5 perforation.
*** Conclusion: Neoadjuvant CRT superior to surgery alone, and result not secondary to poor surgical outcomes but improved outcome of CRT. No SS difference between adeno and SCC.
** Patterns of Recurrence; 2014 PMID 24419108 -- "Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials." (Oppedijk V, J Clin Oncol. 2014 Feb 10;32(5):385-91. doi: 10.1200/JCO.2013.51.2186. Epub 2014 Jan 13.)
*** Prior CROSS I and CROSS II trials. 418 patients; adenocarcinoma 75%.
*** Outcome: overall recurrence surgery 58% vs CRT+surgery 35%. Locoregional recurrence 34% vs 14% (SS). LRR in target volume 5%, margin 2%, outside 6%. Only 1% isolated in-field recurrence after CRT+S. Peritoneal carcinomatosis 14% vs 4% (SS). Hematogenous spread 35% vs 29% (SS).
*** Conclusion: Preop CRT reduced LRR; in-field recurrence in only 5%, and isolated only 1%
** 2015 PMID 26254683: "Neoadjuvant chemoradiotherapy plus surgery vs surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial." (Shapiro J, Lancet Oncol. 2015).
*** Outcome: MS 48.6 mo (CRT) vs 24.0 mo (surgery alone) (p=0.003). MS squamous cell 81.6 mo (CRT) vs 21.1 mo (surgery alone) (p=0.008). MS adenoCA 43.2 mo (CRT) vs 27.1 mo (surgery alone) (p=0.038).
*** Conclusion: Long-term f/u confirms OS benefit for neoadjuvant CRT when added to surgery, confirmed for both squamous and adeno histologies.
* CALGB 9781 / RTOG 97-16 (1997-2000) -- Cisplatin/5-FU/RT 50.4 vs observation
** Randomized. Closed early due to non-accrual. 56 pts (target 500). Stage I-III, squamous cell or adenoCA, thoracic esophagus/GEJ. Randomized to: concurrent RT 50.4/28 + 5-FU 1000 mg/m2 + cisplatin 100 mg/m2 followed by surgery vs surgery alone.
** 2008 PMID 18309943 — "Phase III Trial of Trimodality Therapy With Cisplatin, Fluorouracil, Radiotherapy, and Surgery Compared With Surgery Alone for Esophageal Cancer: CALGB 9781." (Tepper J et al. J Clin Oncol. 2008 Mar 1;26(7):1086-92.) Median F/U 6 years
*** Outcome: median OS trimodality 4.5 years vs. surgery 1.8 years (SS). 5-year OS: 39% vs. 16%; pCR 40%
*** Toxicity: Grade 3+ esophagitis/dysphagia 42%; infection 34% (1 death); pain 24%; hematologic toxicity 57%
*** Conclusion: Long-term OS significantly better with trimodality
* TROG/AGITG (1994 - 2000)
** Randomized. 256 patients, 62% adeno, 37% squamous. Resectable disease, T1-3, N0-1. Randomized to preoperative chemoradiotherapy vs surgery alone. One cycle cisplatin 80 mg/m2 + 5-FU 800 mg/m2/d. RT AP/PA 35/15 @ 2.33 Gy/fx, margins 5cm sup/inf and 2cm radial. Trimodality arm 18% didn't get surgery
** 2005 PMID 16129366 — "Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial." Burmeister BH et al. Lancet Oncol. 2005 Sep;6(9):659-68. Median F/U 5.4 years
*** Outcome: no difference in OS or PFS. Median OS 22 months vs. 19 months (NS). More R0 resections (80% vs. 59%), fewer N+ (43% vs. 67%). Better PFS for squamous cell (SS)
*** Toxicity: Grade 3-4 16% esophagitis, 5% nausea/vomiting
*** Conclusion: No difference, further assessment in squamous cell
* Dublin, Ireland (1990-1995)
** Randomized. Trial closed prematurely after interim survival benefit. 113 of expected 190 patients with adenocarcinoma. Concurrent cisplatin and 5-FU with RT 40/15 @2.67 Gy/fx, followed by another chemo cycle. RT fields: 5cm margins longitudinally, 2-3 cm laterally. Surgery on Week 9.
** 1996 PMID 8672151 -- "A comparison of multimodal therapy and surgery for esophageal adenocarcinoma." (Walsh TN, N Engl J Med. 1996 Aug 15;335(7):462-7.)
*** Outcome: Median OS trimodality 16 months vs surgery 11 months (SS). 3-yr OS 32% vs 6% (SS). pCR in 13/58 pts in combined arm.
*** Conclusion: Multimodality superior to surgery alone
** Comment: Criticized for short follow-up (median 10 months; 7.5m for dead vs 18 months for alive). 11 pts withdrew from combined therapy arm, versus only 1 for surgery arm. Also criticized for poor outcome on surgery alone arm (10-20% less than expected compared to Urba or EORTC).
* EORTC (1989-1995)
** Randomized. 282 patients with squamous cell of thoracic esophagus, excluded T3N1 (>3cm diameter and N+) and T4N0. Randomized to surgery vs pre-op chemo/RT. RT: Split course, two one-week courses two weeks apart, 18.5/5 @ 3.7 Gy/fx to macroscopic tumor/enlarged LNs, 5cm sup/inf and 2cm radial margin. Chemo: cisplatin 80mg/m2
** 1997 - PMID 9219702 — "Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus." Bosset JF et al. N Engl J Med. 1997 Jul 17;337(3):161-7. Median F/U 4.6 years
** Outcome: no difference in overall survival (median OS 19 months), improved DFS (17% vs. 21%, SS), improved cancer-related deaths (SS), improved LC. However, more post-op deaths in trimodality therapy. pCR 26%
** Conclusion: No difference in OS, but improvement in DFS and LC
** Comments: Authors speculated that RT too toxic (given in 3.7 Gy/fx)
* Michigan (1989-94)
** Randomized. 100 patients with squamous or adeno, any stage without distant mets. Randomized to surgery alone vs preop chemo/RT followed by surgery. Chemo: cisplatin 20 mg/m2 C.I. + 5-FU 300 mg/m2 C.I. + vinblastine. Required inpatient stay. RT: 45/30 @1.5 BID to tumor and involved nodes only; no elective nodal irradiation. Surgery after a 3 week rest, in 94% of pre-op pts.
** 2001 - PMID 11208820 — "Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma." (Urba SG et al. J Clin Oncol. 2001 Jan 15;19(2):305-13.). Median F/U 8 years
*** Outcome: median OS surgery 18 months vs. trimodality 17 months (NS); 3-year OS 16% vs. 30% (NS, p=0.15) but powered only to detect increase from 1 year to 2.2 years
*** Prognosis: pCR in 28%: these pts have a MS of 49 months vs. 12 months; 3-year OS 64% vs. 19%. Worse prognosis for squamous cell histology.
*** Conclusion: No difference in OS, DFS, or cause-specific survival. Improved survival for those with pCR after chemo/RT.
** Comment: Intensive preop therapy can be given, with 94% undergoing surgery
* Thailand (1986-1992)
** Randomized. 69 patients with squamous cell. Chemo (cisplatin + 5-FU), RT, surgery vs. surgery alone. 75% completed trimodality arm. pCR 20%
** 1994 PMID 7959579 -- "A prospective study of combined therapy in esophageal cancer." (Apinop C, Hepatogastroenterology. 1994 Aug;41(4):391-3.)
*** Outcome: no difference in survival or complications at 1 and 5 years. Median OS 10 months
* France
** 1994 PMID 8137201 -- "A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus." (Le Prise E, Cancer. 1994 Apr 1;73(7):1779-84.)
** Randomized. 86 patients with squamous cell. Chemo: cisplatin 100 mg/m2 + 5-FU 600 mg/m2. RT 20 Gy
*** Outcome: No difference in survival; median OS 10 months; 1-year OS 47% both groups
*** Toxicity: operative mortality 8.5% and 7%
*** Conclusion: No difference
* Scandinavian (1983-88)
** Randomized. 187 patients with squamous cell only, stage T1-2 NX. Four arm randomization: 1) surgery alone, 2) pre-op chemo then surgery, 3) pre-op RT 35 Gy then surgery, and 4) pre-op chemo+RT then surgery. Chemo: cisplatin + bleomycin x 2 cycles. RT: 35/20, included whole esophagus + mediastinum. No nodal irradiation.
** 1992 PMID 1455880 — "Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer." (Nygaard K et al. World J Surg. 1992 Nov-Dec;16(6):1104-9)
*** Outcome: Pooled analysis for pre-RT groups showed survival benefit. No benefit for pooled analysis of pre-op chemo groups
Response After CRT
* MSKCC; 2007 PMID 17290058 -- "American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma." (Rizk NP, J Clin Oncol. 2007 Feb 10;25(5):507-12.)
** Retrospective. 276 patients treated with CRT followed by surgery.
** Outcome: RPA analysis: LN status and M status best predictors; pretreatment stage not correlated to survival
** Conclusion: Initial AJCC stage not helpful, post CRT LN status and M status most important
** Comment (MD Anderson): PMID 17878485
Paclitaxel-based CRT
* Duke; 2007 (1995-2004) PMID 17889266 -- "Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer." (Kelsey CR, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):770-6.)
** Retrospective. 109 patients treated with CRT->surgery. Median RT dose 45 Gy. Paclitaxel-based chemo 47% vs. cisplatin-based chemo 53%
** Outcome: pCR TAX 39% vs. CIS 40% (NS), 3-year OS TAX 37% vs. CIS 37% (NS)
** Toxicity: TAX group 41% vs. CIS group 24% (NS)
** Conclusion: No benefit to paclitaxel-based chemo

## Neoadjuvant Chemo versus neoadjuvant Chemo-RT

* Only one Phase II RCT and only one Phase III RCT. Both were closed prematurely, due to poor accrual. They are thus not powered to show a survival advantage.
* Both trials only included adenocarcinoma. No SCC.
* Australian Phase II Trial -- Neoadjuvant Chemo vs. neoadjuvant Chemo-RT
** Randomized. Trial terminated early due to poor accrual. 75 patients with adenocarcinoma of the lower oesophagus and gastric cardia.
** 2009 PMID 19139439 -- "Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial." (Burmeister BH et al.,Eur J Cancer. 2011;47(3):354.)
*** Outcome: Histopathologic response rate(CRT 31% versus CT 8%, p = 0.01) and rate of R1 resections (CRT 0% versus CT 11%, p = 0.04) favored chemoradiotherapy. Median overall survival was not significantly better (32 versus 29 months).
*** Toxicity: Toxicity was similar for CT and CRT
*** Conclusion:Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus
* POET (Preoperative Chemotherapy or Radiochemotherapy in Esophagogastric Adenocarcinoma Trial), German Oesophageal Cancer Study Group (2000-2005) -- Only Phase III Trial. Neoadjuvant Chemo vs. neoadjuvant Chemo-RT
** Randomized. Trial terminated early due to poor accrual. 119 of expected 354 patients with locally advanced T3-4 adenocarcinoma of the lower oesophagus and gastric cardia. Arm 1) 2.5 courses PLF (cisplatin, fluorouracil, leucovorin) vs. Arm 2) 2.0 courses PLF followed by Chemo-RT (30/2) and 1 course of EP (etoposid, cisplatin). Surgery 3-4 weeks after completion of neoadjuvant treatment.
** 2009 PMID 19139439 -- "Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction." (Stahl M, J Clin Oncol. 2009 Feb 20;27(6):851-6) Median F/U 3.8 years
*** Outcome: 3-y OS: 47% vs. 28% (p=0.07). Higher rates of pCR and ypN0 with RCT than with CT
*** Toxicity: Postoperative mortality 10% vs. 4% (NS).
*** Conclusion: Although study underpowered (due to early closure) to demonstrate a survival benefit through RCT, strong trend towards OS-benefit through RCT.

## Primary Chemo-RT vs. Chemo-RT + Surgery

* Two European randomized trials in locally advanced patients; both defined primary chemo-RT as the standard group. Majority of the patients had squamous cell histology
* Overall, there was no difference in survival with the addition of surgery compared with more intense primary chemo-RT; non-inferiority was based on less than 10% or 15% difference in outcome
* Local control was higher with trimodality arm (65% vs 41%-57%), but so was perioperative mortality (12% vs 0-4%)
* French FFCD 9102 (1993-2000)
** Randomized. 444 enrolled patients, but only 259 randomized after initial therapy, remainder no improvement/contraindication/refusal/death. Operable T3N0-1 thoracic esophageal CA, squamous (90%) or adenoCA. Everyone treated with neoadjuvant 5-FU/cisplatin x2 cycles + RT (given either conventional 46/23 Gy or split course 15/5 + 15/5 with 2 week rest(became disallowed during study after this trial)). If response (clinical and esophagogram), randomized to surgery vs. further CRT (5-FU/cisplatin x3 cycles + RT (conventional 20/10 or split course 15/5). Total RT dose in primary CRT was 66 Gy (conv) or 45 Gy(split,3 Gy fx). Margin 3-cm sup/inf and 2-cm radial.
** 2007 PMID 17401004 -- "Chemoradiation Followed by Surgery Compared With Chemoradiation Alone in Squamous Cancer of the Esophagus: FFCD 9102" (Bedenne L, J Clin Oncol. 2007 Apr 1;25(10):1160-1168. Median F/U 4 years
*** 90% squamous.
*** Survival: Median OS trimodality 18 months vs. chemo-RT 19 months (NS) vs. unassigned patients 11 months, overall 16 months; 2-year OS: no difference (surgery 34% vs. CRT 40%). 3-month mortality: surgery 9.3% vs. CRT 0.8% (SS). 80% recurrences within 2 years
*** 2-year LC: trimodality 65% vs. CRT 57% (SS); stents required: surgery 5% vs. CRT 32% (SS). High grade dysphagia prevented in 46% chemo-RT vs. 63% trimodality. No difference in DM. Majority of recurrences in first year (60%) or first 2 years (80%)
*** RT: 67% split course
*** Toxicity: QoL higher in chemo-RT at 6 months, no difference thereafter.
*** Conclusion: in advanced thoracic esophageal CA patients who respond to neoadjuvant CRT, no benefit to surgery compared with continued CRT. CRT fewer early deaths, but more LR relapses
*** Editorial PMID 17401002: clinical staging only, no surgical QC, some split-course RT. Surgery should be selective, given morbidity/mortality. Systemic agents needed
** Prognostic factors; 2008 PMID 18372134 -- "Endoscopic ultrasonography is an independent predictive factor of prognosis in locally advanced esophageal cancer. Results from the randomized FFCD 9102 study from the Fédération francophone de cancérologie digestive." (Burtin P, Gastroenterol Clin Biol. 2008 Mar 25 [Epub ahead of print])
*** Prognostic factors: inability to ingest solid food (OR 2.0), >3 subdiaphragmatic LNs on EUS (OR 2.4), age >65 (OR 1.5)
*** By LN status: 2-year OS 3 LN+ 21% vs. 43%; 5-year OS 10% vs. 30%
*** Conclusion: EUS results should be taken into account
* Germany (1994-2002)
** Randomized. Non-inferiority statistical design (alternative hypothesis = equivalence). 172 patients with squamous cell only, upper/mid esophagus only, T3-4N0-1 staged by EUS. Randomized to induction chemo followed by chemo-RT to 40 Gy followed by surgery vs same regimen to 65 Gy without surgery. Induction chemo was FLEP (5-FU, leucovorin, etoposide, cisplatin); concurrent chemo was PE (cisplatin, etoposide). In the chemo-RT alone arm, RT was 50/25 followed by a 1.5 Gy BID for 65 Gy for T4 or obstructive T3 tumors; or 60 Gy followed by HDR brachytherapy 4 Gy @ 0.5cm x 2 for non-obstructed T3 tumors. Margins 3.5 cm sup/inf and 1.5 cm radial. 34% patients didn't undergo surgery (refused after neoadjuvant response or developed mets); R0 resection in 82%
** 2005 PMID 15800321 — "Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus." (Stahl M et al. J Clin Oncol. 2005 Apr 1;23(10):2310-7.) Median F/U 6 years
*** Outcome: Median OS surgery 16 months vs. CRT 15 months (NS); 3-year OS 31% vs. 24% (NS); 2-year freedom from local progression: surgery 64% vs. CRT 41% (SS). 75% of failures in-field. Only prognostic factor was response to neoadjuvant therapy
*** Toxicity: surgery 70% at least one severe complication; treatment mortality surgery 13% vs. CRT 4% (SS)
*** Conclusion: Surgery improves LC but not OS, significantly more complications. Authors recommend primary chemo-RT for patients that respond to initial neoadjuvant CRT, while offering surgery to poor responders
Retrospective
* Wayne State, 1988 (1980-84) - PMID 3138217 — "Chemo/radiation with and without surgery in the thoracic esophagus: the Wayne State experience." Herskovic A et al. Int J Radiat Oncol Biol Phys. 1988 Sep;15(3):655-62.
** "Historical controls" - 89 pts. All squamous. Pts treated with preoperative chemo/RT (cisplatin x 2 cycles on days 1, 29; 24-hr continuous infusion 5-FU over 4 days, x 2 cycles on days 1, 29). RT dose 30 Gy at 2 Gy/fx to tumor plus 5 cm longitudinal margin and 8 cm wide. Surgery was 4 weeks after RT. If positive margins, 20 Gy at 2 Gy/fx additional RT is given, without additional chemo.
*** 50 pts had surgery. 24% had pCR. Only 5 pts with long term survival.
** Other 72 pts ("group 1B"). 24 pts palliative.
** Pilot study: 22 pts. No surgery. Higher RT dose: 30 Gy AP/PA then 20 Gy with 3-field technique, 4 cycles of chemo. Same 5-FU/cisplatin as above, then bleomycin x 2 and mitomycin-C x 1. RT boost was given on week 11.
Role of ERCC1:
* Cologne, 2004 (Germany) PMID 15173087 -- "High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer." (Warnecke-Eberz U, Clin Cancer Res. 2004 Jun 1;10(11):3794-9.)
** 36 bronchoscopy tissue samples prior to treatment evaluated for ERCC1 expression via PCR. Then neoadjuvant chemoradiation (cisplatin, 5-FU, RT 36 Gy). Then surgery, and evaluation of histopathological response
** Response: 12/36 major response, 24/36 minor response. Pretreatment ERCC1 related to response
** Conclusion: Pretreatment ERCC1 level can predict non-responders to neoadjuvant chemoradiation

## Surgery Alone vs. RT Alone

* Shandong Randomized Trial (1998-2002) -- surgery vs RT
** Randomized. 269 patients, resectable esophageal CA. Arm 1) surgery alone vs. Arms 2) definitive RT 50 Gy in conventional fractionation followed by Late Course Accelerated Hyperfractionated Radiotherapy (LCAHR) boost (1.5 Gy BID) to 68.4-71 Gy. Fields gross lesion, bilateral SCV nodes, sup/inf 4cm, if lower esophagus draining gastric nodes. Width 5-6 cm. Reduced fields 2cm margin
** 2006 PMID 17366797 "Randomized clinical study of surgery versus radiotherapy alone in the treatment of resectable esophageal cancer in the chest." (Sun XD, Zhonghua Zhong Liu Za Zhi. 2006 Oct;28(10):784-7.)
*** Outcome: 5-year OS surgery 37% vs RT 35% (NS); PFS 23% vs. 21%
*** Conclusion: RT as given comparable to surgery
* MRC (1986-1988) -- surgery vs RT
** Randomized. Trial stopped prematurely due to lack of accrual. 31 patients from expected 100 patients, esophageal cancer. Arm 1) Surgery vs Arm 2) RT 50/20 or 60/30
** 1991 PMID 1996871 -- "An MRC prospective randomised trial of radiotherapy versus surgery for operable squamous cell carcinoma of the oesophagus." (Earlam R, Ann R Coll Surg Engl. 1991 Jan;73(1):8-12.)
*** No outcome published

## Definitive Chemo-RT
### RT alone vs RT + Chemo

* No evidence for benefit of sequential chemo->RT
* 10 randomized trials of concomitant chemo-RT published, though most were historical and negative
* RTOG 85-01 first to show significant benefit for concurrent approach, which resulted to change in standard of care
* RTOG 85-01 (1986-90) -- RT alone vs concurrent chemo-RT
** Randomized. Stopped early after significant interim OS benefit found. 129/150 planned. Invasive squamous cell (86%) or adenocarcinoma (14%) of thoracic esophagus, no gastric involvement, no distant mets. Mediastinal or SCV LN allowed. Stage T1-3N0-1. Arm 1) RT alone 64/32 (50/25 + 14/7 boost) vs. Arm 2) Concurrent cisplatin 75 mg/m2 (weeks 1,5,8,11) + 5-FU C.I. 1000 mg/m2 (days 1-4;weeks 1,5,8,11) + RT 50/25 (30/15 + 20/10 boost). Fields from SCV fossa to EGJ, if distal 1/3 omitted SCV fossa. Boost GTV + 5cm margin. Additional 73 patients registered onto the chemo-RT arm, nonrandomized.
** First report; 1992 Abstract — "Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus." Herskovic et al. N Engl J Med. 1992 Jun 11;326(24):1593-8.
*** Conclusion: Improvement in survival, 14 m vs 9 m, at the risk of higher severe acute toxicity.
** Race; 1999 PMID 10421537 — "Does race influence survival for esophageal cancer patients treated on the radiation and chemotherapy arm of RTOG #85-01?" (Streeter et al. Int J Radiat Oncol Biol Phys. 1999 Jul 15;44(5):1047-52.)
** 5-years; 1999 PMID 10235156 -- "Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group." (Cooper JS, JAMA. 1999 May 5;281(17):1623-7.)
*** Outcome: 5-year OS RT 0% vs. chemo-RT 26% (SS), subsequent registry group 14%. 8-year OS 22% (plateau), no additional deaths from esophageal cancer. LRF (despite lower RT dose) RT 53% vs chemo-RT 38%. DM 16% vs 30%.
*** Toxicity: Acute Grade 4-5 RT 2% vs. chemo-Rt 10% (2% deaths); Late Grade 3-4 RT 23% vs. chemo-RT 29%
*** Conclusion: Combined therapy increases survival of esophageal CA patients compared with RT alone. Local failure still a significant problem
* ECOG EST-1282, 1998 (1982-88) - PMID 9788404 — "Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group." Smith TJ et al. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):269-76.
** 119 pts. Randomized to chemo/RT (5-FU, mitomycin C) vs RT alone. After 40 Gy, had option to have surgery or continue to 60 Gy without surgery.
** 2-yr and 5-yr OS 12% and 7% (RT alone) vs 27% and 9% (chemo/RT). MS 9.2 mo vs 14.8 mo.
Non-randomized studies:
* U.Penn, 1987 - PMID 2445931 — "Nonsurgical management of esophageal cancer: report of a study of combined radiotherapy and chemotherapy." Coia L et al. J Clin Oncol. 1987 Nov;5(11):1783-90.
** 50 pts (30 definitive, 20 palliative). Definitive: Stage I-II, 60 Gy + 5-FU (24-hr infusion x 4 d, days 2 + 29) + Mitomycin C (day 2). Palliative: Stage III-IV, 50 Gy + chemo.
** For definitive group: 87% cCR. 73% 1-yr LC. OS 68% @ 1 yr, 47% @ 2 yr, 32% @ 5 yr.
** Palliative group: 82% free of dysphagia at end of treatment, 64% remained free of dysphagia until last follow-up. 8 month median survival.

### Neoadjuvant chemotherapy + Chemo/RT

* RTOG 02-46 (2003-2006) ASTRO Abstract -- "A Phase II Study of a Paclitaxel Based Chemoradiation Regimen With Selective Surgical Salvage for Resectable Locoregionally Advanced Esophageal Cancer: Initial Reporting of RTOG 0246" (Swisher S, Int J Radiat Oncol Biol Phys. 2007 69(3):S106-S106)
** Phase II. 40 patients, non-metastatic resectable esophageal CA (T3-T4 75%, N1 70%). Induction chemo 5-Fu 650 mg/m2 + cisplatin 15 mg/m2/d + paclitaxel 200 mg/m2/d x2 cycles, followed by concurrent chemo-RT with 50.4/28 and 5-FU 300 mg/m2/d + cisplatin 15 mg/m2/d. Salvage surgery if locoregionally recurrent disease. Median F/U 15 months
** Outcome: No recurrence 37%, surgical salvage attempted in 45%, met disease 7%, or inoperability/death 10%. 1-year OS 72%, DFS 395
** Toxicity: Acute G3+ nonhematologic 18%, hematologic 70%. 1 death during induction, 1 death due to pneumonitis
** Conclusion: Feasible regimen, though hypothesized 1-year OS not achieved
* RTOG 01-13- Induction 5-FU/taxol vs. induction cisplatin/taxol
** Phase III. 84 pts. Induction chemotherapy x 2 cycles -> concurrent chemo/RT.
*** Arm A - Induction 5-FU + Taxol; 50.4 Gy + concurrent 5-FU (96-hr C.I.) + weekly Taxol. With G-CSF. (Based on MDACC regimen.)
*** Arm B - Induction Cisplatin + Taxol; 50.4 Gy + concurrent Taxol (96-hr C.I.) + weekly Cisplatin. (Based on MSKCC regimen.)
** 2008 - PMID 18574157 — "Phase II Randomized Trial of Two Nonoperative Regimens of Induction Chemotherapy Followed by Chemoradiation in Patients With Localized Carcinoma of the Esophagus: RTOG 0113." (Ajani JA, J Clin Oncol. 2008 Oct 1;26(28):4551-6.)
*** Outcome: MS 28.7 mo (Arm A) vs 14.9 mo (Arm B). 2-yr OS 56% vs 37%. 1-yr OS 75.7% for Arm A.
*** Toxicity: High rate of toxicity: Grade 3/4 in 54%/27% vs 43%/40%. Treatment related death in 3% and 6%.
*** Conclusion: Both arms of RTOG 0113 were associated with high morbidity, and the study did not meet its 1-year survival end point.
* INT 0122 / RTOG 90-12, 1999 - PMID 10078631 — "Final report of Intergroup Trial 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus." Minsky BD et al. Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(3):517-23.
** 38 pts. Phase II based on RTOG 85-01, but intensified radiation + chemo doses (5 days of 5-FU, added neoadjuvant chemo, higher RT dose). Neoadjuvant 5-FU (1000 mg/m2/d,days 1-5) + cisplatin (100 mg/m2) qmonth x 3 cycles. Concurrent chemo/RT: 64.8 Gy + 5-FU (1000) + cisplatin (75) weeks 1,5.
** Conclusion: comparable survival to standard chemo/RT. Higher incidence of treatment related death. Higher RT dose was tolerable and led to INT 0123.

### Dose Escalation

* INT 0123 / RTOG 94-05 (1995-99)
** Stopped early. Randomized. 236 patients with T1-4 N0-1, squamous (85%) or adenoCA (15%). Concurrent chemo cisplatin 75 mg/m2 + 5-FU 1000 mg/m2. Arm 1: standard RT (50.4/28) with 5cm sup/inf and 2cm radial margin to primary + regional LNs, included SCV LN for cervical primary vs. Arm 2: high-dose RT 64.8/36, initial fields 50.4/28 + 14.4/8 boost to primary only with 2cm margin)
** 2002 PMID 11870157 — "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 BD et al. J Clin Oncol. 2002 Mar 1;20(5):1167-74.) Median F/U 1.3 years
*** Toxicity: 11 treatment related deaths in high dose arm, although 7/11 died at less than 50.4 Gy.
*** Outcome: No difference. Median OS high-dose 13 months vs. standard-dose 18 months (NS), 2-year OS (31% vs. 40%), LRF (56% vs. 52%, NS) or persistence of disease.
*** Conclusion: Standard is 50.4 Gy with concurrent 5-FU/cisplatin.
** Comment: Unclear why significantly more on-treatment deaths at <50.4 Gy in high dose arm, but no difference in outcome after correcting for it. Significant prolongation of treatment time in high-dose arm due to treatment breaks, significantly lower dose (65%) of target 5-FU delivered. Outcomes in standard-arm comparable to RTOG-85-01
** 2011: QOL PMID 21673875 -- "Longitudinal Quality-of-Life Analysis of RTOG 94-05 (Int 0123):A Phase III Trial of Definitive Chemoradiotherapy for Esophageal Cancer." (Kachnic LA, Gastrointest Cancer Res. 2011 Mar;4(2):45-52.)
*** Conclusion: Dose escalation to 64.8 Gy does not improve QOL. Lends further support to 50.4 Gy remaining the standard dose.
* RTOG 92-07 — brachytherapy boost
** See brachytherapy section for more detail
** Phase II. EBRT 50/25 + brachy boost HDR 15/3 or LDR 20/1. Concurrent chemo cisplatin 75 mg/m2 + 5-FU 1000 mg/m2.
** Conclusion: Not recommended due to high rate of fistula formation, and significant toxicity

### Hyperfractionated

* Mass General, 1997 - PMID 9375611 — "Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study." Wright CD et al. J Thorac Cardiovasc Surg. 1997 Nov;114(5):811-5
** 40 pts. Phase I/II. Cisplatin, 5-fluorouracil, and paclitaxel. 3 dose levels of chemo with BID RT to 45-58.5 Gy.
** High toxicity. Do not recommend this regimen.
* France, 1998 - PMID 9747816 — "Neoadjuvant chemotherapy and hyperfractionated radiotherapy with concurrent low-dose chemotherapy for squamous cell esophageal carcinoma." Raoul JL et al. Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):29-34.
** 32 pts. Cisplatin/5-FU/folinic acid q3w x 2 with BID RT 45 Gy. Also gave small injection of cisplatin prior to each fraction of RT.
** High operative mortality.
* UT Southwestern, 2002 - PMID 12151965 — "Preoperative chemotherapy and radiation for advanced esophageal carcinoma: comparison between once a day radiation and hyperfractionation, a single-institution experience." Nguyen NP et al. Am J Clin Oncol. 2002 Aug;25(4):358-64.
** Retrospective. 42 pts. 5-FU/cisplatin with once-daily RT 45-50.4 Gy (25 pts) or 5-FU/cispt/vinblastine with BID RT 1.5 Gy to 45 Gy.

### Brachytherapy

* RTOG 92-07 — brachytherapy boost
** Phase II. 49 patients, squamous (92%) or adenoCA. EBRT 50/25 + brachy boost HDR 15/3 or LDR 20/1. Concurrent chemo cisplatin 75 mg/m2 + 5-FU 1000 mg/m2.
** Preliminary; 1997 PMID 9112458 — "A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): preliminary toxicity report." (Gaspar LE, Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):593-9.)
** Swallowing; 2001 PMID 11693897 — "Swallowing function and weight change observed in a phase I/II study of external-beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207)." (Gaspar LE, Cancer J. 2001 Sep-Oct;7(5):388-94.)
*** Conclusion: Swallowing function is satisfactory after this regimen
** Final; 2002 PMID 10699886 — "A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report." (Gaspar LE, Cancer. 2000 Mar 1;88(5):988-95.)
*** Outcome: Median OS 11 months
*** Toxicity: 69% complete entire course; Grade 4 toxicity 24%, death 10%
*** Conclusion: Use significant caution with this regimen
** Conclusion: Not recommended due to high rate of fistula formation, and significant toxicity
* McGill; 2005 PMID 16199311 -- "The safety and usefulness of high-dose-rate endoluminal brachytherapy as a boost in the treatment of patients with esophageal cancer with external beam radiation with or without chemotherapy." (Vuong T, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):758-64.)
** Retrospective. 53 patients (KPS >70, M0), given HDR BT 20/5 + EBRT (50/25 + 5-FU/Cisplatin. Additional 17 patients (KPS <70, M0) given EBRT (35 Gy) alone
** Toxicity: acute bone marrow 55% Grade 2, 15% Grade 3; esophagitis 85% Grade 2
** Outcome: Median OS 21 months, 5-year OS 28%. 2-year local recurrence 25%
** Conclusion: Brachy boost safe and beneficial for local control in radical treatment

## Radiotherapy techniques

Dose
    AP/PA to 30-36 Gy
    Boost (AP and 2 obliques) to 50.4 Gy Preop dose or up to 60 Gy.
    or
    AP/PA to 45 Gy and lateral field boost (spares the cord).
    or
    AP/PA and IMRT technique as below
Margins:
* China (Hebei) / MDACC (2004-5)
** PMID 17236963, 2007 — "Pathological analysis of clinical target volume margin for radiotherapy in patients with esophageal and gastroesophageal junction carcinoma." Gao XS et al. Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):389-96.
** Pathologic study of 66 pts, 34 with SCC of mid-lower esophagus and 32 with GEJ adenocarcinoma. No preoperative chemo/rads. Measurement of microscopic spread from gross tumor, accounting for tissue contraction in formalin. All pts treated at Hebei Medical University but study coordinated through MDACC.
** For SCC: 30 mm longitudinal margin (prox and distal) covers microscopic disease in 94% of pts.
** For GEJ: 30 mm proximal and 50 mm distal (along GEJ and stomach).
** Good correlation of length of gross disease with size reported by endoscopy. CT scan may overestimate size for mid/lower esophageal tumors, and barium swallow may underestimate size for GEJ tumors. Recommend endoscopy for all cases and barium swallow for GEJ.
Dosimetry:
* Harvard; 2007 PMID 17185198 -- "Considerations in treatment planning for esophageal cancer." (Hong TS, Semin Radiat Oncol. 2007 Jan;17(1):53-61.)
** Review
Split Course
* FFCD 9102 (France)(1993-2000)
** See above for detailed trial information about CRT +/- surgery details. Subset 451 patients with induction RT, given either as protracted RT (46/23 + 20/10) in 64% patients or as split course RT (15/5 - 1 week - 15/5 - 1 week - 15/5) in 36% patients
** 2007 PMID 17971585 -- "Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102." (Crehange G, J Clin Oncol. 2007 Nov 1;25(31):4895-901.). Median F/U 4 years
*** Outcome: 2-year LRFR protracted RT 77% vs. split course RT 57% (SS), 2-year OS 37% vs. 30% (NS)
*** Conclusion: Better local control with continuous RT than with split-course RT
* FFCD 9305 (France)(1994-1998)
** Randomized. 202 patients in 16 centers. Concurrent cisplatin/5-FU with standard RT vs. split-course RT (20/5 at week 1 and 5)
** 1999 ASCO Abstract -- "Definitive Concurrent Chemo-Radiation Therapy (CRT) in Squamous Cell Carcinoma of the Esophagous (SCCE): Preliminary Results of a French Randomized Trial Comparing Standard vs Split Course Irradiation (FNCLCC-FFCD 9305)". (Jacob JH, ASCO Abstract 1035)
*** Outcome: Local failure split-course 71% vs. standard 43% (SS), DM comparable
*** Toxicity: Comparable, except cognitive functioning favoring split course
*** Conclusion: Split-course RT less effective than standard RT for LC, EFS, and OS
Patterns of Care Study:
* 1996-99 Patterns of Care Study - PMID 12829133, 2003 — "The national practice for patients receiving radiation therapy for carcinoma of the esophagus: results of the 1996-1999 Patterns of Care Study." Suntharalingam M et al. Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):981-7.
** 50/50% squamous/adeno. Staging: (1983 AJCC clinical staging) 16% Stage I, 39% Stage II, 33% Stage III, 12% unknown. For pts undergoing EUS, 71% had T3 (1997 AJCC). Treatment was concurrent chemo/RT in 56%, 26% preop chemo/RT, 10% RT alone, 6% post-op RT. 27% received chemo/RT before planned surgery. Trimodality treatment used in 46% of adeno vs 19% squamous.
** Conclusion: in comparison to the prior POC study, increased use of EUS, preop chemo/RT, and use of taxol.

## Proton Therapy
### Clinical

* Tsukuba
** 2010 (1985-2005) PMID 20803187 -- "Clinical Results of Proton-Beam Therapy for Locoregionally Advanced Esophageal Cancer." (Mizumoto M, Strahlenther Onkol. 2010 Aug 30. [Epub ahead of print])
*** Retrospective. 51 patients (50 squamous cell), locally advanced esophageal cancer. RT in 33 combination photon/proton median dose 80 GyE, 18 patient protons alone median dose 79 GyE
*** Outcome: 5-year local control 38%, 5-year OS 21%
*** Toxicity: No treatment breaks for toxicity
*** Conclusion: Effective; further studies required
** 2005 (1985-1998) PMID 15629597 -- "Clinical results of proton beam therapy for cancer of the esophagus." (Sugahara S, Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):76-84.)
*** Retrospective. 46 patients (45 squamous cell). 40 patients combination XRT (median 48 Gy) and PT boost (median 31.7 Gy). Median combined dose 76.0 Gy. Remaining 6 patients PT only (median 82.0 Gy). Proton field GTV + 1cm, single anterior field, median fraction size 3 Gy/fx (2.5-3.7). Doses are RBE-uncorrected
*** Outcome: 5-year local control T1 83% and T2-T4 29%; actuarial survival 55% and 13%.
*** Toxicity: No treatment interruption attributable to esophagitis . Post-RT ulcers 15% within 3 months
*** Conclusion: Proton therapy effective; additional studies necessary
** 2003 PMID 14506143 -- "Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas." (Koyama S, Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3571-7.)
*** Retrospective. 30 patients (superficial 43%, advanced 57%). PT alone or XRT + PT. Superficial dose 77.7 Gy, advanced dose 80.7 Gy
*** Outcome: 5-year local recurrence superficial 0%, advanced 57%. 5-year DSS 100%, 49%
*** Toxicity: Esophageal ulcer 67%
*** Outcome: Better local control and DSS with use of higher dose
** 1994 (1985-1991) PMID 8007424 -- "Proton beam therapy for patients with esophageal carcinoma." (Koyama S, Jpn J Clin Oncol. 1994 Jun;24(3):144-53.)
*** Retrospective. 15 patients (superficial 40%, advanced 60%). XRT mean dose 42.5 Gy + PT mean dose 37.6 Gy (total mean dose 80.4 Gy), or PT alone 81.4 Gy
*** Outcome: Local recurrence superficial 0%, advanced 67%
*** Conclusion: High dose could result in improved local control and long terms survival

### Treatment Planning

* MD Anderson
** 4D CT; 2009 PMID 19147024 -- "Impact of using different four-dimensional computed tomography data sets to design proton treatment plans for distal esophageal cancer." (Pan X, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):601-9.)
*** Treatment planning. Effects of 4D CT. Planning strategies based on 1) average, 2) inspiration, and 3) expiration CT
*** Conclusion: Inspiration CT + smearing margin can lead to adequate ICTV coverage for distal esophagus
** 4D CT; 2008 PMID 18722278 -- "Four-dimensional computed tomography-based treatment planning for intensity-modulated radiation therapy and proton therapy for distal esophageal cancer." (Zhang X, Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):278-87.)
*** Treatment planning. 15 patients. IMRT and PT comparisons
*** Conclusion: PT provided significantly better lung sparing than IMRT
* Uppsala; 1998 PMID 9607363 -- "Comparative treatment planning between proton and x-ray therapy in esophageal cancer." (Isacsson U, Int J Radiat Oncol Biol Phys. 1998 May 1;41(2):441-50.)
** Treatment planning. 5 patients. 2 PT plans, 1 XRT plan, 1 mixed plan. TCP/NTCP evaluation
** Conclusion: PT has clear therapeutic advantage over conventional EBRT