Treatment/Prognosis Flashcards
What are the most important features that predict for poor outcomes in pts with T1 esophageal cancers treated with surgical resection alone?
T1b Dz, LVI, and tumor length predict poor outcomes in these pts. (Cen P et al., Cancer 2008; Bolton WD et al., J Thorac Cardiovasc Surg 2009)
What are the types of surgical procedures employed for the management of esophageal cancers?
Minimally invasive esophagectomy using laparoscopy, thoracoscopy, or a combination. Traditional surgical approaches include radical esophagectomy, transhiatal, or transthoracic esophagectomies.
How do transhiatal and transthoracic esophagectomy procedures compare in terms of dissection extent and location of the Dz?
In general: A transhiatal approach may be less morbid but will have less exposure for tumor clearance and thorough LND c/w a transthoracic approach. Anastomotic leak for the transhiatal approach is easier to manage than the transthoracic approach (Cx vs. intrathoracic leaks).
Transhiatal esophagectomy: Pros: good for distal tumors with possible en bloc resection, laparotomy and a Cx approach (no thoracotomy) with Cx anastomosis, less morbid with less pain, and avoids fatal intrathoracic anastomotic leak. Cons: poor visualization of upper/midthoracic tumors, LND limited to blunt dissection, more anastomotic leaks, and more recurrent laryngeal nerve palsy.
Transthoracic esophagectomy: Pros: Ivor–Lewis (right thoracotomy) is the most common and preferred route and best for exposure for all levels of the esophagus, whereas left thoracotomy provides access to only the distal esophagus. Ivor–Lewis (right thoracotomy and laparotomy) provides direct visualization and exposure with a better radial margin and a more thorough LND. Cons: intrathoracic leak that can lead to fatal mediastinitis. Generally considered to have higher morbidity and mortality than transhiatal.
Does the # of nodes removed from esophagectomy predict for better outcome?
Yes. Data suggest that the # of nodes removed is an independent predictor of survival. In 1 large study, the optimal # was ≥23. (Peyre CG et al., Ann Surg 2008)
Is there evidence to prove that either transhiatal or transthoracic esophagectomy would be sup for Dz control and outcome?
No. There are no data to date showing that 1 approach is sup to the other. 2 large meta-analyses comparing transhiatal with transthoracic esophagectomy have shown equivalence. (Rindani R et al., Aust N Z J Surg 1999; Hulscher JB et al., Ann Thorac Surg 2001) In general, transthoracic approaches carry greater operative mortality and pulmonary complications, but transhiatal approaches have greater anastomotic leaks and stricture rates as well as recurrent laryngeal nerve injury. 5-yr OS rates are similar b/t the 2 approaches (20%–25%).
What is the 5-yr OS for pts managed with Sg alone for localized esophageal cancers?
5-yr OS is 20%–25% for pts managed with Sg alone for localized Dz. This is higher for earlier-stage Dz (T1N0 ∼77%) but lower for stage III Dz (∼10%–15%).
Is there evidence to support the use of preop chemo (no RT) for Tx of resectable esophageal cancers?
This is controversial. Several phase II studies have demonstrated benefit, and randomized studies have reported conflicting results on the benefit of preop chemo.
U.S. Intergroup trial (Kelsen DP et al., NEJM 1998; Long-term updated, Kelsen DP et al., JCO 2007): 467 pts (53% adeno, 47% SCC) randomized to 3 × 5-FU/cisplatin preop and 2 × 5-FU/cisplatin postop or immediate surgical resection alone. There were no differences in resectability or survival (4-yr OS 26% vs. 23%, respectively; MS 16 mos vs. 15 mos, respectively). pCR was 2.5%. Pts with complete resection had a 5-yr DFS of 32% vs. 5% with R1–R2 resection.
Is there evidence to support adding radiation to neoadj chemo?
MRC randomized trial of preop chemo (MRC, Lancet 2002): 802 pts (66% adeno, 31% SCC, 3% undifferentiated) randomized to (a) 2 × cisplatin/5-FU preop or (b) immediate Sg. There was a significant benefit of neoadj chemo. MS was 13.3 mos vs. 16.8 mos, respectively, and 2-yr OS was 34% vs. 43%, respectively. The complete resection rate was also improved by chemo (54% vs. 60%, respectively).
German Esophageal Cancer Study Group (POET) trial (Stahl M et al., JCO 2009; Long-term update, Stahl M et al., Eur J Cancer 2017): randomized phase III in pts with T3–4N any M0 adeno of the GE junction or gastric cardia. The study closed early d/t poor accrual (126 of 354 intended). Randomization: (a) induction chemo → Sg or (b) induction chemo → preop CRT → Sg. Chemo was cisplatin/5-FU/leucovorin. RT was 30 Gy in 15 fx. pCR was better in the preop CRT group (15.6% vs. 2%) and in tumor-free LNs (64% vs. 38%). 5-yr OS trended better in the CRT group (39.5% vs. 24.4%, p = 0.055). Postop mortality higher in the CRT group (10% vs. 3.8%, p = 0.26).
Neoadjuvant Chemotherapy Versus Radiochemotherapy for Cancer of the Esophagus or Cardia (NeoRes) (Klevebro F et al., Ann Oncol 2016): 181 pts with esophageal/EGJ adeno or SCC randomized to (a) preop chemo alone cisplatin/5-FU × 3 or (b) same chemo + concurrent RT (CRT) (40 Gy/20 fx). Primary endpoint met showing CRT improved pCR (28% vs. 9%) and also improved R0 rate (87% vs. 74%), but 3-yr OS (47% vs. 49%) and 3-yr PFS (44% both arms) not improved. CRT increased non-cancer causes of death in 1st year post randomization (46% vs. 15%, p = 0.036).
What is the phase III evidence to support preop CRT over Sg alone?
This had been controversial until the recent publication of the CROSS trial. Urba SG et al. (JCO 2007): 100 pts (75% adeno, 25% SCC) randomized to cisplatin/vinblastine/5-FU + RT to 45 Gy bid vs. Sg alone. 3-yr OS was 30% vs. 16%, respectively (p = 0.18). DM same in both arms (60%).
Burmeister B et al. (Lancet 2007, TTROG): 256 pts (67% adeno, 33% SCC) randomized to cisplatin + 5-FU with RT to 35 Gy/15 fx. Less intensive chemo (5-FU 800 mg/m2 vs. 1,000 mg/m2 in other studies) was used. There was no difference in OS overall, but there was a trend to improved OS in SCC.
CALGB 9781 (Tepper J et al., JCO 2008): 56 pts (75% adeno, 25% SCC) randomized (closed d/t poor accrual) to cisplatin + 5-FU with RT to 50.4 Gy. pCR rate was 40%. 5-yr OS was 39% vs. 16% (p = 0.005). MS was 48 mos vs. 22 mos.
FFCD 9901 (Mariette et al., JCO 2014): pts with stage I/II thoracic esophageal adeno or SCC randomized to (a) Sg alone or (b) neoadj CRT (45 Gy + cisplatin/5-FU × 2 cycles) f/b Sg. CRT improved LRR (15.3% vs. 28.9%), but not 3-yr OS (47.5% vs. 53.0%) or R0 rate (93.8% vs. 92.1%). CRT had higher postop mortality (11.1% vs. 3.4%, p = 0.049).
CROSS (van Hagen P et al., NEJM 2012; Long-term update, Shapiro et al., Lancet Oncol 2015): 368 pts (75% adeno, 23% SCC, 2% undifferentiated) were randomized to Sg alone or CRT f/b Sg. CRT arm was 41.4 Gy in 23 fx with concurrent carboplatin (AUC 2 mg/mL/min) and paclitaxel (Taxol) (50 mg/m2) for 5 wks f/b Sg. MS was 49 mos with CRT vs. 24 mos. Nonhematologic side effects were comparable in the 2 groups.
In the CROSS trial, what % of pts had R0 resection in the CRT arm vs. Sg alone arm and what % had a pCR to CRT?
In the CROSS trial, 92% had an R0 resection in the CRT arm vs. 69% in the Sg alone arm. 29% (23% of adeno and 49% of SCC) had a pCR to CRT (typical CR avg of randomized trials 25%–30%). (van Hagen P et al., NEJM 2012)
Is there a role for preop RT alone for esophageal cancers?
No. Studies demonstrate no benefit of preop RT alone.
Is there a role for postop RT alone for esophageal cancers?
Postop RT alone has failed to demonstrate a benefit in several randomized trials. Incomplete resection should rcv definitive CRT or palliative chemo or RT alone. Completely resected stages II–III adeno of the EGJ should rcv postop CRT based on the Intergroup gastric trial (20% EGJ tumors). (MacDonald JS et al., NEJM 2001)
What are the data demonstrating efficacy of definitive CRT vs. RT alone?
RTOG 85-01 (Herskovic A et al., NEJM 1992; Cooper JS et al., JAMA 1999): 130 pts (82% SCC, 18% adeno) randomized to 64 Gy RT alone vs. 50 Gy RT + cisplatin/5-FU × 2 during RT and 2 cycles after RT. There was SCC in 88% pts. 5-yr OS was 27% vs. 0% for RT alone. 10-yr OS was 20% for CRT. No outcome difference b/t adeno and SCC. RT technique used in this trial: initial RT field was the whole esophagus to 50 Gy (RT alone) or 30 Gy (CRT) → CD to 14 Gy (RT) or 20 Gy (CRT) to tumor + 5-cm sup/inf margin.
Is there a benefit of escalating the RT dose during CRT for esophageal cancer?
This is controversial, b/c INT 0123 (Minsky BD et al., JCO 2002) is a phase III study that randomized pts to 50.4 Gy vs. 64.8 Gy with cisplatin + 5-FU × 2 → adj cisplatin/5-FU × 2. There was no difference in LC (44% vs. 48%). Excessive deaths in 64.8-Gy arm (11 vs. 2) were seen even before the 50.4-Gy dose (7 of 11 deaths). However, separate analysis excluding the early deaths still did not find a benefit to a higher dose.
RTOG 9207 (Gaspar et al., Cancer 2000) incorporated a brachytherapy boost and resulted in unacceptable toxicity: 10% mortality and 12% esophageal fistula.
Is there evidence to suggest that Sg can be omitted in operable pts with localized esophageal cancer?
There are no strong data suggesting Sg can be omitted in pts with adeno of the esophagus. However, there are 2 randomized trials examining CRT + Sg vs. CRT alone in pts with SCC that demonstrated an LC benefit of adding Sg but not an OS benefit. This is possibly d/t increased postop mortality in pts with SCC.
Bedenne L et al. (JCO 2007): 444 pts enrolled, treated 1st with CRT (45 Gy or split course 15 Gy × 2); the 230 responding pts (88% SCC) were randomized to Sg or no Sg. LC was better with Sg (66% vs. 57%). There was no difference in survival (34% vs. 40%). The mortality rate was higher in the Sg group (9.3% vs. 0.8%).
Stahl M et al. (JCO 2005): 172 pts with SCC randomized to induction chemo + 40 Gy/chemo + Sg vs. induction chemo + 65 Gy/chemo alone. PFS was better with Sg (64% vs. 41%). Survival was the same b/t arms, with a trend to better survival with Sg. Postop mortality rate was also high in the surgical group (12.6% vs. 3.2%).
The benefit of Sg after CRT may be seen if postop mortality could be minimized, such as operation in high-volume facilities, where postop mortality should be in the range of 2%–4%.
