Radiation Oncology/Esophagus/Review

Esophageal Cancer Review

Epidemiology

 * 2009 U.S. Data: incidence ~16,500; mortality: ~14,500 (88% death rate)
 * High prevalence worldwide: Asia, southern/eastern Africa, southern France
 * Risk factors: age, male gender, Plummer-Vinson, caustic injury
 * Squamous cell: smoking, tobacco; risk decreases with cessation
 * AdenoCA: GERD, Barrett's (40x), smoking, tobacco; risk does not decrease with cessation

Clinical Presentation & Work Up

 * Clinical presentation: dysphagia, weight loss, hiccups (phrenic nerve), reflux (suggests EGJ tumor), satiety (suggests infiltration into stomach wall)
 * EGD: distance from incisors, extent of lesion/mucosal changes
 * CT scan: frequently not helpful, since Barretts shows wall thickening; miss 50% nodes
 * Endoscopic ultrasound: T-stage, LN evaluation/biopsy
 * PET/CT
 * Bronchoscopy: if above carina, to rule out fistulas

Surgery

 * Surgically resectable:
 * Cervical esophagus: typically not treated surgically for larynx preservation, need >5 cm from cricopharyngeus
 * Only 30-40% present with resectable disease, only 50% of these undergo curative (R0) resection
 * Technique: Transthoracic (Ivor Lewis) vs transhiatal
 * Lymph node dissection: based on SEER data, survival better if >10 LN removed
 * Surgery alone:
 * 5-year OS 20-25%; median OS ~1.5 years
 * Local control?
 * Surgery vs RT:
 * 2 older trials showed survival benefit to surgery; recent Chinese trial no difference in 5-year OS (~35%)
 * Pre-op RT:
 * 6 older RCTs. No survival benefit. Meta-analysis using individual patient data showed no conclusive survival benefit for RT
 * Pre-op chemo:
 * 9 RCTs. Two (MRC and Netherlands) showed significant survival benefit. Meta-analysis suggests 2-year 7% OS benefit and 5-year 4% benefit
 * Pre-op chemo-RT:
 * 10 RCTs. Two (Walsh, Tepper) showed significant survival benefit. Meta-analysis showed 2-year 13% OS benefit, which persisted even after excluding Walsh trial
 * Dublin (Walsh): median OS 16 months vs 11 months (SS); 3-year OS 32% vs 6% (SS). Critique poor outcome in surgery only arm
 * CALGB 9781 (Teper): median OS 4.5 years vs 1.8 years (SS); 5-year OS 39% vs 16%. pCR 40%; Grade 3+ toxicity 40%
 * Post-op chemo:
 * 3 RCTs. Meta-analysis showed no significant benefit
 * Post-op chemo-RT:
 * Gastric/EGJ trial (INT 0116, MacDonald): 3-year OS benefit 41% vs 50% (SS); 3-year local relapse 29% vs 19%; Grade 4 toxicity 32%
 * Pre-op chemo-RT + Surgery vs Chemo-RT alone:
 * 2 RCTs, majority squamous cell. Non-inferiority 10-15%, both trials negative for OS difference.
 * Germany (Stahl): Randomized upfront, no lower esophagus. 2-year OS 40% vs 35% (NS). 2-year local control 64% vs 41% (SS). Periop mortality 13% vs 4%
 * French FFCD-9102 (Bedenne): Only responders to CRT randomized. 2-year OS 34% vs 40% (NS). 2-year local control 66% vs 57% (SS). Periop mortality 12% vs 0%
 * Concurrent chemotherapy
 * CALGB 9781: 5-FU 1000 mg/m2 + cisplatin 100 mg/m2
 * RTOG 0436 (ongoing): paclitaxel 50 mg/m2 + cisplatin 25 mg/m2 QW
 * German (Stahl): cisplatin + etoposide
 * Conclusions:
 * If surgery will be done, preop chemo-RT improves 2-year survival
 * In patients with SCC at risk for surgical morbidity/mortality, primary chemo-RT may be comparable/superior
 * NCCN guidelines (v1.2010)
 * T1a: esophagectomy or EMR
 * T1b: esophagectomy for non-cervical, chemo-RT for cervical primaries
 * T2-T4N0-N1: pre-op chemo (adenoCA only), pre-op chemo-RT, or definitive chemo-RT
 * T2-T4N0-N1: if surgery done first, post-op chemo-RT (MacDonald) for distal/GEJ tumors or R1/R2 resections

Non-surgical approaches

 * RT vs Chemo-RT
 * RTOG 8501 (Herskovic)
 * Concurrent chemo: cisplatin 75 mg/m2 + 5-FU 1000 mg/m2 (weeks 1, 5, 8, 11)
 * Survial benefit: 3-year OS 10% vs 40% (SS); 5-year OS 0% vs 26% (SS); median OS 9 months vs 14 months (SS)
 * Locoregional control benefit: 53% vs 38% (SS)
 * Worse toxicity: Acute Grade 4-5 2% vs 10% (including 2% deaths)


 * Chemo-RT: Dose escalation
 * RTOG 9207 (Gaspar) brachytherapy boost
 * EBRT 50/25 + HDR 15/3 or LDR 20/1 with concurrent cisplatin 75 mg/m2 + 5-FU 1000 mg/m2
 * Grade 4 toxicity 24% (fistula 18%), deaths 10%
 * RTOG 9405 (Minsky) 3DCRT boost
 * EBRT 50.4 Gy vs 64.8 Gy with concurrent cisplatin 75 mg/m2 + 5-FU 1000 mg/m2
 * No difference in survival, 2-year 40% vs 31%
 * No difference in local failure: 56% vs 52%
 * Toxicity: 11 deaths in high-dose arm


 * Chemo-RT: Different chemo regimens
 * RTOG 0113: Induction chemo -> chemo-RT comparing cisplatin/paclitaxel vs 5-FU/paclitaxel
 * Neither arm successful


 * Local control: ~50% despite dose escalation or chemo changes
 * Survival: median OS ~1.5 years, 5-year OS ~25%