Radiation Oncology/Toxicity/Esophagus

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Radiation Toxocity: Esophagus

Etiology

Dysphagia = disordered eating potentially caused by a number of mechanisms, both neurologic and non-neurologic
Odynophagia = painful swallowing
Swallowing process includes three phases coordinated from the brainstem
- Oral phase: bolus processing, propelling food from oral cavity to oropharynx. Voluntary process.
- Pharyngeal phase: propelling food from oropharynx downward. Closure of nasopharynx via soft palate, closure of airway via epiglottis, opening of upper esophageal sphincter. Involuntary process. Aspiration significant concern
- Esophageal phase: peristaltic movement to propel food into stomach. Lower esophageal sphincter opened
Dysphagia may be caused by extrinsic compression of the esophagus, intrinsic narrowing of the esophagus, or disorders of the esophageal motility
- Extrinsic compression: Cervical LND, gastric cancer
- Intrinsic narrowing: Esophageal tumor, esophageal stricture
- Dismotility: achalasia, esophageal spasm, scleroderma
Odynophagia suggests disruption of esophageal mucosa (inflammation) or muscle spasms
- Infection, particularly candida and HSV
- Pill esophagitis
- Reflux esophagitis
- Radiation esophagitis
- Ulcerated neoplasm
- Caustic agent (acid/alkali) ingestion
Infectious esophagitis
- Bacteria rarely cause primary esophageal infection
- Most common forms (frequently seen with concurrent chemotherapy: Candida, HSV
- Immunosuppression-associated forms: CMV, HIV
- Treatment:
  - Oral nystatin
  - Ketoconazole or fluconazole for more extensive involvement or if immunocompromized
  - Amphotericin B if evidence of systemic spread
Radiation esophagitis
- Acute reaction leads to inflammation, dysphagia and/or odynophagia, and dysmotility
- Secondarily, patients can develop dehydration and weight loss
- Rarely, patients may develop obstruction, perforation, or fistulas
- Late toxicity usually involves fibrosis leading to stenosis
- Treatment is typically symptomatic

Toxicity Scales

NCI CTCAE v3.0

Adverse Event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Dysphagia	Symptomatic, able to eat regular diet	Symptomatic, altered eating/swallowing; IV fluids <24 hrs	Symptomatic, inadequate oral caloric/fluid intake, need IV fluids >24 hrs, TPN	Life-threatening (obstruction, perforation)	Death
Esophagitis	Asymptomatic findings	Symptomatic, altered eating/swallowing; IV fluids <24 hrs	Symptomatic, inadequate oral caloric/fluid intake, need IV fluids >24 hrs, TPN	Life-threatening (obstruction, perforation)	Death
Fistula	Asymptomatic	Symptomatic, altered eating/swallowing; IV fluids <24 hrs	Symptomatic, severe alteration, IV fluids >24 hrs, tube feeding, TPN	Life-threatening	Death
Heartburn	Mild	Moderate	Severe	--	--
Perforation	Asymptomatic	Medical intervention; IV fluids <24 hrs	Surgery required; IV fluids >24 hrs, TPN	Life-threatening	Death
Stricture	Asymptomatic	Symptomatic, altered eating/swallowing; IV fluids <24 hrs	Surgery required; IV fluids >24 hrs, TPN	Life-threatening, require complete organ resection	Death
Ulceration	Asymptomatic	Symptomatic, altered eating/swallowing; IV fluids <24 hrs	Surgery required; IV fluids >24 hrs, TPN	Life-threatening	Death

RTOG Acute Morbidity Scoring Criteria

Organ	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Esophagus	Mild dysphagia or odynophagia, Topical anesthetics or NSAIDs, Soft diet	Moderate dysphagia or odynophagia, Narcotic analgesics, Puree or liquid diet	Severe dysphagia or odynophagia, Dehydration or weigh loss >15%, IV fluids, NGT, TPN	Complete obstruction, ulceration, perforation, fistula	Death

RTOG/EORTC Late Morbidity Scoring Schema

Organ	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Esophagus	Mild fibrosis, Slight difficulty swallowing solids, No pain on swallowing	Unable to take solid food normally, Swallowing semi-solid food, Dilatation may be indicated	Severe fibrosis, Able to swallow only liquids, May have pain on swallowing, Dilation required	Necrosis, Perforation, Fistual	Death

Emami Data

	TD 5/5			TD 50/5
% Organ	3/3	2/3	1/3	3/3	2/3	1/3
Esophagus (stricture,perforation)	5500	5800	6000	6800	7000	7200

Comment in text: information leading to these estimates was less than adequate
Acute vs. late toxicity was not specified

Acute

Incidence overall: 5-13%. Incidence with chemo/RT: 18-46%.

RT with concurrent chemotherapy:

MDACC, 2006 (2000-2003) - PMID 16839700 — "Risk factors for acute esophagitis in non-small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy." Wei X et al. Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):100-7.
- Retrospective. 215 pts treated with concurrent chemo/RT (127 also with induction CT) and 3D-CRT. Most used carbo/taxol. Median dose 63.5 Gy in 35 fractions. RT was AP/PA followed by oblique off-cord fields.
- 7% - Grade 0, 27% - Grade 1, 45% - Grade 2, 20% - Grade 3, 0.4% - Grade 4.
- Predictors for grade 3 or worse acute toxicity: On univariate - mean dose to esophagus, aV15 (absolute volume > 15 Gy, in mL) through aV45, rV10 (relative volume > 10 Gy, in %) through rV45. Only rV20 was found to be significant on multivariate analysis.
- Conclusion: keep rV20 < 45% and mean esophageal dose < 28 Gy to keep risk of grade 3 or higher esophagitis < 15%.

Werner-Wasik RedJ 2000 - PMID 11020565

Werner-Wasik 1999 - PMID 10760427

Maguire PD Red J 1999 - PMID 10477012

PMID 15890421 - Belderbos J
- V35

PMID 15001251 - Bradley J
- A55, V60

PMID 15849822 - Qiao WB
- Dmax 60

PMID 12527046 - Singh AK
- Dmax > 58

Michigan, 2005 PMID 16256230 -- "Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer." (Chapet O, Radiother Oncol. 2005 Nov;77(2):176-81.)
- Retrospective. 101 inoperable NSCLC. Outcome: Grade 2+ esophagitis
- Toxicity: 16% G2-3, 0% G4-5.
- LKB model: TD50 = 51 Gy (1STD = 40-63 Gy), n = 0.44, m = 0.32 (suggests wider dose dispersion around 51 Gy).
- Volumetric thresholds (Grade 2-3): V40 = 36.6 Gy, V50 = 31.0 Gy, V60 = 23.7 Gy, Max dose = 73.6 Gy

Takeda et al (Japan), 2005 - PMID 15936536 — "Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy." Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):626-9.
- 35 pts, NSCLC + SCLC. Daily fractions of 1.8-2 Gy. Most received concurrent chemo.
- Grade 1 & 2 acute esophagitis: V35 (mean was 28%)

Langer et al, 1997
- Grade 2 or worse: Esophageal length > 16 cm

Bradley et al, 2004
- Grade 2 or worse: surface area > 55 Gy; V60

Patel et al, 2004
- 1.2 Gy BID
- Grade 2 or worse: V50

Werner-Wasik, 2000
- Grade 3 or worse: hyperfractionated worse than once daily

Singh, 2003
- Grade 3 or worse: max dose > 58 Gy

PMID 15936540 -- "Anatomically-correct" dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics." (Kahn D, Int J Radiat Oncol Biol Phys. 2005)
- Conclusion: "The inclusion of corrections, based on anatomic realities, to DVH-based dosimetric parameters may provide dosimetric parameters that are better correlated with clinical outcomes than are traditional DVH-based metrics."

In reirradiation:

PMID 15936541 -- "Combination of longitudinal and circumferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with non-small-cell lung cancer treated in stereotactic body frame." (Poltinnikov IM, Int J Radiat Oncol Biol Phys. 2005)
- Median RT dose was 32 Gy with a median fraction size of 4 Gy
- Conclusion: "Reirradiation using hypofractionated three-dimensional radiotherapy and SBF immobilization is an effective strategy for palliation of symptoms in selected patients with recurrent NSCLC. The length of the esophagus in the RT field does not predict for AE. However, an increasing number of EDs displaying the combination of longitudinal and circumferential three-dimensional dose distribution along the esophagus is a valuable predictor for AE."

Management

Please see the Esophagitis Supportive Care page for further information