# 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 5/5 | TD 5/5 | TD 50/5 | TD 50/5 | 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