Prevention and management of acute esophageal toxicity during concomitant chemoradiotherapy for locally advanced lung cancer
Paolo Borghetti, Jessica Imbrescia, Giulia Volpi , Gianluca Costantino, Gianluca Cossali, Diana Greco,
Abstract
Background: Standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is concomitant chemoradiotherapy. The survival benefit of combined treatment is partially counterbalanced by an increased rate of acute esophageal toxicity. Several pharmaceutical products are available for prevention and management of esophagitis, including Faringel Plus.
Aim: To assess the incidence and the grade, identify the correlations with clinical, dosimetric, and therapeutic variables, and analyse the role of Faringel Plus as a pharmaceutical preventive measure against acute esophageal toxicity.
Methods: Patients with LA-NSCLC treated with concomitant radiochemotherapy were retrospectively reviewed. Acute esophagitis and dysphagia were graded according to Common Terminology Criteria for Adverse Events version 5.0. Clinical, dosimetric, and therapeutic correlations were investigated using 2 test.
Results: Among the 23 analysed patients, 18 (78.3%) and 1 (4.3%) developed G2 and G3 esophagitis, respectively; G1–2 dysphagia were reported in 11 cases (47.8%). No statistically significant correlation between the variables considered and acute esophageal toxicity was identified. In the group of patients who received Faringel Plus as preventive treatment (10 subjects, 43.5%), dysphagia presentation time was significantly longer (p = 0.038); esophagitis onset time was longer and symptoms duration was shorter. Faringel Plus allowed a reduction in the use of analgesic drugs.
Conclusions: Acute mild esophageal toxicity was confirmed to be a common side effect in this setting. No clinical- dosimetric parameter has been demonstrated to be effective in predicting acute esophageal toxicity. The use of Faringel Plus appears effective as a therapeutic and prophylactic tool to manage acute esophageal toxicity.
Keywords
NSCLC, chemoradiotherapy, radiotherapy, lung cancer, esophagitis, toxicities
Introduction
Concurrent radical chemoradiotherapy (CCRT) with a platinum-based doublet is considered the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC).1,2 Following the significant improve- ment demonstrated in phase 3 trials,3 durvalumab added to the armamentarium against locally advanced NSCLC (LA-NSCLC) and maintenance treatment for 12 months Symptomatic patient and capable of having an adequate diet Symptomatic patient with impaired nutrition or swallowing Patient with severely impaired feeding or swallowing; enteral nutrition, NPT, or hospitalization indicated Patient with dysphagia and consequent life-threatening; urgent intervention is indicated after CCRT became standard of care for LA-NSCLC with a PD-L1 expression ⩾1%.
In a meta-analysis published in 2010,2 severe acute esophagitis (grade ⩾3) emerged as the only toxicity sig- nificantly higher in CCRT than in sequential chemother- apy and radiotherapy (SCRT) (18% versus 4%, p < 0.001). However, these data are not updated to more recent trials. A randomized phase II trial comparing the use of hyper- fractionated radiotherapy and chemotherapy in concomi- tant and sequential schedule reported a similar rate of G3 acute esophagitis (8.8% and 8.5% respectively for CCRT and SCRT).4 Similarly, the RTOG 0617 trial reported a rate of G3 esophagitis of 7% in the standard arm of CCRT.5 These lower toxicity rates could be likely attributed to the more sophisticated radiotherapy techniques developed in recent years, including conformal techniques and image- guided radiotherapy (IGRT), which improved conforma- tion and accuracy of treatment planning and delivery, thus minimizing the doses to the organs at risk.
Nonetheless, in clinical practice, mild/moderate esoph- ageal toxicity remains a common critical issue, although mostly reversible and short-lasting. Different measures can be undertaken to manage this side effect, such as anal- gesic or topical drugs. The role of prophylactic regimens to prevent esophageal toxicity is less clear.
Faringel Plus is a topical drug active on esophageal mucosae with an anti-inflammatory, anaesthetic, and re- epithelizing functions. Its effectiveness has been demon- strated in the treatment and prevention of mucositis and acute esophagitis during radiotherapy or chemotherapy.6 It is composed of sodium alginate, calcium carbonate and potassium bicarbonate, honey, chamomile, calendula, depollinated propolis, and aloe vera gel.
The aim of this study was to evaluate the incidence and degree of acute esophageal toxicity related to curative radio-chemotherapy in a recent retrospective series of locally advanced unresectable lung cancer and to investi- gate correlations with clinical, dosimetric, and therapeutic variables. The use of Faringel Plus and other drugs as pre- vention or treatment of acute esophageal toxicity was also analysed.
Materials and methods
This is a retrospective study designed to assess the inci- dence of esophagitis and dysphagia, the pattern of practice of toxicities management, and the effectiveness of Faringel Plus in the prevention and treatment of acute esophageal toxicity.
Eligible patients were required to meet the following inclusion criteria: histologic diagnosis of lung cancer, inoperable stage IIIA or stage IIIB (TNM, 8th edition) dis- ease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) index <2, and radical treatment with CCRT.
According to internal institutional policy and interna- tional recommendations, a CCRT with conventional frac- tionation radiotherapy with a total dose of 60 Gy and concurrent platinum-based doublet chemotherapy was prescribed. A mean dose to the esophagus of less than 35 Gy was recommended as constraint for optimization of radiotherapy planning.5
Patients were visited weekly during the treatment in order to assess toxicities. Symptom appearance was calcu- lated as the time between the start of radiotherapy and the first event reported; radiotherapy dose delivered when symptoms appeared was also registered. The duration of toxicity was calculated as the interval between the begin- ning and the complete resolution of symptoms.
Esophagitis was defined as a disorder characterized by inflammation of the esophageal wall and dysphagia was defined as a disorder characterized by difficulty in swal- lowing; their degrees were classified according to Common Terminology Criteria for Adverse Events (CTCAE) ver- sion 5.0 as shown in Table 1.
The use and duration of drugs for the treatment of esophageal toxicity was reported. The kind of molecules administered such as nonsteroidal anti-inflammatory drugs or paracetamol, opioids, topical drugs, and Faringel Plus was registered. Compliance to the use of Faringel Plus and its tolerability, primarily in terms of taste, were annotated. The use of Faringel Plus was defined as preventive if it was used from the first or second cycle of chemotherapy and in the absence of acute esophageal toxicity; its use was defined as needed if its prescription was due to the pres- ence of symptoms.
Statistical analysis of the collected data provided a description of the numerical frequency and percentage of the variables. Chi-square test was applied for correlations between clinical, dosimetric, and therapeutic variables and toxicity endpoints. A p value < 0.05 was considered statis- tically significant. SPSS v.25 software was used for statis- tical analysis.
Results
An overview of prevention and management of acute esoph- ageal toxicity during concomitant chemoradiotherapy for locally advanced lung cancer is presented in the Figure.
Among patients treated between January 2018 and August 2019, 23 were retrospectively selected for this analysis. Patient characteristics are summarized in Table 2. Median age was 66 years (range 45–82) and 16 were male (69.6%); all patients had ECOG PS 0 or 1. Twenty-one (91.3%) patients had NSCLC; 82.6% were classified as stage III.
The total radiation dose for all the patients was 60 Gy (2 Gy fractions once daily) for 5 days per week with a total of 30 sessions in 6 weeks of treatment.
All patients underwent volumetric modulated arc ther- apy or intensity modulation radiation therapy. In all cases, IGRT was applied. The median planning target volume (PTV) was 372 cm3, ranging between 178 and 843 cm3.
The average of the mean dose to the esophagus was 22.2 Gy (range 11.4–37.4 Gy). The recommend esopha- geal constraint of 35 Gy mean dose was met in all but two cases (35.8 and 37.4 Gy).
All patients underwent concurrent chemotherapy: 20 (87%) were treated with concurrent weekly carboplatin and paclitaxel and 3 with a platinum and etoposide sched- ule; no case required interruptions of the combined treatment.
Almost all patients (95.7%) completed at least 4 weekly cycles of chemotherapy. Seven patients (30.4%) com- pleted at least 75% of the cumulative expected dose of the antineoplastic drugs.
The most frequent reason for chemotherapy dose reduc- tion or temporary suspension was hematologic toxicity (19.2%). No case of definitive interruption of chemother- apy treatment due to esophageal toxicity was reported in the study.
Data regarding Faringel Plus assumption schedule showed that 10 patients used Faringel Plus for prevention and 13 used it as needed to treat the symptoms of esophagi- tis and dysphagia.
Four patients did not report esophageal toxicity (17.4%); 1 (4.3%) and 8 (34.8%) patients reported dyspha- gia and esophagitis alone, respectively; 10 (43.5%) patients had both esophagitis and dysphagia.
Among 18 cases of esophagitis, 17 were G2 (94.1%) and 1 case was G3 (5.9%). The only case of G3 esophagitis occurred after the end of the fourth chemotherapy cycle and required hospitalization to guarantee adequate nutrition through parenteral support and to assess the clinical condi- tion. Characteristics of esophageal toxicities are reported in Table 3. The mean time to esophagitis onset was 25 days after the beginning of radiotherapy (generally corresponding to a mean dose of 33 Gy); its mean duration was about 36 days.
There were 11 cases of dysphagia (47.8%): 7 (63.3%) were G1 (30.4%) and 4 (17.4%) were G2. Median time to dysphagia onset was 23 days from the start of radiotherapy and its duration was 36 days.
None of the clinical, dosimetric, or therapeutic varia- bles significantly affected the time to onset and duration of esophagitis and dysphagia. In particular, PTV volume and average dose to the esophagus did not predict the appear- ance of esophageal toxicity. Neither chemotherapy doses nor cycles correlated with esophagitis or dysphagia.
The preventive use of Faringel Plus was not statistically related to toxicity reduction for esophagitis or for dyspha- gia (Tables 4 and 5).
Comparing time to dysphagia appearance and its dura- tion between the group treated with preventive Faringel Plus and the group that used it as needed, it is evident that the prophylactic use of Faringel Plus lengthened the time of appearance and shortened the duration in respect to those assuming it as needed. In particular, the dysphagia clinical appearance time was significantly longer for patients treated with preventive Faringel Plus (p = 0.038) (Table 6).
Almost all patients (92.9%) referred excellent compli- ance in tolerability for the assumption of Faringel Plus, especially regarding palatability; only one reported diffi- culty in taking it, even for those patients assuming 3 or 4 sticks per day (one before each meal).
Evaluating the use of other drugs, alone or in associa- tion, it is evident that patients using preventive Faringel Plus needed fewer analgesic drugs and, when adopted, use was shorter, particularly for opioids (Table 7).
Discussion
This study confirms that esophageal toxicity is a common side effect of CCRT; only 4 patients did not refer esophagi- tis or dysphagia, but a single case of G3 esophagitis was recordered. Moreover, this series did not show any signifi- cant correlation between esophagitis and dysphagia and the clinical, dosimetric, and therapeutic factors described. The reported incidence of G3 toxicity (4.3%) is in accord- ance with the most recent literature data.4,6 The RTOG 0617 trial showed a rate of G3 esophagitis of 7% in the standard arm.5 The PROCLAIM trial estimated an incidence of G3–G4 dysphagia and esophagitis ranging between 5.9–6.6 and 18.8–20.6 respectively, depending on the chemotherapy regimens.7 These two studies reflect the benchmark for CCRT in terms of radiotherapy doses and chemotherapy combinations, but the recent modern advances in combined treatment, such as IGRT and highly conformal radiotherapy techniques, could explain the further reduction of the toxicity rate achieved in this real-life population.
There is no strong evidence regarding dose constraints that can reliably predict the risk of acute esophagitis; how- ever, data suggest that the incidence of severe esophagitis is over 30% if esophagus volume that receives 50 and 35 Gy is respectively higher than 40% or 50%.8–10
Results from another study suggest that the relative vol- ume and the length of the esophagus irradiated with >40 Gy are the most effective dosimetric factors predicting esophagitis of G2 or higher and that the upper part of the esophagus is the most sensitive.11
Multiple factors contribute to the incidence and degree of acute esophagitis aside from the dose received, including treatment fraction and concomitant administration of chem- otherapy.8 The findings of this analysis confirm that esopha- geal toxicity should not be considered a limitation to the standard use of CCRT, particularly when modern radiother- apy is combined with well-defined prophylaxis and man- agement of the side effects. At toxicity onset, it is mandatory to promptly adopt all the necessary therapeutic measures. In addition to dietary advice, pharmacologic aids can also be associated. Among these, proton pump inhibitors are recom- mended in order to decrease gastric acidity and therefore the corrosive power of gastric contents in the esophagus.11 Sucralfate, which creates a protective layer that prevents the action of hydrochloric acid on the mucus, may also be sug- gested. First-line analgesic treatment includes nonsteroidal anti-inflammatory agents or acetaminophen, while opioids can be used as a second line for severe cases.12 Lastly, hos- pitalization could be necessary for a minority of patients who develop severe toxicities, for example those requiring nutritional supplementation with parenteral or feedingor, rarely, to carry out surgical operations in case of stenosis, perforation, or esophageal fistula.13
In recent years, hyaluronic acid has become relevant in the treatment of radiotherapy acute toxicity and there are studies that demonstrate its value in the management of epithelial and mucosal lesions.11,13,14 Other studies demon- strated the effectiveness of sodium alginate as preventive treatment for acute esophageal toxicity,15 while the admin- istration of honey had no effect.16
The combination of sodium alginate and hyaluronic acid acts as anti-inflammatory, anaesthetic, re-epitheliz- ing, protective, healing, and soothing, and is able to block gastroesophageal reflux and improve digestion. The use of Faringel Plus in this series, especially for preventive treat- ment, showed encouraging results in delaying symptom appearance and reducing the duration of acute esophageal toxicity, remarkably for dysphagia. The main limit of this analysis is represented by the small sample of patients and the retrospective nonrandomized nature of the study, which prevented us from drawing definitive conclusions regard- ing the preventive use of Faringel Plus to reduce esopha- geal toxicity. Nonetheless, our results confirm that modern radiotherapy together with correct and timely management of esophageal toxicity can significantly limit the impact of esophagitis and dysphagia in CCRT treatments for locally advanced NSCLC.
These results need to be confirmed in a prospective trial, adequately powered to estimate the real incidence of esophageal toxicity due to CCRT and the potential benefits of accurate clinical and pharmacologic management of symptoms.
References
1. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in com- bination with mitomycin, vindesine, and cisplatin in unre- sectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17: 2692–2699.
2. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 2181–2190.
3. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017; 377: 1919–1929.
4. Maguire J, Khan I, McMenemin R, et al. SOCCAR: a randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III non-small cell lung cancer and good performance status. Eur J Cancer 2014; 50: 2939–2949.
5. Bradley JD, Paulus R, Komaki R, et al. Standard-dose ver- sus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small- cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16: 187–199.
6. Ippolito E, Floreno B, Rinaldi CG, et al. Efficacy of a prop- olis-based syrup (Faringel) in preventing radiation-induced esophagitis in locally advanced lung cancer. Chemotherapy 2018; 63: 76–82.
7. Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small- cell lung cancer. J Clin Oncol 2016; 34: 953–962.
8. Valentini V. Elementi di radioterapia oncologica. Società Editrice Universo 2013; 401–405.
9. Werner-Wasik M, Yorke E, Deasy J, et al. Radiation dose- volume effects in the esophagus. Int J Radiat Oncol Biol Phys 2010; 76 (3 suppl): S86–S93.
10. Rose J, Rodrigues G, Yaremko B, et al. Systematic review of dose-volume parameters in the prediction of esophagitis in thoracic radiotherapy. Radiother Oncol 2009; 91: 282–287.
11. Chaveli-López B and Bagán-Sebastián JV. Treatment of oral mucositis due to chemotherapy. J Clin Exp Dent 2016; 8: e201–e209.
12. Lalla RV, Bowen J, Barasch A, et al; Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical prac- tice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2014; 120: 1453–1461.
13. Presta G, Puliatti A, Bonetti L, et al. Effectiveness of hya- luronic acid gel (Jalosome soothing gel) for the treatment of radiodermatitis in a patient receiving head and neck radiotherapy Sodium Bicarbonate associated with cetuximab: a case report and review. Int Wound J 2019; 16: 1433–1439.
14. Rosenthal A, Israilevich R and Moy R. Management of acute radiation dermatitis: a review of the literature and pro- posal for treatment algorithm. J Am Acad Dermatol 2019; 81: 558–567.
15. Fogh SE, Deshmukh S, Berk LB, et al. A randomized phase 2 trial of prophylactic manuka honey for the reduction of chemoradiation therapy-induced esophagi- tis during the treatment of lung cancer: results of NRG Oncology RTOG 1012. Int J Radiat Oncol Biol Phys 2017; 97: 786–796.
16. Ninomiya K, Ichihara E, Hotta K, et al. Three-arm rand- omized trial of sodium alginate for preventing radiation- induced esophagitis in locally advanced non-small cell lung cancer receiving concurrent chemoradiotherapy: the OLCSG1401 study protocol. Clin Lung Cancer 2017; 18: 245–249.