Esophagitis and Pneumonitis Related to Concurrent Chemoradiation ± Durvalumab Consolidation in Unresectable Stage III Non-Small-Cell Lung Cancer: Risk Assessment and Management Recommendations Based on a Modified Delphi Process
Abstract
:1. Introduction
2. Materials and Methods
2.1. Expert Working Group Selection
2.2. Preparation, Convergence, Consensus, and Reporting
3. Results and Discussion
3.1. Esophagitis
- Question E1: How should patients be evaluated to ascertain the risk of developing esophagitis during or after cCRT?
- Recommendation E1.1: Before cCRT, all patients should be assessed for risk of developing esophagitis to inform a risk-adapted treatment approach. (Level of agreement: 8 agree, 1 abstains)
- Recommendation E1.2: Radiation exposure to the esophagus is the most critical risk factor contributing to esophagitis during and/or after cCRT. (Level of agreement: unanimous)
- Question E2: What measures should be undertaken to prevent or mitigate the risk of esophagitis during or after cCRT?
- Recommendation E2.1: Early education of patients and caregivers/family members is critical to provide information on potential signs and symptoms of esophagitis, hydration requirements, dietary management, and when to seek care. (Level of agreement: unanimous)
- Recommendation E2.2: Appropriate planning techniques should be used to minimize exposure to radiation therapy. (Level of agreement: unanimous)
- Recommendation E2.3: Dietitian consultation is recommended early in the course of cCRT for patients with high or moderate esophagitis risk. (Level of agreement: unanimous)
- Recommendation E2.4: Proton pump inhibitor therapy should be considered for patients with symptoms suggestive of GERD. (Level of agreement: unanimous)
- Question E3: What treatments are effective for management of esophagitis?
- Recommendation E3.1: For symptomatic esophagitis, provide analgesics and consider dietitian support and PPI therapy if not already initiated; outpatient intravenous hydration can be initiated if patient is clinically dehydrated. Consider temporarily holding cCRT if initial measures prove ineffective. (Level of agreement: unanimous).
- Recommendation E3.2: For esophagitis requiring hospitalization, consider holding or discontinuing cCRT (if ongoing), provide continuous intravenous hydration, optimize pain management, and increase dietitian support. (Level of agreement: unanimous)
- Question E4: Which HCPs should be involved in the care of patients who experience esophagitis?
- Recommendation E4.1: Multidisciplinary team care is essential for optimizing management of esophagitis and must involve shared responsibilities, clear communication, and collaboration. (Level of agreement: 8 agree, 1 disagree)
- Recommendation E4.2: Patient follow-up frequency and HCP responsibility should be determined by esophagitis severity and timing of presentation. (Level of agreement: unanimous)
- Recommendation E4.3: Healthcare professionals should share clear follow-up care instructions, including point-of-care contacts at the cancer center, during cCRT and consolidation treatment phases. (Level of agreement: unanimous)
3.2. Pneumonitis
- Question P1: How should patients be evaluated to ascertain the risk of developing pneumonitis after cCRT ± durvalumab consolidation?
- Recommendation P1.1: Before initiating cCRT ± durvalumab, all patients should be assessed for risk of developing pneumonitis to inform a risk-adapted treatment approach. (Level of agreement: unanimous)
- Recommendation P1.2: Key factors identified to increase risk of symptomatic pneumonitis include large radiation volume (V20, mean lung dose) and poor lung function or the presence of interstitial lung disease at baseline. (Level of agreement: unanimous)
- Question P2: What measures should be undertaken to prevent or mitigate the risk of pneumonitis after cCRT ± durvalumab consolidation?
- Recommendation P2.1: Strategies should be implemented to reduce the volume of radiation delivered to normal structures and to address other modifiable risk factors. (Level of agreement: 8 agree, 1 abstains)
- Recommendation P2.2: For patients at very high risk of pneumonitis, determine whether definitive cCRT ± durvalumab consolidation is appropriate and safe to deliver on a case-by-case basis. (Level of agreement: unanimous)
- Question P3: What approach is recommended to determine the etiology of symptomatic pneumonitis?
- Recommendation: P3.1: Presentation of pneumonitis during durvalumab consolidation therapy may reflect RP or IO-related pneumonitis. Patients should be assessed by the treating radiation oncologist to help determine underlying etiology. (Level of agreement: 8 agree, 1 disagree)
- Recommendation P3.2: The radiation oncologist should compare the radiation plan with changes on CT imaging. In RP, lung parenchymal changes generally conform to the radiation treatment field, while IO-related pneumonitis is more likely to present with bilateral or diffuse lung changes. (Level of agreement: unanimous)
- Question P4: What treatments are effective for management of RP?
- Recommendation P4.1: Asymptomatic (grade 1) RP is common after cCRT and does not warrant investigation or treatment; however, increased monitoring may be warranted for patients presenting with new radiological changes after initiation of durvalumab consolidation therapy. (Level of agreement: unanimous)
- Recommendation P4.2: Patients with confirmed grade 2 RP should be followed under close observation. Prompt initiation of corticosteroid therapy should be considered in the event of worsening symptoms, as well as supplemental oxygen as clinically appropriate. Consider holding durvalumab if patient has initiated consolidation therapy. (Level of agreement: unanimous)
- Recommendation P4.3: Patients with confirmed grade 3/4 RP should promptly receive corticosteroid therapy and supplemental oxygen as clinically appropriate. Consider whether referral to respirology and/or hospitalization are warranted. Hold durvalumab if patient has initiated consolidation therapy. (Level of agreement: unanimous)
- Recommendation P4.4: Recommended corticosteroid therapy is oral prednisone 1 mg/kg/day up to 60 mg. Treatment should be tapered slowly over a duration of at least 6 weeks once RP has clinically improved. Simultaneous initiation of PPI therapy is also recommended, as well as consideration of prophylaxis for PJP. (Level of agreement: unanimous)
- Question P5: What treatments are effective for management of IO-related pneumonitis?
- Recommendation P5.1: Patients with asymptomatic (grade 1) IO-related pneumonitis should receive more frequent follow-up with oxygen saturation and chest X-ray. Consider holding durvalumab on a case-by-case basis. (Level of agreement: 8 agree, 1 abstains)
- Recommendation P5.2: Patients with confirmed grade 2 IO-related pneumonitis should have durvalumab suspended, corticosteroid therapy promptly initiated, and supplemental oxygen provided as clinically appropriate. Monitor closely; if pneumonitis persists or worsens after 48 to 72 h, treat as grade 3 or 4. (Level of agreement: 7 agree, 2 abstain)
- Recommendation P5.3: Patients with confirmed grade 3/4 IO-related pneumonitis should have durvalumab suspended or discontinued and corticosteroid therapy promptly initiated. Supplemental oxygen, hospitalization, and respirology referral are warranted. If pneumonitis persists or worsens after 48 h, consider initiating a non-steroidal immunosuppressive agent. (Level of agreement: 8 agree, 1 abstains)
- Recommendation P5.4: Recommended outpatient corticosteroid therapy is oral prednisone 1–2 mg/kg/day; treatment should be tapered slowly over a duration of at least 6 weeks once pneumonitis has clinically improved. Simultaneous initiation of PPI therapy is recommended, as well as consideration of prophylaxis for PJP. (Level of agreement: 8 agree, 1 abstains)
- Question P6: Which patients with RP are suitable for initiation of durvalumab consolidation?
- Recommendation P6.1: Consider initiating durvalumab for patients with asymptomatic RP after cCRT; more frequent follow-up with chest X-ray may be warranted. (Level of agreement: unanimous)
- Question P7: Which patients are suitable for durvalumab re-initiation after resolution of pneumonitis?
- Recommendation P7.1: For patients with confirmed RP who have resolution of symptoms and corticosteroids tapered to ≤10 mg/day, consider re-initiating durvalumab. (Level of agreement: unanimous)
- Recommendation P7.2: For patients with IO-related pneumonitis who have symptom resolution and corticosteroids tapered to ≤10 mg/day, the decision to re-initiate durvalumab should be individualized on the basis of patient characteristics and shared decision-making. (Level of agreement: 8 agree, 1 disagree)
- Question P8. Which HCPs should be involved in the care of patients who experience pneumonitis?
- Recommendation P8.1: Multidisciplinary team care is essential for optimizing follow-up of pneumonitis and must involve shared responsibilities, clear communication, and collaboration. (Level of agreement: 8 agree, 1 disagree)
- Recommendation P8.2: Radiation and medical oncologists should communicate regarding patient status and classification of pneumonitis etiology. If RP, the radiation oncologist should be responsible for management and follow-up until resolution; if IO-related, the medical oncologist should be responsible. (Level of agreement: unanimous)
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Esophagitis | Pneumonitis | |
---|---|---|
Frequency | Symptomatic grade ≥ 2: ~50% [17] | Grade ≥ 2 RP: 30–44% [18,23,24] Any-grade IO-related: 11–22% a (grade 3/4: 1.9%) [20,25] |
Typical time to onset (any grade) | 2–3 weeks after initiation of cCRT [26] b | RP: 1–6 months after cCRT [26,27] IO-related: 54 days (median) after durvalumab initiation (range, 2–342 days) [25] |
Typical time to resolution | ~8 weeks after end of cCRT [26] | 53 days (median; range, 22–588 days) [25] |
Signs and symptoms [16,26,28] c |
|
|
Risks and complications [16,26,27,28,29] |
|
|
Differentiation of etiology [30,31] e | N/A | RP: Changes typically conform to radiation treatment field with sharp border. IO-related pneumonitis: Typically, bilateral or diffuse lung changes. |
Grade | Esophagitis a | Pneumonitis |
---|---|---|
1 | Asymptomatic Clinical or diagnostic observations only—intervention not indicated. | Asymptomatic Clinical or diagnostic observations only—intervention not indicated. |
2 | Symptomatic; altered eating or swallowing Oral supplements indicated | Symptomatic; limiting instrumental ADL Medical intervention indicated |
3 | Severely altered eating/swallowing Tube feeding, TPN, or hospitalization indicated | Severe symptoms; limiting self-care ADL Oxygen indicated |
4 | Life-threatening consequences Urgent operative intervention indicated | Life-threatening respiratory compromise Urgent intervention indicated (e.g., tracheotomy or intubation) |
5 | Death |
Target Population | Patients with stage III unresectable NSCLC treated with cCRT ± durvalumab consolidation therapy | |
Target Audience | Radiation oncologists; medical oncologists; oncology nurses, nurse practitioners, and physician assistants; respirologists; pulmonologists; radiologists; family physician/community primary care team members; geriatric oncologists; pharmacists; patients | |
Clinical Question | Recommendations and Level of Agreement | Key Considerations |
E1. How should patients be evaluated to ascertain the risk of developing esophagitis during or after cCRT? | Recommendation E1.1: Before cCRT, all patients should be assessed for risk of developing esophagitis to inform a risk-adapted treatment approach. (Level of agreement: 8 agree, 1 abstains) Recommendation E1.2: Radiation exposure to the esophagus is the most critical risk factor contributing to esophagitis during and/or after cCRT. (Level of agreement: unanimous) |
|
E2. What measures should be undertaken to prevent or mitigate the risk of esophagitis during or after cCRT? | Recommendation E2.1: Early education of patients and caregivers/family members is critical to provide information on potential signs and symptoms of esophagitis, hydration requirements, dietary management, and when to seek care. (Level of agreement: unanimous) Recommendation E2.2: Appropriate planning techniques should be used to minimize exposure to RT. (Level of agreement: unanimous) Recommendation E2.3: Dietitian consultation is recommended early in the course of cCRT for patients with high or moderate esophagitis risk. (Level of agreement: unanimous) Recommendation E2.4: Proton pump inhibitor therapy should be considered for patients with symptoms suggestive of GERD. (Level of agreement: unanimous) |
|
E3. What treatments are effective for management of esophagitis? | Recommendation E3.1: For symptomatic esophagitis, provide analgesics and consider dietitian support and PPI therapy if not already initiated; outpatient IV hydration can be initiated if patient is clinically dehydrated. Consider temporarily holding cCRT if initial measures prove ineffective. (Level of agreement: unanimous) Recommendation E3.2: For esophagitis requiring hospitalization, consider holding or discontinuing cCRT (if ongoing), provide continuous IV hydration, optimize pain management, and increase dietitian support. (Level of agreement: unanimous) |
|
E4. Which HCPs should be involved in the care of patients who experience esophagitis? | Recommendation E4.1: Multidisciplinary team care is essential for optimizing management of esophagitis and must involve shared responsibilities, clear communication, and collaboration. (Level of agreement: 8 agree, 1 disagree) Recommendation E4.2: Patient follow-up frequency and HCP responsibility should be determined by esophagitis severity and timing of presentation. (Level of agreement: unanimous) Recommendation E4.3: Healthcare providers should share clear follow-up care instructions, including point-of-care contact(s) at the cancer center, during cCRT and consolidation treatment phases. (Level of agreement: unanimous) |
|
Target Population | Patients with stage III unresectable NSCLC treated with cCRT ± durvalumab consolidation therapy | |
Target Audience | Radiation oncologists; medical oncologists; oncology nurses, nurse practitioners, and physician assistants; respirologists; pulmonologists; radiologists; family physician/community primary care team members; geriatric oncologists; pharmacists; patients | |
Clinical Question | Recommendation and Level of Agreement | Key Considerations |
P1. How should patients be evaluated to ascertain the risk of developing pneumonitis after cCRT ± durvalumab consolidation? | Recommendation P1.1: Before initiating cCRT ± durvalumab, all patients should be assessed for risk of developing pneumonitis to inform a risk-adapted treatment approach. (Level of agreement: unanimous) Recommendation P1.2: Key factors identified to increase the risk of symptomatic pneumonitis include large radiation volume (V20, MLD) and poor lung function or presence of ILD at baseline. (Level of agreement: unanimous) |
|
P2. What measures should be undertaken to prevent or mitigate the risk of pneumonitis after cCRT ± durvalumab consolidation? | Recommendation P2.1: Strategies should be implemented to reduce the volume of radiation delivered to normal structures and to address other modifiable risk factors. (Level of agreement: 8 agree, 1 abstains) Recommendation P2.2: For patients at very high risk of pneumonitis, determine whether definitive cCRT ± durvalumab consolidation is appropriate and safe to deliver on a case-by-case basis. (Level of agreement: unanimous) |
|
P3. What approach is recommended to determine the etiology of symptomatic pneumonitis? | Recommendation P3.1: Presentation of pneumonitis during durvalumab consolidation therapy may reflect RP or IO-related pneumonitis. Patients should be assessed by the treating RO to help determine underlying etiology. (Level of agreement: 8 agree, 1 disagree) Recommendation P3.2: The RO should compare the radiation plan with changes on CT imaging. In RP, lung parenchymal changes generally conform to the radiation treatment field, while IO-related pneumonitis is more likely to present with bilateral or diffuse lung changes. (Level of agreement: unanimous) |
|
P4. What treatments are effective for management of RP? | Recommendation P4.1: Asymptomatic (grade 1) RP is common after cCRT and does not warrant investigation or treatment; however, increased monitoring may be warranted for patients presenting with new radiological changes after initiation of durvalumab consolidation therapy. (Level of agreement: unanimous) Recommendation P4.2: Patients with confirmed grade 2 RP should be followed under close observation. Prompt initiation of corticosteroid therapy should be considered in the event of worsening symptoms, as well as supplemental oxygen as clinically appropriate. Consider holding durvalumab if patient has initiated consolidation therapy. (Level of agreement: unanimous) Recommendation P4.3: Patients with confirmed grade 3/4 RP should promptly receive corticosteroid therapy and supplemental oxygen as clinically appropriate. Consider whether referral to respirology and/or hospitalization are warranted. Hold durvalumab if patient has initiated consolidation therapy. (Level of agreement: unanimous) Recommendation P4.4: Recommended corticosteroid therapy is oral prednisone 1 mg/kg/day up to 60 mg/day; treatment should be tapered slowly over a duration of at least 6 weeks once RP has clinically improved. Simultaneous initiation of PPI therapy is also recommended, as well as consideration of prophylaxis for PJP. (Level of agreement: unanimous) |
|
P5. What treatments are effective for management of IO-related pneumonitis? | Recommendation P5.1: Patients with asymptomatic (grade 1) IO-related pneumonitis should receive more frequent follow-up with oxygen saturation and chest X-ray. Consider holding durvalumab on a case-by-case basis. (Level of agreement: 8 agree, 1 abstains) Recommendation P5.2: Patients with confirmed grade 2 IO-related pneumonitis should have durvalumab suspended, corticosteroid therapy promptly initiated, and supplemental oxygen provided as clinically appropriate. Monitor closely; if pneumonitis persists or worsens after 48 to 72 h, treat as grade 3 or 4. (Level of agreement: unanimous) Recommendation P5.3: Patients with confirmed grade 3 or 4 IO-related pneumonitis should have durvalumab suspended or discontinued and corticosteroid therapy promptly initiated. Supplemental oxygen, hospitalization, and respirology referral are warranted. If pneumonitis persists or worsens after 48 h, consider initiating a non-steroidal immunosuppressive agent. (Level of agreement: unanimous) Recommendation P5.4: Recommended outpatient corticosteroid therapy is oral prednisone 1–2 mg/kg/day; treatment should be tapered slowly over a duration of at least 6 weeks once pneumonitis has improved clinically. Simultaneous initiation of PPI therapy is recommended, as well as consideration of prophylaxis for PJP. (Level of agreement: 8 agree, 1 abstains) |
|
P6. Which patients with RP are suitable for initiation of durvalumab consolidation? | Recommendation P6.1: Consider initiating durvalumab for patients with asymptomatic RP after cCRT; more frequent follow-up with chest X-ray may be warranted. (Level of agreement: unanimous) |
|
P7. Which patients are suitable for durvalumab re-initiation after resolution of pneumonitis? | Recommendation P7.1: For patients with confirmed RP who have resolution of symptoms and corticosteroids tapered to ≤10 mg/day, consider re-initiating durvalumab. (Level of agreement: unanimous) Recommendation P7.2: For patients with IO-related pneumonitis who have symptom resolution and corticosteroids tapered to ≤10 mg/day, the decision to re-initiate durvalumab should be individualized on the basis of patient characteristics and shared decision-making. (Level of agreement: 8 agree, 1 disagree) |
|
P8. Which HCPs should be involved in the care of patients who experience pneumonitis? | Recommendation P8.1: Multidisciplinary team care is essential for optimizing follow-up of pneumonitis and must involve shared responsibilities, clear communication, and collaboration. (Level of agreement: 8 agree, 1 disagree) Recommendation P8.2: Radiation and medical oncologists should communicate regarding patient status and classification of pneumonitis etiology. If RP, the RO should be responsible for management and follow-up until resolution; if IO-related, the MO should be responsible. (Level of agreement: unanimous) |
|
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Brade, A.M.; Bahig, H.; Bezjak, A.; Juergens, R.A.; Lynden, C.; Marcoux, N.; Melosky, B.; Schellenberg, D.; Snow, S. Esophagitis and Pneumonitis Related to Concurrent Chemoradiation ± Durvalumab Consolidation in Unresectable Stage III Non-Small-Cell Lung Cancer: Risk Assessment and Management Recommendations Based on a Modified Delphi Process. Curr. Oncol. 2024, 31, 6512-6535. https://doi.org/10.3390/curroncol31110483
Brade AM, Bahig H, Bezjak A, Juergens RA, Lynden C, Marcoux N, Melosky B, Schellenberg D, Snow S. Esophagitis and Pneumonitis Related to Concurrent Chemoradiation ± Durvalumab Consolidation in Unresectable Stage III Non-Small-Cell Lung Cancer: Risk Assessment and Management Recommendations Based on a Modified Delphi Process. Current Oncology. 2024; 31(11):6512-6535. https://doi.org/10.3390/curroncol31110483
Chicago/Turabian StyleBrade, Anthony M., Houda Bahig, Andrea Bezjak, Rosalyn A. Juergens, Charmaine Lynden, Nicolas Marcoux, Barbara Melosky, Devin Schellenberg, and Stephanie Snow. 2024. "Esophagitis and Pneumonitis Related to Concurrent Chemoradiation ± Durvalumab Consolidation in Unresectable Stage III Non-Small-Cell Lung Cancer: Risk Assessment and Management Recommendations Based on a Modified Delphi Process" Current Oncology 31, no. 11: 6512-6535. https://doi.org/10.3390/curroncol31110483