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Fitness for commercial flying in a case of non-Hodgkin lymphoma: Aeromedical risk assessment
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Received: ,
Accepted: ,
How to cite this article: Karthik J, Krishnegowda AB, Maridoss S. Fitness for commercial flying in a case of non-Hodgkin lymphoma: Aeromedical risk assessment. Indian J Aerosp Med. doi: 10.25259/IJASM_42_2024
Abstract
Non-Hodgkin lymphoma (NHL) comprises a category of malignant neoplasms that arise from lymphoid tissues, which primarily affect the lymph nodes. Histologically, diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL. The various clinical manifestations depend on the site, stage, and extent of disease and are generally treated with Chemo-immunotherapy. A 39-year-old civil aircrew, diagnosed as a case of DLBCL, treated with chemo-immunotherapy (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone regimen), after complete remission and drug-free status for 25-month duration, reported to an Indian Air Force boarding center for aeromedical evaluation and disposal. The survival rate post-treatment for DLBCL is 94% as per the International Prognostic Index. However, in the first 1–2 years, the recurrence rate is between 30 and 40%. Aeromedical concerns include treatment efficacy, recurrence/relapse, post-chemotherapeutic effects, aviation risk on disability, prognosis and follow-up duration, and investigations to be carried out. The risk assessment matrix was carried out in this case using 5-year prognosis survival, and the risk of incapacitation fell between 0.1% and 1%. The fitness for flying was considered on the basis of the incapacitation risk of <1% and upgraded to the restricted flying category. The certification assessment for malignancy can be based on the survival rate post-treatment due to the lack of evidence on the risk of recurrence. Hence, the certification for aircrew with any malignancy can be assessed by treatment efficacy, risk of recurrence, and risk of incapacitation. The survival curve can be used as a tool for calculating the risk of recurrence matrix and risk of incapacitation.
Keywords
Diffuse
Immunotherapy
Large B-cell
Lymphoma
Prognosis
Survival rate
INTRODUCTION
Non-Hodgkin lymphomas (NHL) are malignancies of mature natural killer, T and B cells. The identification of Reed-Sternberg cells in HL allowed them to be differentiated from HL, and their biologic and clinical features are different.[1] Diffuse large B-Cell lymphoma (DLBCL), one of the most common histologic subtypes of NHL, represents about one-third of all cases (31%) [Figure 1]. The causal factor of NHL may be due to chromosomal translocation, viral infection agents such as human immunodeficiency virus and Epstein–Barr virus, environmental factors like pesticides, herbicides, and immunodeficiency states such as Hashimoto’s thyroiditis and Sjogren syndrome.[2]
Particular “B symptoms” such as fever, night sweats, and weight loss (>10% within 6 months) are prevalent in the natural history together with waxing and waning lymphadenopathy. During the course of the disease, 10–30% patients will have primary extra nodal involvement during the diagnosis.[1,2] Workup to evaluate the extent and stage of NHL is depicted in Table 1.
| Tests | Findings |
|---|---|
| Complete blood count | Anemia, thrombocytopenia/ leukopenia/pancytopenia, lymphocytosis/thrombocytosis |
| Serum analysis | LDH, B-2 microglobulin, and Calcium |
| Serology | HIV, Hepatitis B and C |
| Lymph node biopsy | Lymph node protocol |
| Chest X-ray | Pulmonary involvement |
| PET scanning (whole body) | Staging |
| Bone marrow aspiration and biopsy | Staging |
PET: Positron emission tomography, LDH: Lactate dehydrogenase, HIV: Human immunodeficiency virus
The Ann Arbor staging technique was adapted for the staging of NHLs in 1971 after it was first created for Hodgkin lymphoma. The number of tumor locations, whether nodal or extranodal, as well as the existence or lack of systemic or B symptoms, are highlighted by this stage. It also includes serum lactate dehydrogenase (LDH) levels and performance status based on two scales. The two performance status scales are Eastern Cooperative Oncology Group performance status scale[3] and Karnofsky performance status scale.[4] The NHL will be managed with rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemo-immunotherapy.[1,2] Table 2 and Figure 2 summarize the essential features of the Ann Arbor staging system for NHL.
| Stages | Description |
|---|---|
| Stage I | Involvement of a single lymph node region (I) or single extranodal site (IE) |
| Stage II | Involvement of two or more lymph node regions or lymphatic structures on the same side of the diaphragm alone (II) or with involvement of limited, contiguous, extralymphatic organ or tissue (IIE) |
| Satge III | Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS), or limited, contiguous, extralymphatic organ or tissue (IIIE), or both (IIIES) |
| Stage IV | Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without associated lymphatic involvement |
CASE REPORT
A 39-year-old pilot from civil commercial airlines with a flying experience of approximately 6600 h had an acute onset of generalized weakness and difficulty in breathing on exertion, relieved by rest/lying down for 15 days. During evaluation for breathlessness, computed tomography (CT) pulmonary angiography showed ground glass opacity in the left lingular region with no evidence of pulmonary thromboembolism, suggestive of probably hypersensitive pneumonitis. Complete blood count (CBC) reports showed leukopenia. Serum analysis was suggestive of elevated LDH levels, low Vit B12, and Vit D levels. In view of low vitamins, endoscopy and colonoscopy were done. Endoscopy showed antral atrophy and colonoscopy showed terminal ileal and rectal ulcers. Biopsy was taken and histopathology was suggestive of poorly differentiated malignant tumor in the terminal ileum. Immunohistochemistry panel showed features suggestive of ileal involvement by high-grade B-cell non-Hodgkin’s lymphoma. Positron emission tomography (PET) scan of the whole body shown hyper metabolic eccentric wall thickening in the terminal ileum and multiple nodal involvement in abdominal, pelvic, and mediastinal regions. He was managed with 6 cycles of chemotherapy with R-CHOP regimen. He tolerated chemotherapy well and showed good clinical recovery without any symptoms/signs post-treatment and drug-free status for the past 15 months. Repeat PET scan (whole body) was taken twice (once post 4 cycles of treatment and another post 6-month completion of treatment) and it was found that complete remission was achieved without any evidence of active disease in rest of the body. Hematooncologist opined that follow-up is required 3 monthly with CBC, renal function test, liver function test, and serum LDH reports. He reported to the boarding center for his renewal and special medical examination, and the medical board recommended temporary unfitness for 12 weeks, followed by TU-24 weeks and TU -12 weeks. At present, the aircrew is asymptomatic and able to do routine activities without any discomfort/limitations. He reported to the boarding center for aeromedical evaluation and disposal post remission and drug free/symptom free for the past 15 months.
DISCUSSION
As most malignancies lack information on recurrence, the certification assessment technique for malignant cases might rely on population survival statistics. When it comes to incapacitation risk, using survival data rather than recurrence data are typically “fail-safe.” Based on how the cancer presents itself, different tumor types have different survival rates. Of these prognostic indicators, the stage of presentation is typically the most significant; nevertheless, other criteria to be taken into account are grade, tumor markers, location, and metabolic characteristics. Furthermore, the person’s age and gender may have an impact on the result. The certification assessment approach uses the most prognostic indicators to consider survival data for homogeneous groups. Depending on whether the prognostic factors that were in place at the time of presentation would have led to a significantly better or worse outcome overall, the level of certification for that person could be changed.[5] Figure 3 demonstrates the likelihood of survival for the survival period after completion of primary treatment for three stages of NHL.
One percent of the total annual risk is the highest that can be tolerated for an incapacitated pilot conducting multicrew operations.[6,7] A pilot can only be certified without restrictions if there is a significantly lower risk of incapacitation. An individual’s risk of experiencing a malignant disease recurrence within a year is determined by three primary factors. The factors include the likelihood of a recurrence, the type of metastasis most likely to result in incapacitation, and a weighting factor based on the likelihood that the metastasis will induce incapacitating symptoms [Figure 4].[5,8]
Present state of the case
This 39-year-old male aircrew diagnosed as a case of DLBCL. He was adequately managed with 6 cycles of chemoimmunotherapy (R-CHOP Regimen) and drug free since then for 15 months. He had shown good recovery throughout the treatment with no signs of recurrence/relapse which was confirmed by hematological investigations, serum markers like LDH levels, repeat whole body PET scan twice during and after completion of treatment. He was monitored by a concerned hemato-oncologist periodically and concluded that complete remission was achieved without any recurrence/relapse. The aircrew was observed in non-flying category for 15-month duration along with monitoring and close follow-up.
In view of the above, the following aeromedical aspects were considered in this case:
International prognostic index (IPI)
On application of IPI, the disability of this aircrew belongs to the high intermediate risk group (03 out of 05 clinical risk factors present before treatment) and it suggests that 5-year survival before treatment was 43% and 4-year survival rate post-treatment (complete remission – no factor present) was 94%, respectively.[9,10] Despite the 94% survival rate, the risk of recurrence is higher in the first 1–2 years (30–40%). The IPI for DLBCL was depicted in Table 3.
| Five clinical risk factors | |
| • Age ≥60 years • Serum lactate dehydrogenase levels elevated • Performance status ≥2 Eastern Cooperative Oncology Group (ECOG) or ≤70 (Karnofsky) • Ann Arbor stage III or IV • >1 site of extranodal involvement |
|
| For diffuse large B-cell lymphoma | |
| 0, 1 factor=Low risk | 35% of cases; 5-year survival, 73% |
| 2 factors=Low- intermediate risk | 27% of cases; 5-year survival, 51% |
| 3 factors=High- intermediate risk | 22% of cases; 5-year survival, 43% |
| 4, 5 factors=High risk | 16% of cases; 5-year survival, 26% |
| For diffuse large B-cell lymphoma treated with R-CHOP | |
| 0 factor=Good | 10% of cases; 4-year survival, 94% |
| 1, 2 factors=Intermediate | 45% of cases; 4-year survival, 80% |
| 3, 4, 5 factors=Poor | 45% of cases; 4-year survival, 53% |
NHL: Non-Hodgkin lymphoma, R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisolone
Recurrence/relapse
The aircrew does not show any recurrence post completion of treatment. However, the chance of recurrence cannot be ruled out since the recurrence rate is higher in the first 1–2-year post-treatment (30–40%).[11] The primary involvement of the brain/heart which can cause sudden incapacitation inflight is rare in this case, since the extent of disease is very rare in the brain/heart for NHL. The aircrew with an age of <40 years shows a good prognosis. However, the chances of 6% mortality rate (94% with survival rate) are unacceptable in commercial aircraft flying.[6,7]
Post-chemotherapeutic effects
The most common complication post-chemotherapy in any malignancy is immune-related (infections) which are detectable by routine investigations. Furthermore, due to post-chemotherapy status, the aircrew requires follow-up since the anthracycline derivatives like doxorubicin has long time cardiological side effects and vincristine has long-term neurotoxicity. However, these side effects can be monitored periodically through follow-up with clinical examination and investigations. Thus, the complications although being beyond an acceptable range, the aircrew can identify those effects and would be capable of seeking medical assistance timely.[1,2]
Risk recurrence after treatment
The certification assessment was done based on the population survival rate of DLBCL. The risk recurrence matrix was calculated using 5-year survival curve (fail-safe) and it was found that the risk of recurrence at 1-year, 2-year, 3-year, 4-year, and 5-year post-completion of treatment was 0.12%, 0.021%, 0.021%, 0.021%, and 0.021%, respectively [Table 4 and Figure 5]. These risk recurrence values are falling between 0.1% and 1% which is acceptable for restricted flying in commercial airlines.[5,8,12]
| Stage | Years since completion of primary treatment | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| I (No factor present) | 6/100×2%× 100%=0.12% | 1/94×2%× 100%=0.021% | 1/93×2%× 100%=0.021% | 1/92×2%× 100%=0.021% | 1/91×2%× 100%=0.021% |
| II (1–2 factors present) | 10/100×2%× 100% = 0.2% | 5/90×2%× 100%=0.111% | 3/85×2%× 100%=0.070% | 2/82×2%× 100%=0.048% | 2/80×2%× 100%=0.05% |
| III (3–5 factors present) | 32/100×2%× 100%=0.64% | 5/68×2%× 100%=0.151% | 6/62×2%× 100%=0.19% | 5/56×2%× 100%=0.183% | 4/52×2%× 100%=0.154% |
Calculation of annual risk of incapacitation from recurrence rate using the formula (Risk recurrence×type of risk causing incapacitation×weighting factor). Same was calculated for NHL (Survival rate–94%, Cerebral metastasis–2%, weighting factor–100%)
Effect of aviation environment on disability
The probability of recurrence due to exposure to aviation stressors is negligible, and the progression of disease is no higher than any passenger in commercial flying. Nevertheless, the possibility of unwanted flying consequences in-flight due to any unanticipated events could not be completely negated in this case.
Extant policy for disposal of cases of lymphoma
Most of the international guidelines available are only for lymphoma/Hodgkin lymphoma and are not specific to NHL. According to the guidelines from FAA, EASA, UK CAA, and Rayman’s textbook of Civil Aviation Medicine, an aircrew with NHL can be considered on a case-to-case basis, and full fitness for flying can be considered based on treatment efficacy, recurrence rate, incapacitation risk, and observation post-complete remission with a minimum period of 1 year. In accordance with ICAO Manual of Civil Aviation Medicine Doc 8984 (3rd Edn, 2012), cases of Lymphoma should be evaluated on an individual basis and restricted certification is possible after disease-free status post completion of treatment with regular annual follow-up.[8]
Aeromedical disposition
In this case, the aircrew was upgraded to fit to fly as a pilot only in multicrew operations, along with an experienced pilot with a caveat that he is unfit for instructional duties, i.e., pilot in Command with Qualified Experience Pilot for the duration of 6 months before consideration for unrestricted flying status in view of completing the period of at least minimum 2-year post-completion of treatment.
CONCLUSION
NHL is a type of lymphoid malignancy which has multiple subtypes and DLBCL is one of the most common causes. Due to the advancement in treatment, the 5-year survival rate is 94% after complete remission of treatment. The certification assessment for aircrew with NHL can be based on survival rate post-treatment, treatment efficacy, risk of recurrence, and risk of incapacitation. The survival curve can be used as a tool for calculating the risk of recurrence matrix and risk of incapacitation.
Acknowledgment:
Our sincere and heartfelt gratitude to Dr. Yashvir Singh Dahiya, Chief Research Officer and Senior Advisor in Aerospace Medicine, IAM, Dr. Suja MB, President, Medical Evaluation Centre, IAM, and Dr. Yateendra Dinker, Medical Specialist, IAM, for their valuable guidance and mentorship throughout the case study.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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