Immune checkpoint inhibitor (ICIs) enhance the body’s anti-tumor immune response by blocking negative costimulatory signaling pathways and activating T-cell function . According to the Surveillance, Epidemiology, and End Results (SEER) Program (https://seer.cancer.gov), patients aged 80 and older account for 14% of the total non-small cell lung cancer (NSCLC) cases. However, the age criterion of enrollment in clinical trials is typically below 75 years, and there is a lack of data from clinical studies conducted in patients aged 80 and older . Through this study, we report a clinical case of advanced lung squamous cell carcinoma (LUSC) in the elderly, treated with first-line anti-PD-1 (programmed death 1) antibody monotherapy to achieve long-term complete response (CR)，which will help clinicians make better choices for elderly patients with lung cancer.This case report has been reported in line with the SCARE Criteria .
An 80-year-old male was admitted to the Second Affiliated Hospital, Soochow University on April 1, 2017, presenting with a intermittent cough and a small amount of blood in the sputum for 2 months, without chest pain, chest distress, fever, or night sweats. A previous chest computed tomography (CT) performed at another hospital showed a lesion in the right lung (Figure 1), indicating lung cancer, but no treatment was initiated. Prior to being admitted at our hospital, the patient was hospitalized in a local hospital after experiencing a cough with blood in the sputum. Lung puncture biopsy results suggested lung squamous cell carcinoma. Amplification refractory mutation system (ARMS) technology suggested wild-type epidermal growth factor receptor (EGFR); Fluorescence in situ hybridization (FISH) technology suggested wild-type anaplastic lymphoma kinase (ALK) in the tumor tissue specimen. The patient’s symptoms were relieved after symptomatic treatment. However, one day before admission to our hospital, the patient again observed blood in the sputum.
The patient underwent a splenectomy 30 years ago owing to a trauma. In addition, the patient had a history of smoking 40 cigarettes/day for more than 60 years.
On admission, the patient’s temperature was 36.6℃; pulse rate was 76 beats/min; respiratory rate was 16 breaths/min, and blood pressure was 138/70 mmHg (1 mmHg = 0.133 kPa). The patient was conscious; breath sounds in his right lung were diminished, and no dry or moist rales were heard. After admission, routine blood, urine, and stool, biochemical, electrolyte, coagulation examinations and autoantibody screening did not show any significant abnormalities. The concentrations of tumor markers were as follows: carcinoma embryonic antigen (CEA), 1.55 ng/mL; cytokeratins 211 (CYFRA 211), 7.50 ng/mL↑; and neuron-specific enolase (NSE), 14.11 ng/mL. Thyroid function indicators were as follows: free triiodothyronine (FT3), 3.28 pg/mL; free thyroxine-4 (FT4), 0.81 ng/dL; triiodothyronine (T3), 1.18 ng/mL; thyroxine-4 (T4), 8.20 μg/dL; thyroid-stimulating hormone (TSH), 2.24 μIU/mL; antithyroglobulin antibody (TGAb), 10.00 IU/mL↑. In addition, the patient›s cranial, abdominal and pelvic CT performed at another hospital on March 10, 2017 did not suggest any significant abnormalities. Systemic bone imaging showed no obvious abnormalities on April 10, 2017.
We performed a bronchoscopic cryotherapy on April 14, 2017 (Figure 2A). Specifically, we performed cryotherapy with a cryoprobe (Beijing Kooland Medical Equipment Co., LTD) at the mucosal bulge of the right principal bronchus and at the root of the right upper lobe bronchial neoplasm in 8 spots for 90 seconds each. Subsequently, a biopsy forceps was used to clean the necrotic tissue from the surface of the neoplasm. The right upper lobe bronchus was partially revealed with little bleeding (Figure 2B). The patient›s clinical symptoms, results of CT and results of lung puncture and bronchoscopic biopsy suggested that the patient developed the cT4N3M0-IIIC stage of LUSC in the right lung, with no distant metastasis. Programmed death-ligand 1 (PD-L1) of the tumor tissue was shown in Figure 2D. Immunohistochemical results were as follows: CK7 (–), CK5/6 (+), TIF (–), Napsin A (–), P40 (foci +), P63 (+), Ki67 (+, 40%). We performed next generation sequencing (NGS) of the tissue specimen in September 2018, and the results suggested a positive TP53 R282W mutation, 5–50% PD-L1 expression (SP142 antibody), and a 14.77 Muts/Mb tumor mutational load (TMB).
We started the 1st cycle of anti-PD-1 antibody therapy on April 7, 2017, with the final treatment on June 25, 2018. The CR was achieved before the 3rd cycle of anti-PD-1 antibody therapy according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), with a follow-up CT suggesting stable disease conditions. Positron Emission Computed Tomography (PET)/CTPET/CT in the 13th cycle did not suggest significant nodules or foci of increased 2-Deoxy-2-fluoro-D-glucose (FDG) uptake and confirmed CR (Figure 3). In this case, the patient discontinued the treatment and was followed up.
The patient’s safety assessment prior to the 2nd cycle of anti-PD-1 antibody therapy (May 2, 2017) suggested asymptomatic hyperthyroidism with the following indicators: T3, 1.86 ng/mL; T4, 15.74 μg/dL; FT3, 6.2 pg/mL; FT4, 2.72 ng/dL, TSH, 0.03 μIU/mL; TGAB, 72.8 IU/mL; and anti-thyroid peroxidase antibody, 287.2 IU/mL, and no medication was administered. The patient›s tests prior to the 4th cycle of anti-PD-1 antibody therapy (June 15, 2017) suggested hypothyroidism with the following indicators: T3, 0.56 ng/mL; T4, 5.85 μg/dL; FT3, 2.01 pg/mL; FT4, 0.52 ng/dL; TSH, 8.93 μIU/mL; TGAB, 93.9 IU/mL; and anti-thyroid peroxidase antibody, 342.5 IU/mL. Thyroid function examinations before the 6th cycle (July 29, 2017) still suggested hypothyroidism with the following indicators: T3, 0.36 ng/mL; T4, 0.86 μg/dL; FT3, 1.64 pg/mL; FT4, 0.09 ng/dL; TSH > 100 μIU/mL; TGAB, 417.5 IU/mL; and anti-thyroid peroxidase antibody, 619.6 IU/mL, and the patient was treated with Levothyroxine Sodium Tablets (50 μg/tablet, 1 oral tablet daily). The patient›s adrenocorticotrophic hormone (ACTH) level increased before the 2nd cycle of anti-PD-1 antibody therapy (May 2, 2017) with the following indicators: ACTH (8 A.M.), 55.41 pg/mL; ACTH (4 P.M.), 40.65 pg/mL; and ACTH (24 P.M.), 33.03 pg/mL. As the patient was asymptomatic, these indicators were monitored dynamically, and the patient was not treated with medication. All ACTH indicators returned to normal levels before the 8th cycle of anti-PD-1 antibody therapy (October 13, 2017).
Levels of the tumor marker CYFRA211 were monitored dynamically, and they were 2.35 ng/mL (0–3 ng/ml) when the last examination was performed on June 17, 2021. Chest CTs performed on September 12, 2018, April 10, 2019, January 1, 2020, May 18, 2020, and June, 17 2021 (Figure 4) also suggested stable disease conditions compared with CT on April 4, 2018. Diagram of the course of disease management is in Figure 5.
Lung cancer has the highest morbidity and mortality in China, and NSCLC cases account for approximately 85% of all lung cancer cases . The majority of patients with NSCLC are already at an advanced stage at the time of diagnosis, facing distant metastases and a poor prognosis. The results of the KEYNOTE-024 study suggest that NSCLC patients with PD-L1 ≥50% treated with pembrolizumab alone had a 5-year survival rate of 31.9%, higher than that on being treated with conventional chemotherapy (16.3%) . Currently, immune monotherapy has become the standard first-line treatment for patients with upregulated expression of PD-L1.
Dysregulated immune responses to pathogens; diminished responses to vaccination; and increased susceptibility to cancer, autoimmune diseases, and other chronic inflammatory diseases in older patients suggest differences in the immune microenvironment (IME) between older and younger patients, with an increase in pro-inflammatory and immunosuppressive cell phenotypes in older patients . Recent studies have shown that the effect of immunotherapy is similar and equally safe in older and younger patients with lung cancer . However, the number of instances of discontinuation of immunotherapy owing to immune-related adverse reactions (irAEs) may be higher in the older group, and poor physical status (PS) scores may have led to poor clinical outcomes . Although retrospective real-world studies have provided insight into immunotherapy in older patients, these studies have small sample sizes, and larger real-world cohort studies are still needed.
The patient in this study was an elderly male, whose histopathological examination suggested LUSC. However, he was not suitable for the typical first-line targeted therapy as genetic testing revealed wild-type EGFR and ALK. A immunohistochemical test suggested positivity of PD-L1. Given the patient’s age and his unwillingness to undergo chemotherapy, we treated him using local cryotherapy combined with anti-PD-1 antibody immunotherapy, which afforded substantial clinical benefits and a good prognosis. The patient’s post-diagnostic thyroid function indicators suggested hyperthyroidism with subsequent conversion to hypothyroidism. Studies have shown that irAEs occurring in the skin, gastrointestinal, and endocrine systems are associated with good clinical benefit of progression free survival (PFS) and overall survival (OS), whereas irAEs, such as cardiotoxicity and severe pulmonary toxicity, do not suggest a good clinical prognosis . As irAEs occur at different times and have different clinical manifestations, they need to be managed throughout the study period. In addition, the patient should be monitored for abnormalities and, management will be graded according to different irAEs, sometimes requiring treatment with glucocorticoids, immunosuppressive agents, or even permanent withdrawal of ICIs . Notably, the patient underwent a splenectomy 30 years ago owing to a trauma. Studies have shown that since the spleen is the largest secondary lymphoid organ in the body, both adaptive and innate immune responses are impaired after a splenectomy. However, whether the splenectomy was associated with his irAEs remains to be further explored . The patient’s follow-up NGS examination results were as follows: PD-L1 expression, 5–50% (SP142 antibody) and TMB, 14.77 Muts/Mb, which may explain his better clinical efficacy. Moreover, local treatments such as cryotherapy may lead to increase the release of tumor neoantigens and facilitating the immunotherapeutic effect.
The decline in immune system function is inevitable with increasing age. Chronic inflammation or structural lesions in the organs where the tumor is located lead to an increased probability of severe irAEs in the elderly. Therefore, the use of immune checkpoint inhibitors in elderly patients should receive more attention. However, this case study shows that monotherapy has the potential to achieve rapid lesion regression in elderly lung cancer patients, when combined with effective local treatment, and the presence of immunological memory in T lymphocytes may be responsible for long-term response of the tumor lesions. However, there were some limitations associated with our study. The patient did not undergo a second PET/CT review or bronchoscopy, a complete response cannot be confirmed pathologically. In the future, clinical trials are needed in aged which will contribute to the understanding of immunotherapy.
In a conclusion, we reported a long-term complete response of advanced lung squamous cell carcinoma in aged treated with first-line anti-PD-1 antibody monotherapy. We demonstrated a clinical benefit from anti-PD-1 antibody monotherapy as the first-line treatment in patient more than 80 years old. More studies are needed to evaluate the efficacy and safety of immune checkpoint inhibitors in the aged.
ICIs, Immune checkpoint inhibitor; SEER, Surveillance, Epidemiology, and End Results; NSCLC, non-small cell lung cancer; LUSC, lung squamous cell carcinoma; PD-1, programmed death 1; CR, complete response; CT, computed tomography; ARMS, Amplification refractory mutation system; EGFR, epidermal growth factor receptor; FISH, Fluorescence in situ hybridization; ALK, anaplastic lymphoma kinase; CEA, carcinoma embryonic antigen; CYFRA 211, cytokeratins 211; NSE, neuron-specific enolase; FT3, free triiodothyronine; FT4, free thyroxine-4; T3, triiodothyronine; T4, thyroxine-4; TSH, thyroid-stimulating hormone; TGAb, antithyroglobulin antibody; PD-L1, Programmed death-ligand 1; NGS, next generation sequencing; TMB, tumor mutational load; RECIST 1.1, Response Evaluation Criteria in Solid Tumors 1.1; PET/CT, Positron Emission Computed Tomography; FDG, 2-Deoxy-2-fluoro-D-glucose; ACTH, adrenocorticotrophic hormone; IME, immune microenvironment; irAEs, immune-related adverse reactions; PS, physical status; PFS, progression free survival; OS, overall survival.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief on request.
This work was supported by the Suzhou Science and Technology Development Plan Project (grant SLT201930).
The authors have no competing interests to declare.
X.P. and W.Y. contributed equally to this work and shared first authorship. They contributed to write the manuscript, to gather the clinical data as well as the relevant imaging information. Y.X. contributed to gather the clinical data and the follow-up of patients. M.S. did the overall supervision and contributed in finalizing the manuscript.
Not commissioned, externally peer-reviewed.
Remon J, Facchinetti F, Besse B. The efficacy of immune checkpoint inhibitors in thoracic malignancies. Eur Respir Rev. 2021; 30(162): 200387. DOI: https://doi.org/10.1183/16000617.0387-2020
Naltet C, Besse B. Immune checkpoint inhibitors in elderly patients treated for a lung cancer: a narrative review. Transl Lung Cancer Res. 2021; 10(6): 3014–3028. DOI: https://doi.org/10.21037/tlcr-20-1239
Agha RA, Franchi T, Sohrabi C, et al. For the SCARE Group. The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines. International Journal of Surgery. 2020; 84: 226–230. DOI: https://doi.org/10.1016/j.ijsu.2020.10.034
Lee J, Ahn MJ. Brain metastases in patients with oncogenic-driven non-small cell lung cancer: Pros and cons for early radiotherapy. Cancer Treat Rev. 2021; 100: 102291. DOI: https://doi.org/10.1016/j.ctrv.2021.102291
Qiao N, Insinga R, de Lima Lopes Junior G, et al. A review of cost-effectiveness studies of Pembrolizumab regimens for the treatment of advanced non-small cell lung cancer. DOI: https://doi.org/10.1007/s41669-020-00255-2
Iacono D, Vitale MG, Basile D, et al. Immunotherapy for older patients with melanoma: From darkness to light? Pigment Cell Melanoma Res. 2021; 34(3): 550–563. DOI: https://doi.org/10.1111/pcmr.12917
Samani A, Zhang S, Spiers L, et al. Impact of age on the toxicity of immune checkpoint inhibition. J Immunother Cancer. 2020; 8(2): e000871. DOI: https://doi.org/10.1136/jitc-2020-000871
Ikeda H, Togashi Y. Aging, cancer, and antitumor immunity. Int J Clin Oncol. 2021; 1–7. DOI: https://doi.org/10.1007/s10147-021-01913-z
Hattersley R, Nana M, Lansdown AJ. Endocrine complications of immunotherapies: a review. Clin Med (Lond). 2021; 21(2): e212e222. DOI: https://doi.org/10.7861/clinmed.2020-0827
Smithy JW, Faleck DM, Postow MA. Facts and hopes in prediction, diagnosis, and treatment of immune-related adverse events. Clin Cancer Res. 2021. DOI: https://doi.org/10.1158/1078-0432.CCR-21-1240
Casciani F, Trudeau MT, Vollmer CM, Jr. Perioperative Immunization for Splenectomy and the Surgeon’s Responsibility: A Review. JAMA Surg. 2020; 155(11): 1068–1077. DOI: https://doi.org/10.1001/jamasurg.2020.1463