The journal ONCOLOGY® provides oncology professionals with practical and timely clinical information necessary to deliver the highest level of patient care. Expert authors and peer review ensure the quality of the journal’s articles and features. Focused discussions capture key clinical take-aways for application in today’s time-constrained practice environment.

Systemic inflammation has long been associated with poor outcomes in many types of solid tumors. Peripheral blood biomarkers, such as absolute lymphocyte count (ALC) and the ratio of absolute neutrophil count to absolute lymphocyte count (ANC/ALC), have been shown to be immune-inflammatory parameters highlighting an individual’s immune status. The prognostic role of ALC and ANC/ALC on overall survival (OS) was examined in patients with advanced non–small cell lung carcinoma (NSCLC) receiving pembrolizumab. Of a total of 239 patients, 52% were male, with a median age of 67 years (interquartile range [IQR], 59-73). Most patients had a diagnosis of adenocarcinoma (76%), with stage IV disease (82%). PD-L1 expression was >50% in 44% of the patients. The median time on treatment with pembrolizumab was 5.8 months (IQR, 2.9-12.7). An ANC/ALC <5 was associated with improved OS at initiation of pembrolizumab (

 = .002), whereas an ALC >1.4 deciliter (dL) trended toward improved OS compared with ALC <1.4 dL (

 = .053). After adjusting for potential cofounders with a multivariate analysis, a baseline ANC/ALC of 5 or higher was associated with a significantly increased risk of death (HR, 1.93; 95% CI, 1.27-2.93; 

 = .002). An ANC/ALC <5 at the time of initiation of treatment with pembrolizumab was associated with improved OS in patients with advanced NSCLC. The median ALC and ANC/ALC were significantly lower after 6 weeks of treatment with pembrolizumab.


: pembrolizumab; non–small cell lung cancer; absolute lymphocyte count; absolute neutrophil count to absolute lymphocyte count ratio; immunotherapy; peripheral blood counts; anti–PD-1



Lung cancer is the most common cause of cancer-related deaths, both in the United States and internationally.

 Non–small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of these cases. The discovery of immune checkpoint inhibitor therapy has led to significant improvement in both overall survival (OS) and progression-free survival (PFS) and represents a paradigm shift in treatment of NSCLC. In 2019, 2 anti–PD-1 antibodies, pembrolizumab (Keytruda) and nivolumab (Opdivo), and 1 anti–PD-L1 antibody, atezolizumab, were approved by the FDA for the treatment of metastatic NSCLC.

 PD-1 is an immune checkpoint transmembrane protein that is expressed on macrophages, dendritic cells, and T and B lymphocytes. When PD-1 binds to one of its ligands that are expressed on human cancer cells— PD-L1 or PD-L2—it inhibits cytotoxic T-cell response and evades the body’s immune surveillance system.

While PD-L1 receptor positivity in tumor cells has been shown to predict the responsiveness of the cancer to these agents, it has its limitations. Several small studies have been performed to assess the utility of hematologic biomarkers in predicting the effectiveness of immunotherapy. However, these studies have been small retrospective studies with small sample sizes. These peripheral markers include absolute neutrophil count (ANC), absolute lymphocyte count (ALC), the ratio of absolute neutrophil count to absolute lymphocyte count (ANC/ALC), absolute eosinophil count, and absolute monocyte count (AMC). These biomarkers have been shown to be immune-inflammatory parameters highlighting an individual’s immune status. Aggressive cancers are associated with an increased systemic inflammatory state, creating a microenvironment that promotes angiogenesis, survival of malignant cells, and metastasis. The response to immunotherapy in these cases is poor.

 Therefore, this question has arisen: Can these peripheral blood biomarkers predict patient outcomes in patients treated with immunotherapy?


The aim of this study is to investigate ALC and ANC/ALC in patients with advanced NSCLC receiving pembrolizumab and to determine if a correlation exists between these key biomarkers and OS. To our knowledge, of studies investigating this relationship, this is the largest in terms of number of patients with NSCLC treated with pembrolizumab.



This retrospective observational study was approved by the Northwell Health Institutional Review Board, which waived the requirement for informed consent. Data for all patients with advanced NSCLC treated with pembrolizumab between September 2016 and May 2020 at Northwell Health hospital sites were collected by reviewing their electronic medical records. Patients treated with immunotherapy other than pembrolizumab were excluded. This helped to minimize heterogeneity related to different immunotherapy treatments.




All records were reviewed retrospectively and organized in the REDCap database. Parameters such as age at diagnosis, sex, histologic type, tumor PD-L1 status, stage of disease, line of treatment, history of radiation to the tumor, presence or absence of central nervous system (CNS) disease, and ECOG performance status were defined and adjusted for confounding. Peripheral blood counts including ALC, ANC, and AMC were examined at initiation of pembrolizumab and at 6 weeks on treatment. Patients without follow-up blood counts at 6 weeks were excluded.




Based on literature review and previous studies that investigated this relationship, ANC/ALC cut-off values were ≥5 and <5, and ALC cut-off values were ≥1.4 dL and <1.4 dL. The primary outcome was OS, as defined as date of first dose of pembrolizumab to death or last follow-up. Patients discontinued their immunotherapy due to disease progression or death, or because they experienced adverse events (AEs). Descriptive statistics were used to present patient characteristics. Chi-square or Fisher’s exact test were used to compare categorical variables, and the Wilcoxon-Mann-Whitney test was used to compare continuous variables. OS rates were plotted on Kaplan-Meier curves and differences were evaluated with the log-rank test. A multivariable Cox regression model was used to determine the effect of baseline ANC/ALC on the risk of death after adjusting for potential confounders. All statistical tests were 2-sided and conducted using SPSS version 25.0 (IBM). 

 <.05 was considered statistically significant.



A total of 239 patients with advanced NSCLC treated with pembrolizumab at Northwell Health hospital centers were included. Baseline characteristics are presented in 

. Median age at diagnosis was 67 years (interquartile range [IQR], 59-73). Of all patients, 52% were male and most (76%) had a diagnosis of adenocarcinoma, with stage IV disease (82%). The majority (52%) of the included patients were former smokers. PD-L1 expression was >50% in 44% of the patients. ECOG performance status was 0 or 1 in 70% of patients. Radiographic evidence of CNS disease at the time of pembrolizumab therapy was present in 28% of patients, and 20% had received radiation therapy to the tumor prior to the initiation of pembrolizumab. Pembrolizumab was first-line therapy in 65% of patients. Pembrolizumab monotherapy was being used for treatment in 119 patients (50%), whereas 120 patients (50%) received a combination of pembrolizumab plus platinum-based chemotherapy.

Comparison of Peripheral Blood Biomarkers at Baseline and at 6 Weeks of Treatment

The median ALC and ANC/ALC ratio were significantly lower after 6 weeks of pembrolizumab therapy compared with the start date of treatment (1.3 dL [IQR, 0.9-1.7] vs 1.4 dL [IQR, 1.0-2.0]; 

 <.001, and 3.6 [IQR, 2.1-6.1] vs 4.6 [IQR, 2.8-7.0] respectively; 

Comparison of OS Based on Baseline Peripheral Blood Biomarkers

Median OS was 10.8 months (IQR, 4.9-17.4) and overall time on treatment was 5.8 months (IQR, 2.9-12.7). An ALC of ≥1.4 dL trended toward improved OS compared with ALC <1.4 dL (

). Patients with a baseline ANC/ALC of ≥5 had a worse median OS rate compared with those with ANC/ALC <5, at 8.8 months (IQR, 3.98-15.65) vs 11.75 months (IQR, 6.68-20.51; 

), and after adjusting for potential cofounders in multivariate analysis (HR, 1.93; 95% CI, 1.27-2.93; 

). There was no difference in OS in patients who received pembrolizumab monotherapy compared with those who received pembrolizumab plus platinum-based chemotherapy (HR, 1.51; 95% CI, 0.92-2.47; 

This is the largest study analyzing the effect of the baseline serum levels of ANC and ALC, and of the ANC/ALC ratio, on the OS of patients treated with pembrolizumab for NSCLC. We show here that patients with an ALC of ≥1.4 dL and an ANC/ALC ratio <5 at the initiation of pembrolizumab therapy had an improved OS compared with their respective counterparts. After adjusting for potential cofounders, we found that patients with baseline ANC/ALC ratio of ≥5 treated with pembrolizumab had almost 2 times increased risk of death (all-cause mortality) (HR, 1.93; 95% CI, 1.27-2.93), compared with those with a baseline ANC/ALC <5.


Our findings are consistent with those of previous studies on peripheral blood biomarkers in patients being treated with anti–PD-1 antibodies. In a metanalysis of 16 studies that included 1700 patients, a high blood neutrophil-to-lymphocyte ratio (NLR) or ANC/ALC was found to be associated with shorter OS and PFS in patients getting treatment with PD-1/PD-L1 inhibitors for NSCLC.

 In a retrospective study of 22 patients with NSCLC treated with nivolumab, baseline ALC levels and ANC/ALC ratios were positively and negatively correlated, respectively, with OS on nivolumab.

 Another study of 109 patients with advanced NSCLC treated with nivolumab found that posttreatment ANC/ALC ≥5 after 2 cycles of nivolumab was associated with poor OS.

 Soyano et al studied this effect in patients treated with nivolumab (n = 146) and pembrolizumab (n = 11), finding that a baseline ANC/ALC ratio of 5.9 or more was associated with a significantly increased risk of death (HR, 1.94; 95% CI, 1.24-3.03; 

 Hasegawa et al demonstrated that high NLR (>4.55) at the pretreatment stage was significantly associated with shorter PFS and OS in a study of 51 patients with NSCLC who had a tumor proportion score >49%.

 Unlike our study, this was studied solely in patients who received pembrolizumab monotherapy. Zer et al studied these peripheral biomarkers in correlation with OS, disease control rate, and time to progression, and they found improved outcomes in patients with NLR of ≤4, in the patients with NSCLC who were under treatment with PD-1/PD-L1 for NSCLC.

The results of several studies have shown that tumor-related neutrophils are predictive of a poor prognosis in patients with malignancies. These neutrophils are attracted by cytokines such as interleukin-8 (IL-8), which further promotes the angiogenesis, local invasion of vessels, and growth factor release that causes metastatic spread of disease, leading to poor outcomes.

 One study demonstrated that lung carcinomas release IL-6 and granulocyte monocyte colony-stimulating factor that leads to increased peripheral leukocyte count, predicting ominous outcomes.

 PD-1/PD-L1 inhibitors act by blocking the interaction of negative regulators of T-cells that increase the antitumor immunity and decreases the antitumor immune tolerance, and it is plausible that these changes alter the count of peripheral neutrophils and lymphocytes. Increased peripheral neutrophil count correlates with reduced CD8-positive T-lymphocyte counts in NSCLC, and lymphopenia reflects impaired cellular immune response.

 Conversely, high lymphocyte counts have been considered a positive prognostic factor due to an improved antigen-driven immune response. The exact mechanism by which NLR affects immunotherapy or checkpoint blockade is not known, but it has been repeatedly shown to be associated with better outcomes in malignancies and other systemic diseases.


The use of PD-1 and PD-L1 inhibitors have revolutionized cancer immunotherapy and have led to improvement in patient outcomes. Their effect, however, seems to be limited to certain patient subgroups. Given the significant immune-related AEs that can occur with these drugs, along with their financial toxicity, there is a need to individualize treatment for every single patient. Tumor PD-L1 immunohistochemical testing is often used as a predictor of response, but it has limitations. Complete blood count measures and differential testing are inexpensive and routinely performed before the initiation of immunotherapy and before every treatment cycle.




This study sought to determine the usefulness of hematologic biomarkers in predicting patient outcomes. However, it did have limitations due to its retrospective study design. Concurrent inflammatory states and use of immunomodulatory agents or steroids could not be ruled out; these could alter the cell counts. Furthermore, the ANC/ALC could not be assessed separately at the tumor site and could differ from that of the peripheral blood. Future studies should be designed to address these issues.


An ANC/ALC <5 at the time of initiation of treatment with pembrolizumab was associated with improved OS in patients with advanced NSCLC. However, further prospective studies are warranted to establish if ANC/ALC can be reliably used as a predictive biomarker in patients with advanced NSCLC who are treated with immunotherapy.


Department of Hematology & Medical Oncology, Oklahoma University of Health Sciences, Oklahoma City, OK, USA


Department of Internal Medicine, Zucker School of Medicine at Hofstra/Northwell at Staten Island University Hospital, Staten Island, NY, USA


Department of Hematology & Medical Oncology, SUNY Downstate Medical Center, Brooklyn, NY, USA


Division of Hematology & Medical Oncology, Zucker School of Medicine at Hofstra/Northwell at Staten Island University Hospital, New York, NY, USA

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Articles

Original Research

Kira MacDougall, MD, and co-investigators, research the importance of peripheral biomarkers in patients with advanced non–small cell lung cancer who are treated with pembrolizumab. 

The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced Non–Small Cell Lung Cancer Treated With Pembrolizumab: A Clinical Study

 Thymoma is an uncommon intrathoracic malignant tumor and has a long natural history, with overall survival (OS) in these patients lasting decades. It is uncertain whether the survival of a patient with thymoma is affected by their prior cancer history (PCH). Finding out the impact of PCH on thymoma survival has important implications for both decision-making and research.

 The Surveillance, Epidemiology, and End Results database was queried for patients with thymoma diagnosed between 1975 and 2015. Kaplan-Meier methods and the Cox proportional hazards model were used to analyze OS across a variety of stages, ages, and treatment methods, in patients both with and without PCH.

 A total of 3604 patients with thymoma were identified, including 507 (14.1%) with a PCH. The 10-year survival rate of patients with a PCH (53.8%) was worse than that of those without a PCH (40.32%; 95% CI, 35.24%-45.33%; 

 < .0001). However, adjusted analyses showed that the impact of a PCH was heterogenous across ages and treatment methods. In subset analyses, PCH was associated with worse survival among patients who were treated with chemoradiotherapy (HR, 2.80; 95% CI, 1.51-5.20; 

 = .001) and among those who were ≤ 65 years (HR, 1.33; 95% CI, 1.02-1.73; 

 PCH provides an inferior OS for patients with thymoma. However, it does not worsen the survival in some subgroups, and these patients with thymoma may be eligible for study.

 prior cancer history, thymoma, survival, SEER database, clinical trial.

Thymoma is a rare tumor deriving from the epithelial cells of the thymus, although it is the most common primary tumor in the anterior mediastinum. The prevalence of thymoma has been reported as 0.13 per 100,000 person-years in the United States.

 Unlike most other cancers, thymoma has a long natural history and the overall survival (OS) of patients with thymoma can regularly be measured in decades.

 Nonetheless, patients with thymoma with multiple primary cancers are still worthy of study. Some studies have found that patients with thymoma had a broadly increased risk for future cancers; certain patients even experience worse survival.

 Still, the full impact of prior malignancy on thymoma outcomes remains unknown.

Clinical trials play a pivotal role in improving the survival of patients with cancer. However, cancer history is a commonly used exclusion criterion in oncology clinical trials, due to concerns that previous treatment and survival impact could interfere with clinical results. Still, the exclusion of patients with a personal cancer history may be problematic, because it is common for clinical trials to struggle to recruit enough patients with thymoma.

 What’s more, no data exist to clearly support the hypothesis that prior cancer history (PCH) impacts the survival of patients with thymoma. Further, it is uncertain whether the results of clinical trials that excluded patients with PCH could then apply equally to patients with such history. Therefore, determining the impact of PCH on thymoma survival is important for both patients and the oncology community.

Until recently, no study has specifically evaluated the impact of PCH on thymoma outcomes, and we know little about the features of patients with thymoma with PCH. In this study, we aimed to identify the relationship between cancer history—in patients with thymoma who had such history—and the prognosis for their thymoma. Mortality risk of thymoma, as it related to a patient’s PCH, was evaluated using a cohort of patients with thymoma in the Surveillance, Epidemiology, and End Results (SEER) database.

All data were extracted from the SEER database through SEER*Stat Software version 8.3.6. We searched all records of patients diagnosed with thymoma between 1975 and 2015. A diagnosis of any thymoma, excluding thymic carcinoma, was identified by histology and primary site (tumor site code). The SEER sequence number variable represented the order of reportable tumors diagnosed in a lifetime and was used to determine the prevalence of prior cancer.

The patients with thymoma were divided into 2 cohorts based on whether or not they had a PCH. The PCH cohort included patients who had a cancer diagnosis before the thymoma diagnosis, and the first primary (FP) cohort included those patients for whom thymoma represented their first and only malignancy. All patients must have been diagnosed with microscopic confirmation by cytology or histology. Patients were excluded if: (1) they had only death certificates or autopsy records, with no cytological or histological confirmation of disease; (2) they were diagnosed when younger than 18 years; or (3) had incomplete follow-up information or survival data.

Extracted from the SEER database were demographic and clinicopathological characteristics, including age, sex, race, marital status, year of diagnosis, histological subtype, stage, and surgery, chemotherapy, and radiotherapy records. Survival data were calculated in months, and any survival times of 0 months were recorded as 0.5 months. Masaoka-Koga staging was estimated using an approach modeled which was proposed by Fernandes et al.6 Briefly, patients were categorized into 4 groups: stage I/IIA (“invasive tumor confined to gland of origin” or “localized, not otherwise specified”), stage IIB (“adjacent connective tissue”), stage III/IV (“adjacent organs/structures” or “further contiguous extension” or “any positive lymph nodes”), and unknown (unknown extent of disease).

Data were presented as mean values, using standard deviations for continuous variables and percentages for categorical variables. Continuous variables were compared using 

 tests; categorical variables were analyzed using the Pearson χ2 test. Survival curves were plotted by using the Kaplan-Meier method and compared by using the log-rank test. Cox proportional hazards regression models were adjusted for demographic and clinicopathological characteristics. Survival time was calculated as months from diagnosis to death or end of follow-up. The primary end point of this study was OS, and the cutoff date for follow-up was December 31, 2016. All 

 values < .05 were considered statistically significant. Statistical analysis was performed using Stata 16.0 (StataCorp).

A total of 3604 patients with thymoma who met the inclusion criteria were collected from the SEER database, including 507 (14.1%) with PCH. The baseline patient characteristics are shown in the 

. The median (SD) age was 58 (15) years and 1739 (48.3%) patients were female. A total of 1239 patients (34.4%) with thymoma were older than 65 years. The prevalence of patients with PCH was concentrated between 2003 and 2015 (72%). None of the patients in the PCH cohort were seen to have died of thymoma. In general, the PCH cohort had more elderly patients, more deaths, and smaller tumors compared with the FP cohort. Patients were further divided into 6 subgroups based on the thymoma treatment they received: surgery only, surgery and adjuvant therapy, radiation only, chemotherapy only, radiation and chemotherapy, and no treatment.

With a median follow-up of 68 months (range, 0-468), as shown in 

, the 10-year OS rate of the FP cohort (53.8%; 95% CI, 51.76%-55.86%; 

 < .0001) was better than that of the PCH cohort (40.32%; 95% CI, 35.24%-45.33%; 

 depict stratified Kaplan-Meier survival curves by stage. Patients with PCH with thymoma of stages I to IV exhibited worse survival than those in the FP cohort; however, the difference was statistically different only for those patients with stage II disease (

 = .005). Among patients with stage II thymoma, the 10-year OS rate for the FP and PCH cohorts, respectively, were 48.24% (95% CI, 44.42%-51.95%) and 37.68% (95% CI, 26.4%-48.91%).

 present stratified Kaplan-Meier curves by age. Patients with PCH displayed worse survival if they were ≤65 years (

 = .004), while patients aged >65 years with PCH showed survival similar to that of the FP cohort.

Cox proportional hazard models were adjusted for patient demographics and stratified by treatment. As shown in 

, PCH was associated with worse survival for 5.4% of patients with thymoma, but the impact of PCH was not statistically significant for 94.6% of those patients. The patients treated with radiation and chemotherapy in the PCH cohort had worse OS compared with the FP cohort (HR, 2.80; 95% CI, 1.51-5.20; 

 = .001). For the patients with PCH who were treated with other methods, having PCH made no statistical difference. Multivariate Cox proportional hazard model analysis showed that PCH was not associated with significantly worse survival for stage II thymoma (HR, 1.03; 95% CI, 0.72-1.46; 

 = .889) but was associated with worse survival for patients ≤65 years (HR, 1.33; 95% CI, 1.02-1.73; 

To our knowledge, this is the first study to analyze the impact of PCH on outcomes in thymoma. Our study results indicate that PCH had a significant but heterogenous effect on the survival of patients with thymoma. To some degree, the unadjusted survival analyses for thymoma show that PCH is associated with worse OS vs FP (Figure 1A). PCH was seen to have an adverse effect on OS in patients younger than 65 years. For patients with stage II thymoma, patients with PCH showed worse survival than those in the FP cohort (Figure 1C) but had no statistical difference in survival after multivariate Cox proportional hazard model analysis.

Patients may have competing priorities to make treatment decisions, and treatment modalities may have implications for survival.

 The adjusted survival analyses were stratified by treatment modalities for further analysis, which revealed that the chemoradiotherapy subgroup of the PCH cohort had significantly worse survival than members of the other subgroups.

The cancer survivor population has been growing rapidly in the United States over the past 30 years, largely driven by the aging population, the improvement of treatment, and expanding cancer screening efforts.

 These factors have led to an increased prevalence of multiple primary cancers.

 In our study, 20% of older patients (> 65 years) and more than 10% of younger patients (≤ 65 years) who were diagnosed with thymoma had PCH. As shown in Figure 2A, the patients in the younger adult subgroup with PCH had significantly worse prognosis than those in the corresponding FP subgroup.

A study conducted by Andrew et al found that PCH did not adversely affect clinical outcomes in patients with thymoma. The authors also suggested that patients with PCH should not be excluded from clinical trials recruiting patients with advanced lung cancer.

 They argued that older patients were more likely to die from the progression of cancer and comorbidities; therefore, PCH had less impact, relatively. Younger patients with thymoma tend to have a better prognosis than older patients and are more likely to be cured.

 On the other hand, prior cancer treatment could increase the risks of treatment intolerance, thus worsen the survival of younger patients with thymoma.

Although several staging systems exist, the Masaoka-Koga staging classification system is the most extensively used and is a reliable predictor for the prognosis of thymoma.

 The 5-year OS rate was approximately 85% in the patients with stage I to III thymoma and 65% in those with stage IV thymoma.

For stage I and stage II thymoma, complete surgical resection is the recommended standard treatment. What’s more, postoperative radiotherapy is suggested in incompletely resected or high-risk stage II thymomas.

 Adjuvant radiotherapy can reduce local recurrence rates, and completely resected stage II tumors may benefit from adjuvant radiotherapy, but this seems to have no impact on OS.

 It is not yet clear whether patients with a PCH and stage II thymoma could benefit from postoperative radiotherapy. In our work, we found that patients with PCH didn’t display significantly worse OS than those without PCH, when patients had stage II thymoma.

Thymomas are representative of slow-growing tumors that can spread locally. Metastases are usually restricted to the pericardium, diaphragm, or pleura, and extrathoracic regional metastases are uncommon.

 Because of their rarity, various studies are necessary to explore and improve current therapeutic standards. Surgery is the cornerstone of the multimodal treatment strategy for thymoma. Complete removal of the tumor and total thymectomy are recommended for most resectable tumors.

Incompletely resected tumors or tumors with a positive resection margin are generally treated with radiotherapy. Chemotherapy combined with radiotherapy is recommended in unresectable thymomas or advanced thymomas.

 As seen in Figure 3, the patients in the PCH cohort who received radiation and chemotherapy experienced worse OS compared with the FP cohort. Intriguingly, our results showed that the impact of PCH was not statistically significant for most patients with advanced thymomas. Nonetheless, prior cancer treatment increased the toxicity and intolerance of chemoradiotherapy prescribed to treat thymoma, and patients with unresectable thymoma with PCH tended to have more complex conditions than their FP counterparts.

The current study suggested that PCH have a variable impact on the selection of retrospective study and clinical trial. We suggest including PCH as a stratification or covariate variable when PCH is known to modify the effect of 1 or more independent variables. The relationship between OS and PCH most probably reflects interactions among (1) the recurrence or lethality of prior cancer, (2) the recurrence or lethality of the newly diagnosed thymoma, and (3) the personal circumstances of patients.

Undeniably, the present study has several limitations. Firstly, we confirmed a PCH according to the sequence number only, without detailed prior cancer characteristics. Therefore, we could not distinguish whether the index thymoma was from local recurrence. Secondly, the current study focused on PCH in general, without description of the specific prior cancer type. Prior cancer type could affect results, as the previously diagnosed cancer could be “likely lethal” or “likely irrelevant” to prognosis. Thirdly, the SEER database lacked detailed information on therapeutic regimens for chemotherapy and radiotherapy or toxicity, as well as on comorbidities and adverse events. In addition, the data acquired from the SEER database cover approximately 34.6% of the population in the United States. Further studies are required to confirm the generalizability of our findings.

A prior cancer history has variable impact on the survival of patients with thymoma, depending upon age and treatment method. PCH is associated with worse survival for patients who were younger and treated with chemoradiotherapy. However, further studies are required for confirmation.

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Wenfa Jiang, MD, and Chenyang Xu, MD, 16 Meiguan Road, CO 341000, Ganzhou, China.

Department of Thoracic Surgery, Ganzhou People’s Hospital, Ganzhou, China.

These authors contributed equally to this work.

Ethics approval and consent to participate: All data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Institutional review board approval was waived for this study because the SEER database is a public anonymized database.

 The authors have no conflicts of interest to declare.

Shilong Wu, MD, and co-authors discuss how patients with thymoma are affected by prior cancer history. 

The Effect of Prior Cancer on Survival of Patients With Thymoma

Prostate-specific antigen (PSA) values above 100 ng/mL often suggest metastatic prostate cancer. We present the case of a patient with a PSA of 110 ng/mL, 4 negative prostate biopsies, and 4 negative prostate MRIs. After his fifth MRI revealed a PI-RADS 5 lesion, he underwent his fifth transrectal biopsy; this revealed Gleason 3 + 4 = 7. He was found to have organ-confined pT2 disease on subsequent radical prostatectomy pathology. This case highlights that there may be no PSA for which one can assume metastatic disease with certainty. Depending on life expectancy, patients with extremely elevated PSA may still warrant a full staging workup

A man, aged 73 years, presented to our care in early 2021 with a prostate-specific antigen (PSA) of 110 ng/mL after 4 negative prostate biopsies and 4 negative prostate MRIs. His journey had begun in 2002 when his PSA was 3 ng/mL. Two years later, in 2004, at a PSA level of 3.8 ng/mL, he had his first transrectal ultrasound-guided (TRUS) biopsy. All 6 cores were negative. His PSA continued to oscillate between 3 and 10 ng/mL for the next 5 years, warranting 12-core TRUS biopsies in 2007 and 2009. These were negative, and his prostate size of 40 grams was thus cited as the cause of his PSA elevation.

In 2010, as his PSA rose above 10 ng/mL, he had the first of 4 prostate MRIs; it did not reveal suspicious lesions. It was followed by a negative 12-core TRUS biopsy in 2011. His PSA rose from 65 ng/ml to about 100 ng/mL from 2014 to 2019, and repeat MRIs in 2014 and 2017 did not demonstrate any suspicious lesions. However, a mix of stromal and hyperplastic nodules in the transition zone (TZ) of the prostate were exhibited. Prostate MRI in 2019, at an outside academic center, again did not demonstrate a suspicious prostatic lesion. His prostate exam remained benign, with hypertrophy of the gland to
60 grams. In late 2020, his PSA measured above 100 ng/mL and he was referred to us for care.

At presentation to our clinic in early 2021, the patient’s PSA was 110 ng/mL, with minimal lower urinary tract symptoms and a negative review of systems. His prostate was 60 grams and smooth. An Exosome Dx urine test (EXO Dx; Exosome Diagnostics/Bio-Techne) revealed an extremely elevated score of 69 (normal is below 15.6). His Prostate Health Index (PHI; Beckman Coulter) was 259, and his percent free PSA was 7.5%. These prompted his fifth and final MRI.

A PI-RADS 5 lesion was identified in the left anterior TZ (

), and an 18-core TRUS fusion biopsy shortly thereafter revealed 2 cores of Gleason 3 + 4 = 7, Gleason grade (GG) 2 disease (

). After metastatic staging with a negative CT and nuclear medicine bone scan, he underwent open radical prostatectomy (RP) in May 2021. Final pathology revealed a 66-gram prostate, Gleason 4 + 3 = 7, GG3, organ-confined disease with negative lymph nodes, pT2N0Mx (

We used several novel secondary screening tests in this case: the PHI and the EXO Dx.

Many contemporary patients are skeptical and reluctant to undergo an invasive prostate biopsy based only on total elevated PSA. Tutrone et al showed that compliance in following through on a biopsy using PSA alone was 39% vs 72% for men who also had an abnormal EXO Dx test to consider.

 Our patient was reluctant to have further invasive testing considering his prior negative work-up.

Although his high total PSA was outside the labeled indication for both tests, we felt the tests were useful in this most unusual case.

While infectious etiologies such as prostatitis, prostate abscess, and even tuberculosis can be considered, studies have shown that a PSA elevation due to an inflammatory prostatic process is often to a level much lower than what was seen with our patient.

 PSA values above 100 ng/ml do often suggest metastatic prostate cancer. In 1993, Stamey et al presented 3 similar patients with TZ lesions, PSA between 150 and 456 ng/mL, and Gleason 4 + 3 = 7: All were found to have organ-confined disease.

 TZ lesions have been shown to have higher PSA density than their peripheral zone (PZ) counterparts, and while large tumor volumes may be observed in the TZ, they are more likely to have favorable pathologic features and lower biochemical recurrence (BCR) rates.

 A more recent study in 2015 by Lee et al showed similar findings, with higher preoperative PSA values and larger tumor volume in TZ lesions compared with PZ lesions. Furthermore, they showed decreased odds of seminal vesicle invasion, extracapsular extension, and hazard of tumor recurrence.

 Additional study is needed to verify if the capsule around the TZ could be restricting tumor spread.

While a high PSA may be an excellent predictor, it is not perfect. A 2020 Swedish study of 8850 men with PSA above 100 ng/mL found that 71% had metastatic prostate cancer, and among men with PSA of above 500 ng/mL, the rate of metastases still ranged from 50% to 94%.

 Even if the disease is localized at the time of treatment, BCR is significantly higher for patients with PSA above 100 ng/mL who have undergone RP.9 BCR-free survival is only 29% at 10 years for PSA above 100 ng/mL for these patients.

Q: Dr Moul, did you believe this patient had cancer when he presented to you? How did his past 4 MRIs and 4 biopsies impact your approach?

A: I do not recall seeing a prior patient with such a prolonged work-up and a PSA this elevated who did not have prostate cancer. When the PSA is above 100 ng/mL, the chance of finding prostate cancer is at least 75%.

I am very fortunate to be at a major center with multidisciplinary care where we have access to secondary screening tests such as PHI and EXO Dx urine testing. When the EXO Dx returned at 69, I knew there was a high probability not only of cancer, but of Gleason 7 or higher. While the EXO Dx test is officially marketed for use in men with a total PSA between 2 and 10 ng/ml, I ordered the test to help convince this patient, who had already endured so much and felt well, to have another MRI and possibly another biopsy.

 Although the PHI is not approved for use in men with a total PSA of above 20, I also ordered this test, for similar reasons. In the end, we were able to identify what we believe to have been occult disease, and not interval cancer development, as anterior lesions can be missed in up to 46% of 12-core biopsies.

Q: Dr Moul, had his repeat MRI not shown a lesion, what would your next step have been?

A: That is a great question. With total PSA, EXO Dx urine, free PSA, and PHI pointing to previously missed occult prostate cancer, I would likely have pushed the patient toward another biopsy. I would likely have recommended a saturation biopsy with special attention to anterior cores. The patient was understandably hesitant about more invasive testing and I believe it may have been challenging to convince him to do more testing, given that he felt perfectly fine. Fortunately, MRI did find the lesion that had been eluding his caregivers for [so long].

Q: Dr Moul, did you immediately consider surgery? What was your biggest concern in offering surgery?

A: I am very careful about offering RP to men 70 years and older due to concern for increased sexual and urinary morbidity in the group aged 70 to 79 years. However, this gentleman was enjoying excellent health and had a normal body mass index so I was a bit less concerned about incontinence. I did explain to him that age alone made him less likely to regain potency even with a bilateral nerve-sparing technique. I estimated his likelihood of regaining erections firm enough for intercourse, either spontaneously or with the help of oral medications, was about 20% to 25%. I also told him that he faced a 5% to 10% chance of still requiring a pad for stress incontinence at 1 year post surgery even though the risk of total incontinence was 1% or less in my series. Only RP pathologic assessment could help us understand why his cancer had been so elusive over the past 18 years. I did have the patient consult with radiation oncology as part of our multidisciplinary program and would have supported his decision for local therapy.

Q: Dr Moul, what clinical pearls can we take away from this case from the perspective of a urologist?

A: Don’t give up in healthy men who have elevated and rising PSA. This is an extreme and prolonged example of occult prostate cancer eluding multiple diagnostic and imaging efforts. I do not recall, in my 30-plus years of practice, ever seeing a patient with a PSA above 100 ng/mL who did not have prostate cancer. I think we were able to utilize the latest in technological advancements—those that did not exist 18 years ago when this patient first presented with an elevated PSA. Finally, this case had a happy ending with organ-confined disease on surgical pathology. No one would have presumed that this man with a PSA above 100 would have pT2 disease and at his 3-month follow up visit, the patient had a PSA less than 0.1 ng/mL and only mild stress incontinence (1 pad per 24 hours).

Q: Dr Gupta, what makes reading these MRI images so difficult?

A: Prostate MRI is a challenging imaging study to interpret, especially in the TZ. The TZ is challenging because of the overlap in imaging appearance of certain types of benign prostatic hyperplasia nodules with malignancy. Specifically, the degree of restricted diffusion and contrast enhancement can overlap with stromal and hyperplastic nodules, respectively. That said, there are morphologic features of anterior TZ lesions that are critical to recognize. Specifically, T2 weighted imaging is the dominant imaging sequence used to diagnose and characterize TZ lesions and these are characterized by an “erased charcoal” appearance, as in this case. Also, these lesions should have markedly restricted diffusion as evidenced by low signal on apparent diffusion coefficient (ADC) maps and high signal on high b-value diffusion weighted imaging (DWI).

Q: Dr Gupta, do you believe the 4 MRIs the patient had (2010, 2014, 2017, 2019) were all warranted? At what interval do you usually view meaningful changes in an MRI read?

A: This question really comes down to suspicion of clinically significant cancer. Clearly the patient had a PSA that was persistently elevated without imaging or biopsy findings to explain this. To that end, I think that repeat MRIs can be warranted. That said, it is critical to ensure high-quality MRI, with interpretation performed by radiologists with significant experience in prostate MRI. As for the interval during which we see meaningful changes on MRI, we can take some guidance from imaging performed as part of active surveillance protocols. In these cases, imaging can be helpful every 1 to 2 years, looking for changes in a lesion that would suggest that it is suspicious for clinically significant disease. This would include increase in size and/or increased restricted diffusion, as evidenced by lower signal on ADC maps and high signal on high b-value DWI.

Q: Dr Gupta, what imaging pearls can we take away from this case from a radiologist’s perspective?

Dr. Judd W. Moul, MD, and colleagues present the case of a man, aged 73 years, with a prostate-specific antigen level of 110 ng/mL after 4 negative prostate biopsies and 4 negative prostate MRIs. 

ONCOLOGY Vol 36, Issue 3 | Oncology

The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced Non–Small Cell Lung Cancer Treated With Pembrolizumab: A Clinical Study

The Effect of Prior Cancer on Survival of Patients With Thymoma

Successful Diagnosis and Treatment of Occult Prostate Cancer Despite Multiple Negative Prostate Biopsies and Negative Prostate MRIs

Expert Commentary on the Product Profile of Amivantamab-vmjw

Matulonis Provides Overview of Gynecologic Treatment Landscape Advances

The Emerging Value of ctDNA in Colon Cancer Adjuvant Therapy Decisions