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Non-Hodgkin Lymphoma Survivors: Secondary Malignancy Risk

Non-Hodgkin Lymphoma Survivors: Secondary Malignancy Risk

The number of non-Hodgkin lymphoma (NHL) cases is rising, with an estimated 81,560 new diagnoses in the US in 2021. As survival rates improve, more NHL survivors face potential late effects, including secondary malignancies (SM) linked to treatments like chemotherapy and radiation. This research revisits and extends an earlier study to better understand SM risks and inform follow-up protocols. It utilizes an expanded database and 15 more years of follow-up data and also incorporates chemotherapy’s impact on SM risk among NHL survivors.



Non-Hodgkin lymphoma (NHL) constitutes a significant burden on public health, with its prevalence increasing over the past five decades. In 2021 alone, an estimated 81,560 individuals in the United States were projected to receive NHL diagnoses, underlining the urgency of comprehensive research into this condition [1]. The augmentation of NHL survivorship is a testament to advancements in therapeutic strategies, yet it ushers in new challenges in understanding and managing potential long-term consequences.

A pivotal concern for NHL survivors is the emergence of secondary malignancies (SM) that may arise due to the disease or the treatments employed. This spectrum of SM, which encompasses diverse forms, poses a critical threat to the well-being of NHL survivors [2]. Intrinsic to these risks is the utilization of various treatment modalities, including chemotherapy, stem cell transplantation, and radiotherapy, all of which have been implicated in fostering the development of SM [3-7].

Central to this investigation is the evolution of treatment guidelines for NHL, where the choice of therapy varies according to subtype and stage. Although chemotherapy and radiation constitute the predominant modalities employed, understanding the nuances of SM risk associated with each treatment regimen is imperative for ensuring comprehensive follow-up and screening protocols [8]. 

Previous research utilized the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to explore the incidence of SM in NHL survivors to address these challenges [9]. However, this initial study was limited in its scope, needing more inclusion of chemotherapy data. Since the publication of this work, the SEER database has expanded to encompass a broader array of treatment modalities, thereby providing a unique opportunity to revisit and extend the examination of SM risk in the context of NHL survivorship.

Therefore, the present study aims to bridge this gap by revisiting and expanding upon prior research, leveraging the updated SEER database to accommodate an additional 15 years of follow-up data. By incorporating information on chemotherapy as a crucial treatment modality, the study seeks to unravel the evolving landscape of SM risk among NHL survivors, thereby contributing invaluable insights to the design of enhanced follow-up and screening protocols [10].



This study utilized the comprehensive dataset provided by the Surveillance, Epidemiology, and End Results (SEER) program, a collection of cancer registries encompassing a notable fraction of the US populace. These registries amassed extensive records detailing patient demographics, tumor characteristics, treatments administered, and subsequent monitoring.

The investigation focused on individuals whose initial cancer diagnosis was non-Hodgkin lymphoma (NHL) within the period spanning from 1975 to 2016. A two-pronged analysis was undertaken, involving the determination of both secondary malignancy (SM) incidence and the comparative elevated risk of SM compared to the general population.

Stratification variables such as age, gender, race, and the year of NHL diagnosis were considered to ensure precise computations. Exclusions were made for instances where the occurrence of a second malignancy immediately followed NHL diagnosis or when NHL was not the primary cancer.

Temporal intervals spanning NHL diagnosis to subsequent follow-up or study termination were established for each individual. The observed frequency of second malignancies was juxtaposed with the anticipated occurrences, benchmarked against standard US population rates.

Distinct subgroups were examined, encompassing variations in gender, age, time since NHL diagnosis, and treatment modality. The resultant outcomes underwent scrutiny to ascertain statistical significance. The central objective of this study was to enhance the understanding of secondary malignancy risks among NHL survivors.



The research analysis capitalized on the extensive dataset curated by the SEER program to investigate secondary malignancies (SM) in non-Hodgkin lymphoma (NHL) cases spanning 1975 to 2016. By employing the SEERStat Multiple Primary-SIR tools, the study computed the standard incidence ratio (SIR) and absolute excess risk (AER) for SM, juxtaposing observed occurrences with anticipated numbers based on US population incidence rates. Age, gender, race, patient-years at risk (PYs), and year of NHL diagnosis were integrated as adjusting factors. 

Inclusions were confined to patients for whom NHL represented primary cancer, with exclusion criteria applied to those with immediate SM development or non-primary NHL cases. Solely invasive malignancies were considered for SM assessment, while in situ diseases and specific skin cancers were omitted. Stratified analyses explored SM risks based on gender, age at NHL diagnosis, latency, and treatment modalities. Statistical significance, gauged through 95% confidence intervals, compared subgroup risks to their corresponding endemic populations. This research gave more detailed information about SM risks in NHL survival.



In this study, the authors comprehensively analyzed secondary malignancy (SM) risk among patients with non-Hodgkin lymphoma (NHL) to assess the impact of various factors such as treatment modalities, patient characteristics, and latency periods. The research encompassed a large patient population of 141,451 individuals, with extensive follow-up durations of up to 10 years. The aim was to determine the incidence and specific types of SMs in NHL survivors and evaluate how factors like chemotherapy, radiation therapy, age at diagnosis, and latency periods influenced SM risk. The study yielded valuable insights into the complex relationship between NHL treatment and subsequent cancer risks, shedding light on the nuances of long-term survivorship for this patient population as thus:

Patient Population

  • Over one hundred and forty thousand (145,451) patients were included in the analysis.
  • Fouty-six percent of the patients (46%) had follow-up appointments beyond five (5) years, and twenty-five percent (25%) had follow-ups beyond ten (10) years.
  • A total of 923,475 patient-years of follow-up were recorded.
  • SM occurred in 11.3% of patients, with a mean latency of 94 months.


Overall SM Risk

  • SMs occurred significantly higher in NHL survivors than in the general U.S. population.
  • Specific malignancies at increased risk included head and neck, stomach, colon, anal, liver, lung, bone and joint, soft tissue, melanoma, breast cancer in males, bladder, kidney, thyroid, Hodgkin lymphoma, leukemia, and Kaposi sarcoma.
  • The highest excess risks were observed for lung cancer and leukemia.
  • Rectal cancer, female breast cancer, and prostate cancer had lower risks in the study cohort.


SM Risk by Diagnosis Timing

  • Patients diagnosed in 2002 or later had significantly greater SM risk.
  • Increased risk was seen in both B-cell and T-cell lymphoma, with a more significant effect size in B-cell lymphoma.
  • Increased risk was observed in patients receiving no therapy, chemotherapy alone, and radiation alone.


SM Risk by Patient Characteristics

  • There was no substantial difference in SM risk between genders.
  • Minority patients had a higher SM risk compared to white patients.
  • An advanced disease stage at diagnosis was associated with elevated SM risk.
  • Younger patients with NHL diagnoses had higher SM risk.


SM Risk by Treatment Modality

  • Radiation therapy did not alter overall SM risk significantly.
  • Radiation was associated with a raised risk of female breast cancer and decreased risk of leukemia.
  • Chemotherapy increased overall SM risk, including head and neck, kidney, thyroid cancers, leukemia, and Kaposi sarcoma.
  • Chemotherapy patients had decreased risk of prostate cancer.


SM Risk by Latency

  • There was no overall difference in SM risk by years from NHL diagnosis.
  • Specific cancers showed associations with latency, with some becoming more common at more extended latency periods.
  • Age at NHL diagnosis was associated with the latency period of SM.

The research highlights increased SM risks in NHL survivors, varying by diagnosis timing, patient characteristics, treatment modality, and latency. Certain cancers showed higher risk, while others exhibited lower risk relative to endemic rates.



The study under discussion expands upon prior investigations that have reported an elevated risk of secondary malignancies (SM) among survivors of non-Hodgkin lymphoma (NHL) [1-4]. This current study represents the most extensive examination of SM in NHL survivors to date and provides novel insights into the extent and patterns of this risk [1].

The findings of this study confirm the heightened risk of SM in NHL survivors; notably, this risk has escalated compared to earlier research [1]. Specifically, the risk was notably elevated in patients diagnosed after 2001, with various treatment approaches exhibiting amplified SM risk in this cohort [1]. Noteworthy contributing factors to this increased risk include the addition of rituximab to chemotherapy regimens like the R-EPOCH regimen [1].

This study aligns with previous investigations regarding gender-related disparities by not detecting a substantial gap in SM risk between male and female NHL survivors [1,4]. However, a significant observation identified non-white patients as having a heightened susceptibility to SM compared to their white counterparts, highlighting pertinent concerns regarding healthcare inequalities [1]. 

Although the overall SM risk was not significantly associated with radiation treatment, an intriguing finding was the heightened risk of secondary breast cancer in patients subjected to combined radiation and chemotherapy [1]. Additionally, younger patients (<25 years) treated with radiotherapy alone demonstrated an augmented risk of secondary breast cancer, implying the necessity for early breast cancer screening for this subgroup [1].

Chemotherapy emerged as a critical factor, with patients exposed to chemotherapy manifesting an increased SM risk [1]. It encompassed a range of cancers, including hematologic, bladder, head and neck, thyroid, and kidney cancers, which exhibited elevated risks even when considering patients subjected to chemotherapy without accompanying radiotherapy [1].

The present study’s contributions are substantial; it provides a thorough understanding of the complex landscape of SM risk among NHL survivors and highlights the need for continued research and interventions to reduce healthcare disparities and improve screening practices [1]. Further exploration is warranted to gain deeper insights into the mechanisms underlying these associations and to facilitate improved management strategies for NHL survivors [1].



Some caveats in this study need to be considered. They include:

  • Treatment Coding Accuracy: The accuracy of treatment coding in the SEER database is not perfect, with reported sensitivities of 68% for chemotherapy and 80% for radiation.
  • Heterogeneity of NHL: The SEER database does not fully account for the heterogeneity of non-Hodgkin lymphoma (NHL) subtypes, which could lead to variations in disease characteristics among different treatment groups.
  • Comorbid Conditions and Risk Factors: The database lacks information on comorbid conditions and potential cancer risk factors such as smoking status, genetic mutations, and HIV status, which could impact the calculation of standardized incidence ratios (SIR) and absolute excess risks (AER).
  • Limited Granularity of Chemotherapy Data: The granularity of chemotherapy data is limited, preventing detailed exploration of specific drugs or stem cell transplants associated with increased SM risk.
  • Radiation Data Limitations: Similarly, the data on radiation therapy lacks information on radiation field or dose, limiting the ability to assess associations with specific radiation treatments.
  • Comparison Groups: Subgroups, such as different treatment modalities, are not directly compared in a controlled manner; instead, each subgroup is standardized relative to its endemic population, which may affect the interpretation of results.
  • True SM vs. Synchronous/Metachronous Cancers: The study’s definition of secondary malignancies (SMs) excludes cancers diagnosed within two months of the initial NHL diagnosis; however, this distinction might still include some cancers that are more accurately considered synchronous or metachronous.
  • General Limitations of Retrospective Analysis: The study’s retrospective design inherent to database analysis introduces inherent limitations in data collection, causality assessment, and potential unaccounted confounding factors.

It’s important to note that while these limitations may impact the precision and scope of the study’s findings, they are inherent to retrospective database analyses and do not necessarily invalidate the study’s overall contributions to understanding secondary malignancy risk in NHL survivors.



This pivotal study extensively explores secondary malignancy (SM) risk in non-Hodgkin lymphoma (NHL) patients with extended follow-up. Contrary to radiotherapy, which exhibited no overall increase in SM risk, chemotherapy emerged as a contributor to heightened risk. Notably, distinct sub-sites displayed varying risk patterns based on treatment type, age, race, and time since treatment. Although individual risk remains elusive, these findings empower clinicians with invaluable insights for vigilant screening and sustained follow-up in NHL survivors.



  • Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: Differences by lymphoma subtype. J Clin Oncol. 2010;28(30):4935-4944. Https://
  • Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1995;87(7):524-530. Https://
  • Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol. 2000;18(3):498-509.
  • Myrehaug S, Pintilie M, Tsang R, et al. Assessment of a chemotherapy-only treatment policy in stage I and II aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2003;14(5):734-742.
  • National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. SEER Research Data (1973-2021). Available from:


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