In this case report, we present a non-Hodgkin lymphoma survivor who was incidentally found to have non–small-cell lung cancer 30 years after undergoing treatment that included mantle radiation. We discuss the treatment-related risk factors for lung cancer in this population and potential implications for long-term follow-up.
Survivors of childhood and young adult cancer are at risk for developing subsequent malignant neoplasms, including lung cancer. As survival rates in this group continue to improve and patients enter later decades in life, determining the optimal surveillance and counseling strategies with regards to subsequent cancers remains a challenge. In this case report, we present a non-Hodgkin lymphoma survivor who was incidentally found to have non–small-cell lung cancer 30 years after undergoing treatment that included mantle radiation. We discuss the treatment-related risk factors for lung cancer in this population and potential implications for long-term follow-up.
As a result of improving treatment and supportive care, the population of childhood and young adult cancer survivors is expected to continue to rise over the coming years. Childhood and young adult cancer survivors are at increased risk for a multitude of adverse late effects, including subsequent malignant neoplasms.[2-5] The historical mainstay for treatment of non-Hodgkin lymphoma has been chemotherapy with or without radiation therapy (RT); both alkylating chemotherapy and RT have been associated with the development of subsequent malignant neoplasms, including malignancies of the skin, breast, thyroid, gastrointestinal tract, and lung.[2, 6-12]
In the general population, results from the National Lung Screening Trial (NLST) indicate that surveillance for lung cancer among smokers who are at high risk confers a mortality benefit. What remains unclear is what the optimal lung cancer surveillance strategy is for childhood and young adult survivors who received RT to the lung fields. In the absence of a large definitive randomized controlled trial directly investigating this question, clinicians taking care of these survivors must rely on retrospective epidemiological studies, registry data, and statistical modeling where available. The aim of this paper is to describe a case of non–small-cell lung cancer (NSCLC) following mantle RT for non-Hodgkin lymphoma and to briefly review the epidemiology of lung cancer in childhood and young adult cancer survivors, with the goal of assisting the clinician in thinking about lung cancer risk in this population.
A 61-year-old woman who was a survivor of non-Hodgkin lymphoma was referred for abdominal CT by her outside gynecologist for a chief complaint of left flank pain. An 8-mm left pulmonary nodule was incidentally noted in the left lower lobe. A repeat scan showed no growth in the nodule 2 months later. However, a subsequent scan 8 months after the first demonstrated interval growth of the nodule to a size of 14 × 11 mm. At that point, she was referred to thoracic surgery for biopsy and definitive treatment.
Her previous medical history was significant for non-Hodgkin lymphoma diagnosed at age 30, for which she received cyclophosphamide, vincristine, prednisone, methotrexate, doxorubicin, mercaptopurine, carmustine, and L-asparaginase. She also underwent mantle and pericardial irradiation (total dose, 35 Gy). At her annual survivorship appointment, her other medical problems were noted to be hypothyroidism and hyperlipidemia. She had no history of tobacco, alcohol, or drug use, and she denied environmental exposures, including to asbestos.
To evaluate her pulmonary nodule, she underwent a PET scan, which showed increased 18F-fluorodeoxyglucose (FDG) uptake, raising suspicion for lung neoplasm. A fine needle aspiration biopsy of the left lung nodule revealed lung adenocarcinoma. She underwent a left lower lobe anterior segmentectomy and mediastinal lymph node dissection. After an uneventful recovery from surgery, she was followed with periodic re-imaging. Pathology of the nodule confirmed a diagnosis of stage IA NSCLC (T1aN0m0). She has remained disease-free for longer than 3 years after surgery.
We performed a brief review of the English language literature using PubMed from inception to March 12 of this year, with combinations of the search terms "childhood cancer," "lymphoma," "survivor," "lung cancer," and "subsequent neoplasm,"Â as well as their derivatives. Bibliographies of literature identified by our search strategy were also hand searched for additional relevant articles and reviews of this population. Case reports, case series, institutional experiences, registry studies, and reviews discussing the incidence and clinical characteristics of lung cancers diagnosed in childhood and young adult survivors were all included. Studies not commenting on lung cancer specifically were excluded.
In our report, we describe the case of a female non-Hodgkin lymphoma survivor who at age 61 had an incidental finding on imaging that was later revealed to be NSCLC. Given the absence of any identifiable environmental exposures, our case raises the concern that her earlier treatment with mantle RT contributed to her lung cancer risk. In addition, her disease-free survival 3 years after surgical resection illustrates the potential benefit of an early diagnosis and raises the question of whether other survivors with a history of RT to fields including the lungs would benefit from a CT-based lung cancer detection program.
In the cancer survivor population, the development of malignancies after RT is well-recognized, but heterogeneity in risk factors (including primary tumor biology, age at treatment, duration of follow-up, environmental exposures, and hereditary predisposition) has made attempts to estimate attributable risk difficult. In a 2009 study on the Childhood Cancer Survivor Study (CCSS) cohort, the 20-year overall cumulative incidence of subsequent malignant neoplasms in 14,358 5-year childhood cancer survivors was estimated to be approximately 3% to 4%. This group included patients treated for leukemia, lymphoma, neuroblastoma, soft-tissue sarcoma, bone cancer, central nervous system cancer, or Wilms tumor. Of these patients, 67% received RT, which was identified as a significant risk factor. Using Surveillance, Epidemiology, and End Results (SEER) Program cancer registries, Inskip et al reported a similar pattern of epidemiology in subsequent malignant neoplasms, including 7 cases of lung cancer among a cohort of 25,965 2-month survivors of childhood cancer. Though the absolute number of cases was small, the expected number of lung cancers in this age group was even smaller, resulting in an observed-to-expected ratio (O/E) of 7.4 (P < .05). Importantly, survivors with a history of RT had an O/E ratio for cancers of the lung and bronchus of 17.0 (P < .05), while those without a history of RT had an O/E ratio of 5.4 (not significant).
A 2011 meta-analysis of 23 studies by Pirani et al sought to investigate the overall risk for secondary malignancies in non-Hodgkin lymphoma survivors; pooling the results of 12 studies, the lifetime risk of developing lung cancer after non-Hodgkin lymphoma was 1.53 (233,293 total patients; 95% CI, 1.36-1.73) compared with controls without a history of the disease. A 2013 meta-analysis of 21 studies by Ibrahim et al estimated that the cumulative incidence of lung cancer at 20-year follow-up after treatment for Hodgkin lymphoma ranged from 0.1% to 6.2%, with a mean latency of 11.5 years between primary treatment and development of lung cancer. A pooled analysis of German cancer registry data estimated that the standardized incidence ratio for lung cancer in non-Hodgkin lymphoma survivors was 2.08 (95% CI, 1.84-2.33); in Hodgkin lymphoma survivors, it was 3.64 (95% CI, 2.9-4.47).
Higher treatment doses with radiation appear to impart a higher risk for lung cancer, as illustrated in an institutional retrospective study by Almagro-Casado et al in 2016. Exposure to RT was associated with solid neoplasm development in these survivors, with an increased risk for lung cancer (hazard ratio, 4.0; 95% CI, 1.1-11.6) in patients receiving RT doses greater than 42 Gy compared with patients receiving less than 42 Gy. The median overall survival (OS) after lung cancer diagnosis was 12.6 months. However, patients diagnosed incidentally prior to the onset of symptoms had more favorable staging and better prognoses compared with patients who had been diagnosed after the onset of symptoms (median OS, 49.1 months vs 5.9 months).
It remains unclear to what extent underlying biological or genetic factors in the non-Hodgkin lymphoma survivor population could contribute to the risk of subsequent lung cancer. Friedman et al noted a statistically significant increase overall in the risk of malignancy (standardized incidence ratio [SIR], 1.8; 95% CI, 1.3-2.5) in siblings of patients with non-Hodgkin lymphoma compared with the general population, suggesting a genetic or environmental component; notably, however, no increased risk for lung cancer was noted in siblings (SIR, 1.3; 95% CI, 0.6-2.9). Similarly, in a study by Landgren et al, non-Hodgkin lymphoma survivors with a positive family history of cancer did not have a statistically significant increased risk of developing lung cancer compared with similar survivors without a family history of cancer (risk ratio, 1.99; 95% CI, 0.73-5.39).
A 2018 paper by Holmqvist et al sought to investigate the risk of subsequent malignant neoplasms after treatment for childhood Hodgkin lymphoma; they examined a cohort of 1,136 patients with Hodgkin lymphoma who were treated before age 17 between 1955 and 1986. The cumulative incidence of lung cancer was 2.3% by age 50 years, though the highest at risk were men treated with chest RT at age < 10 years, with a cumulative incidence of 4.2% by age 50 years; indeed, 10 of the 11 lung cancer cases they identified were in men, and were diagnosed a median of 28 years after Hodgkin lymphoma. When compared with the general population, male survivors had an SIR of 26.7, whereas the SIR for women was 3.3 (95% CI, 0.2-14.6). Notably, all 11 lung cancer cases developed in patients who had received chest RT.
A limitation voiced by most investigators in these retrospective studies is that patient smoking status is commonly unavailable, but is suspected to contribute significantly to lung cancer risk in lymphoma survivors.[17-20] The male predominance (76%) of lung cancer cases has been speculated to be due to historical differences in tobacco use between men and women.[18,24] A synergistic mechanism between radiation exposure and smoking is suggested,[19,23] and highlights the need to address smoking status with cancer survivors.
Another ongoing area of investigation is on how the risk of lung cancer changes over time as survivors age. Early reports from the CCSS cohort reported few cases of lung cancer: in fact, none were reported in their 2001 paper (median age, 23 years; range, 8-47 years); 4 cases were reported in the 2006 paper, of which 3 were Hodgkin lymphoma survivors. Though few in number, these cases represented an elevated risk compared with the general population (overall SIR, 3.1; 95% CI, 1.2-8.2). A CCSS report in 2015 by Turcotte et al that investigated subsequent malignant neoplasm incidence during the fifth and sixth decades of life showed that most of the lung cancers they identified occurred after age 40 (5 cases after age 40, 1 case before; all cases had received radiation). Of note, no excess risk for lung cancer was identified compared with the general population; this finding was speculated to be due to the risk of lung cancer also increasing in the general population in later decades of life, which would mitigate the difference in risk between the two groups.
The NLST demonstrated a mortality benefit from screening high-risk patients (age, 55-74 years, with at least a 30 pack-year tobacco history) with low-dose CT compared with chest radiography. Patients screened with low-dose CT had earlier staging and fewer deaths compared with those screened with chest radiography. The results of this trial impacted guidelines, with multiple expert groups recommending the incorporation of lung cancer screening with low-dose CT in patients at high risk.[28-30] The current Children's Oncology Group guidelines recommend that survivors exposed to chest or axillary radiation during treatment be counseled on the potential benefits and harms of spiral CT scanning for patients at highest risk. Risks of spiral CT scanning in this setting include the possibility of a false-positive finding, which could result in patient distress, biopsy-associated morbidity, and unnecessary surgery. In the NLST, the rate of false-positive findings was very high in both screening groups (96.1% for CT, 93.9% for chest x-ray). Other important questions that remain are: What is the radiation dose threshold that should be used to identify patients at highest risk? Should there be an optional screening interval? And, how do we incorporate the possible interaction between RT and tobacco use into screening decisions?
In any patient, the news of a cancer diagnosis can be devastating; however, as our case demonstrates, diagnosis at an early stage can result in a favorable outcome. Current survivorship guidelines do not recommend lung cancer surveillance based on a history of RT or chemotherapy. Yet, these exposures are likely relevant to risk.
At this time, the existing evidence does not appear to support a role for a CT-based lung cancer detection program among survivors who never smoked. Whether the demonstrated benefit of a CT-based lung cancer detection program can be applied to childhood and young adult cancer survivors without a history of smoking or to other survivors who have received radiation to the lungs is unknown. Future studies that include modeling of surveillance strategies may be helpful. Regardless of their baseline risk or exposure to radiation, all patients should be counseled on smoking cessation.
Financial Disclosure:This work was supported by the Meg BertÃ© Owen Fund and the National Institutes of Health (P30 CA008748).
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