The incidence of a new lung cancer in patients with metastatic kidney cancer is not currently known. As both cancers are associated with tobacco smoking, it is likely that metastatic kidney cancer patients have an increased risk of developing lung cancer. However, literature on this subject is lacking. As patients with metastatic cancer are living longer thanks to new therapies, increased awareness and care for other competing causes of morbidity and mortality need to be considered, including new primary malignancies.
Since the introduction of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKIs), starting with sorafenib in 2005, the landscape of the management of kidney cancer has dramatically changed for the better. Before this, therapy was limited to immunotherapy with interferon or interleukin-2, which yielded durable responses in only a small fraction of patients. Cytotoxic chemotherapy was of very limited benefit.
Now with the newer targeted therapies, median overall survival has more than doubled to more than 24 months, and patients with good risk disease can expect to survive around 4 years. The recent introduction of immune checkpoint inhibitors is likely to increase this further still.
True Incidence Is Unknown
While tobacco smoking is an established risk factor for both lung and kidney cancer, a link between these two malignancies has not been well-established. Two series of patients, one by Rabbini and colleagues at Memorial Sloan Kettering Cancer Center published in 1998 and an Italian series by Antonelli and colleagues published in 2012, describe the pattern of co-occurring malignancies in patients undergoing surgery for kidney cancer. The most common malignancies were prostate, breast and gynecologic cancers, and colorectal. This likely reflects both the high frequency of these cancers and their relatively good prognosis. Among smoking-related malignancies, the rates of bladder cancer are increased in these series, but lung cancer was not represented more often than in the general population.
Both series, however, contained primarily early-stage kidney cancer patients. A review of the literature only identified four patients described in two case reports where a new lung cancer developed during treatment for metastatic kidney cancer. We sought to examine the true incidence of lung cancer in our patients.
To answer this question, we retrospectively reviewed metastatic kidney cancer patients treated at the Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center. We identified 151 patients treated between 2006 and 2013. All patients received systemic targeted therapy, which included VEGF-TKIs, mammalian target of rapamycin complex 1 (mTORC1) inhibitors, anti-programmed death-1 (PD-1) immune checkpoint inhibitors, and/or investigational drugs. Eighty-five patients (56.3%) were diagnosed with pulmonary metastasis at the time of presentation with metastases. Among these patients, three were diagnosed with a new primary lung cancer that developed while receiving treatment for metastatic kidney cancer. This represents 2 percent (95% CI, 0.68%-5.68%) of all metastatic RCC patients, and 3.5 percent (95% CI, 1.21%-9.87%) of the 85 patients with known pulmonary metastasis.
Two of the three patients who developed lung cancer were smokers; however, the smoking status was not known for the cohort as a whole. It is reasonable to surmise this incidence of lung cancer would be higher still for patients with a significant smoking history. The median follow-up for patients in our cohort was 21.5 months. The incidence rate of lung cancer in our cohort was 0.87 per 100 person-years.
One patient was treated with curative-intent radiotherapy (stereotactic body radiation therapy [SBRT]) and another with surgical resection consisting of a lobectomy and mediastinal lymph node dissection. The patient who received SBRT was without evidence of lung cancer recurrence for 9 months. The patient treated surgically remains lung cancer free over 2 years later. A third patient had metastatic disease by the time of his lung cancer diagnosis and passed away several months later, having progressed after two cycles of a platinum doublet and the PD-1 inhibitor nivolumab. Detailed descriptions of the three patient cases were published in Clinical Genitourinary Cancer in February 2017 (doi:http://dx.doi.org/10.1016/j.clgc.2017.01.026).
The study was supported in part by the UT Southwestern Cancer Center SPORE (Specialized Program of Research Excellence) award from the NCI, one of two in the country.
While radiographic findings cannot confidently predict whether a nodule is malignant, or if that malignancy is a primary lung neoplasm, they can offer clues. Pulmonary metastases from kidney cancer are typically small (often less than 2 cm), round, and well-circumscribed. These are the so-called “cannonball metastases.” Mediastinal lymph node involvement is also common.
On the other hand, primary lung neoplasms often have a spiculated appearance with poorly-defined margins, resulting from fibrosis, an infiltrative growth pattern, and lymphangitic spread into the surrounding lung parenchyma. Pleural tags caused by bands of fibrosis extending from the tumor to the adjacent pleura may also cause pleural retraction resulting in a tent-like appearance. Patent bronchi within the tumor (air bronchograms) are also frequently associated with lung malignancy. These differences are illustrated in the figure.
Vigilance Is Needed
Our intent in presenting these data are twofold. The first is to raise awareness of the risk of lung cancer in metastatic kidney cancer patients. The lack of reported cases in the literature is surprising given the documented increased incidence of lung cancer with other smoking-related malignancies, such as bladder cancer. It is likely that lung cancer is significantly underdiagnosed in patients with metastatic kidney cancer. Historically, this may have been due to a relatively short survival in metastatic patients. The high frequency of pulmonary metastasis from kidney cancer could also obscure the diagnosis.
However, as metastatic patients are living longer they now have time to develop new cancers. Based on our data, as many as 6 percent of metastatic kidney cancer patients may have lung cancer. A higher suspicion for lung cancer is warranted, particularly in patients with known pulmonary metastasis who may be less likely recommended for another biopsy of a progressing pulmonary nodule. The most common site of kidney cancer metastasis is the lung, making the detection of a primary lung cancer difficult. Because lung cancer is typically more aggressive than kidney cancer, if undetected, it may spread and eventually kill the patient, as it is believed to be the case for one of our patients.
Second, it is critical to stay vigilant for new primary neoplasms in all metastatic cancer patients with an intermediate to good prognosis. In all three cases at our institution, the primary oncologist, rather than the radiologist, raised suspicion of a second cancer based on the atypical behavior of a single nodule. Diagnosis of a second cancer at an early stage allowed two patients to have their lung cancers treated with curative intent. One patient remains without evidence of recurrence over 2 years later. Without a high index of suspicion, it is likely that progressing lung nodules could be attributed to metastatic disease, and new cancers would have gone undiagnosed.
I. ALEX BOWMAN, MD, is a Fellow in Hematology and Oncology at the University of Texas Southwestern Medical Center, Dallas.