Cytoreductive surgery, systemic treatment, genetic evaluation, and patient perspective in a young adult with metastatic renal cell carcinoma

Abstract

A man aged 41 years who had a past medical history significant for bilateral lower extremity varicosities and a prior 20-pack-year smoking history reported several days of fatigue to his primary care physician. His family history was notable for metastatic kidney cancer in his father. On laboratory testing, he was anemic (hemoglobin, 11.2 g/dL), with iron studies suggestive of iron-deficiency anemia. He denied any melena, hematochezia, or hematuria and underwent a full workup, including colonoscopy and capsule endoscopy, which were negative for sources of occult bleeding. The patient eventually underwent computed tomography (CT) scans of the chest, abdomen, and pelvis, which demonstrated a large, heterogeneously enhancing right renal mass measuring 9.5 × 8.2 × 6.8 cm with tumor thrombus invasion of the right renal collecting system, right renal vein, and inferior vena cava (IVC) above the hepatic veins. In addition, there was a pulmonary nodule in the left lower lobe measuring 0.8 cm, which was believed to be concerning for metastatic disease and subcentimeter retroperitoneal lymph nodes. One month later, he proceeded with a CT-guided biopsy of the pulmonary nodule at an outside hospital, with pathology revealing metastatic renal cell carcinoma (RCC). The tumor cells were positive for PAX8 and CAIX and negative for TTF1, which were suggestive of clear cell RCC (ccRCC) histology. He proceeded with a fluorodeoxyglucose F18 positron emission tomography (PET) scan for further evaluation, which demonstrated abnormal uptake in the right renal mass, a soft tissue mass in the IVC, and several small pulmonary nodules in bilateral lower lobes. His Eastern Cooperative Oncology Group (ECOG) performance status was 0. The patient was started on nivolumab plus ipilimumab (3 mg/kg and 1 mg/kg every 3 weeks, respectively), both of which are immune checkpoint inhibitors (ICIs), for intermediate-risk, metastatic RCC (according to the International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk model) by an outside medical oncology team before presentation at Emory University Hospital.

After completing four cycles of combination immunotherapy, the patient was re-evaluated for potential cytoreductive surgery. He underwent magnetic resonance imaging (MRI) of the abdomen and pelvis for presurgical planning, most importantly as it related to the extent of the caval thrombus. The right renal mass was unchanged in size (8.8 × 6.3 × 8.7 cm); however, there was progression of the IVC tumor thrombus up to the right atrium, along with multiple (>10) new arterially enhancing lesions in the liver measuring up to 1.4 cm, compatible with metastasis (Figure 1). Transesophageal echocardiogram showed a large mass in the right atrium originating from the IVC; however, right ventricular size and function were normal, and the left ventricular ejection fraction was 60%.

In April 2023, after a multidisciplinary genitourinary tumor board, the consensus was to proceed with the surgery because >90% of the patient's disease resided within the kidney and thrombus. [Correction added on 11 June 2024, after first online publication: In the preceding sentence “2022” has been corrected to read “2023.”] A cytoreductive right radical nephrectomy and IVC tumor thrombectomy with concurrent right adrenalectomy were performed by a multidisciplinary team of urology, surgical oncology, and cardiothoracic surgery.

The kidney measuring >10 cm was excised, and the right renal vein was longitudinally divided, leaving the tumor thrombus transfixed within the renal vein stump and the IVC. Median sternotomy with cardiopulmonary bypass was not performed because the cardiothoracic surgeon determined that it was possible to obtain proximal control of the IVC through an abdominal transdiaphragmatic intrapericardial window. Once the porta hepatis, contralateral renal vein, and proximal and distal IVC were controlled and clamped, the vena cava was opened, and all tumor thrombus was excised and cleared with no evidence of retained thrombus at the end of the case. He was discharged home on postoperative day 14.

Final pathology demonstrated ccRCC, nuclear grade 3, measuring 7.6 cm in greatest dimension. The tumor invaded the renal vein and sinus fat with no evidence of tumor necrosis, direct adrenal invasion, sarcomatoid, or rhabdoid features. The thrombus was positive for carcinoma, and the final IVC margin was negative. Pathologic stage classification (the American Joint Committee on Cancer's AJCC Cancer Staging Manual, eighth edition) was pT3cN0 given supradiaphragmatic extension of the IVC tumor thrombus with no metastatic lymph nodes (n = 0 of 8 interaortocaval nodes). His status remained clinical M1 given the known pulmonary metastasis at diagnosis and the evolution of liver metastases.

Kidney cancer is the seventh most common malignancy in the United States, with an estimated 81,800 new cases to be diagnosed in 2023, of which 16% and 15% will present with regional lymph node spread or distant metastatic disease, respectively.¹ Our patient at the time of surgery demonstrated two unique sites of metastatic disease along with a stable supradiaphragmatic tumor thrombus, in which we decided to proceed with cytoreductive nephrectomy (CN). The role of debulking or CN in patients with metastatic RCC (mRCC) has been widely debated but was initially supported according to four primary observations: (1) the rare, but reported, spontaneous regression of metastatic lesions after nephrectomy^{2, 3}; (2) ex vivo evidence of the primary tumor inducing immune system dysregulation and suppression^4-6; (3) poor primary tumor response to historical cytokine therapy (i.e., interferon-α2b [IFN-α2b], interleukin-2)^7-9; and (4) two early randomized trials, as discussed below.

In August 2023, after 4 months of lenvatinib plus everolimus therapy, imaging demonstrated disease progression, with new contralateral renal metastases and stable liver lesions. At this time, everolimus had been held secondary to fatigue, worsening cough, and dyspnea, which further prompted the treatment team to suggest a phase 2 HIF-2α inhibitor trial. Although the efficacy of belzutifan has not been examined in individuals who have a somatic VHL mutation, the theoretical benefit and promising results from other clinical trials encouraged our patient's participation. After the team concluded he was a candidate for the trial, he was consented to the study. The oral HIF-2α inhibitor was started on a daily regimen in September 2023, which he has tolerated with no AEs reported. The patient is currently on protocol as of January 2024, greater than 27 months since his initial diagnosis and 22 months since the date of his surgery.

The journey began somewhere in March 2021, when I was diagnosed with low hemoglobin levels. The primary care physician tried to resolve it by giving iron supplements, but still the hemoglobin levels kept falling. I was referred to an outside oncologist in September 2021. Multiple advanced-level blood and gastrointestinal tests were done to find the source of blood loss, which all came negative. Eventually, in December 2021, as per protocol, an MRI was done to discover a 10-cm tumor that had filled my right kidney, moving into the IVC and causing thrombus. The oncologist advised getting the kidney removed and treatment to be started immediately, as the cancer had already spread to my lungs as well. The oncologist was not very hopeful of survival and gave a timeline of 6 months to 3 years, depending on how well I respond to treatment. Surprisingly, except for low hemoglobin, there were no other symptoms. A lot of precious time was wasted on waiting and making appointments in the process. I believe the oncologist should have taken a decision on getting scans done immediately based on their experience, which could have avoided the issue of kidney cancer to reach an advanced stage. This is my perception.

CT, PET scans, and lung biopsy were done in January 2022 following the diagnosis to confirm the cancer type and stage. The hemoglobin levels kept dropping to 7, and two bags of blood were given on February 1, 2022, to help recover some of the falling hemoglobin levels (9 after receiving blood). My condition started to deteriorate, with dropping hemoglobin and increasing tumor size in January 2022. Symptoms were excessive fatigue, loss of memory, shortness of breath, inability to walk without assistance, loss of appetite, and severely weakened immune system.

My treatment started on February 7, 2022, with ipilimumab plus bivolumab (four treatments over 2 months, every 3 weeks), with the goal to shrink the tumor before surgery can be performed. Meantime, we decided to meet the outside urologist as well as at Emory for the surgical procedure. Dr Master at Emory gave us so much more confidence about his expertise in surgically operating on the kidney with a complex cancer issue (IVC thrombus). It was a no brainer for us to sign up with Emory after that. With ipilimumab-nivolumab treatment, I got severe allergic reactions, like shortness of breath and intolerable back ache. I had to be premedicated with steroids, Benadryl, and Tylenol before every treatment. Also, the delivery time was changed from standard 30 minutes to 1 hour for my body to accept the intake. After each treatment, I would have up to 1 week of excessive fatigue and loss of appetite as a side effect. MRI and CT after four treatments showed no positive results.

Surgery was scheduled for April 15, 2023, at Emory University Hospital. Before surgery and based on different imaging, I was informed that the surgery can last up to 8–10 hours, involving removing the right kidney, operating on the IVC for thrombus removal, and doing an open heart. Presurgery MRI revealed that there was an increase in cancer growth in the chest and new spread in the liver. I wasn't scared or concerned because I knew I was in the right hands with Dr Master and team. I was in the hospital for 2 weeks due to the time it took to recover from chest cavity fluid and gastrointestinal issues. Everyone in the hospital was very supportive. I was introduced to Dr Bilen before surgery as a part of the Emory Oncology team by Dr Master. A plan was designed to start a new line of treatment 1 month postsurgery. [Caregiver] It was very critical that our Oncologist at Emory was able to help me understand the meaning of stage IV prognosis. Each patient is different, and each case is different. It is important to understand that the 5-year timelines do not consider the latest medical advancements. Dr Master and Dr Bilen ensured all the questions and concerns were understood and addressed them.

The surgical wounds took up to 1 month to heal, after which I started my treatment of lenvatinib and pembrolizumab on June 24, 2022. The reason was that lenvatinib decreases the healing process, and I was advised to wait until outside surgical wounds completely closed in a month. The actual recovery from surgery took up to 4 months after, and there was additional fatigue associated with surgery and treatment. There was some noticeable reduction in the spread in the first two MRI/CT scans. In March 2023, the treatment became ineffective. During treatment, I had to go through excessive fatigue, loss of appetite, foggy brain, irritability, hand–foot syndrome, mouth rashes, etc., as side effects of the combination.

The combination was changed to lenvatinib and everolimus in March 2023. Very similar side effects were noted as with the previous treatment. Additionally, a small spread in pelvic bone metastasis was also discovered for which radiation therapy was suggested by Dr Bilen. I was given three high-dose radiation therapy treatments over the course of 1 week. The cancer cells in the area of radiation were treated. I started on denosumab injections (once a month) after that to increase bone density. The fatigue levels were three times more excessive than the previous treatment.

In January 2023, I also had the onset of hypothyroidism. The treatment started with levothyroxine 50 mcg and is now up to 75 mcg and ongoing. The combo of lenvatinib and everolimus became ineffective by July 2023. I also had gotten a hereditary study done in 2023 just to be sure that my siblings can benefit by knowing the reasons for the advance renal cell cancer that impacted me and my father, who passed away due to the same disease in September 2021. Hopefully, my sibling can start their diagnosis journey a bit sooner.

As of August 2023, I was presented with two treatment options by Dr Bilen. Either take the next line of approved drugs like cabozantinib or enroll on a phase 2 clinical trial. We chose the clinical trial based on two reasons: (1) it aligns more with my specific gene sequence called VHL, and (2) it will help other patients with a similar diagnosis. The clinical trial is nonbinding, and I could choose to terminate the treatment option at any time during the period of 12 months since it started. In addition, Dr Bilen and the team were kind and patient to educate us. It took us the same day to decide to move forward. The first 2 weeks were a nightmare due to the dosage strength, and there were extreme levels of fatigue and loss of appetite. Once on maintenance, I have noticed no side effects (except some fatigue here and there). My quality of life has substantially improved after a few weeks into the clinical trial. As per the last MRI reports in January 2024, I'm happy to share that the results have been positive. Cancer cells have stopped spreading and have been shown to start the reduction process by 10% since the last MRI in November 2023.

As a patient still undergoing the disease and treatment, I believe that there is much that goes into handling and getting better with treatment. I attribute my current great health to my spouse; my team of doctors, nurses, parents, friends; and, to the greatest extent, a positive healing mindset that works along with the nurturing environment and treatment plan. A mind and body healing are an absolute must for patients to practice with such debilitating diseases.

Patients with RCC carcinoma present with metastatic disease in 15% of cases, often requiring multidisciplinary management from urologic oncology, medical oncology, radiation oncology, and palliative care. Despite improvements in cancer-specific survival and OS, mRCC has a notoriously poor prognosis, with questions regarding cytoreductive surgical management, frontline therapies, and subsequent systemic therapies. Here, we described the current paradigm in treating a young adult who had mRCC, from induction immunotherapy, to CN and tumor thrombectomy, and, ultimately, to genetic testing for clinical trial enrollment.

Mani A. Daneshmand reports personal/consulting fees from Abbot Laboratories outside the submitted work and is a fiduciary officer of Procure on Demand. Mehmet A. Bilen reports personal/consulting and/or advisory board fees from Exelixis, Bayer, Bristol Myers Squibb, Eisai Inc., Pfizer, AstraZeneca, Janssen Biotech, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi; and grants to his institution from Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome and Company, AAA, Peloton Therapeutics, and Pfizer outside the submitted work. Viraj A. Master reports support from Pfizer, Merck, Exelexis, Ethicon; and support for additional professional activities from Ethicon, Exelixis, and Telix outside the submitted work. The remaining authors disclosed no conflicts of interest.