Case study 95.1

A 53-year-old man with metastatic clear cell renal cell carcinoma presents for a second opinion. He is asymptomatic and has an excellent performance status. On imaging, a large, right renal mass and pulmonary nodules are identified. His bloodwork is only notable for hemoglobin of 11 mg/dl. He asks whether or not there is a role for nephrectomy in his treatment plan.

1. How do you respond?

No data support the role of nephrectomy
Nephrectomy should be considered only for patients with symptoms
He should be referred to a urologic oncologist for consideration of nephrectomy
Surgery should only be considered if he responds to systemic therapy first

Resection of a primary renal lesion in the setting of metastatic disease is referred to as a cytoreductive or debulking nephrectomy, and its practice is initiated in conjunction with immunotherapy.

Whether or not a benefit of cytoreductive nephrectomy exists with the advent of targeted therapies for renal cell carcinoma remains in question. However, in the initial trials of many of the targeted agents, the majority of patients had undergone nephrectomy prior to enrollment. In a retrospective analysis of patients who received vascular endothelial growth factor (VEGF)-targeted therapies, those who underwent cytoreductive nephrectomy appeared to experience an improvement in overall survival. On univariate analysis, the overall survival of the surgery arm was 19.8 months versus 9.4 months for those treated with systemic therapy alone (hazard ratio (HR): 0.44; 95% confidence interval (CI): 0.32–0.59; P < 0.01). An improvement in survival persisted on multivariate analysis. In subgroup analyses, those patients with poor-risk disease or a Karnofsky performance status of <80% did not appear to benefit. Thus, we consider cytoreductive nephrectomy for patients with good- or intermediate-risk disease with an adequate performance status who we plan to treat with targeted therapy. An industry-sponsored phase III trial is ongoing, randomizing patients with metastatic renal cell carcinoma to nephrectomy followed by sunitinib or to sunitinib alone (NCT00930033). Another phase III trial sponsored by the EORTC is also ongoing and is randomizing patients to immediate or delayed nephrectomy, both in combination with sunitinib (NCT01099423).

Patient selection for cytoreductive nephrectomy is critical. Proposed selection criteria have included greater than 75% debulking of tumor burden possible; no central nervous system, bone, or liver metastases; adequate pulmonary and cardiac function; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and predominantly clear cell histology. A retrospective analysis identified the following characteristics to be predictors of an inferior overall survival with nephrectomy prior to systemic therapy: elevated lactate dehydrogenase (LDH), hypoalbuminemia, symptoms at presentation due to a metastatic site, liver metastases, retroperitoneal lymphadenopathy, supradiaphragmatic adenopathy, and clinical tumor classification as T3 or greater. Inferior overall survival and increased risk of death correlated with the number of risk factors, and patients with four or more risk factors did not appear to benefit from cytoreductive nephrectomy.

Case study 95.2

A 45-year-old woman with a recent diagnosis of a renal mass that is concerning for renal cell carcinoma presents to your office, stating that she has been experiencing double vision as well as right shoulder pain. On laboratory testing, her calcium is normal, but her alkaline phosphatase is elevated.

1. Routine staging evaluation should include all of the following EXCEPT which?

Chest, abdomen, and pelvis computed tomography (CT)
Bone scan
Brain magnetic resonance imaging (MRI)
Positron emission tomography (PET) scan

Current National Comprehensive Cancer Network (NCCN) guidelines recommend a staging evaluation of patients with a renal mass to include complete blood count (CBC), comprehensive metabolic profile, CT or MRI of the abdomen and pelvis with contrast, and chest imaging. A bone scan and MRI brain are recommended if clinically indicated based on symptoms, hypercalcemia, or elevated alkaline phosphatase. CT imaging is most typically utilized for staging with a sensitivity of up to 100% and specificity of over 90% for retroperitoneal disease, venous tumor thrombus, and metastases. Although data exist to suggest MRI is superior to CT in determining the extent of vascular invasion, the presence of which impacts prognosis and surgical approach, recent reports demonstrate CT and MRI to be similar in terms of their ability to detect vascular invasion. However, the combination of the two increases the ability to identify the extent of tumor thrombus to 95%.

When detecting specific sites of metastatic disease, particular imaging modalities may have advantages. While commonly used to detect bone metastases, bone scans have been reported to have a sensitivity of 10–60% and to underestimate the extent of metastases with a false-negative rate of 30%. MRI may be more sensitive and specific for bone metastases. The sensitivity of PET scans to detect metastases has been reported to range from 63% to 100%, and they are thought to be less sensitive for the detection of retroperitoneal lymphadenopathy, lung metastases, and bone metastases. However, at least one report suggests that fluoro-deoxyglucose PET (FDG-PET) may be superior to bone scans, in terms of both sensitivity and accuracy, in the ability to detect bone metastases. Nonetheless, while positive studies are suspicious for disease, negative studies cannot reliably exclude the spread of disease. Thus, we do not routinely include PET scans in a staging evaluation of our renal cell carcinoma patients. Brain metastases may be detected by both CT and MRI with contrast, but MRI is more sensitive than CT for the detection of small brain metastases.

Case study 95.3

A 62-year-old man with a history of a T2, grade 3 clear cell renal cell carcinoma underwent a left nephrectomy 5 years ago. Last week, he presented to his PCP with a cough and right-sided chest pain, and on a chest X-ray, he was noted to have a 2 cm pulmonary nodule. You ask him to undergo a CT scan of his chest, abdomen, and pelvis, and only a 2 cm right upper lobe nodule is noted. An interventional radiology (IR) guided biopsy of the lesion confirms recurrent, clear cell renal cell carcinoma.

1. What is the most appropriate treatment option at this time?

Observation
Sunitinib
High-dose interleukin-2 (IL2)
Refer to surgical oncology for resection

At least a portion of patients with recurrent disease may benefit from metastectomy, defined as the surgical resection of metastases. While no randomized data exist, retrospective analyses have reported that metastectomy yields 5-year survival rates on the order of 35% to 60% for patients with solitary metastases. Further, patients with multiple sites of involvement may also experience prolonged survival following metastectomy provided the disease is completely resected. Patients with recurrences to the liver, lung, brain, and bone have benefited from surgical resection. Patient selection is of paramount importance, and predictors of long-term survival after surgical metastectomy include having a solitary metastasis as opposed to multiple lesions and a disease-free interval from treatment of the primary tumor to the time of developing recurrent disease of at least 12 months. Site of involvement may also be predictive. Patients with metastases to glandular sites (thyroid, salivary gland, pancreas, adrenal, and ovary) may have a more favorable prognosis, while a metastasis to the brain is likely associated with a poorer outcome. Finally, the risk category (per Memorial Sloan Kettering criteria) may also be predictive of outcome, with favorable-risk patients potentially experiencing a survival benefit with metastectomy.

We typically consider surgical resection of metastatic disease on an individual basis, weighing factors such as time to recurrence, number and location of metastases, feasibility, Memorial Sloan Kettering risk category, performance status, and comorbidities. Such an approach potentially affords patients a prolonged disease-free status, potentially sparing or delaying exposure to and toxicity from systemic therapies until a time at which they are clearly necessary.

Case study 95.4

A 55-year-old man undergoes a right nephrectomy for a 10cm renal mass. Pathology is consistent with a T3b, grade 3 clear cell renal cell carcinoma. He presents for follow-up post-nephrectomy, and he is feeling well other than slight fatigue and incisional pain, consistent with postoperative recovery. Based on examination, laboratory studies, and postoperative imaging, he is without evidence of recurrent disease.

1. What would appropriate therapy include?

Adjuvant sunitinib
Adjuvant radiation
Adjuvant high-dose IL2
Observation

While nephrectomy is curative for a number of patients with clinically localized renal cell carcinoma, on the order of 20% to 40% of patients will subsequently develop metastatic disease. The risk of recurrence appears to increase with advancing stage and increasing grade, and other factors potentially associated with risk of recurrence include histologic subtype, presence of sarcomatoid features, collecting system invasion, and performance status. A number of studies have evaluated the utility of adjuvant therapy to reduce the risk of recurrence following nephrectomy, and these have included chemotherapy, vaccines, immunotherapy, and biochemotherapy. A meta-analysis of 10 such studies, including over 2500 patients, concluded that adjuvant therapy provided no benefit in terms of overall survival or disease-free survival when compared to no treatment. Rather, adjuvant therapy was associated with an increased frequency of serious adverse events. Similarly, a meta-analysis of seven trials assessing postnephrectomy radiation concluded that while adjuvant therapy may decrease rates of locoregional failure, postnephrectomy radiation does not improve survival outcomes.

Based on favorable outcomes with targeted agents in metastatic populations, studies are underway to evaluate their utility in the adjuvant setting. The ASSURE trial (NCT00326898), sponsored by ECOG, randomized patients post-nephrectomy to single-agent sorafenib, sunitinib, or placebo. While the trial has completed accrual, results are pending. Other large adjuvant trials are ongoing and are comparing sunitinib (NCT00375674), sorafenib (NCT00492258), or pazopanib (NCT01235962) to placebo. The primary endpoint of these trials is disease-free survival.

With no adjuvant therapy proven effective to date, our preference is to consider a clinical trial for our postnephrectomy patients, particularly those patients at high risk for recurrence. If a trial is not available, or if patients are ineligible or decline participation, then we recommend observation only.

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