Historical perspective

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

Prior to the prospective randomized trials showing a survival advantage to CN, removal of the primary tumor was performed for three reasons: (1) palliation in patients with significant local symptoms from the primary tumor, (2) to induce spontaneous regression of metastatic sites, and (3) to improve response to endocrine or immune therapy.

Historically, surgical removal of the primary tumor in the setting of metastatic disease was performed for palliation of medically intractable symptoms attributed to the tumor [6, 7]. Refractory symptoms included gross hematuria, flank pain, bowel obstruction, high-output cardiac failure secondary to intratumoral arteriovenous fistulae, clot colic/urinary obstruction, and uncontrollable paraneoplastic syndromes [8]. The indication for a palliative nephrectomy was relatively rare and today is almost nonexistent with current medical, endovascular, and endourologic interventions (i.e., bisphosphonates, angioinfarction, ureteral stenting, etc.) [9–11].

In addition to the early use of CN in the palliative setting, surgical removal of the primary tumor in asymptomatic patients was performed in some centers on the basis of anecdotal reports of spontaneous regression of distant metastases subsequent to CN. Early hypotheses behind the spontaneous regression of mRCC were based on tumor-host interactions of the endocrine and immunologic systems [12, 13]. The incidence of spontaneous tumor regression was very rare (<0.8%) with many of the reported cases occurring in patients that had not received CN [14]. This phenomenon appears to be a reflection of the heterogeneous behavior of mRCC and the potential for misclassification of “metastatic disease” rather than a consequence of surgical intervention. When considering the operative mortality and significant morbidity, performing CN for the sole expectation of inducing spontaneous regression is not justified.

Many of the initial reports of endocrine and immunotherapies for mRCC suggested an improved response in patients after removal of the primary tumor [15–17]. The question of whether these findings were due to biases in patient selection would not be answered until nearly a decade later. The potential benefit of CN had to be balanced with the risk of early progression or morbidity from surgery, which would have precluded subsequent systemic therapy. In one of the early reports on interleukin-2 therapy (HD-IL-2), investigators at the NCI showed that 40% of patients initially deemed eligible for systemic therapy would subsequently fail to receive IL-2 due to a combination of rapid disease progression or complications occurring after CN [16]. Although inherent biases in these reports limited the evaluation of CN on patient outcomes, these series provided a basis for two randomized clinical trials in the 1990s which would change the standard of care in mRCC.

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