History of metastasectomy and evolvement of general prognostic factors

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

Before the advent of effective systemic therapy, patients with untreated metastatic RCC had a median overall survival of 10 months, with a 5-year survival rate of less than 10%. After the introduction of cytokine therapy, overall survival rates were only marginally improved. Surgery was the only chance for cure. Therefore, most of the literature on metastasectomy dates back to the 1960s and 1970s of the last century, when it became evident that patients with a solitary resectable metastasis or multiple metastases restricted to one resectable organ site may have a survival benefit. In 1939 a report was published on a patient who survived 23 years following the resection of pulmonary metastases [11]. One of the first series describing metastasectomy in 41 patients with solitary lesions in the lungs, pleura, central nervous system, and abdomen dates from 1978, an era devoid of effective systemic therapy. In patients in whom complete surgical resection was possible, the median disease-specific survival was 27 months with 59% of the patients alive at 3 years [23]. Several authors reported a 3-year and 5-year survival after resection of a solitary lesion of 45% and 29–34%, respectively [85, 127, 140]. Others observed a significant difference in survival in patients with metachronous and synchronous metastases [97, 110, 141]. In 179 patients the 5-year survival rate after resection of solitary lesions at various sites was 22% for synchronous versus 39% for metachronous metastases [133]. In addition, multiple clinical trials involving cytokine therapy revealed a strong association between clinical outcome and metastatic sites [41, 136]. These findings were supported by a series including 101 patients who underwent resection of a total of 152 metastatic lesions at different organ sites [145]. The median survival was 28 months for the entire series. Survival was improved after resection of lung metastases compared to other tumor locations (p = 0.0006) and for patients that were clinically tumor-free after metastasectomy (p = 0.0230). Additional immunoor radiotherapy did not independently influence survival. Again, time interval between primary tumor resection and metastasectomy correlated positively with survival: a tumor-free interval of more than 2 years between primary tumor and metastasis was accompanied by a longer disease-specific survival after metastasectomy. Patients with bone and liver metastasis had a worse outcome than those with pulmonary lesions [41, 145]. Five-year  survival rates for solitary metastases were 56% for lungs, 28% skin, 20% visceral organ, 18% peripheral bone, 13% brain, and 9% axial bone metastases [133]. In an attempt to define selection criteria for patients with solitary metastases, 278 patients with recurrent RCC were retrospectively analyzed [64]. The 5-year overall survival rate for 141 patients who underwent complete metastasectomy for their first recurrence, 70 patients who underwent incomplete metastasectomy, and 67 patients who were treated nonsurgically was 44%, 14.5%, and 11%, respectively. Five-year overall survival rate was 55% with a disease-free interval greater than 12 months versus 9% with 12 months or less (p < 0.0001), 54% for solitary versus 29% for multiple sites of metastases (p < 0.001), and 49% for age younger than 60 years versus 35% if older (p < 0.05). Among 94 patients with a solitary metastasis, the 5-year overall survival rate was 54% for the lungs. Factors associated with a favorable outcome by multivariate analysis included a solitary site and single metastasis, complete resection of first metastasis, a long disease-free interval, and a metachronous presentation with recurrence. Since then, multiple retrospective series have been published that support these favorable factors [5, 41, 115] (Table 11.1). In particular complete metastasectomy is a cross-cultural favorable prognostic factor. In a series of patients from Japan who had nephrectomy and metastasectomy, survival was approximately twice as long as that of previous studies without metastasectomy [94]. In a recent large multicenter analysis from Japan, incomplete resection, elevated C-reactive protein, brain metastases, and high nuclear grade were confirmed as poor prognostic factors [93]. A caveat of the retrospective series remains the inherent bias of comparing patients with solitary and oligometastatic disease and a prolonged metachronous interval to those who did not undergo resection due to extensive metastatic burden, rapid disease progression, and reduced performance. The most important determinant of outcome may be the biological behavior of the tumor [64]. In one series the only adverse factor for survival was having an aggressive tumor grade [66]. In an attempt to develop a metastasectomy-specific prognostic model, the Leuven-Udine group identified primary tumor T stage =3, primary tumor Fuhrman grade =3, the presence of nonpulmonary metastases, a diseasefree interval =12 months, and multiorgan metastases as independent pretreatment prognostic factors for survival after metastasectomy in a multivariable analysis [142]. In contrast to the general MSKCC and Heng prognostic models, the results have not yet been externally validated. Currently, evidence stems almost exclusively from retrospective studies and no prospective randomized trials on metastasectomy for RCC have been performed to guide decision making. Though the factors related to prognosis seem to be generally applicable to metastasectomy at any site, some sites may demand specific management strategies, especially when a solitary site if disease or oligometastases are present, and will be discussed in detail.

Other focal therapeutic strategies

Historically, surgical resection has been the preferred approach to metastasectomy, but recent data on stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) suggest that this treatment modality is a valid noninvasive alternative [21]. Apparently, the ceramide pathway is activated when high doses of radiotherapy are given per fraction, which lends the stereotactic approach a biological rationale. In addition, an indirect abscopal effect caused by immunological processes induced by a combination of targeted therapy and SBRT is observed. Contrary to surgical metastasectomy, SRS, SBRT, or ablative techniques have been for the most part applied to certain metastatic sites [27]. Although therapy of RCC metastases with SRS is gaining ground and is likely to be expanded to multiple anatomical regions, most of the experience has been gained with treatment of brain and bone metastases and will be discussed under the respective sites. While ablative techniques are minimally invasive, they can still cause bleeding and thermal damage. Cranial and extracranial SRS can induce adverse events such as cough, fatigue, skin rash, and local pain. Side effects are generally frequent, but mild (grades I–II in 96%) [132].


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