Strides Made in Renal Cell Cancer
Metastatic renal cell carcinomas still are the most lethal in the US. In 2015 alone there were 14,080 deaths attributed to it. Removal of the involved kidney continues to be the mainstay treatment for localized disease. Even with all our advancements in treatment, it continues to have a poor prognosis. Chemotherapy is considered a standard therapy for patients with some renal cell variants. The role in treating clear cell renal cell carcinoma is poorly defined. What exactly causes this resistance is currently undefined. Ideally, doctors should be able to characterize tumors according to DNA. In reality, this method has been largely limited by varying gene expression signatures. For years development of treatment has been largely unsuccessful. Better understanding disease biology and treatment resistance patterns have led to emerging therapies with a better understanding in pathogensis and mechanisms of treatment resistance there are hope treatments will continue to expand (Tsao et al, 2017).
Until recently there were a lot of systemic therapies for kidney cancer. The incidence of the disease steadily rose from 1975 to 2008 then seemed to plane off after 2008. As of the date of this journal, it is among the top 10 most frequently diagnosed cancers in men and women. In the US there were more than 62,000 new cases found in 2016. Much like ovarian cancer, the prognosis from this disease has been poor. The current five-year survival rate is 74% overall and decreasing to 53% among patients with stage three of this disease and 8% of those with metastatic disease. Usually, kidney cancer strikes the middle-age and elderly with 91% of patients diagnosed at 45 or older and 48% diagnosed at 65 or older (Choueiri & Motzer, 2017).
However, renal cell carcinomas while rare do occur in young patients. Knowledge of their pathologic spectrum remains limited with no prospective studies performed to date in this population. This study that has been released by the American Cancer Society in their publication Cancer delineates the frequency of distinct renal cell carcinoma subtypes in a large prospective series of young patients. This study contributes knowledge to the diagnosis, clinical and genetic features of MiT-renal cell carcinoma, and the most common subtype among this age group. Finding and identifying rare subtypes expands the spectrum of renal cell carcinoma in young patients, supporting the need for a thorough diagnostic workup. It is hoped these studies will help find therapies for these specific subtypes (Cajaiba et al, 2018).
Renal cell carcinoma is the most common form and strikes twice as many men as it does women. The five-year survival rate has increased from 57% in 1987-1989 to 74% in 2006-2012. Part of this reason is seen as screening methods have been improved and now catch some tumors at an earlier stage. Even so one-third of patients with kidney cancer present with metastases. Distinct metastases are found most often in the lungs, lymph nodes, liver bone, and brain.
Researchers have achieved a better understanding of the most common type of renal cell carcinoma clear-cell variety. This type makes up 70% of all renal cell carcinoma. Hormonal therapy and cytotoxic chemotherapy have little to no activity in metastatic renal cell carcinoma. Interferon alfa was mostly used until 10 years ago but with the increased side effects of both this and interleukin-2, they are now regulated to last line medications.
Now there are treatments that have both better response and longer progression-free survival. Despite the significance of these new treatments, there still continues to have a great effect on activities of daily living and reflect a poor quality of life reported by patients. New drugs and new targets and mechanisms of action relevant to renal cell carcinoma are needed (Choueiri & Motzer, 2017).
Renal cell carcinoma is a growth that has originated in the renal epithelial tissue and is the cause of more than 90% of kidney cancer. This disease has over 10 histological and molecular subtypes with clear cell renal cell carcinoma the most common. This form also accounts for the most cancer-,related deaths.
Localized renal cell carcinoma can be treated with removal of the kidney (nephrectomy) involved. Unfortunately 30% of patients with renal cell carcinoma eventually develop metastases to another part of the body. Renal cell carcinoma incidence increases markedly with age and is higher in men than women. Risk that has been attributed to this disease includes smoking, hypertension, chronic renal disease, and injury to the kidney, environmental exposure to toxins as well as occupational exposures to toxins.
This type of cancer was first described 40 years ago, genetic diversity within tumors are thought to allow tumors to adapt to new pressures and demands. Renal cell carcinoma tumors are very vascular making metastases a real problem especially with later stage growths. Before, patients were found to have renal cell cancer after presenting with flank pain, gross blood in their urine or abdominal mass that could be felt.
Staging for renal cell carcinoma depends on size of the tumor and how much it has left the structure of the kidney. There are modifiable risk factors that are important for patients to be told about. Tobacco use is a risk factor even though the risk is lessened if the patient quits. Obesity is an elevated BMI was associated with renal cell carcinoma especially in the age group 18-35 years. Hypertension was independently shown to increase the long-term risk of renal cell carcinoma in men along with use of aspirin as found in one out of five studies.
Management usually includes surgical removal of kidney and tumor, then active surveillance to watch for recurrence. Quality of life and patient reported outcomes have become an easy way to assess therapeutic strategies. For metastatic renal cell carcinoma quality of life measures become more important as these usually become palliative in nature (Hsieh et al, 2018).
More than 121,000 newly diagnosed patients and 52,000 deaths each year kidney cancer is the seventh most common cancer in Europe. In addition, 90% of these are renal cell cancers. Surgery is effective 70% to 80% of localized disease but continues to be largely dependent on what state it has been found. Fifteen to 20% of patients experience immediate disease progression and nearly all patients become resistant and toxic leading to dose reduction.
This study was done in the hope that finding the biomarkers of the renal cell carcinoma could lead to a more targeted type of treatment. In an effort to promote further research the results of the study were made freely available in March 2018. Eurotarget is a European collaborative project aiming at discovering and validating biomarkers to personalize treatment of patients with metastatic renal cell carcinoma.
Unfortunately the number of patients with metastatic renal cell carcinoma and clinical data is limited. This limits the value of the data from this study for prognostic biomarker studies in metastatic renal cell carcinoma. In fact, up to the date of this article, the biomarker studies in metastatic renal cell carcinoma have been mainly derived from randomized clinical trials. That is why this study is so important. More than 60 centers in five European countries were involved in this study. The importance of replication and validation of the biomarker findings cannot be overstressed. It is hoped that easy access to these results will promote further progress in personalization of treatment in metastatic renal cell carcinoma patients (van der Zander et al, 2017).
The European Association of Urology renal cell carcinoma guidelines panel updated their recommendation on adjuvant therapy due to conflicting results from two available studies. One study showed 62% of patients developed grade three or four toxicity and 34% to 44% withdrew from the trial. And neither trial showed an overall survival rate that was statistically significant. Definition of early metastatic disease is a grey area. Presence of metastasis is determined by cross-sectional imaging that only can identify sizable cancer cells from molecular perspective.
And data available for this study did not show any benefit to VEGF targeted therapy to prevent relapse or extend survival time. It is preferable to look at adjuvant studies together rather than in isolation. Despite imbalances in risk assessment inclusion of non clear cell renal cell carcinoma and starting dosages, the studies have more in common with one another than differences. Reasons for disease free survival are contradictory and the reason is not clear. Without a consistent trend toward a disease free survival signal it is not possible to say with any confidence that there is likely to be a benefit.
Considerations for future testing needs to include outcomes of other trials and long-term overall survival rate. European Association of Urology Renal Cell Cancer Guidelines Panel, made up of both patients and clinicians, considered number of different scenarios to determine what is needed to change practice. Results from the most recent study found only 6% of the panel would consider a change in their standard of care. In addition, when patients were asked if they were willing to take the chemotherapy agent for one year, approximately one third said no when faced with the test results (Bex et al, 2017).
Bex, A. et al. (2017). Updated European association of Urology guidelines regarding adjuvant therapy for renal cell carcinoma. European Association of Urology,71(5).
Cajaiba, M.M. et al. (2018). The classification of pediatric and young adult renal cell carcinomas registered on the children’s oncology group protocol AREN03B2 after focused genetic testing. Cancer, 124(16).
Choueiri, T.K. & Motzer, R.J. (2017). Systemic therapy for metastatic renal cell carcinoma. New England Journal of Medicine,376(4).
Hsieh, J. J. et al. (2018). Renal Cell Carcinoma. Nature Review. Disease Primers,3(17009).
Tsao, C-K. et al. (2017). Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: Latest evidence and therapeutic implications. Therapeutic Advances in Medical Oncology,9(4).
van der Zanden, LFM.et al. (2017). Description of the Eurotarget cohort: A European collaborative project on targeted therapy in renal cell cancer-genetic- and tumor-related biomarkers for response and toxicity. Urologic Oncology: Seminars and Orignial Investigations, 35(8). Elsevier.