Does renal disease increase one’s risk of developing cancer? We know there is a well-studied association between end-stage renal disease and cancer risk, but whether or not less severe forms of kidney disease place patients at an increased risk for various cancers is uncertain. A recent study from Huntsman Cancer Institute (HCI) at the University of Utah, Kaiser Permanente Division of Research, and Memorial Sloan Kettering Cancer Center (MSKCC) has shed some new light on this question. The researchers found that people with reduced renal function or chronic kidney disease were at an increased risk of renal and urothelial cancer but not at higher risk for other specific cancer types.

These findings are interesting, especially if one considers that both chronic kidney disease and cancer are major public health issues in the United States. Over 11% of the US population is estimated to have some level of chronic kidney disease. More than 13 million Americans are thought to have at least stage III chronic kidney disease, defined as an estimated glomerular filtration rate (GFR) of less than 60 ml/ min/1.73m

. Likewise, cancer remains one of the primary causes of morbidity and mortality in the United States, and it is projected there will be over 1.6 million new cancer cases diagnosed and over 585,000 cancer deaths in the United States during 2014.

Investigators from the University of Utah’s HCI, MSKCC, and Kaiser Permanente retrospectively studied nearly 1.2 million adults with known renal function and recently published their results in the Journal of the American Society of Nephrology.

During 6,000,420 person years of follow-up, 76,809 new cancers were diagnosed within the cohort. After adjusting for potential confounders (age, race, sex, income, education, smoking, BMI, comorbidities, medications, health care utilization, hematuria, and imaging utilization) we found that lower estimated GFR was associated with an increased risk of kidney cancer. (HR = 1.39; 95% CI, 1.22-1.58 for estimated GFR = 45-59; HR = 1.81; 95% CI, 1.51-2.17 for estimated GFR = 30-44; HR = 2.28; 95% CI, 1.78-2.92 for estimated GFR <30).

This increased risk of renal cancer was greater for conventional clear cell renal cancer as compared with non-clear cell renal cancers. Additionally, an increased risk of urothelial cancer was found for estimated GFR <30 but no significant associations between lower renal function and prostate, breast, lung, colorectal, or all cancers combined.

The researchers went to great lengths to attempt to control for variables that may confound the relationship of renal function and cancer risk. A broad list of potential confounding variables was incorporated into the extended Cox regression models to better delineate the independent association of renal function and incident cancer risk. Furthermore, any cancer diagnoses during the first two years of follow-up and any estimated GFR measurements performed within three months of the cancer diagnosis were excluded from the final models.

Underlying biologic mechanisms for the association between chronic kidney disease and renal or urothelial cancers are not fully understood, but several possible explanations exist. Chronic kidney disease can result in a state of inflammation, oxidative stress, or even immunodeficiency, thus leading to an inflammatory microenvironment that could impact cancer development.

More research is needed to further delineate the physiologic mechanism underlying the association between renal function and renal or urothelial cancer risk.

Clinically, this research may help to inform the debate about whether or not patients with chronic kidney disease should have some sort of targeted cancer screening. If the results of this research are corroborated, then it may have implications for directing cancer screening efforts in selective populations of patients with chronic kidney disease.

			Lowrance WT, Ordonez J, Udaltsova N, Russo P, Go AS. CKD and the risk of incident cancer [published online May 29, 2014]. 

			Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer 

Articles

Does renal disease increase one's risk of developing cancer? 

Chronic Kidney Disease Associated With Increased Risk of Renal and Urothelial Cancers

		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

The changes seen in multiple myeloma are a perfect illustration of a potentially shifting paradigm in cancer care. For decades, the standard treatment of multiple myeloma was a combination of the chemotherapy agent melphalan and prednisone (MP), reported and established by Dr Alexanian (still practicing at MD Anderson) in JAMA in 1969!

The poor outcome of either primary resistant or relapsed patients led to high-dose therapy and autologous stem cell transplant (ASCT), which became the new standard in younger patients. Before high-dose therapy, patients were given a variety of induction regimens (chemotherapy/cytotoxics and steroids) to debulk the tumor burden, though patients typically had significant residual disease prior to consolidation and ASCT and they frequently relapsed.

Several novel therapies have truly changed the world of multiple myeloma in the last decade, particularly proteasome inhibitors, such as bortezomib and carfilzomib, which disrupt/block the intracellular protein degradation leading to cell death, and IMiDs with thalidomide— specifically, lenalidomide and pomalidomide&mdash;which act through direct cytotoxicity, antiangiogenic effects, and activation of antitumor immunity. Other promising therapies are also being developed.

These new agents have naturally opened the door to combinations of biologics, with very impressive activity leading to high-quality responses, including complete remission in the frontline setting prior to transplantation (something that was previously accomplished in only some patients after high-dose therapy followed by ASCT).

This progress raises the question as to whether autologous transplantation will be rendered obsolete in the era of new therapies. It seems natural to think that could be the case and that patients should only be transplanted at the time of relapse once they fail these nonchemotherapy-based options, which are easily preferred by patients for their safety profile and convenience in the ambulatory care setting.

Not surprisingly, an active debate is currently ongoing in the field. Data recently published will help shed some light on this critical question. In a large trial, more than 500 patients aged ≤65 years with newly diagnosed multiple myeloma received induction therapy with lenalidomide and dexamethasone and then were randomized to either high-dose therapy with ASCT (using two tandem high-dose of melphalan) versus six cycles of standard-dose melphalan/prednisone/lenalidomide (MPR; 6 months total).2 Patients were then randomly assigned to receive no maintenance therapy or lenalidomide maintenance therapy until disease progression.

The study showed that tandem courses of high-dose chemotherapy, as compared with consolidation therapy with MPR, resulted in improved progression-free survival (the primary endpoint) and overall survival (secondary endpoint). As in previous studies, maintenance with lenalidomide was associated with improved progression-free survival after either high-dose or standard-dose consolidation therapy (but no difference in overall survival) and importantly, did not compensate in the nontransplant arm for the superior outcomes associated with high-dose therapy. Though other studies are looking at the same question using bortezomib and lenalidomide in combination, this study suggests that in multiple myeloma patients aged ≤65 years, high-dose chemotherapy with stem cell transplantation remains a standard of care associated with prolongation of progression-free and overall survival.

Induction by combination of biologics provides a high-quality response with less toxicity prior to transplant and as maintenance, might even further reduce the risk of relapse. In patients who are not eligible for high-dose therapy, combinations of biologic agents might provide an alternative to standard chemotherapy because they allow continuous therapy typically including maintenance. Of note, high-risk multiple myeloma patients (defined by poor outcomes with standard regimens) still benefit from these novel therapy combinations as induction, but might also benefit from allogenic transplantation early on, due to the now well-documented graft-versus-myeloma effect, which leads to better outcome as suggested by our group as well as others.

In summary, new therapies bring new opportunities to add to our armamentarium in cancer—as shown here in multiple myeloma&mdash;and do not replace or eliminate all prior approaches. A similar observation could be made for other agents that are radically changing the field, including BCR-targeted agents such as ibrutinib in chronic lymphocytic leukemia and some lymphoma subtypes. The goal is to build the best line of therapy early on for the longest “mileage” for a given patient. This will also involve a better characterization of patients (ie, precision medicine for relevant stratification) and will matter even more in the era of bundled payment and value-based care. The paradigm is shifting for the better…

			Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208(9):1680-1685.

			Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.

			Donato ML, Siegel DS, Vesole DH, et al. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant. 2014;20(8):1211-1216.

			Alsina M, Becker PS, Zhong X, et al. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20(8):1183-1189.

The changes seen in multiple myeloma are a perfect illustration of a potentially shifting paradigm in cancer care.

Shifting the Paradigm?: Where Is Chemotherapy-and Particularly, High-Dose Therapy-Going in the Era of Biologic Agents?

The prostate cancer team at the Comprehensive Cancer Center at Wake Forest Baptist Medical Center has recently focused on two primary areas: minimally invasive care and clinical research.

In Spring 2013, our prostate cancer team launched a program to provide nonsurgical management options for prostate cancer in a common setting that allowed the involvement of physicians from different specialties. This minimally invasive program gave specific attention to four procedures: transperineal prostate biopsy, cryotherapy, low dose rate brachytherapy (commonly referred to as a “seed implant”) and high dose rate brachytherapy. All four of these procedures share a common OR and a common staff dedicated to making the entire process as painless and pleasant for the patient as possible.

In addition to offering low dose rate and high dose rate brachytherapy, which are relatively common components of a minimally invasive program, we also offer cryotherapy. Prostate cryoablation, performed by Daniel B. Rukstalis, MD, professor, Urology, is performed as a percutaneous surgery under intravenous anesthesia with ultrasound guidance. The ability to kill specific regions of the prostate with cold temperatures allows for a very flexible procedure that can be individualized to the specific circumstances of each patient’s cancer.

Similar to low dose rate brachytherapy, cryoablation is performed as an outpatient procedure with only a short recovery period. Importantly, prostate cryoablation has demonstrated a positive effect on the benign enlargement of the prostate that often accompanies prostate cancer, resulting in an improved ability to urinate following the procedure.

In early 2012, our prostate cancer team joined forces with all interested researchers to form a working clinical research team. This team is composed of physicians from the three core treating specialties (urology, radiation oncology, and medical oncology), as well as scientists doing specialized work in the field of prostate cancer management.

In the time this group has been working together, we have increased the number of clinical trial options available for men with prostate cancer at all stages. As a result, we have greatly increased the number of men involved in clinical trials.

We are especially pleased to have recently completed a trial created by members of our own group in the setting of recurrent prostate cancer. The lead investigator on the trial is Gary Schwartz, PhD, MPH, associate professor of Cancer Biology and head of the Prostate Cancer Center of Excellence. The rationale for this trial is based on the findings from three prospective studies indicating that men with serum calcium levels that are high but normal are significantly more likely to die from prostate cancer. This led us to attempt to lower serum calcium (which is a known mitogen for prostate cancer cells) in men with recurrent prostate cancer using a drug proven to lower calcium in the setting of chronic kidney disease. The last participant has completed the trial and the results will be available soon for review by the scientific community.

We are also excited to have recently opened a trial exploring new means to control prostate cancer that recurs following surgery. This trial was co-authored by one of our medical oncology team members, Rhonda Bitting, MD, assistant professor, hematology and oncology, and will be conducted at Wake Forest and two other institutions in the United States. The STREAM study (Salvage Therapeutic Radiation with Enzalutamide and ADT in Men with Recurrent Prostate Cancer; NCT02057939) looks at the value of adding systemic hormonal therapy to standard external beam radiation in hopes of improving the rate of cure in men with rising PSA after surgery.

In addition to salvage radiation therapy to the prostate bed, men will be treated with 6 months of androgen deprivation therapy along with the androgen receptor inhibitor enzalutamide. Enzalutamide is known to slow cancer progression and improve survival in more advanced prostate cancer, and preclinically, androgen receptor inhibitors have been shown to synergize with radiation therapy. Therefore, this combination therapy approach is hypothesized to improve cure rates in men with recurrent prostate cancer. The primary objective for the trial will be to describe the 2-year progression- free survival.

Any man with a nonmetastatic biochemical recurrence of his prostate cancer within 4 years of surgery will be eligible for the STREAM study as long as his PSA is between 0.2 and 4.0. Physicians interested in referring patients for this study should contact Rhonda Bitting, MD, at (336) 716-0327.

Advancing Prostate Cancer Care

A high level of tumor infiltrating lymphocytes (TILs) may be a marker of pathologic complete response (pCR) to neoadjuvant chemotherapy in breast cancer, especially in patients with triple-negative or HER2-positive disease, said Yan Mao, PhD candidate, at the 2014 Breast Cancer Symposium.

She and colleagues at Shanghai Jiatong University in China conducted a systematic review and meta-analysis of 13 studies that included 3555 patients with the goal of examining the relationship between TILs and pCR associated with neoadjuvant chemotherapy for breast cancer. Studies included were those in which the predictive significance of intratumoral and/or stromal TILs and/or CD3+, CD4+, CD8+, and FOXP3+ lymphocytes was determined.

In a pooled analysis, a high number of TILs in the pretreatment biopsy correlated with a higher pCR rate with neoadjuvant chemotherapy, with an overall odds ratio (OR) for pCR of 3.82. The result was consistent across studies, regardless of the tumor site selected. “Whether in the tumor stroma or the center, or combined together, the presence of TILs indicated a good pCR rate,” said Mao. The OR for a pCR with neoadjuvant chemotherapy for intratumoral TILs was 3.32, for TILs in the stroma, 4.15, and for TILs in combined sites, 8.98.

The presence of TILs predicted a higher pCR rate in triple-negative breast cancer (OR = 5.03) and in HER2-positive disease (OR = 5.54), but not in hormone receptor—positive/HER2-negative disease (OR = 2.57; 95% CI, 0.20-33.24).

An analysis of specific subsets of TILs showed that CD8+ T-lymphocytes (OR = 5.07) and FOXP3+ T-lymphocytes (OR = 2.82) predicted pathologic response to neoadjuvant chemotherapy in the pretreatment biopsy but a lower number of CD8+ cells (OR = 2.85) and FOXP3+ cells (OR = 4.27) predicted a response when tested after neoadjuvant chemotherapy. “The reason is unclear; translational or basic research is needed to shed some light on this finding,” Mao said.

The predictive role of CD3+ and CD4+ T-lymphocytes was also examined but results are not conclusive, as each was assessed in only one study.

One limitation to the meta-analysis was that the determination of cutoff points varied between the studies, said Mao. Some studies used 10% TILs as a positive cutoff value, whereas others used absence versus presence of TILs.

“This abstract further supports existing data that high levels of TILs at diagnosis in early triple-negative breast cancer and HER2-positive breast cancer is associated with higher rates of pCR or higher sensitivity to chemotherapy and better outcomes,” said Sherene Loi, MBBS, PhD, who was lead investigator of one of the studies included but was not involved in the meta-analysis.

She added that the potential added prognostic value of various TILs subsets over TILs as a whole is unknown and could be minimal. “The question remains on how we can potentially boost host antitumor immunity in those who don’t have TILs at baseline and if we can optimize the immune response by adding other immunotherapies in addition to chemotherapy to those who do have TILs in their tumor at diagnosis,” said Loi, head of the Translational Breast Cancer Genomics Laboratory at the Peter MacCallum Cancer Centre in East Melbourne, Victoria, Australia.

	Mao Y, Qu Q, Zhang Y, et al. Tumor infiltrating lymphocytes (TIL) to predict response to neoadjuvant chemotherapy in breast cancer: A systemic review and meta-analysis. 

A high level of tumor infiltrating lymphocytes (TILs) may be a marker of pathologic complete response (pCR) to neoadjuvant chemotherapy in breast cancer, especially in patients with triple-negative or HER2-positive disease

October 2014 | Oncology & Biotech News

Chronic Kidney Disease Associated With Increased Risk of Renal and Urothelial Cancers

Shifting the Paradigm?: Where Is Chemotherapy-and Particularly, High-Dose Therapy-Going in the Era of Biologic Agents?

Advancing Prostate Cancer Care

Tumor Infiltrating Lymphocytes Predict Response to Neoadjuvant Chemotherapy in Breast Cancer