Neuroendocrine Carcinomas of the Genitourinary Tract – Treatment Options Are Desperately Needed… Even During the COVID-19 Pandemic

I’m starting this article out a bit differently than my typical Clinical Trials Portal article. Given the recent events of the world with the COVID-19 pandemic, our lives have all been significantly impacted. This includes daily patient care and clinical research activities, with significant inhibitory effects on our ability to accrue patients and maintain study-related activities for those patients who are already accrued to clinical trials. There are countless considerations for clinical trials at this time, including social distancing, limiting patient/employee touchpoints, scarcity of personal protective equipment, limited hospital bed, and operating room availability, and substantial overall stressors on our health care delivery systems. Many institutions have halted new patient accruals to clinical research trials or devised rational plans that take the above and other important considerations into account. These are critical measures at this juncture, given the potential risk to our society that COVID-19 poses. As a result of this worldwide crisis, I considered forgoing this month’s article.


Yet, you are still reading my commentary. For obvious and full disclosure, I am not an Infectious Disease expert or an epidemiologist, and I will not be commenting on exactly what we should or shouldn’t be doing as a nation or as a worldwide community to combat the COVID-19 pandemic. I will, however, provide thoughts on our response from the oncologic research community and important considerations for clinical research. The most definitive message would be to completely suspend all new patient accruals to clinical trials temporarily during this pandemic. We are, undoubtedly, in a situation where we have to limit accruals to trials when there is limited to no early efficacy data for the therapeutic agent. This could include dose-finding Phase I clinical trials and trials where there is no clinical experience in a disease. Additionally, for the time being, when there is an effective standard of care treatment option, we should emphasize a therapeutic pathway over clinical trials. This leaves us to seriously ruminate over unmet need situations where our patients may not have a decent treatment option. There may be agents that have extremely exciting early signs of efficacy and the standard of care option might be of greater potential toxicity. For instance, the standard of care may be cytotoxic chemotherapy or another agent that could lead to profound patient immunocompromise, increasing the risk of infection, including surging risk from COVID-19. Additionally, there may be trials that allow delay in surgery or procedure that would consume personal protective equipment, recognized as paramount for health care providers during this crisis.

With no definitive clarity on how to manage this situation, I will focus this month’s article on a clear unmet need, where our patients have no other reasonable treatment option outside of a clinical trial. This includes neuroendocrine cancers of the genitourinary tract. Although these can rarely ever develop de novo, a more common pathway is through lineage plasticity, usually as an adaptive mechanism to avoid treatment stress.1 An example of this treatment-induced adaptive mechanism of a tumor is prostate cancer which is typically driven by androgen receptor (AR) signaling. With improved AR-targeted therapies, loss of AR expression and downstream signaling is occurring in approximately 15-20% of castration-resistant prostate cancers.2 As a likely result, we are seeing tumors reprogram towards an alternative pathway, resulting in more treatment-emergent neuroendocrine tumors.3 Some of these tumors may exhibit small cell morphology, although that is not a uniform characteristic. Histopathologically, it is typical to see low AR expression and positive chromogranin and synaptophysin immunostains. Greater biologic understanding of the molecular drivers of this process is necessary, and there are some hints that Rb loss has an important role in facilitating neuroendocrine differentiation.4,5

Given that there is limited understanding of the molecular drivers and limited treatment options for neuroendocrine tumors of the genitourinary tract, our field is still limited to platinum combination chemotherapy as initial therapy. Beyond that, there are no decent treatment options and limited clinical trial investigation. Interestingly, neuroendocrine small cell lung cancer recently had a breakthrough with the United States Food and Drug Administration's approval for pembrolizumab, based on response rates.6,7 Hence, many of the trials for neuroendocrine cancers of the genitourinary tract are evaluating immune-oncology approaches.

Below, I list some active trials for patients with neuroendocrine cancers of the genitourinary tract. Most of the trials below are for patients with previous platinum exposure and refractory disease, although some offer welcome alternatives from cytotoxic chemotherapy. Many of the trials take a treatment-emergent neuroendocrine focus, relevant to prostate cancer, but some also include patients with bladder neuroendocrine cancers, another clearly unmet need. Limiting clinical trial accruals is the correct thing to do at this time, however, we must take a tactful approach, especially for those patient populations with no other legitimate treatment options. This includes patients with neuroendocrine cancers of the genitourinary tract, and I believe this is a situation that warrants trial by trial and even case by case scrutiny of the risk versus benefit ratio.

Ongoing clinical trials including neuroendocrine cancers of the genitourinary tract
Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References: 

  1. Beltran, Himisha, Andrew Hruszkewycz, Howard I. Scher, Jeffrey Hildesheim, Jennifer Isaacs, Y. Yu Evan, Kathleen Kelly et al. "The role of lineage plasticity in prostate cancer therapy resistance." Clinical Cancer Research 25, no. 23 (2019): 6916-6924.
  2. Meacham, Corbin E., and Sean J. Morrison. "Tumour heterogeneity and cancer cell plasticity." Nature 501, no. 7467 (2013): 328-337.
  3. Aggarwal, Rahul, Jiaoti Huang, Joshi J. Alumkal, Li Zhang, Felix Y. Feng, George V. Thomas, Alana S. Weinstein et al. "Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study." Journal of Clinical Oncology 36, no. 24 (2018): 2492.
  4. Labrecque, Mark P., Mandeep K. Takhar, Rebecca Nason, Stephanie Santacruz, Kevin J. Tam, Shabnam Massah, Anne Haegert et al. "The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells." Oncotarget 7, no. 17 (2016): 24284.
  5. Tan, Hsueh-Li, Akshay Sood, Hameed A. Rahimi, Wenle Wang, Nilesh Gupta, Jessica Hicks, Stacy Mosier et al. "Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma." Clinical cancer research 20, no. 4 (2014): 890-903.
  6. Strosberg, Jonathan R., Nobumasa Mizuno, Toshihiko Doi, Enrique Grande, Jean-Pierre Delord, Ronnie Shapira-Frommer, Emily K. Bergsland et al. "Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase 2 KEYNOTE-158 Study." Clinical Cancer Research (2020).
  7. Ott, Patrick A., Elena Elez, Sandrine Hiret, Dong-Wan Kim, Anne Morosky, Sanatan Saraf, Bilal Piperdi, and Janice M. Mehnert. "Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study." J Clin Oncol 35, no. 34 (2017): 3823-3829.