Jeopardy! fans were shocked last week when Alex Trebek, who has hosted the show since 1984, posted a YouTube video revealing his recent health scare:
“Now, just like 50,000 other people in the United States each year, this week I was diagnosed with stage 4 pancreatic cancer. Now normally, the prognosis for this is not very encouraging, but I’m going to fight this, and I’m going to keep working. And with the love and support of my family and friends and with the help of your prayers also, I plan to beat the low survival rate statistics for this disease. Truth told I have to! Because under the terms of my contract, I have to host Jeopardy! for three more years! So help me. Keep the faith, and we’ll win. We’ll get it done. Thank you.”
Two days later, a tweet from Jeopardy! thanked fans for their support:
“The outpouring of good wishes and support in response to Alex’s recent health news has been humbling and overwhelming. Please know that your messages are being conveyed to him and are deeply appreciated. From everyone at Jeopardy! – thank you.”
It has not been revealed what specific treatments Mr. Trebek will receive but stage 4 means that the tumor has spread beyond the pancreas and therefore surgery could not result in a cure. Undoubtedly, Mr. Trebek will receive chemotherapy using drugs such as gemcitabine or a combination of four drugs known as FOLFIRINOX.
Based on our modern understanding of the molecular causes of PDAC, there could be individualized therapies based on a tumor’s genetic makeup (see below).
What is pancreatic cancer and what causes it?
First of all, there is more than one type of “pancreatic cancer” and there is a big difference between the two main types. Mr. Trebek has exocrine pancreatic cancer which is also called pancreatic ductal adenocarcinoma or PDAC. In contrast, Apple founder Steve Jobs had a pancreatic neuroendocrine tumor or PNET which carries a more favorable prognosis and longer survival time.
Multiple combinations of gene mutations are commonly found in PDACs. These include:
- Activating mutations in cancer-causing genes (oncogenes) such as KRAS
- Inactivating mutations in genes that suppress tumors such as TP53, CDKN2A, and SMAD4
- Inactivating mutation in genes that repair damage to DNA, such as MLH1 and MLH2
In addition, some pancreatic cancers run in families and involve genes such as BRCA1, BRCA2, and PALB2.
There is hope that tumors harboring these mutations can be treated with drugs that target specific genetic defects or immunotherapies that help the body’s own immune system to fight the cancer.
First-Line Chemotherapy for Stage IV Pancreatic Cancer
In general, multiagent regimens have a higher response rate than single agent regimens, although they may be associated with more adverse effects that can impact quality of life.
Gemcitabine is the hydrochloride salt of an analogue of the antimetabolite nucleoside deoxycytidine. Gemcitabine is converted intracellularly to the active metabolites difluorodeoxycytidine di- and triphosphate (dFdCDP, dFdCTP). dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis; dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis. It can be used as a single-agent therapy or with nanoparticle albumin-bound paclitaxel.
FOLFIRINOX includes the drugs fluorouracil (also known as 5-FU), leucovorin, irinotecan, and oxaliplatin. Because of serious side effects, the treatment is not suitable for all patients with metastatic disease, several pancreatic cancer researchers cautioned. But for patients who are candidates, based on having what is called a good performance status (a measure of how well a patient is able to perform ordinary tasks and carry out daily activities), the regimen will likely become the standard of care, researchers of a 2011 clinical trial noted. In the study, the objective response rate was significantly higher with FOLFIRINOX compared to gemcitabine alone (32 vs 9%), as was median progression-free survival (6.4 vs 3.3 months) and overall survival (11.1 vs 6.8 months).
Treatment toxicity was higher with FOLFIRINOX with neutropenia, febrile neutropenia, thrombocytopenia, sensory neuropathy, vomiting, fatigue, and diarrhea being the most significant side effects. Despite this, patients in the FOLFIRINOX group has a significantly improved global health score compared to those on gemcitabine only.
A number of clinical trials are underway and can be found at clinicaltrials.gov.
Michele R. Berman, MD, and Mark S. Boguski, MD, PhD, are a wife and husband team of physicians who have trained and taught at some of the top medical schools in the country including Harvard, Johns Hopkins, and Washington University in St. Louis. Their mission is both a journalistic and educational one: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.