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STAGE IV PANCREATIC CANCER: A GOOD OPTION AFTER FOLFIRINOX?

In early April of 2022, I was asked to cross-cover for a colleague. One of his patients was a 40-year-old Hispanic female who had been transferred from UCSD after presenting several weeks earlier with widely metastatic pancreatic cancer and near complete replacement of her liver. She had undergone a very thorough evaluation and with the diagnosis established she began the standard-of-care combination FOLFIRINOX.

The patient was desperately ill, jaundiced, with extremely elevated tumor markers and rapidly re-accumulating ascites fluid. When we met I felt deeply concerned that despite her young age and a cycle of treatment already completed, she would not survive.

I conducted not one, but two, paracenteses removing almost three liters a week apart.

During my brief time covering the patient, I felt she was not responding to FOLFIRINOX but hesitated to change the regimen on someone else’s patient mid-stream as she was just completing her second dose.

For those of you familiar with pancreatic adenocarcinoma there are two principal treatments: FOLFIRINOX and Gemcitabine plus Abraxane. These treatments are mechanistically different as one, FOLFIRINOX relies upon the DNA damage associated with the Oxaliplatin while the other, Gemcitabine plus Abraxane targets cellular mitosis, the process by which cancer cells divide.

Upon my colleague’s return, I recommended that he change her treatment from FOLFIRINOX to a combination that I had originally developed in my laboratory years earlier, the Cisplatin plus Gemcitabine doublet.

This was where the story took an interesting turn.

As the patient had already failed a platinum-based regimen (FOLFIRINOX) virtually all physicians would immediately move to the taxane-based, Abraxane plus Gemcitabine.

This reflects the widely held belief by oncologists that the mechanisms of action (DNA damage vs mitosis inhibition) are different enough to render them “non-cross resistant”. On the other hand, it is widely believed that you “Cannot go back to the well” with a platinum-based treatment as it cannot work in a “platinum-resistant” patient.

But in this patient’s case, I felt confident that Cisplatin plus Gemcitabine would work and she began her first cycle in mid-May. By this time, she was desperately ill with a CA 19-9 tumor marker that had climbed to 21,348 (normal under 35) .

She remained hospitalized for rapidly re-accumulating ascites and required blood transfusions, hydration, and pain control as her husband maintained a vigil at the bedside.

With one dose of my recommended treatment, the May 21st CA 19-9 fell to 16,000 and then on June 17th to 6,500, and by July 29th, 1422, while the CEA fell from 2665 to 7.7.

I was largely unaware of all this until today, when during my clinic, I was introduced to a healthy-appearing young woman, there for routine blood work. This was the very same young woman upon whom I had conducted two urgent paracenteses several months earlier. Instead of requiring hospitalization or transport by her husband, she had driven herself to the clinic looking for all the world, the picture of health.

I marveled at her well-being and asked my nurse if this was indeed the same young woman. Yes, she explained the response had been nothing short of miraculous.

What is striking about this case is that the patient had already received very appropriate care at UCSD. FOLFIRINOX is the most widely used combination in this setting. It is just that in her case FOLFIRINOX was not the right treatment for her.

For the vast majority of cancer specialists, following FOLFIRINOX, a platinum-based regimen there would be almost no expectation that Cisplatin plus Gemcitabine; a different platinum-based regimen would possibly work: None! Except, that in this particular patient’s case it worked extremely well.

Any self-respecting academic would review this case and say “Yes, but wouldn’t the Gemcitabine plus Abraxane have worked as well?” My response to this all-too-common line of reasoning is very simple.

First: Abraxane plus Gemcitabine can be quite toxic, much more so than dose-adjusted Cisplatin plus Gemcitabine. Second: Abraxane based regimens are mechanistically very different and didn’t appear active for this patient consistent with our published analysis showing very low synergy (<20%) for Abraxane plus Gemcitabine (Nagourney, RA in Deoxynucleosides in Analogs in Cancer Therapy). Third: We cannot waste the time of dying patients. Time is not their friend. Finally: “Nothing Succeeds Like Success”.

This 40-year-old woman is alive and well despite almost insurmountable odds a few months earlier. All patients deserve the best possible outcome and our assay-guided individualized therapy offers just that.

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Interstate Oncology: Breast Cancer Patient On the Run

Repost: https://www.nagourneycancerinstitute.com/blog/interstate-oncology-breast-cancer-patient-on-the-run

Of the one million new breast cancer patients diagnosed each year worldwide, approximately 170,000 of these cases are triple negative.

The term applies to patients who do not express the hormone receptors for estrogen or progesterone and are also HER2 negative. About 75% of these patients are of the basal type and the diagnosis is more common in young woman and the black population. Triple negative breast cancer is a distinct subtype of breast cancer and requires its own unique approaches.

Case: Triple Negative Breast Cancer

In August of 2017, I met a delightful 50-year-old British woman who had traveled to California from her home in Saratoga Springs, Utah. The patient was seen by her local physician for palpable mass in the right breast. A biopsy confirmed high grade triple-negative breast cancer. Staging identified eight positive axillary lymph nodes.

The patient was referred to a prestigious research center and obtained an opinion from a breast cancer oncologist. Despite the high-grade disease, high risk presentation, and triple negative finding, she was offered the standard chemotherapy combination of Cytoxan/Adriamycin followed by Taxol.

As a young woman and mother of six children, this patient had no intention of taking “off the shelf therapy.” She drove the many hours from Utah to California for an opinion.

I referred the patient to one of my skilled surgeons who conducted a biopsy in August and the tissue was evaluated in our laboratory.

Her Functional Profiling Results

The results were striking. Every platinum-based regimen killed virtually every cell. The other more standard regimens were less effective.

I suggested to the patient that a modification in the pre-operative (neoadjuvant) chemotherapy regimen would be warranted. In the interim, the patient was evaluated at the molecular level and found positive for the BRCA1 mutation.

At this point, everything fit together, the triple negative finding, the exquisite sensitivity to Cisplatin-based therapies, and the BRCA1 mutation are all “peas in a pod” for triple negative breast cancer. It was evident that a platinum-based regimen was essential.

With the recent memory of her interaction with the cancer center physician, the patient made a decision. She was going to commute to California for care.

Treatment Begins

In August, we began Carboplatin-based therapy and the tumor disappeared. Within two cycles, the large tumor and axillary nodes were gone.

Several cycles later, they were undetectable by radiographic means. With PET scan confirming a complete remission, and the BRCA1 mutation identified, the patient underwent bilateral mastectomies and was referred for future evaluation and prophylactic hysterectomy with oophorectomy.

Complete Remission Achieved

Now two years since diagnosis, the patient is in complete remission and having undergone the necessary surgical procedure to address any additional risks associated with the BRCA1 mutation is now living a normal life.

Her story is the subject of a recent breast cancer blog posting and serves as an interesting example of patients following their instincts as they seek the best possible and potentially curative therapy for their own individual cancers.

Conclusion

Although the patient was sensitive to several forms of chemotherapy and might have benefited from standard treatment, the therapies that she received were exactly right for her and provided immediate benefit with the least toxicity. Adriamycin-based treatments, widely used in this disease, are both less active than the platin and demonstrably more toxic.

We are delighted that the patient received exactly the right treatment for her, that she tolerated it well, and she gives us a call occasionally on her way from a soccer game or band practice with her six children in the car – a victory for intelligent cancer therapy.

As always, I appreciate your thoughts and comments.

 

Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years.  He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California.  For more info go to NagourneyCancerInstitute.com

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There’s Something Sweet About Evolutionary Biology

Repost: https://www.nagourneycancerinstitute.com/blog/something-sweet-about-evolutionary-biology

Humans evolved around their food supply. The foods we eat, the herbs we consume, our sources of nutrition, indeed everything that makes it possible for us to meet our caloric needs can be traced through evolution. A new study examining the enzyme amylase has now traced the origin of this carbohydrate metabolizing enzyme through 47 different species.

Amylase, critical for the digestion of carbohydrates, hydrolyzes starch into sugars. It is found in the pancreas and in some species in the saliva. The authors examined duplication of the amylase gene which allows for multiple copies to produce more of the enzyme, allowing carbohydrates to be consumed in the diet and shows how evolution drives #nagouradaptation.

Species that live in close proximity to humans develop higher levels of amylase.

In fact, wild dogs have virtually no amylase, while domesticated species have high quantities of amylase in their saliva. Thus, adaptation to the human diet through table scraps drove the production of amylase. Monkeys that store food in their cheeks have large quantities of amylase, while mountain lions have none.

But what has this got to do with cancer?

Possibly quite a lot. Investigators in the UK have begun to apply evolutionary principles to cancer therapy. Under Dr. Charles Swanton the clinical trial TRACERx (Tracking Cancer Evolution through Therapy) is using liquid biopsies to examine how cancer cells evolve and become resistant to therapy.

The similarity between the amylase study and cancer are interesting.

For one, amylase levels reflect a specific environmental pressure that provides an advantage to species with higher levels. Secondly, the evolutionary process is relatively rapid, as the domestication of dogs and the infestation of rats and mice in the human environment is historically comparatively recent. Thirdly, the adaptation is not driven by mutations, per se, but instead up-regulation of an existing normal gene.

If we consider cancer adaptation to the stressors that we call therapy, we can imagine that the process of evolution is accelerated as cells divide and live comparatively short periods of time compared to dogs and humans that proliferate comparatively slowly and live a rather long time. By condensing evolutionary adaptation, cancers can outdo our best therapies quickly.

In oncology, patients who show brilliant responses to initial therapy, breast cancer to estrogen withdrawal or prostate cancer to androgen deprivation, generally become resistant within two or three years as selective pressures lead to an outgrowth of resistant clones.

What are the lessons?

Among them is the growing thought that cancer therapy should not be continuous but instead episodic or intermittent. This may offer the opportunity to avoid selective pressures.

This approach has been utilized successfully in prostate cancer and may apply in other diseases. Unfortunately, most oncologists are afraid to find out, as removing therapy could result in progression even death. At least that is a very real fear.

Where the principle has been applied, however, it has shown some early signs of success. Among them is the use of chemotherapy in diseases like small cell cancer and even non-small cell cancer of the lung for defined periods of time with cessation or low-dose maintenance as the subsequent treatment.

One widely used approach in colon cancer is dubbed OPTIMOX which stops patient treatments after FOLFOX and observes them until recurrence, only then reinstating treatments. Survivals have been similar with improved tolerance for those patients who stop active treatment.

There are several questions that remain unanswered. For the amylase study, did amylase arise first and animals then seek starch or did the accessibility of starch render the expression of amylase an evolutionary advantage? Similarly, for those patients with relatively indolent cancers, does the introduction of therapy, particularly mutagenic chemotherapy set in motion the very process of resistance that we seek to avoid?

The field of evolutionary biology will provide extraordinary insights into cancer once we begin to apply its principles. Scientists around the world are beginning to take new looks at the way we think about and treat cancer. It will be refreshing to get the input of physicists, mathematicians, and biochemists in a field that has been uniformly managed by genomic scientists.

The future could be bright, maybe even sweet, as we move in these new directions.

As always, I appreciate your thoughts and comments.

 

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For Mantle Zone Lymphoma: What Goes Around Comes Around

For Mantle Zone Lymphoma: What Goes Around Comes Around
MAY 15, 2019 BY ROBERT A. NAGOURNEY, MD

Mantle zone lymphoma represents approximately 6% of all non-Hodgkin lymphomas diagnosed in the US each year.

It is named for the region in the lymph node where the malignant cell population arises. The cells characteristically express a cell surface protein known as CD5 and over-express cyclin D1 associated with a commonly identified t(11;14) chromosomal translocation.

It usually occurs in patients 60 or older and can be aggressive, with lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen) and in some patients with high circulating lymphoma cells.

Case Study: Recurring Mantle Zone Lymphoma
In 2004, I consulted upon a 74-year-old gentleman with mantle zone.

The biopsy revealed activity for the drug combination R-EPOCH and he achieved a complete remission that lasted 10 years.

He then presented with lymphadenopathy and a biopsy of his axillary lymph node confirmed recurrence, but now the pattern of sensitivity favored the drug Bendamustine.

He received 6 cycles of R-Bendamustine and again achieved complete remission. He did well except for some respiratory infections that were managed with intravenous immunoglobulin.

It Comes Back Again – His Third Encounter
At year 3 he returned with a markedly elevated white blood cell count.

One concern was that he might have drug-induced acute leukemia, an uncommon but serious side effect from chemotherapy and I submitted his cells for flow cytometry. While we awaited the results he required hospitalization to manage his underlying congestive heart failure.
I then had the opportunity to review his peripheral blood smear and recognized that the white cells were indeed mantle zone cells and not leukemic blasts as I had feared. A small quantity of residual blood from his ER admission CBC was submitted to the laboratory for analysis.

His Functional Profiling Results Are Again Very Revealing
The results were extremely interesting.

Having received the EPOCH combination, the patient was now resistant to the principal agents in that combination i.e. Cytoxan, Doxorubicin, etc. He was also resistant to Bendamustine, the drug he had received most recently.

I was more intrigued by the other results.

Despite the use and appeal of the class of drugs known as Bruton tyrosine kinase inhibitors, he was completely resistant to Ibrutinib, the oral drug of this class.

Without my lab results, Ibrutinib, would probably have been my first choice as it is widely used as a salvage regimen in this setting. More unexpected was his resistance to Gemcitabine plus Oxaliplatin, 2 drugs that he had never received and that I have used to great success in other patients in the past.

Recalling My Past Work with the Assay-Directed Drug Choice
What struck me was the patient’s exquisite sensitivity to Bortezomib (Velcade), a proteasome inhibitor that disrupts nominal protein metabolism in cancer cells and has proven profoundly important for the management of another B-cell malignancy known as Multiple Myeloma.

The results for Bortezomib truly resonated.

Over fifteen years earlier, in collaboration with investigators at Millennium Pharmaceuticals in Cambridge, Massachusetts I had used our laboratory platform to identify Mantle Zone lymphoma as a target for their new small molecule Bortezomib.

I remember meeting with their principal investigator, Mark Rolfe, PhD at the ASH (American Society of Hematology) meeting in San Diego to forge a relationship for the study of Bortezomib. At that time, the drug had not received FDA approval for any indication.

Bortezomib is one of the most interesting therapeutic small molecules as its activity is based upon the atom Boron.

By disrupting the cell’s ability to clear itself of damaged proteins it unleashes one of the most potent cell death cascades, the mis-folded protein response.

While it was not surprising that our laboratory identified activity for myeloma, a disease characterized by excessive protein production in the form of antibodies, the findings for mantle zone were unexpected and ultimately led to an FDA approval of Bortezomib for this form of lymphoma some years later. Nagourney RA, Su, YZ, Horlick D, Chow C, Kollin C, Evans SS. Bortezomib (PS-341) alone and in combination with cytotoxic drugs: Ex vivo analysis in human tumor primary cultures. (3690) Amer Assoc of Canc Res 45, 2004 (abst)

Here, 15 years later, was an opportunity to take that discovery and apply it to one of my own patients.

Complications Arise
The patient was suffering from congestive heart failure, requiring aggressive diuresis.

Confident that I could help him, once he stabilized, I transferred him to the oncology unit to begin treatment but he continued to feel poorly enough to warrant observation in the ICU overnight after only a small dose of therapy.

Let’s Not Give Up Yet!
During his stay in the ICU he was seen by the intensivist, the pulmonologist, the cardiologist, respiratory therapists and a host of other staff.

With his advanced age, the cardiologist felt it was his duty to engage in end-of-life discussions, something that I had absolutely NO intention of doing.

With only a portion of one dose completed, the patient’s white count dropped by 50% in a matter of hours.

I immediately transferred him back to the oncology ward to continue therapy and a day later his white count fell to normal as he visited comfortably with family members.

I feel a sense of particular gratification that this earlier discovery made in collaboration with investigators at Millennium (now Takeda) Pharmaceuticals may be the very thing that saves the life of my long-term patient.

How fortunate that we had access to that sample of blood the day of his admission, a sample that forged his successful therapy.

Life Starts Again
At 89 years of age, it is difficult to know whether he can be cured, but I fully expect that he will return home where he lives independently in a lovely retirement apartment.

When I spoke with him on the day of his return from the ICU, I marveled at his vigor and well-being, the cardiologist’s gloomy predictions notwithstanding. “Not bad for an alter cocker” (Yiddish term of endearment for grouchy old men) he replied.

Not bad for an alter cocker, not bad at all.

As always, I appreciate your thoughts and comments.

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Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com