A Pancreatic Cancer Patient – Seven Years Later

More than seven years ago, I was asked to see a patient in consultation. This vigorous 54-year-old gentleman had already undergone a Whipple procedure for the treatment of a pancreatic carcinoma. His skilled-surgeon had resected most of the tumor, but could not clear the margins. With each successive attempt, he identified additional tumor. Unable to achieve a complete surgical resection, the patient was closed, recovered and visited me for a discussion of therapeutic options.

We identified a two-drug combination to be used in conjunction with external beam radiation, a regimen that few — if any — investigators would have suggested. Adjusting the doses to achieve a tolerable schedule, he completed the entire course of therapy with acceptable toxicities. Contrary to his surgeon’s expectations, the patient achieved a complete and durable remission. He returned to his active lifestyle, remarried and became an advocate for the aggressive management of pancreatic cancer.

Now, seven and a half years later with a rising CA 19.9, he is identified to have a focus of uptake on PET CT in the body of the pancreas. A surgical exploration to remove the tumor provided adequate tissue for an EVA-PCD analysis. The patient was once again tested against the standard therapies used in this setting. Among the drugs we examined are the EGFR inhibitors, the taxanes, the combination of EGFR inhibitor + gemcitabine and the platinum + 5FU combination. Each one of these would be a reasonable choice. Indeed, FOLFOX, Tarceva + gemcitabine, the GTX regimen and — most recently — Taxol-gemcitabine based combinations, would all be favored choices for medical oncologists in the U.S. today. Yet, this patient was sensitive only to cisplatin + gemcitabine and none of the others.

Following publications from a group in Scottsdale, Arizona, many oncologists are utilizing Taxol + gemcitabine. There are proponents for Tarceva + gemcitabine, and those who prefer FOLFOX. At least for this patient, none of them would’ve been right. Interestingly, after more than seven years later the patient’s profile reflects the same combination that was used initially. It is interesting to ponder, based on this finding, whether this is a new primary or a sanctuary-site recurrence with so long a disease-free interval to remain sensitive to the platinum-based combination. We now hope to provide him seven and a half more excellent years… at the very least.

Circulating Tumor Cells and Early Diagnosis

A recent report describing a novel application of the cell search technology developed by Veridex, LLC (a subsidiary of Johnson & Johnson) may provide an extremely sensitive tool for the early detection of cancer. Four major cancer centers in the United States will conduct an analysis to determine the accuracy of this method for early diagnosis.

Over recent years, it has been recognized that cancer patients circulate small numbers of tumor cells in their blood. Using microbead technology, these tumor cells can be isolated from the blood stream and characterized. The original application of the technology was a prognostic marker by which patients with breast, colorectal or prostate cancers and high levels of circulating tumor cells, fell in the “high-risk” groups. I have been highly supportive of the application of this technology and have applied it extensively for patients with prostate and breast cancers.

The more recent iteration of this technique will allow investigators to not only identify but also characterize the isolated tumor cells. This provides an exciting new opportunity for early diagnosis.

As we speculate on the ramifications of this discovery, certain questions are raised. The most immediate being: What to do with the data? It has previously been suggested that many cancers arise 20 or 30 years before they are clinically detected. Malignant populations measuring in the hundreds of thousands, millions or even hundreds of millions, may still lie below the radar screen of modern diagnostic tools. If we have the capacity to identify patients 10 or 20 years before their cancers can be clinically detected, would we then begin therapy decades before clinical disease arises? If so, what treatments will we administer? Will the early detection of cancer cells be associated with the further characterization of tumors, such that targeted agents can be utilized to eliminate these clones at their earliest inception?

We will watch the development of these clinical studies with great interest. It will be even more interesting to see how we answer the questions that arise.

The Emperor’s New Gene Profile

The role of genomic testing for predicting response to chemotherapy

I read — with great interest — the recent study by Von Hoff, et al. in the Nov. 20, 2010 issue of the Journal of Clinical Oncology, as well as the associated editorial in the same issue. The manuscript, titled Pilot Study Using Molecular Profiling of Patient Tumors to Find Potential Targets and Select Treatments for the Refractory Cancers, reported the results obtained in 106 patients who consented to study using immunohistochemistry and microarray analysis for the identification of treatment process.

Of the original 106 patients:

  • There were 86 who underwent profiling and were considered for therapy
  • Of those, 68 were treated
  • Of whom, 66 received the recommended treatment.

The objective of the trial was to improve progression-free survival over that associated with the most recent prior therapy; to determine the percentage of time a target was identified; and finally, to gauge objective response rates by RECIST criteria.

The patients in the study:

  • Were a mixture of solid tumors, including breast, colon, ovary and others.
  • Had failed prior therapy.
  • The median age was 60 years and the majority of patients were female
  • Only the breast cancer patient population was defined in terms of the number of prior therapies — five.

At first blush, this paper would suggest that the era of molecular profiling has arrived. We need only obtain a small biopsy of tissue to identify the “targets” most likely to respond to available or investigational agents. At a closer look, however, we find that the investigators on the trial invented a criterion of response, namely a 1.3 fold improvement in time to progression. What that means is that patients who received an ineffective therapy and showed disease progression, need only improve upon that short response by a mere 30 percent to be counted among the “responders.”

Thus, a patient who failed a therapy after 10 days could theoretically be counted among the successes if their subsequent response to directed therapy was a meager 13 days in duration.

Even using this soft-boiled endpoint, only 18 of the 66 patients (27 percent) met criteria for response. However, these 18 responders should really be calculated against the total 88 patients approved for study, providing an even lower 20 percent result. Indeed, the most rigorous investigators would demand that these 18 be measured against the total 106 patient cohort, which would provide a response rate of a mere 16.9 percent.

Since most investigators don’t have the luxury of inventing their own criteria for response, we might examine this manuscript in the context of more widely used criteria like RECIST. In this context, the objective response rate of six out of 66 was 10 percent, with an additional 14 patients (21 percent) revealing stable disease for four months. However, again using the intention-to-treat analysis (the criteria other investigators must live by) the objective response rate falls to more like 6.8 percent (6/88) or most rigorously 5.7 percent (6/106).

Furthermore, four of the six (66 percent) objective responders, by RECIST criteria, and nine of the 18 (50 percent) were found in breast and ovarian cancers (mostly breast) known to be among the most chemo-responsive of all epithelial neoplasms. By these standards, the capacity of molecular profiling to identify responders begins to seem a bit underwhelming.

The design of the trail also raises some questions:

  • First, the principle end point is IHC (immunohistochemistry), followed by microarray
  • Yet, the specific predictive validity of the micro-array analysis is not addressed

While the authors note that IHC is a well-established and widely used methodology, they largely skirt the second issue noting only that “For MA (microarray), excellent reviews and commentary have been written on the subject of gene arrays and their potential and actual use for predicting clinical response for chemotherapy.”

In essence, we are left with a report that provides a very low objective response rate and succeeds only by meeting its own invented criteria to support the predictive validity for what appears to be mostly an established use of IHC. Should we consider this the birth of molecular profiling? By comparison, our functional platform in similarly heavily pretreated patients has consistently provided significantly higher response rates than those reported in the current analysis. Is it not time for the molecular profiles to match our results?

Are New Cancer Drugs Always Better?

Few cancers instill a greater sense of fear in the medical oncologist that metastatic renal cell carcinoma, the most common form of which is known as clear cell cancer. This type of kidney cancer — driven by a mutation in a gene know as VHL — spreads rapidly, metastasizes to almost any and all organs and historically responded to almost no therapies. The development of Interleukin-2 (IL-2) in the 1980s offered a glimmer of hope. Yet, even this breakthrough ultimately yielded complete and durable responses in a mere 10 percent of patients.

By focusing on the hyper-vascular nature of this disease, investigators then developed a second line of defense that attacked the blood supply of these cancers. Following the introduction of Avastin, a number of small molecule VEGF inhibitors were introduced. Most recently, a class of drugs known as mTOR inhibitors gained popularity by providing objective responses and showing evidence of improved survival.

But what happens when all the really “hot new drugs” fail to provide benefit?

This was a question I confronted in a charming, 68-year-old neurologist who traveled to visit me from Stanford University where he received highly appropriate, yet unfortunately ineffective therapy. The patient presented in July 2010 with rapidly progressive kidney cancer that had overtaken his lungs. He was started on oral Sutent (the treatment of choice). His management was complicated by a hemolytic anemia. When I met the patient in October, I was concerned that he could not survive long enough to take on another treatment, no matter how effective it might ultimately prove to be.

As a physician, he beseeched me to study his tumor in the hope of finding any therapy to salvage him from his rapidly deteriorating course. A small biopsy was obtained with the help of one of our surgical colleagues. The results were striking — no evidence of activity for sorafenib, sunitinib (Sutent), nor the Rapalogs (Rapamycin derivatives). In one fell swoop, all of the newest therapies were swept aside with little likelihood of benefit. Despite the established literature, this patient was clearly sensitive to chemotherapeutics. It was evident to me that the treatment outline, a combination of three drugs, could provide meaningful clinical benefit if the patient could tolerate even the most modest associated side effects. With the kind cooperation of the treating physician in Northern California, our recipe was followed to a T.

The treating oncologist pulled no punches in his description of this patient’s prognosis. Nonetheless, he kindly assisted in the management of the treatment we described. While the cancer-related hemolytic anemia raged, and the patient fought for air, the treatments were delivered. Too ill to leave the hospital, his entire first course of therapy was delivered on an inpatient basis.

For several weeks, we anticipated the worst. And then, a phone call from a chipper-sounding patient. Breathing comfortable, his chest x-ray had cleared, his anemia had resolved and he was being readied for discharge. A short time later, an abdominal ultrasound revealed measurable improvement in the kidney cancer, further confirming objective response.

The patient, now home, could not be happier. The excellent outcome is as gratifying as it is unexpected. There is no question that no one else would have given this treatment. And there is further no question that the patient would not be alive today had he not received it. There are many lessons to be learned from this experience. Among them, that every patient deserves the opportunity to get better; that laboratory analyses can identify unexpected options for patients, even with the worst malignancies; that new drugs aren’t always better drugs; and finally, that nothing succeeds like success.