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Pancanology Is On YouTube

Date	Title	Description
2017-04-23	Pancanology Explains Kaplan-Meier Graphs	An explanation of Kaplan-Meier graphs in cancer research
2017-05-11	Pancanology Explains Causes of CA19-9	Why pancreatic cancer patients have high CA19-9 readings
2017-12-02	Pancanology Explains CA19-9 and Treatment Effectiveness	CA19-9 can be used to track pancreatic adenocarcinoma treatment effectiveness
2018-01-21	Pancanology Explains White Blood Cell Counts During Chemotherapy	What happens to white blood cell counts during chemotherapy?
2019-01-23	Pancanology Answers Pancreatic Cancer New Patient FAQ	Pancreatic Cancer patient FAQ. What are the best treatments and hospitals? What should I ask my oncologist? Get the answers here!
2019-12-19	Pancanology Explains Why Chemotherapy Stops Working	In this video, I use drawings to explain why chemotherapy ultimately stops working in most cases. Once we know why, we can employ better treatment strategies.
2020-10-07	Pancanology Explains PubMed Clinical Trials Searches	In this video, I demonstrate a PubMed search of clinical trials for a specific drug candidate (CPI-613) and provide brief explanations of the results, an overview of a phase 1 clinical trial abstract, and access the full paper.

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Pancanology Blog Posts

Date	Title	Description	Views
2020-01-03	Pancanology Is On YouTube	Pancanology started a YouTube channel. 3 years ago! That may explain the lack of updates on this blog?	226
2014-06-18	White Blood Cell Counts	What are white blood cells?	13133
2016-08-26	Long-Term Pancreatic Cancer Survivors Without Surgery	Details on 11 long-term survivors who never had surgery.	4841
2015-10-01	Clonal Evolution Model	The widely accepted theory of how cancer grows and how it affects treatment options.	3087
2017-01-09	The Case for Low Dose FOLFIRINOX	Low dose FOLFIRINOX has fewer side effects and comparable effectiveness	3055
2016-08-02	How Chemotherapy Works (or Doesn’t)	How chemotherapy works. And why it stops working.	1100
2015-07-03	Phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial Results	Results of every phase 3 metastatic clinical trial for pancreatic cancer. Tell me if I've missed one!	1000
2015-10-01	Cancer Stem Cell Model	A new(er) theory of how cancer grows and its implications on treatment options.	708
2014-07-04	WBC During Chemotherapy	How do white blood cell counts respond during chemotherapy?	561
2014-09-29	Gemcitabine Dose Escalation Study – a Paper Review	What's the scoop on phase 1 clinical trials? Here's a look at PanCan's most important one.	538
2017-11-12	Worst Medical Advice	Worst Medical Advice I've Ever Received	415
2015-08-18	What Researchers Know and You Don’t	One paper is behind almost every new cancer treatment. It all makes sense now!	404
2014-06-18	Introduction	About me.	325
2015-09-25	Cancer Models	How do researchers come up with new treatment ideas? It's based on models.	308
2015-01-31	Immunotherapy of Pancreatic Cancer – a Webinar	Johns Hopkins GVAX vaccine developer Dr. Elizabeth Jaffee gives a run-down of PanCan immunotherapy options. I annotated it so you can find what you're interested in.	285
2014-09-21	Stockdale Paradox & Cancer	Admiral Stockdale endured 7 years as a Vietnam POW. How can you get through tough times?	254

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Long-Term Pancreatic Cancer Survivors Without Surgery

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Overview

Curative resection is not offered to most pancreatic cancer patients and information about long-term survivors in this group is scarce. In late 2015, Virginia Mason Medical Center (VMMC) authors documented the characteristics of their eleven long-term pancreatic cancer survivors that never had curative surgery.

Here I’ll present relevant insights into these patients that succeeded at long-term survival. I’ll break down and summarize important information from this paper. Perhaps you will find yourself in one of these patients? Keep in mind that these patients were all treated at VMMC and their therapies will be similar to VMMC’s protocol.

Paper	Rare long-term suvivors of pancreatic adenocarcinoma without curative resection
Authors	Oh SY, Edwards A, Mandelson MT, Lin B, Dorer R, Helton WS, Kozarek RA, Picozzi VJ
Publication	World J of Gastroenterol, 2015 Dec 28; 21(48): 13574-13581
Links	[Abstract] [PDF]

Key Points for Patients

This paper documents 11 long-term pancreatic adenocarcinoma survivors treated at VMMC (Seattle, WA) who never had curative surgery
At diagnosis, all long-term survivors were fully active (ECOG status 0), had normal albumin levels, and tumors at the head of the pancreas
2% [95% CI: 1.0% – 3.5%] of VMMC’s non-resected patients from 1995 to 2009 were ≥5-year survivors
All non-metastatic patients were treated with some type of combined chemoradiation
Most long-term survivors were overweight which the authors indicate may confer a survival advantage with diseases associated with wasting
Long-term survivors were less likely to develop distant metastases with peritoneal metastases being the most survivable
Of the 6 deaths recorded, 4 were not directly related to the tumor
These patients were treated with VMMC’s preferred treatments. This report does not indicate superiority of their treatment regimen. Data from other institutions would be needed for valid comparisons.

Introduction

Very few publications concerning long-term pancreatic adenocarcinoma (PDAC) survival concentrate on patients who could not have curative resections. A 1988 Gastrointestinal Tumor Study Group paper suggested that long-term survival without surgery might be possible for some patients.¹ A 2014 Korean review of 482 inoperable PDAC patients identified characteristics of long-term survivors, defined as >18 months for stage 4 and >27 months for stages 2-3.² However, the paper I review here provides much more clinical detail on 11 long-term (≥5-year) pancreatic adenocarcinoma survivors treated at VMMC in Seattle, WA who never had curative surgery.

Virginia Mason Medical Center Pancreatic Cancer Patients (1995-2009)

The Long-Term Survivors

The table below summarizes the VMMC’s long-term pancreatic cancer survivors diagnosis and treatment histories with additional details in the paper. At publication time, five long-term survivors survived. Of the remaining six, four died from sepsis not directly related to their tumor and the two metastatic patients died from disease progression.

The authors suspect these patients happened to have unique tumor biology that was susceptible to these treatments.

Treatment and survival details of VMMC’s long-term survivors without curative surgery

Common Attributes

All long-term pancreatic cancer survivors were in excellent health upon diagnosis. All had tumors in the head of the pancreas. Most were overweight or obese, a risk factor for pancreatic cancer, but which may also be a survival advantage as wasting is a common symptom.

Radiation

VMMC treated all locally advanced long-term pancreatic cancer survivors with some form of radiation. Most received the Virginia Mason protocol consisting of interferon-alpha-2b, 5-FU, cisplatin and radiation while the others received chemoradiation consisting of 5-FU and radiation (one had both). Radiation use is controversial and its importance in long-term pancreatic cancer survival is unknown.

Neither metastatic long-term pancreatic cancer survivors was treated with radiation.

Chemotherapy

As you might expect, Virginia Mason gave all long-term pancreatic cancer survivors their preferred treatments for pancreatic adenocarcinoma – especially the VM protocol and Gemcitabine/Doxetaxel. These treatments are not commonly used elsewhere. We won’t understand the importance until other institutions publish details about their long-term pancreatic cancer survivors using their preferred treatments. I suspect that a different set of their patients would thrive if they used another regimen.

Genetics

Patient #5 had a family history of cancers and a BRCA2 mutation. Due to other considerations, treatment lasted only 4 months but was unusually effective. The authors note that the VM protocol uses cisplatin which has been effective against BRCA2 tumors.³

Tumor Progression

In long-term survivors, tumors commonly progressed only in or near the tumor bed (local, lymph node, or peritoneum).

Conclusion

This paper gives a rare look at long-term pancreatic cancer survivors without curative surgery. Long-term survivors had excellent health, pancreas head tumors, local or no metastases, and effective treatments with long treatment holidays. Stenting of liver ducts was often necessary.

These patients were given VMMC’s preferred treatments. This report does not indicate superiority of their treatment regimen. Data from competitive institutions is needed for valid comparisons. I would not focus on the specific VMMC treatments.

The findings I find important are:

first-line treatment was effective
second-line treatment was effective
distant metastases rarely appeared
maintenance of body weight

Long-term survival of pancreatic cancer is possible. I believe that we need Investigation into matching treatments to patients to improve outcomes for more patients.

Read the paper for additional details.

Discrepancies

Here I note discrepancies between the paper and my interpretation.

The paper says: “Non-resected ≥5-year survivors represented 2% (11/544) of all non-resected patients undergoing treatment for pancreatic cancer…”. By my count, there were 555 (544 <5-year survivors + 11 ≥5-year survivors) total patients. It does not change the 2% ratio, but I used 555 total patients when calculating the 95% Confidence Interval reported here.

Driving treatment decisions on 28 Aug 2016

References

[1]Gastrointestinal Study Group. (1988). “Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone”. J Natl Cancer Inst 80(1):751-755. PMID: 2898536.

[2]Jo JH, et al. (2014 Oct). “Clinical characteristics of long-term survivors of inoperable pancreatic cancer: an 8-year cohort analysis in Korea”. Pancreas 43(7):1022-31. PMID: 24991970.

[3]Vyas O, Leung K, et al. (2015). “Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation”. Anticancer Drugs 26:224-226. PMID: 25304989.

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Phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial Results

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Overview

Metastatic pancreatic adenocarcinoma patients (PDAC) don’t have a lot of good options. In this post, I’ve summarize the completed chemotherapy-based phase III trials for metastatic patients, providing links to publications, outlining the survival statistics, and identifying key subgroups that may have benefited from the treatment.

From a patient’s perspective, not much progress has been made on new treatments. It’s not for a lack of trying. Over 90% of phase 3 clinical trials result in no added benefit.

However, I believe that these treatments are effective on a minority of patients. The data used to measure effectiveness (like median OS) ignores outstanding responses to less than half the patients. I propose that looking at longer term survival rates gives clues to treatments effective on a minority of patients. Further digging into the results by researchers can uncover reasons behind the effectiveness and help us match treatments to patients.

Key Points for Patients

Several treatments available. We need to better match the right treatment to the right patients. Some studies have published information about subgroups that benefited substantially from treatment in a trial. This can help you choose whether that treatment is right – or wrong – for you.
A patient’s treatment goals should determine which trial results are important.
Directly comparing results between trials is misleading due to the fact that patient selection is key to the results and each trial has its own selection criteria.
Results in italics are values I’ve read from published graphs, not specifically published by the study paper.
Results in bold are for treatments often used for pancreatic cancer.

Observations

In reviewing the information to put together this information, I’ve formed some interesting opinions that I’ll share.

First, I should state that the results provided here are for the actual patients that were under clinical trial. Your results will almost certainly not be “typical”. There are uncertainties in the outcomes that are hopefully minimized because these are phase 3 clinical trials with large numbers of patients. One of my goals here is to identify the best performing treatments that can maximize your outcomes. If we can identify some treatments that work best for patients in your particular situation, this posting has done its job.

This summary lists very little about side effects of the treatments. For some, this can also be a big factor in a treatment decision. If you are in poorer health, try looking for the best performing trials that included patients with poor health (ECOG 2/3 or KPS≤70).

In the data listed, numbers provided directly from the clinical trial results are listed in normal fonts. Rates in Italics have been interpolated from graphs provided by the clinical trials publications.

Click on the following picture to show a PDF file with the results.

Pancreatic Adenocarcinoma Phase III Clinical Trials

Subgroups Benefited

I think this is the most useful information available from the data I’ve collected.

Some clinical trial reports are superior to others. Take for instance, the reports for FOLFIRINOX and Gemcitabine/Abraxane. Both of these reports include what are called forest plots to identify subgroups of patients that did well on one treatment versus the other.

The FOLFIRINOX forest plot is here (I provide the link because I’m unsure whether I can legally embed the figure, which might be clearer). For each subgroup listed, a hazard ratio has been computed (square box), with 95% confidence intervals shown (horizontal line). Subgroups listed that have the entire confidence interval (horizontal line) to the left of 1.0 (which is just about everything) performed better under FOLFIRINOX than Gemcitabine. This kind of information can be vital to patients who belong to one of these subgroups when they’re trying to decide on a particular treatment.

In the column Subgroups Benefited, I try to list groups indicated within these reports that did benefit from one treatment arm. Sometimes, a follow-on report has the information and I have provided hyperlink in the column for these cases.

ORR

This is the percentage of patients that had at least a 20% reduction in the size of their tumor. FOLFIRINOX has the best ORR at 32%. Understand that 2/3d’s of treated patients did not have their tumors shrink using the best treatment available.

The key is finding out why these patients had their tumors shrink. Are you more likely to belong in this group? Again, this is why the subgroup analysis is important.

CR

If your treatment goal is to remove all metastases to enable a chance at surgery, CR (Complete Response) is your result of interest. These are pitifully small numbers. But what this tells me is that some small subgroup of patients do respond remarkably well to some treatments. One example might be BRCA2 mutation patients that respond extraordinarily well to platinum-based treatments [reference needed].

PFS

If your treatment goal something like living as long as possible without worsening symptoms., this might be your series of results to look at. Often, only the median is reported, but I favor looking at the 12- or 18-month PFS percentages. This tells me how many patients had a sustained response to the treatment. Their tumor shrunk and they’re tolerating the treatment.

OS

This is usually a clinical trial’s primary end statistic. Median numbers are what researchers compare but I find them largely irrelevant to patients. I want to see the 18- and 24-month OS percentages. These are the long-term survivors. Compare the PFS and OS percentages and know what fraction of survivors are still benefiting from the treatment.

Clinical Trial Progress

Often we patients are frustrated by the lack of progress towards more effective treatments. Here I’ve documented over 38 different chemotherapy phase III clinical trials since 2002 (I’m certain there are more). Only four of these trials led to approval, a success rate of about 10%.

In general, these are drugs that had successful phase II results and then failed during phase III. First, it helps to demonstrate that there is still significant effort being put into new treatments. But second, how many very promising treatments fail to show patient benefit.

Interesting Results

When a trial fails to show benefit, often that is the end of the road. However, sometimes the researchers see interesting things buried in their data. Here are a few I’ve uncovered.

Gemcitabine/S-1

Here’s a stellar performer that I think should be approved pronto! For Asians. And therein lies one of our problems with the clinical trial system. It is stacked in favor of Caucasians. This combination works well and is well tolerated by Asians only. Caucasians – not so much.

Gemcitabine/Cisplatin & Gemcitabine/Oxaliplatin

The trial results for these platinum-based chemotherapies did not identify any subgroups that performed well, but it has since been recognized that many patients with a wild-type BRCA2 mutation (about 5-10% of all pancreatic cancers) have responded quite well (2009 Dramatic Response; 2011 Complete Response; 2012 Complete Response; 2014 Meta-analysis). I credit my complete response to Gemcitabine/Cisplatin because of my BRCA2 mutation.

Gemcitabine/Masitinib

According to the traditional measurement criteria (median PFS and/or OS), this trial failed miserably. A closer reading of the results (kudos researchers!) identifies that PDAC patients with overexpression of ACOX1 in their blood did much better than others (Figure). What’s less clear is whether this finding also says that patients with an overexpression of ACOX1 in their blood should avoid Gemcitabine monotherapy.

Gemcitabine/Ganitumab

Another research report (behind a paywall, so not fully reviewed by me) of a failed clinical trial. But a later closer analysis of the results in another paper delivers news of biomarkers (IGF-1+; IGF-2+; IGFBP-3+; IGFBP-2-) that identified a subgroup of patients that survived 3X longer than the others.

Gemcitabine/Erlotinib

Erlotinib (aka Tarceva) was expected to target tumors that overexpress EGFR, like pancreatic cancer. While the EGFR status of patients did not seem to affect the outcomes, development of rashes did. The more severe the rash, the better the outcomes (Figure). In fact, some oncologists are increasing the doses of erlotinib until a rash develops.

Summary

There have been a surprising number of phase III clinical trials for metastatic pancreatic adenocarcinoma. Most do not pan out. And researcher responsibilities should not stop there. It appears unlikely we will soon find a treatment that works for most pancreatic cancer tumors. More effort is being made to identify subgroups that respond well, but that information is not widely disseminated to patients. Hopefully this blog entry will bridge some of that gap.

The Worst Medical Advice I’ve Ever Received

Couch Potato Dreams of Cycling

A few months after my cancer diagnosis, the medical costs were accumulating and the insurance carrier was questioning every treatment, compounding the stress levels.

The insurance carrier decided they’d like to send a nurse expert to my house to evaluate my condition and care. We reviewed my diagnosis and what I was doing to ‘stay healthy’. Her stated goal was to get me the best care possible, but I suspected another motive to minimize insurer costs.

Prior to diagnosis, I was very physically active, riding bicycles around 10 hours a week, for the last 25 years. I often rode to work and back – logging in extra miles, 25-50 miles on some work days, 60+ on the weekends. My diet was poultry and fish, with fresh veggies every day – a pretty good diet except for a love of pizza. Beside genetics, there was really little reason for me to have pancreatic cancer – at age 48.

I talked to the nurse about how difficult it was to ride the bike while on chemotherapy. While still riding every day, two days after chemo I could only manage about 3 miles and others up to 30. The long bike rides helped me release stress while giving me time to process the thoughts running through my head.

And this is where I received the worst medical advice ever:

You don’t need to ride your bike any more. Now is the time that you get to sit back, relax, and use up all that fitness you’ve got stored.

Wow.

With one recommendation she dismissed my stress relief and suggested I wouldn’t survive long.

Apparently I should sit on the couch and watch TV for the brief remainder of my existence?

I disregarded her advice and suggestion. Six years later, I’m still riding my bicycle and surviving.

Driving treatment decisions on 11 Nov 2017

The Case for Low Dose FOLFIRINOX

How Treatment Doses are Set

I’ve written previously here how researchers set doses with phase 1 clinical trials. Briefly, in a 3×3 trial design, groups of 3 patients receive a specified dose level and are then assessed for toxic effects. If nothing “bad” happens, the next group of 3 patients receive a slightly increased dose. This cycle repeats until patients experience too many toxic effects. An additional group of patients receives a lower dose to assure the limited toxicity.

The adverse reactions of a handful of patients determines the dosages for all other patients. Note that the treatment effectiveness is not a consideration in setting was is aptly called the Maximum Tolerated Dose (MTD). To be sure, later clinical trials may see additional toxicities and modify the doses or schedule a little, but usually not much. The key idea driving this is that more chemotherapy is better.

Minimum Effective Dose

Ideally, we’d like to discover the Minimum Effective Dose (MED) for any treatment. That could entail large clinical trials with several cohorts taking different doses. To detect small differences in treatment outcomes, we must enroll large groups of patients. Tying up the few patients willing to participate in clinical trials in MED studies would delay development of new treatments.

Is More Always Better?

Smaller doses may be just as effective in treating tumors, and almost certainly result in fewer adverse side effects. Fewer side effects allow patients to stay with treatments longer. There have been a few studies with low dose FOLFIRINOX, so let’s review what they found.

The Evidence for Less FOLFIRINOX

I summarize four studies that report on efficacy and side effects of low dose FOLFIRINOX in metastatic pancreatic cancer. The following table summarizes these studies and the phase III PRODIGE 4/ACCORD 11 approval trial.

Overview of Low-Dose FOLFIRINOX Studies

I’ve reported the median dose levels, when available, as compared to the phase 3 FOLFIRINOX clinical trial. Many patients did not start at a full dose, and most had dosage reductions sometime during each study.

About the Studies

The Gunturu KS, et al² retrospective review included Yale University previously-treated patients from June 2010 to July 2011, documenting their doses, toxicities, and survival results. Reduced doses were not by design, but rather a result of physician discretion. All patients received preventative G-CSF (i.e. neupogen) to prevent neutropenia. This study had a high percentage of healthiest patients.

The Peddi PF, et al³ retrospectively reviewed the FOLFIRINOX experiences of Washington University, the Mayo Clinic, and the University of Wisconsin to compare US “real-world” experiences to the phase 3 clinical trial held in France. Physicians reduced doses at their discretion, not by study design.

Mahaseth H, et al⁴ retrospectively reported on Emory University’s modified FOLFIRINOX regimen that omitted bolus 5-FU and administered G-CSF to all patients.

Yale University later conducted the Stein SM⁵, et al prospective study after the promising results in the Gunturu KS study. Starting Irinotecan and bolus 5-FU doses were reduced by 25%, and further at physician discretion. This phase 2 clinical trial (NCT01523457) may provide the most rigorous results.

Patient Responses

I’ve summarized these study’s adverse patient reactions and tumor response statistics in the table below. Relative Risks of greater and less than 1.0 indicate that the study recorded more or less of a particular event, respectively, compared to the phase 3 clinical trial. As an example, a relative risk of 0.3 means that particular event happened 30% as often as in the phase 3 clinical trial. Bold numbers indicate statistically significant findings (p-value < 0.05). Because of the small study sizes, many promising findings did not reach statistical significance.

Patient Responses in Low-Dose FOLFIRINOX Studies

Progression-Free (PFS) and overall survival (OS) were similar in all studies (the accurate statement is that they were “not found to be different”). Toxicity levels were almost uniformly lower in all low dose FOLFIRINOX studies.

Colored bars represent tumor responses to treatment, with width corresponding to patient counts. Depending upon an individual’s treatment goals, you may want to know different results. For instance, a patient needing to shrink a tumor for surgery may want to look at the PR+CR result. A patient desiring long-term stability may want to minimize the PD result.

Blood-Related Adverse Events

The table below contains more detail and 95% confidence intervals on blood-related adverse events. Studies with fewer participants have less certain results and wider confidence intervals. For adverse event analysis, I included both locally advanced and metastatic patients from each study.

Blood Related Adverse Events in Low-Dose FOLFIRINOX Studies

Most adverse events for lower dose FOLFIRINOX were less than the baseline phase 3 clinical trial. However, except for neutropenia, sample sizes or adverse effects were too small to show statistical significance.

Note that the phase 3 clinical trial’s neutropenia rates were especially high. Three studies (Gunturu, Mahaseth, and Stein) used C-GSF for all participants which likely reduced the rate of neutropenia. The Peddi study used C-GSF at higher rates than the phase 3 trial, also reducing the neutropenia rates.

Non-Blood Related Adverse Events

The table below contains more detail and 95% confidence intervals on non-blood-related adverse events. For adverse event analysis, I included both locally advanced and metastatic patients from each study.

Non-Blood Related Adverse Events in Low-Dose FOLFIRINOX Studies

Here again, most adverse events for lower dose FOLFIRINOX were less than the baseline phase 3 clinical trial, with sample sizes usually too small to show a statistically significant effect. The Peddi study had significantly less fatigue, and the Stein SM study with a 25% reduction in the initial dose of irinotecan and bolus 5-FU had significantly less vomiting.

How Low Can We Go?

Let’s take a look back at the phase 1 dose escalation trial for FOLFIRINOX⁶. The study establisged a MTD for oxaliplatin and irinotecan at 85mg/m² delivered over 120 minutes and 220mg/m² delivered over 90 minutes respectively. The reduced the recommended level to 85/180 mg/m² when they realized the cumulative effect would not allow patients to maintain a 2 week schedule.

The dose escalation started with lower oxaliplatin/irinotecan doses as shown in the following table. Important to this discussion, almost every dose level showed anti-tumor activity – including complete responses at the two lowest levels. Participants experienced no dose-limiting toxicities at the three lowest dose levels.

Patient Responses in Phase 1 FOLFIRINOX Dose Escalation Study

The primary goal to determine the dose-limiting toxicity, not effectiveness, opened enrollment to 41 patients with 8 different types of cancers. Of the 6 pancreatic cancer patients, 1 enjoyed a complete and another a partial response (dose levels not specified).

Summary

These peer-reviewed, published studies proved evidence of low dose FOLFIRINOX efficacy similar to the phase 3 trial results. Positive or negative differences in progression-free or overall survival rates cannot be seen with the small studies thus far.

Even with these small study sizes, we have statistically significant evidence of a reduction in toxicity with the low dose FOLFIRINOX regimens.

In the FOLFIRINOX dose escalation trial, patients at the two lowest oxaliplatin/irinotecan levels recorded complete responses with no limiting side effects.

Low dose FOLFIRINOX is better tolerated with significant anti-tumor activity. Oncologists should consider this regimen as an option for patients desiring efficacy but unwilling to endure severe toxic events. Patient experiences with low dose FOLFIRINOX will produce more retrospective studies that will help pinpoint a most effective dose.

I propose that oncologists start patients with low dose FOLFIRINOX and in the absence of severe side effects, increase the dose. The first rounds are often the most difficult as a patient must quickly learn how to deal with chemotherapy-induced nausea and fatigue in addition to their new cancer diagnosis.

References

[1]Conroy T, et al. (2011 May 12) “FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer”. N Engl J Med 364(19):1817-25 PMID: 21561347.

[2]Gunturu KS, et al. (2013 Mar) “FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity”. Med Oncol 30(1):361 PMID: 23271209.

[3]Peddi PF, et al. (2012 Sep 10) “Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma”. JOP 13(5):497-501 PMID: 22964956.

[4]Mahaseth H, et al. (2013 Nov) “Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma”. Pancreas 42(8):1311-5 PMID: 24152956.

[5]Stein SM, et al. (2016 Mar 29) “Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer”. Br J Cancer 114(7):737-43 PMID: 27022826.

[6]Ychou, et al. (2003 Mar) “An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors”. Ann Oncol 14(3):481-9 PMID: 12598357.

How Chemotherapy Works (or Doesn’t)

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Why did my chemotherapy stop working? Your oncologist doesn’t have the time to give you an answer – but I do. I’m going to give you one look at how chemotherapy works. Chemotherapy changes the tumor. Understanding this allows you to prepare for the next question: what do I do next?

When I first learned this information, frankly it was somewhat depressing. I’m reminded of Simon Wardley’s graph of knowing versus expertise. A little knowledge is dangerous. A little more can be empowering.

For example, I’m disappointed when people glance at the dismal survival statistics and say that they’re not a statistic. Guess what? I’m a long term survivor and I’m in those statistics. There’s knowing the statistics and then there’s understanding the statistics. I admit that at first look the statistics is quite depressing. But a deeper look at the statistics reveals the story of the survivors. Understanding that story uncovers the path to be a survivor.

So let’s try to walk you through the area of a little knowledge to the area of understanding where there is hope and guidance. On to the land of survivors!

How a Tumor Cell is Made

In the clonal evolutionary cancer model, a normal cell gains a set of mutations over time. These mutations could happen during cell division (mitosis), when a cell divides into two cells. A random mistake in the replication process means that one of the two “daughter” cells receives a mistake in its copy of DNA. The starred arrows denote these mutation events. Here, one daughter cell gains a mutation while the other does not.

Pancreatic Cancer Progression of Mutational Changes

Pancreatic Cancer Mutation Progression

DNA mutations can block the building of proteins critical to proper cell function. For instance, a mutation halting the production of proteins necessary for cell repair makes the cell susceptible to even more mutations. You may have heard that the KRAS gene is mutated in about 95% of all pancreatic cancers. This would be how one of these mutations might happen.

As this mutated cell splits further, these mistakes are copied to both “daughter” cells. When these cells split, another mutation may happen during replication that brings these cells another step closer to becoming a tumor cell. Each time we move to the right, one of the cells has gained a new mutation.

In pancreatic cancer, it takes around 12 years¹ and at least a dozen of these mutations to disable the built-in protection mechanisms in the human body and create a tumor cell. Fortunately, it is an extremely rare set of circumstances. But not rare enough.

The takeaway:

Tumor cells have multiple DNA mutations that make them cancer cells

How a Tumor Grows

By the time the cell is cancerous, it has accumulated many mutations. One mutation allows the tumor cell to grow uncontrollably and a tumor cell can divide many more times than a normal cell. Another mutation breaks the verification checks on DNA replication, resulting in more and more mutations as it divides. Still another mutation prevents the immune system from recognizing the cell as unwelcome.

Many mutations are incompatible with survival and these cells die off quickly. But a few mutations provide a new advantage over the parent cells. This is an evolutionary process played out very rapidly. Many new mutations happen throughout the tumor to try their luck at survival. The tumor cells best able to reproduce begin to dominate by numbers. The result is a heterogeneous tumor. The tumor cells are not identical copies of the first tumor cell. Each succeeding generation of cells add more DNA mutations and possibly even changes some of the original mutations.

Tumor Growth

Over a period of around 7 years¹, the tumor grows large enough to cause symptoms and be detected on scans. This cancer has been growing quite slowly and for a long time. It has been forming over the last two decades. This is one reason why pancreatic cancers occur relatively late in life (average age: 65 years old).

This may be the most important takeaway:

the tumor is heterogeneous, composed of tumor cells that are not genetically identical

Why is that important? Because each tumor cell may respond to treatment differently.

Treatment Selection

After the tumor has been detected and confirmed as cancer, we often select a treatment based on chemotherapy. In pancreatic cancers, we have almost no clue which treatment will be best. One major exception is a tumor with a BRCA1 or BRCA2 mutation.

Treatments may only be effective on tumor cells with specific mutations. When chemotherapy is active in the body, cell division slows, but when divisions happen, new mutations continue to be generated. Some new mutations may find a way to get around the treatment and continue growing despite the treatment. These cells out-reproduce the other tumor cells. It’s an evolutionary survival of the fittest of tumor cells.

Let’s review ineffective, stable, and effective treatments to understand why the tumor responds the way it does. In these figures, the colors represent tumor cells with different sets of mutations.

Ineffective Treatment

Ineffective chemotherapy works only on a small set of tumor cells (red and light blue). The dominant blue and rarer pink tumor cells resistant to treatment and continue to divide. The blue and pink cells generate new mutations, creating the white and green cells resistant to the treatment.

As the few susceptible cells die off, the unaffected cells continue reproducing. The tumor consists of mainly the same types of cells as when treatment started, plus some with new mutations. On scans the tumor is seen to be growing and it’s time to select a different treatment.

Ineffective Tumor Treatment

Stable Treatment

This chemotherapy is effective on the dominant blue tumor cells – which is good news! However, most others (red, dark-blue and pink) are resistant to treatment. Resistant cells replace dying cells and the tumor stays about the same size. More treatment-resistant cells emerge as mutated versions of previous tumor cells.

Stable Tumor Treatment

While the tumor is about the same size, the cell mutation composition is completely different than when treatment started. It is now dominated by cells that are resistant to the treatment and will begin growing again. We don’t have sufficient information to know when the treatment may fail. The tumor’s overall size may remain stable for months or even years. Many oncologists will continue the same treatment on this tumor until it is bigger or the patient can no longer handle the side effects.

Effective Treatment

Effective chemotherapy works on most, but usually not all tumor cells. Treatment-resistant tumor cells slowly emerge and multiply. Over a period of months, the tumor shrinks quickly and may even become too small to detect on scans. NED! Time to celebrate! Done with chemo! Not so fast.

Unfortunately, chemotherapy is curative in very few of cancers, like testicular cancer^2,3 and Hodgkin lymphoma³. Likely, tumor cells remain and will recur with a possibly different composition of tumor mutations. What’s a patient to do?

Effective Tumor Treatment

An effective treatment does leave you with more options.

You have a treatment that is known to be effective against the tumor’s original composition. If there is a recurrence, you can hope that the composition is similar and try the same treatment.
You may become eligible for surgical resection. This is the only reliable curative option for pancreatic cancers.
An effective treatment may last for years. You have bought some time for new treatments to come online.

Implications for Treatment

I think that this is the key takeaway of this post:

cancer tumors are composed of a heterogeneous mass of genetically altered cells that don’t all respond identically to treatment.

What treatment outcomes support this model of how tumors react to chemotherapy?

The most effective treatments target mutations present throughout the entire tumor, such as one of the original set as the normal cell mutated into the first cancer cell. If you’ve had an exceptional response, perhaps your oncologist can contribute your treatment information to the NCI’s Exceptional Responders Initiative and help improve outcomes for others?

Successful treatments target mutations found in both tumor and germline DNA with the goal of eliminating the entire tumor before a resistant mutation develops. Cases like this have been demonstrated in BRCA2 pancreatic cancer patients^4,5,6. A cancer panel test could identify germline mutations in many cancer-related genes.

Heterogeneity helps these tumors elude chemotherapy’s effects. In pancreatic cancers, this means that tumors treated with chemotherapy alone return and that surgical removal is the most reliable cure.

Mutational differences of tumor cells within the same tumor limits treatment effectiveness. Perhaps PanCan’s most successful chemotherapy is the four drug combination FOLFIRINOX because it targets multiple types of mutations simultaneously?

PanCan.org‘s Know Your Tumor program tests the tumor for DNA mutations. A report informs patients about treatments suspected to be effective against the identified mutations. Mostly, these treatments are only available through clinical trials, except for the important BRCA2/platinum and BRCA2/PARP inhibitor mutation/treatments combinations. Some hospitals and independent testing companies also provide this service.

The Future

I propose that every pancreatic adenocarcinoma patient have their germline (inherited) DNA tested for cancer-related mutations with pancreatic cancer panel tests like Ambry Genetics PancNext, GeneDx Pancreatic Cancer Panel, or Invitae‘s Pancreatic Cancer Panel. GetColor offers a direct-to-consumer hereditary cancer test. Some major cancer centers implement these tests for all their PanCan patients. Finding a mutations such as BRCA1 or BRCA2 greatly increasing your chances of effective treatments. More details on that in another post.

We need researchers to match tumor mutations and the effective treatments. Finding these matches is what PanCan.org’s Know Your Tumor program is all about.

When we apply chemotherapy to the tumor, evolutionary mutation changes favor cells unaffected by the treatment. Some cancer treatments try to counteract this effect by alternating between two treatments. Each treatment beats down one type of cell while allowing the others to exist, like the game of whack-a-mole. It is a delaying tactic that treats the cancer as a chronic condition always needing treatment. Pancreatic cancer does not yet have this type of treatment.

Several clinical trials are attempting to match specific mutation to treatments now. You can join in these or await the results.

Driving treatment decisions on 1 Aug 2016

References

[1]Fokas E, O’Neill E, et al. (2015). “Pancreatic ductal adenocarcinoma: From genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic”. Biochim Biophys Acta 1855(1):61-82. PMID: 25489989.

[2] American Cancer Society web page: Treatment options for testicular cancer, by type and stage: (accessed 31 Jul 2016) http://www.cancer.org/cancer/testicularcancer/detailedguide/testicular-cancer-treating-by-stage

[3] Cancer Research UK web page: How chemotherapy works: (accessed 31 Jul 2016) http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/chemotherapy/about/how-chemotherapy-works

[4] Sonnenblick A, Kadouri L, et al. (2011). “Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy”. Cancer Biol Ther 12(3):165-8. PMID: 21613821.

[5] Lohse I, Borgida A, et al. (2015). “BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts”. Br J Cancer 113(3):425-32. PMID: 26180923.

[6] Golan T, Kanji ZS, et al. (2014). “Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers”. Br J Cancer 111(6):1132-8. PMID: 25072261.