nanoknife IRE for pancreatic cancer

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RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Thu Jan 11, 2018 03:02 AM

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Stress & Beta-Blocker
Role in Longevity

Everyone:
          I am not a medical professional, but a physicist, which aids the understanding of scientific terms and medical reports.  Danny, act fast on the CPI-613.  Your mother might get lucky and turn out to be a rare super-responder.

Beta-Blockers & Longevity
          We should always be reluctant to rely on data from pre-clinical (non-human) trials.  However, the following information comes from major research centers and is probably harmless to implement.  And, the pancreatic cancer victim is desperate for any reasonable means to fight this disease.
          We’ve always suspected that stress does not help pancreatic cancer victims.
          Researchers at Columbia University and centers in Germany, Japan, Italy and Australia report in the 08Jan2018 edition of Cancer Cell:
(1) that NON-selective beta-blockers (used to treat hypertension and likely to reduce “brain stress”) dramatically increased the longevity of mice suffering from pancreatic cancer, and
(2) that surgically-resected Stage-2 and Stage-3 patients, those receiving non-selective beta-blockers (propranolol, carvedilol, or sotalol), experienced a nearly doubled Overall Survival (40 versus 23 months), compared to patients who received NO beta-blockers.
          There is a significant flaw in this retrospective analysis: Only 17 patients consumed non-selective beta-blockers; 151 received selective beta-blockers (which were ineffective), and 427 received none.  So, there are great promises, but little to base them on.  See the report summery and full report here:
http://jaxelection.altervista.org/pancreatic/StressAffectsPC
http://www.sciencedirect.com/science/article/pii/S1535610817
          And, “The analysis was limited by the uncertain duration and dosage of beta-blockers.”
          The Columbia report references another study which apparently supports the Columbia claim: Udumyan et al, Beta-blocker drug use and survival among patients with pancreatic adenocarcinoma, Cancer Res. 2017.  In the Udumyan study only 21 of 2,394 patients utilized non-selective beta-blockers.  Nevertheless, “patients who used beta-blockers (numbering 522) had a lower cancer-specific mortality than nonusers.”  See the report
http://refhub.elsevier.com/S1535-6108(17)30510-X/sref54
          And, a second study, cited by Columbia, is said to find “improved survival in patients with PDAC on beta-blocker therapy.”  The study report: Beg et al. Impact of concurrent medication use on pancreatic cancer survival-SEER-Medicare analysis, Am. J. Clin. Oncol., 2017.  See the report
https://doi.org/10.1097/COC.0000000000000359
          So, the thesis is: If you have undergone resection or primary IRE, take a non-selective beta-blocker.

Bacteria Deactivates Gemcitabine
          The only other preclinical data I’ve posted appeared a few months ago – pre-clinical information on intra-tumor bacteria and how it may deactivate Gemcitabine.  That study speculated that, in non-response cases, certain antibiotics may restore Gemcitabine’s effectiveness.  So, if you are not responding to a Gemcitabine-based regimen, consider adding a suitable antibiotic.  Please refer to the earlier posting for more information.
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by cdaley2 on Thu Jan 11, 2018 04:02 PM

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Everyone, 

On the subject of Nanoknife, (still on my quest for the right lung mets treatment), I "e-spoke" with Dr. Robert Donoway, who will do IRE on selected Stage IV patients unlike Dr. Martin, for example. My question was whether or not there was a role for nano-knife with lung mets. His response was that w/r/t lungs, this is one of the few circumstances where IRE is not appropriate. The reason is that because of the nature of the open procedure (I think he mostly does open), there is a real risk of puncture, lung collapse, etc. 

Separately, but related, I paid a visit to a thoracic surgeon at JHH, who reviewed my scans and case, etc. and he said that he thought I was operatable, ie resection  to the mets in the lung, all of which are "subpleural". He would do the one with the biopsied confirmed nodule first (right) and then watch the left one and see if there is any activity or just barnicles. If I did both lungs, it would be 2 operations, 6 weeks apart. About a 2 week hospital stay. IMPORTANTLY,

all this is dependent upon my ability to get the mets at least stabilized on chemo. The scan after 4 treatments of FOLFIRINOX showed no growth in some tumors but slight growth in others, pluls a pleural effusion whcih may be associated with the biopsy. Because there was one-month gap between the last scan, and the initiation of chemo, Dr. O'Reilly thought it was premature to conclude it was not going to work, so I'm still on it and will have a scan next month. Hoping for the best. I asked her why and under what circumstances does FOLFIRINOX not work - she said usually it was because of 2 heavy a tumor burden, which is not my situation. We'll see. I keep wondering if this bacteria thing mentioned by Philip Jax could be a culprit as well. I have searched and searched but couldnt find anything as to why it wouldn't work. Frustrating. Chris

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Thu Jan 11, 2018 07:34 PM

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Lung Metastases
Predicting FOLFIRINOX Response

Cdaley2,
          I have omitted links to get this message to you without the usual 2-day delay.
1. If undergoing FOLFIRINOX, consider adding CPI-613, which is available on compassionate use.  The topic is covered thoroughly in a previous post.  Do not worry about offending the oncologist.  She is not the one who is dying.
2. True, IRE is not suitable for lungs.  However, there are other ablation methods, described with detailed journal articles in a previous post.
3. The bacteria issue, to date, applies only to Gemcitabine.  However, it is possible that that may change.
4. A previous post includes a link to HowToPredictResponseToFOLFIRINOX2015PancreaticDuctalAdenocarcinoma.doc.  Just substitute this file name into previous links.  That report will tell you how to test (in advance) whether the regimen will help.  Ask yourself: Why did the oncologist not order the Carboxylesterase 2 (CES2) test?
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by GinaGB on Thu Jan 11, 2018 08:16 PM

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Do you know if alpha liopic acid can be used instead of CPI-613 (alpha-lipoic acid analogue)? Thanks

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Thu Jan 18, 2018 02:49 PM

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PEGPH20 Fails

ASCO 2018 Gastrointestinal Cancers Symposium

Everyone:
          I will be reporting on the ASCO 2018 Gastrointestinal Cancers Symposium taking place this week.
          I am very sorry to report that, in an unexpected, devastating turnaround, PEGPH20 researchers have found that all past hopes for the agent’s success have been proven wrong and that the "addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental."
          The control group (the patients NOT receiving PEGPH20) appears to have performed BETTER than the PEGPH20 group.  What a terrible setback for pancreatic cancer victims.
          The abstract is below.
         PhilipJax

A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).

Sub-category: Multidisciplinary Treatment
Category: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Meeting: 2018 Gastrointestinal Cancers Symposium
Abstract No: 208
Poster Board Number: Poster Session B (Board #A5)
Citation: J Clin Oncol 36, 2018 (suppl 4S; abstr 208)
Author(s): Ramesh K. Ramanathan, Shannon McDonough, Philip Agop Philip, Sunil R. Hingorani, Jill Lacy, Jeremy S. Kortmansky, Jaykumar Ranchodbhai Thumar, E. Gabriela Chiorean, Anthony Frank Shields, Deepti Behl, Paul Tracy Mehan, Rakesh Gaur, Tara Elisabeth Seery, Katherine Guthrie, Howard S. Hochster; Mayo Clinic, Scottsdale, AZ; Fred Hutchinson Cancer Research Center, Seattle, WA; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Yale School of Medicine, Yale University, New Haven, CT; Medical Oncology and Hematology, Hamden, CT; Saint Francis Medical Group, Inc., Middletown, CT; Sutter Medical Center, Sacramento, CA; Missouri Baptist Hosp, St Louis, MO; Kansas City NCORP, Lenexa, KS; University of California, Irvine, Irvine, CA

Abstract:

Background:
PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA.

Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power).

Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm.

Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139.

Selected GR 3-4 Toxicity

mFFOX

mFFOX+PEGPH20

Diarrhea

19%

24%

Dehydration

13%

8%

Fatigue

11%

20%

Nausea

15%

25%

Vomiting

13%

22%

TE Events (All grades)

4%

18%

TE events (all Grade, after LMWH)

5%

9%

 

RE: nanoknife IRE for pancreatic cancer

by GinaGB on Thu Jan 18, 2018 07:03 PM

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Hello Has anyone here been able to get hold of CPI-613 on compassionate bases? I contacted the company and based on their requirements, it’s almost impossible for anyone who already started the treatment to be qualified? Any tips/advice is highly appreciated. Thanks

RE: nanoknife IRE for pancreatic cancer

by danny4mami on Thu Jan 18, 2018 10:18 PM

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Hi all, My mum was diagnosed as stage 4 pan can in late Oct 2017 with a PET-CT scan, and started FOLFIRINOX immediately. As heard there are about 5-10% patients who can't secrete CA19-9 and I guess my mum is one of them, coz her CA19-9 is ALWAYS within normal range. (At diagnosis, 12.1. During treatment it's about 6-8) However, my mum's CA125 and CEA kept elevating during the treatment. So my oncologist arranged a PET scan after round 3 of FFX. PET scan result is positive. All tumors were either shrinking or weakening, despite the slightly increased mildly metabolic ascites. No new detectable mets. So my mum continued with FFX. But CEA and CA125 kept rising. Until after the round 5 of FFX, CEA and CA125 rises in a significant amount (CEA from 4xx to 6xx. CA125 from 9xx to 12xx). So my oncologist arranged one more CT scan. The result is strange. The primary tumor on pancreas head is shrinking, with originally infected lymph nodes cleared of cancer. But mets on liver are enlarging, some even larger than that when diagnosed. No new detectable mets. While ascites mildly increased too. My oncologist claimed the followings possibilities. 1. There may be "partial" drug resistance to my mum, that cancer cells on liver and peritoneal resist the chemo drugs whereas the primary tumor does not. 2. There are primary tumors on liver. For situation 1, oncologist recommended change of regimen to gemzar plus abraxane. For situation 2, which onco claimed to be a more difficult case, FFX / gemzar abraxane plus targeted thereupetic drugs of liver cancer will be added. If FFX is no longer suitable for my mum, the CPI-613 compassionate use is no longer applicable too. Hopefully next Monday we will know the biopsy result. But situations are a bit too complicated for me. Can anyone give advice to me or comment on my mum's case? Things turn complicated when systemic chemo seems not systemic at all... Best regards, Danny

RE: nanoknife IRE for pancreatic cancer

by danny4mami on Thu Jan 18, 2018 10:28 PM

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Hi all,

My mum was diagnosed as stage 4 pan can in late Oct 2017 with a PET-CT scan,  and started FOLFIRINOX immediately.

As heard there are about 5-10% patients who can't secrete CA19-9 and I guess my mum is one of them, coz her CA19-9 is ALWAYS within normal range.

(At diagnosis, 12.1. During treatment it's about 6-8)

However, my mum's CA125 and CEA kept elevating during the treatment. So my oncologist arranged a PET scan after round 3 of FFX. 

PET scan result is positive. All tumors were either shrinking or weakening, despite the slightly increased mildly metabolic ascites. No new detectable mets.

So my mum continued with FFX.

But CEA and CA125 kept rising. Until after the round 5 of FFX, CEA and CA125 rises in a significant amount (CEA from 4xx to 6xx. CA125 from 9xx to 12xx).

So my oncologist arranged one more CT scan. The result is strange. The primary tumor on pancreas head is shrinking, with originally infected lymph nodes cleared of cancer. But mets on liver are enlarging, some even larger than that when diagnosed. No new detectable mets. While ascites mildly increased too.

My oncologist claimed the followings possibilities. 1. There may be "partial" drug resistance to my mum, that cancer cells on liver and peritoneal resist the chemo drugs whereas the primary tumor does not. 2. There are primary tumors on liver. For situation 1, oncologist recommended change of regimen to gemzar plus abraxane. For situation 2, which onco claimed to be a more difficult case, FFX / gemzar abraxane plus targeted thereupetic drugs of liver cancer will be added. If FFX is no longer suitable for my mum, the CPI-613 compassionate use is no longer applicable too.

Onco arranged a biopsy for my mum and it's done. Result will hopefully be out on next Monday. But situations are a bit too complicated for me. Can anyone give advice to me or comment on my mum's case? Things turn complicated when systemic chemo seems not systemic at all... Best regards, Danny

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Fri Jan 19, 2018 02:24 AM

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Upcoming CPI-613 Trial

Gina & Everyone,
          A Phase-2 CPI-613 trial begins soon.  However, it is restricted to therapy naïve (no prior therapy) patients.
          Researchers establish such restrictions to achieve the most reliable assessment of the agent’s effectiveness.  Patients with prior therapy may have developed resistance to some traditional therapy agents, creating a false outcome for the experimental agent.
          When I asked the CPI-613 project leader in July 2017 about patient Inclusion Criteria, he said: “We . . . consider compassionate use on a case by case basis, but if the phase I inclusion criteria are met that does help.”  That approach may have changed, now that a Phase-2 trial is coming, or the lower staff may not be so flexible as upper management.
          Also, the 2018 ASCO GI Cancers Symposium MAY reveal a better therapy.  If that happens I will post the information immediately.
          The coming CPI-613 trial will enroll only 45 patients at one institution so far: Sidney Kimmel Cancer Center in Philadelphia.  The trial is detailed here:
https://clinicaltrials.gov/show/NCT03374852
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Fri Jan 19, 2018 08:25 PM

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2018 Gastrointestinal Cancers Symposium
In Installments

Everyone,
          Today, I begin reviewing  abstracts from the 2018 GI Cancers Symposium.  There are at least 40 relevant abstracts; so, over a period of several days or weeks, I will cover the “best”.  If you can’t wait, the abstracts are found here:
http://abstracts.asco.org/210/CatAbstView_210_59_AA.html
          The order in which I present the abstracts does NOT signify their importance.  I am merely beginning with abstract 348, among the first in the pancreatic series.
         PhilipJax

Abstract 348: Secondary resectability in locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/gemcitabine- versus FOLFIRINOX-based induction chemotherapy: Interim results of a randomized phase II AIO trial (NEOLAP)
          In this interim report on research in Germany, all 86 patients underwent two cycles of Nab-Paclitaxel/Gemcitabine (nPG).  Then, half received an additional two cycles of nPG, and half received four cycles of FOLFORINOX.
          Before chemotherapy the resection rate was approximately 26%.
          But, following chemotherapy, the complete macroscopic resection (R0/R1) rate was 43% for nPG + nPG and 62% for nPG + FOLFIRINOX, for those patients (a total of 44) who received surgical exploration by laparotomy.
          This suggests that the mixed nPG + FOLFIRINOX regimen may be superior.  Keep in mind that these were locally-advanced (not metastatic) patients.  Also, the number of patients is relatively small, making it unreliable to extrapolate the outcome to the most patients.
          Trial information is here, although a patient does not have to participate in this trial to adopt the mixed regimen.
http://clinicaltrials.gov/show/NCT02125136
          The abstract is here:
http://abstracts.asco.org/210/AbstView_210_202317.html

Abstract 349: The Canadian Cancer Trials Group PA.7 trial: Results from the safety run in of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D), and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC)
          Early in this research, which adds Durvalumab and Tremelimumab to Gemcitabine / Nab-Paclitaxel, 8 metastatic patients have experienced Partial Responses among 11 patients, a 73% Response Rate, which is very good.  Progression Free Survival was 7.9 months.  Overall Survival is not yet known.
          Again, because the group sizes are small, the outcomes are difficult to extrapolate.  The trial is apparently ongoing, but it may be limited to previously untreated patients.
http://clinicaltrials.gov/show/NCT02879318
          The abstract is here:
http://abstracts.asco.org/210/AbstView_210_203275.html

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