nanoknife IRE for pancreatic cancer

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RE: nanoknife IRE for pancreatic cancer

by cdaley2 on Wed Feb 14, 2018 05:18 PM

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Philip, Dr. O'Reilly  will request the CPI_613 on compassionate basis. However, the form says you must be folfirinox naive, which doesnt seem very compassionate to me!. My scan after 8 FOLFORINOX sessions shows mostly stability but slight growth in a couple. So while the Folfirnox is doing something, it's not gangbusters. If I can't get the 613, will go to Gem/Abrax, to which she agreed to at Cisplatin and Vitamin D as per Honor Health protocol.

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Thu Feb 15, 2018 04:15 AM

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Nab-Paclitaxel + Gemcitabine Upgrades
Benefits to adding Cisplatin, Nivolumab, Paricalcitol, Anakinra

Dear CDaley2,
          My posts are usually delayed by the forum system for 2 days, due to the links.
          Regarding CPI-613, I agree, not very compassionate.  The compassion may have taken place BETWEEN trials.  But, now that the manufacturer has a Phase 3 trial, it probably wants all CPI-613 use to conform to that trial.  Another patient informs me that Compassionate Use is also limited to USA and Israel.
          Regarding Cisplatin, you are an excellent advocate for yourself.  You’re proof of the Rule: Patients will not get special treatment unless they press for it.  You are likely to have good fortune.  Misfortune comes to those who are passive, lack skepticism and fail to do the hard work of medical journal research.
         Some other therapy options to consider. Monitor your new chemo regimen frequently, hopefully with PET. If there are problems, immediately consider a further modification of the Nab-P+Gem+Cisplatin regimen. As you know, time is an enemy.

>>> Perhaps switch to the components of the following regimen (an Honor Health design): Gemcitabine, Nab-Paclitaxel, Cisplatin, Nivolumab and Paricalcitol, if your oncologist can be persuaded.
          See Abstract 358 of the 2018 GI Cancers Symposium, which showed, for 10 patients, a Response Rate of 80% and a Disease control rate of 100%, which is Partial Response (80%) plus Stable Disease (20%).  See
http://clinicaltrials.gov/show/NCT02754726
         All the agents are available. Paricalcitol, similar to a Vitamin D2 analog, treats hyperparathyroidism.

>>> Perhaps switch to the components of the following regimen: Gemcitabine, Nab-Paclitaxel, Cisplatin and Anakinra.  You are almost there already.
          See GI Symposium Abstract 449.  Anakinra is a readily available arthritis drug.  For 13 months no patient developed metastases while treated with this regimen.
https://clinicaltrials.gov/ct2/show/NCT02550327

          Note that most of the well-performing regimens, presented at 2018 GI Cancers Symposium, contain Cisplatin, if the backbone was initially Nab-P+Gem.  The abstracts are here:
http://jaxelection.altervista.org/pancreatic/2018ASCOGICance
         PhilipJax

PS: Often, oncologists make a God’s judgment: Shall I make every effort to treat this patient responsible and cleverly, which might help her somewhat but postpone the inevitable, or should I use this life in an uncertain trial which may help all mankind?
         Frequently, they push the patient into the trial without telling her the grave uncertainties. And, sometimes these oncologists oversee trials which need experimental subjects – that conflict-of-interest is unethical and frequent.

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Wed Feb 21, 2018 01:51 PM

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Third-Line Chemotherapy Regimens
What to Use When the 1st & 2nd Lines Fail
Or, How to Plan the Sequence

Everyone:
          There is a great need for Third-Line therapies for Pancreatic Adenocarcinoma.  So, I have tried to gather what is known.
          The NCCN guide does not address the subject, although, its Evidence Block section (around page 4 and around pages 39-44) offers information on the performance of numerous chemo regimens, some of which are non-mainstream.
          But for Third-Line therapy, NCCN merely suggests clinical trials, which is not helpful.  If a clinical trial is sought, it is wise to choose a combination which adds an experimental therapy to a known core regimen.  It is very unwise to select a trial whose components have NOT been tested in human trials, whose performance numbers (Response Rate, Progression Free Survival and Overall Survival) are unknown.
          The NCCN guidelines can be found via this link.  And, I will post the 2018 edition when it is published in a few weeks.
http://jaxelection.altervista.org/pancreatic/NCCN3.2017Pancr
          The following 2016 German article offers some reasonable options for Third-Line agents.  And, the article’s Therapeutic Algorithm (Figure 6), available here in a cleaner format, offers many alternatives for each of the three treatment lines.
http://jaxelection.altervista.org/pancreatic/3rdThirdLine201
http://jaxelection.altervista.org/pancreatic/TherapeuticAlgo
          The Figure 6 algorithm repeats Gemcitabine in two different lines with some success.  And, the authors rely frequently on Erlotinib (an EGFR tyrosine kinase inhibitor) for part of a Third Line therapy, although other targeted therapies, for example Refametinib, might be used in the pair.
          In one Figure 6 path (G/P, G+E, C+E) Oxaliplatin might be added to G+E for more impact.  And, Cisplatin might be added to G/P in at least two treatment paths (G/P, G+E, C+E and G+E, G/P, C+E).  More on Cisplatin below.
          In addition, the tables of the following document give comparative data on KNOWN agent combinations.  The table data provide only a rough comparison, because patient groups often have different physical conditions and different therapy failures.
http://jaxelection.altervista.org/pancreatic/14_TargetedTher
          Some additional Third-Line regimens are discussed during the following interview with oncology leaders.
http://jaxelection.altervista.org/pancreatic/GoodTranscript_
          Found in other oncology journals is the regimen series: Gemcitabine+Nab-Paclitaxel, then Nal-IRI+5FU, then FOLFOX – which assures that each key agent (Gemcitabine, Irinotecan and Oxaliplatin) is used only once.  However, FOLFOX is a relatively ineffective regimen.  So, a better one, also containing Oxaliplatin, might be preferred for the Third-Line.
          Nevertheless, FOLFOX did well when combined with AM0010.  See
http://jaxelection.altervista.org/pancreatic/AM0010+FOLFOX_2017GastrointestinalCancersSymposium.doc
http://jaxelection.altervista.org/pancreatic/AM0010+FOLFOXMetastatic2017.pdf
          The GTX regimen (Gemzar® Gemcitabine, Taxotere® Docetaxel, Xeloda® Capecitabine) has also performed fairly well, and, according to one trial report, “survival did not correlate with the number of prior regimens,” meaning that its effectiveness did not seem affected by prior chemotherapy.
          Component dosages for the core chemo regimens are detailed in this document:
http://jaxelection.altervista.org/pancreatic/Pancreatic2017T
          In addition, when Gemcitabine+Nab-Paclitaxel is used, it may be wise to add Cisplatin, and perhaps other agents.  See this document.
http://jaxelection.altervista.org/pancreatic/AddCisplatinToGem+NabPaclitaxel2017.doc
          The addition of Cisplatin (and other agents) is described in Abstracts 358 and 449 of the 2018 Gastrointestinal Cancers Symposium, which report very good performance due to the additions of Cisplatin, Nivolumab, Paricalcitol and Anakinra to Gemcitabine+Nab-Paclitaxel.  However, the test groups were small creating less reliability.
          The two abstracts can be found in the following document.  Each abstract gives a link to its clinical trial website, so you can determine the agent dosages.
http://jaxelection.altervista.org/pancreatic/2018ASCOGICance
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by Barbara19 on Sun Feb 25, 2018 09:14 PM

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@PhilipJax Can NANOKNIFE be accomplished if SBRT fidicuals are already in place? My bro didn’t have SBRT .. markers were placed for a clinical trial that he was subsequently deemed not eligible for. We are here in Miami & went to see Dr DONOWAY last week. PET SCAN shows no Mets outside of pancreas Malignant ASCITES under control. He is eligible for IRE Dr

RE: nanoknife IRE for pancreatic cancer

by Barbara19 on Sun Feb 25, 2018 09:21 PM

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Did the markers get in the way of having NANOKNIFE? Was Dr able to go around them? MY BRO had the markers put in but has never had SBRT. Can they be taken out before the surgery? Did you have SBRT after NANOKNIFE as well?

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Mon Feb 26, 2018 01:43 PM

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IRE, Stents & Fiducial Markers for Radiation

Dear Barbara19
          Markers.  The following article by IRE leader Robert CG Martin, page 1, speaks of the inability to utilize IRE around metal stents and potentially metal fiducial markers because of the significant conductive electrical energy that is achieved.”
          Regarding fiducial markers, there are numerous cases of IRE performed AFTER radiotherapy.  So, the markers were clearly managed.  You have Dr Donoway’s email address.  Please inquire of him how he would handle the case, and let us know.
http://jaxelection.altervista.org/pancreatic/IRE2016Update_M
          A possible concern about Fiducial Markers is that the insertion needle may cause the seeding (spreading) of tumor cells to sites along the needle track.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861831/
          Stents.  Further, metal stents can often be removed or bypassed surgically, but not always.  So, initially it is better to install stents that are removable.
          Plastic stents and certain “covered” self-expanding metal stents can be repositioned or fully removed.  Some are equipped with retrieval loops.  The exterior coverings consist of membranes made of polytetrafluoroethylene, polytetrafluoroethylene/fluorinated ethylene propylene or silicone.
          Radiation. In addition, on page 2 of his article, Dr Martin cautions against undergoing radiation BEFORE IRE, stating: “Similarly, IRE should be used with caution after high dose radiation therapy because of the significant damage that the radiation therapy induces and the inability for reparative effects after IRE to be obtained.”
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Tue Feb 27, 2018 12:19 AM

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Napabucasin (BBI-608)
Cancer Stemness Inhibitor

Everyone
          For metastatic patients there is a helpful development, especially if you have not yet started any therapy.
          The cancer stemness inhibitor (a new class of drugs) Napabucasin (BBI-608) performed favorably in a Phase 1b/2 clinical trial when combined with Gemcitabine (Gem) and Nab-Paclitaxel (NabPTX).
          There is no report on the agent’s performance when combined with backbone regimes, mFOLFIRINOX, FOLFIRI or 5FU+Nal-Iri, although they were part of the research.  And, the new Phase 3 trial uses Gen + NabPTX only, suggesting that other backbones are not suitable.
          Among 66 Intent To Treat (ITT) patients, the Disease Control Rate (DCR) was 77% (51/66), which include 2 (3%) Complete Responses, 28 (42%) Partial Responses and 21 (32%) Stable Disease.  The Response Rate was 45% (30/66)
          Maturing median progression free survival and overall survival (OS) in ITT pts were >7.1 months and >10.7 months, respectively.  The study reports are here:
http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-
http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-
          The study included both therapy naïve patient and those having 1-2 prior therapies.  We don’t know which of the two fared better.
          The Phase 1b trial (link below) is now closed.  For the Phase 3 trial, the patient “must not have previously received chemotherapy or any investigational agent.”  There are more limitations, so study the eligibility criteria carefully.
          The Phase 1b/2 non-randomized trial is no longer open.  Details at
https://clinicaltrials.gov/show/NCT02231723
          A Phase 3 trial is underway at 158 sites worldwide (USA, Europe, Australia, Asia), with an enrollment of 1,132.  It is randomized, so only about half of patients receive the experimental agent.  See
https://clinicaltrials.gov/show/NCT02993731
          Both trials meet the definition of “prudent” trial choices, since, at minimum, everyone receives standard therapy: Gemcitabine + Nab-Paclitaxel.
          Of course, there is no cure with the exception of resection (surgery), and surgery does not guarantee cure.  The objective is to get the patient resectable, or, if not that, to buy time until the next helpful therapy comes along.
          Napabucasin’s “Orphan Drug” status, assigned by FDA in 2016, COULD make the drug available sooner.  But, it is not generally available yet.
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by juliejones40 on Wed Feb 28, 2018 10:54 PM

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Hi Philipjax,

Regarding third line therapies, if folfirinox and gem/abr have not worked for 1st and 2nd line chemos, is there any benefit in having them in the third line therapies ?

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Thu Mar 01, 2018 04:06 PM

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Third Line Therapy Possibilities
Erlotinib+Capecitabine or Erlotinib+Gemcitabine

Dear juliejones40& Everyone:
          My replies are often delayed a day or two while the forum system approves the web links.
          After First and Second Line regimens FOLFIRINOX and Nab-Paclitaxel+Gemcitabine have failed, medical oncologists usually do not return to their key components which are Irinotecan, Oxaliplatin and Gemcitabine.
          As a Third Line therapy the authors of the following research article suggest either Capecitabine+Erlotinib (C+E) or Gemcitabine+Erlotinib (G+E).  In fact the authors, in the case described, used both Erlotinib and Gemcitabine in two different therapy lines and unexpectedly found them still helpful.
          Unfortunately, the C+E and G+E therapies are not as effective as the usual first and second line regimens.  Capecitabine is an oral form of 5FU.
          However, this and other research shows that Erlotinib is performing better, if the patient develops a skin rash.  The two articles and an enlargement of Figure 6 are downloadable here:
http://jaxelection.altervista.org/pancreatic/3rdThirdLine201
http://jaxelection.altervista.org/pancreatic/TherapeuticAlgo
http://jaxelection.altervista.org/pancreatic/ErlotinibRashMa
          Some genetics-related thoughts.  You might also consider adding Cisplatin to the regimen, especially if there is a BRCA mutation, which occurs in less than 10% of patients, usually those with hereditary familial disease.  BRCA also plays a role in hereditary breast and ovarian cancers.
          Given that the researchers used Gemcitabine in two therapy lines with some success, you might consider the regimen: Gemcitabine+Docetaxel+Capecitabine (the GTX regimen), followed by single agent Nal-Iri, a microencapsulated form of Irinotecan – especially if the patient is strong, and BRCA is suspected.  But, you may have to fight to get oncologist cooperation which is a worthy fight.
          In addition, if the patient is MicroSatellite Instability-High (MSI-H), which is rather rare, you should consider the anti–PD-1 antibody Pembrolizumab.  It has been shown to be helpful, often very helpful.  See the one-paragraph discussion in this interview:
http://jaxelection.altervista.org/pancreatic/CheckpointInCRC
          Some of the genetic-related possibilities are long shots. But, when the patient gets to the Third Line it is worthwhile to buy time in the hope that the next best thing will arrive.
          Also, be sure to read my post about one week ago on Third Line Therapies, including the lengthy interview document:
http://jaxelection.altervista.org/pancreatic/GoodTranscript_
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Fri Mar 02, 2018 12:29 PM

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NEW Third Line Therapy
Another Possibility

Everyone:
          A new chemo regimen MAY work well for patients after FOLFIRINOX and Nab-Paclitaxel+Gemcitabine have failed.
          The new regimen is Nab-Paclitaxel plus “simplified” 5FU/Leucovorin (the de Gramont simplification LV5FU2).
          According to a 2017 report, it did as well or better then Nab-Paclitaxel+Gemcitabine in mostly therapy-naïve patients.
          However, because it does not use the key components of First Line and Second Line regimens (Irinotecan, Gemcitabine and Oxaliplatin), the new regimen may also work well in heavily pre-treated patients.
          According to the research (the report is linked below) which took place at 15 French institutions:
1. The Response Rate was 35% vs 36%, LV5FU2 vs Gemcitabine, respectively, each with added Nab-Paclitaxel.  See Table 2 of the report.
2. The Progression Free Survival was 5.9 vs 4.9 months, LV5FU2 vs Gemcitabine.
3. The Overall Survival was 11.4 months vs 9.2 months.
4. The LV5FU2 group had better Overall Survival rates at 12 months (48% vs 41%) and 18 months (34% vs 13%).
          It should be noted that approximately half of all study patients eventually received Second Line and/or Third Line therapy.  So the above performance numbers do not represent the LV5FU2 vs Gemcitabine therapies alone.
          Nevertheless, LV5FU2+Nab-Paclitaxel generally performed better than Gemcitabine+Nab-Paclitaxel; so, it MAY function as a potent Third Line therapy when Gemcitabine+Nab-Paclitaxel and FOLFIRINOX have already failed.
          If the patient is strong, there may be other agents which could be added to the new LV5FU2 regimen, agents like Cisplatin and Erlotinib, especially if the hereditary BRCA condition is present.
          The report is here
http://jaxelection.altervista.org/pancreatic/5FU+NabPBeatsGem2017France0468HiLite1.pdf
          Be sure to study the two previous essays on Third Line therapies, posted within the past several weeks.
         PhilipJax

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