nanoknife IRE for pancreatic cancer

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RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Sat Jan 20, 2018 02:57 AM

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2018 Gastrointestinal Cancers Symposium, Part 2
Better First Therapy: Nab-P / Gemcitabine or FOLFIRINOX?

Everyone,
         Two Symposium reports address the dilemma: For metastatic patients which of the standard regimens is better, Gemcitabine / Nab-Paclitaxel or FOLFIRINOX?

Abstract 354: Efficacy of nab-paclitaxel plus gemcitabine (AG) vs. FOLFIRINOX as first line chemotherapy for metastatic pancreatic cancer (mPC)
          South Korean researchers report on 308 metastatic patients, assigned nearly equally to the two regimens.  They found that
>> Progression Free Survival for the AG group was 6.8 months vs. 5.1 months for the FOLFIRINOX group.
>> Overall Survival was significantly better in the AG group compared to the FOLFIRINOX group (median 12.3 months vs. 9.7 months).
          Among the patients who showed progression, 81% (180/223) received second-line chemotherapy: 5-FU monotherapy or combination with Oxaliplatin were given in 97% (73/75) of the AG group, and gemcitabine-based regimens (including 2 cases of AG) were given to 97% (102/105) of the FOLFIRINOX group.
         It should be noted that Asians may respond differently then Europeans to chemotherapies for GI cancers.

Abstract 376: Comparative effectiveness of nab-paclitaxel plus gemcitabine (nab-P+G) versus FOLFIRINOX (FFX) in metastatic pancreatic cancer: A nationwide chart review in the United States
          Researchers analyzed the medical records for 654 metastatic patients, 337 receiving nab-P+G, and 317 receiving FFX as first line therapy.
>> Median Overall Survival was 12.1 and 13.8 months for nab-P+G and FFX, respectively
>> Weaker patients often receive nab-P+G.  But, when a subgroup of stronger patients was evaluated, the Median Overall Survival was 14.1 and 13.7 months, respectively, nab-P+G vs. FFX.
>> Those who went on to a second line regimens experienced Overall Survival of 16.3 and 16.6 months, respectively.
>> Nab-P+G was associated with significantly lower rates of common adverse events compared with FFX.
          The abstracts can be found here:
http://abstracts.asco.org/210/AbstView_210_202809.html
http://abstracts.asco.org/210/AbstView_210_203775.html
          Stay tuned.  More abstracts to come.
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Sat Jan 20, 2018 09:48 PM

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Liver Infusion Chemotherapy

Danny,
          If your mother is strong enough, you may wish to try the technique described in Abstract 360 (link below) presented this week at the ASCO 2018 Gastrointestinal Cancers Symposium.
          This could be a primary hepatic tumor – such coincidences do occur. The technique (with a suitable agent) may not work, but your oncologist’s current path won’t work either.
         PhilipJax

Impact of adjuvant hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil with systemic gemcitabine for resectable pancreatic cancer
          Ignore the reference to “resectable”.  It is the technique that is imaginative.  Add Nab-P (at minimum) to the Gemcitabine.
http://abstracts.asco.org/210/AbstView_210_203667.html

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Sun Jan 21, 2018 09:30 PM

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2018 Gastrointestinal Cancers Symposium, Part 3
More FOLFIRINOX vs. Nab-P / Gemcitabine

Everyone,
          In Part 2, two studies suggested that the regimen Nab-Paclitaxel + Gemcitabine is superior to FOLFIRINOX in the First Line treatment of metastatic patients.
          However, some of the following findings may challenge that judgment.
         PhilipJax

Abstract 414: Folfirinox (FFX) versus gemcitabine with nab-paclitaxel (GNP) in the first line treatment (1LTx) of metastatic pancreatic cancer (mPC): A tertiary center experience
          Researchers undertook a retrospective analysis of 75 metastatic patients treated at one Canadian institution.  Forty-four (44) received FOLFIRINOX (FFX) and 31 received Nab-Paclitaxel + Gemcitabine (GNP).
          The median Progression Free Survival for the FFX and GNP groups were 5.75 and 4.63 months, respectively, and the OS with FFX and GNP was 9.23 vs. 6.6 months.
          This outcome does not agree with Abstracts 354 and 376 (summarized in Part 2), which may be more reliable because their sample sizes were far larger.  And, in the earlier Abstract 376, the researchers accounted for the frequent assignment of weaker patients to GNP.
          We should also rely slightly less upon Korean Abstract 354, since Asians may respond differently than Europeans to GI cancer agents.  One MIGHT conclude, therefore, that for First Line treatment of metastatic patients, the two regimens are almost equal.
          Abstract 414 can be found here:
http://abstracts.asco.org/210/AbstView_210_202689.html

Abstract 402: FOLFIRINOX versus Gemcitabine/Nab-Paclitaxel for neoadjuvant treatment of resectable and borderline resectable pancreatic adenocarcinoma: A propensity matched analysis
          This relatively-small single-institution study of 193 patients also appears to contradict the metastatic research described in Part 2.  However, Abstract 402 deals with Resectable and Borderline Resectable patients who received either FOLFIRINOX or Gemcitabine/Nab-Paclitaxel (G-nP) BEFORE resection.
          So, the effectiveness data refer to resected patients.  The use of FOLFIRINOX increased Overall Survival by 4.9 months above G-nP.  And, FOLFIRINOX was associated with a reduction in regional node metastases.
          Finally, regardless of the regimen, the number of neoadjuvant cycles was found to be an independent predictor of survival.
          Abstract 402 can be found here:
http://abstracts.asco.org/210/AbstView_210_203555.html

Abstract 370: Three fluoropyrimidine-based regimens in second-line therapy following nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: Efficacy and tolerance in clinical practice
          For metastatic cases researchers at 11 French centers sought to learn which of three fluoropyrimidine-based regimens performed best after failure of First Line Nab-Paclitaxel / Gemcitabine (N+G).
          Sixty-one (61) patients received Second Line chemotherapy, either FOLFOX, FOLFIRINOX or FOLFIRI.  The outcomes were the following:
> FOLFOX (24 patients): PFS 1.9mo, OS 3.3m
> FOLFIRINOX (16 patients): PFS 3.4mo, OS 6.1mo
> FOLFIRI (21 patients): PFS 6.6mo, OS 9.9mo, where PFS is Progression Free Survival, and OS is median Overall Survival.
          A Third Line regimen was used in 32.8% of Second Line patients, with “no statistical significance between the subgroups,” according to the researchers.
          The results suggest the importance of Irinotecan (IRI) and the underperformance of Oxaliplatin (OX).  This is not the first time Oxaliplatin has been shown valueless.  See
http://jco.ascopubs.org/content/early/2016/09/07/JCO.2016.68
          However, the overall conclusions of this study may be debatable, because the group sizes are so small.  Nevertheless, this is a clue for decision-making, and a reminder of how difficult it is to defeat this disease.
          Abstract No: 370 can be found here:
http://abstracts.asco.org/210/AbstView_210_201519.html

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Mon Jan 22, 2018 08:37 PM

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2018 Gastrointestinal Cancers Symposium, Part 4
New Regimens

Everyone,
          The performances of several new regimens were reported at the 2018 GI Symposium. I’ve presented two below, and will detail more when I encounter them among the abstracts.
         PhilipJax

Abstract 358: A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC).  The abstract is here:
http://abstracts.asco.org/210/AbstView_210_204281.html
          Nivolumab, Paricalcitol and Cisplatin were added to a standard regimen of Gemcitabine and Nab-Paclitaxel to treat 10 previously-untreated patients suffering from metastatic Pancreatic Ductal Adenocarcinoma (PDAC).  The outcome was very promising:
>> Of the 10, 8 experienced Partial Response, and 2 had Stable Disease, for and 80% Response Rate.
>> Progression Free Survival was 8.2 months.  Median Overall Survival has not been reached.
          The Response Rate is exceptionally good.  However, the sample size is very small; so, the good results may diminish when a far larger patient population is treated.
          The trial is expanding slightly, to 25 patients.  So, act quickly.  Unfortunately, the trial likely wants treatment-naïve patients (those have not prior therapy).  Trial details are here:
http://clinicaltrials.gov/show/NCT02754726
          Important.  It is conceivable that the regimen’s good performance is due largely to the addition of Cisplatin to Gemcitabine + Nab-Paclitaxel, which does not require a trial to access.  The exceptional performance numbers for Cisplatin (which include 2 Complete Responses) are found in this report:
http://jaxelection.altervista.org/pancreatic/AddCisplatinToGem+NabPaclitaxel2017.doc

Abstract 374: Overall survival of PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).  See
http://abstracts.asco.org/210/AbstView_210_204049.html
          I have previously reported on the AM0010 + FOLFOX regimen, whose abstract was presented at the 2017 GI symposium.  The report bears repeating, however, although the performance numbers are approximately the same.  Patient enrollment was very small at 21, of which 19 were evaluable.
          All subjects suffered from “advanced” metastatic disease and had failed an average of 2 prior therapies (ranging from 1 to 5 failed therapies):
>> 2 patients (10%) experienced Complete Response, a complete absence of disease.
>> 1 patient (5%) experienced Partial Response with 100% reduction in tumor burden.
>> 12 patients (63%) experienced Stable Disease.
>> Progression Free Survival was 3.5 months, and Overall Survival was 10.2 months, and 1-year survival was 43%.
          A Complete Response is a nearly unheard-of event, especially for “advanced” disease with no prior surgery.  And, this therapy had the equivalent of three Complete Responses.
It is not known why some patients did so well and others gained nothing.
          FOLFOX is not a particularly effective regimen.  See Part 3, posted yesterday and this report:
http://jaxelection.altervista.org/pancreatic/PostGemTrialsOx
          One wonders how patient would manage, if a better regimen, other than FOLFOX, were used.  Phase 1b trial details can be found at
http://clinicaltrials.gov/show/NCT02009449
          The new Phase 3 trial of AM0010 + FOLFOX has distinct features:
** Patients must have failed a prior “gemcitabine-containing regimen”;
** Only metastatic patients are eligible; the enrollment is 566, and the trial is randomized, meaning that about half will receive only FOLFOX, not AM0010; see
https://clinicaltrials.gov/ct2/show/NCT02923921
** FOLFOX is an infrequent therapy; there are likely better regimens.  See
http://jaxelection.altervista.org/pancreatic/Transcript_Rese
** Most of the 11 US AM0010 treatment sites are not major cancer centers.

Immunotherapy Cautions
          Both of these trials have an immunotherapy component.  There are some disturbing concerns about immunotherapy in general.
>> Immunotherapy tends to be unsuccessful with pancreatic cancer.  For the reasons see page-3 of
http://jaxelection.altervista.org/pancreatic/Interview_Immun
>> Some immuno agents (for example IMM-101) may benefit metastatic patients but may harm locally-advanced-patients.  See Table 3 of
http://jaxelection.altervista.org/pancreatic/IMM-101+Gem_bjc2016271a.pdf
>> And, in an alarming development, some immuno agents unpredictably cause “hyperprogression” of the disease.  Specifically cited in the literature are Nivolumab (Opdivo) and Pembrolizumab.  See
http://jaxelection.altervista.org/pancreatic/HyperprogressOn
http://jaxelection.altervista.org/pancreatic/ImmunotherapySi

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Tue Jan 23, 2018 03:16 PM

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2018 Gastrointestinal Cancers Symposium, Part 5
High Volume Facilities

Everyone,
          Vital information was presented at the Symposium on the immense advantage of being treated at High Volume Facilities.
          This research is a clarion warning: Life-taking diseases, like pancreatic cancer, should be treated at High Volume Facilities, like the top 10 institutions ranked by US News.  See
https://health.usnews.com/best-hospitals/rankings/cancer
          Community facilities, even if they call themselves “centers”, are for broken bones and stitches, not for treating pancreatic cancer.
          Travel to distant High Volume Facilities may seem inconvenient.  But, in the long run, the missed opportunities, additional suffering and lesser innovation at local facilities produce far greater inconvenience.  And, High Volume Facilities often aid convenience somewhat by arranging reduced-prices at designated hotels and by providing free shuttle services.
         PhilipJax

Abstract 392: Treatment at high-volume facilities and academic centers in relation to overall survival in patients with locally advanced pancreatic cancer: A National Cancer Database analysis.  The abstract is here:
http://abstracts.asco.org/210/AbstView_210_204005.html
          Researchers studied the National Cancer Database to learn the value of treatment facility type and patient volume.  A total of 10,139 patients were selected for analysis, those having non-metastatic Stage 3 (T4) locally-advanced disease (selection ignored nodal metastases).
          Of these, 4779 pts were treated at Academic Centers (AC), and 5260 were treated at a Non-Academic Centers (NAC), for a total of 10,039.  Presented another way: 588 were treated at High Volume Facilities (HVF), and 9551 were treated at Low Volume Facilities (LVF), for a total of 10,139.  A HVF was defined as the top 5% of facilities by number of patients treated.  ACs often were HVFs.  Researchers found that:
>> ACs and HVFs were associated with improved OS when compared to non-AC and LVFs.
>> The Odds Ratios for undergoing surgical resection at an HVF and an AC were 1.68 and 1.37, respectively, when compared to LVF and NAC.
         So, the odds are 68% greater that a locally-advanced patient will be resected at an HVF than at a LVF, and 37% greater odds of resection at an AC than at a NAC.

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Wed Jan 24, 2018 08:29 PM

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2018 Gastrointestinal Cancers Symposium, Part 6
Modified FOLFIRINOX is better than Full FOLFIRINOX

Everyone,
          The following abstract suggests that modified FOLFIRINOX (mFFX) is more effective than the traditional full FOLFIRINOX (fFFX).
          The sample size is small, however.  So, the apparent superiority may not be certain.
          There is another concern: That results may be unreliable due to differences in Asian and Caucasian metabolism of 5FU.  But this concern may not be supportable, since (1) only S-1 (a form of 5FU) has been shown to be metabolized differently, and (2) the subject trial compares different doses of the SAME regimen by the SAME ethnic group (which tends to cancel ethnic differences).  It is not a comparison of different regimens, which would be far more troublesome.
          So, the research outcome is very promising, and would merit great confidence if the study groups were larger (in the hundreds).
         PhilipJax

Abstract 469: Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience
          To determine which regimen is better, Japanese researchers divided patients into two groups.  Of 56 patients, 26 were treated with Modified FOLFIRINOX (mFFX), and 30 were treated with Full FOLFIFINOX (fFFX).
>> Median Overall Survival (OS) was 19.0 months for the mFFX group, compared to 13.2 months for the fFFX group.
>> Median Progression-Free Survival was 8.3 months for the mFFX group and 5.9 months for the fFFX group.
>> The Response Rate was 35% in the mFFX group versus 30% in the fFFX group.
>> Adverse Events were fewer in the mFFX group.
          The researchers conclude that mFFX had equivalent or higher efficacy and improved safety compared to fFFX.
         The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. In the second cycle, doses were reduced for 38% of the mFFX patients and for 62% of fFFX patients.

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Fri Jan 26, 2018 02:47 PM

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2018 Gastrointestinal Cancers Symposium, Part 7
ChemoRadiation
Liver Infusion
Surgery-First vs Neoadjuvant-First

Everyone,
          The following abstracts are unrelated.  Do not rely greatly on findings based on small group sizes.
          In the first abstract (391) neoadjuvant (pre-surgery) ChemoRadiation for Locally Advanced patients did not significantly enable surgical resection, which is near-universally required for cure, although Overall Survival was extended notably.
          Resection for Locally Advanced disease is more likely gained by Irreversible Electroporation performed by highly-skilled IRE leaders.  And, the IRE patient doesn’t have to wait months to learn whether the procedure worked.
          Further, photon radiation (not Proton radiation) can damage adjacent organs and the spinal cord, and sometimes cause therapy-delaying (and thus fatal) gut perforations and ulcers.
          Finally, the 2018 GI abstracts are no longer available at the ASCO website.  However, I have captured those I reviewed and make them available here:
http://jaxelection.altervista.org/pancreatic/2018ASCOGICance
          I am near the end of the commentary.  There may be a few more abstracts worthy of comment, but less than a handful.
         PhilipJax

Abstract 391: Effect of multiagent chemotherapy and chemoradiotherapy on rates of resection and survival in patients with locally advanced pancreatic cancer: a National Cancer Database Analysis
          Researchers at three USA institutions reviewed the national database records of 10,139 Locally Advanced patients to learn whether neoadjuvant (pre-surgery) ChemoRadiation might be more helpful than neoadjuvant chemotherapy alone.
          All patients had clinical Stage 3 (T4) disease (nodal metastases were disregarded).  Patients who received post-resection radiotherapy were excluded.
          Only 5% of patients (506) underwent resection following any form of neoadjuvant therapy.  The Overall Survival of those receiving multi-agent Chemotherapy vs. those who received ChemoRadiation were 19.4 months and 25.6 months, respectively.
          Neither neoadjuvant therapy was more likely to assure surgical resection (the “Odds Ratio for undergoing surgical resection . . . was not significant”).

Abstract 360: Impact of adjuvant hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil with systemic gemcitabine for resectable pancreatic cancer
          Japanese researchers studied 251 resected patients (primary tumor resection) to learn whether 5FU infusion into the liver (HAI: Hepatic Arterial Infusion), using a port-catheter, might reduce the likelihood of liver metastases.
          Of the 251 patients, 138 (55%) completed the HAI treatment.  All 251 patients received concurrent Gemcitabine alone or Gemcitabine followed by S-1 (a form of 5FU which, at higher doses, is less debilitating in Asians than Caucasians).  The results were:
>> The initial hepatic metastasis rate was significantly lower in the HAI group than the control group: 15.2% vs. 26.3%.
>> The HAI group had a better Overall Survival than the control group: 58.1 months vs. 26.9 months, respectively.

Abstract 406: Resection of pancreatic cancer following induction chemotherapy
          Researchers at five USA institutions sought to learn whether Resectable, Borderline Resectable and Locally Advanced patients fared better if they went directly to surgery or first underwent neoadjuvant (pre-surgery) chemotherapy.  The study of 415 patients helps to resolve the Surgery-First vs. Neoadjuvant-First controversy.
          The investigators began with 144 Resectable (R), 158 Borderline Resectable (BR) and 108 Locally Advanced (LA) patients; some received neoadjuvant chemotherapy; others went directly to surgery.
>> For Surgery-First patients, the median Overall Survival was R 16.9 months, BR 14.6 months, and LA 10.9 months.
>> Of the Neoadjuvant-First patients, the Overall Survival was 31.5 months for BR patients who undertook FOLFIRINOX first, more than twice the 14.6 months of BR Surgery-First patients.
         Some Surgery-First vs. Neoadjuvant-First comparisons could not be made because sample sizes were too small. For example, of 144 R patients, only 3 received neoadjuvant therapy. And, the LA data was not presented in the abstract.

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Tue Jan 30, 2018 02:48 PM

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2018 Gastrointestinal Cancers Symposium, Part 8
New Regimens: OXIRI & AGAP
Sleep Remedy for Cancer Patients

Everyone,
          Below, two abstracts explore new chemotherapy combinations which use readily-available agents.
          The third title, which describes a sleep remedy, is NOT an abstract from the GI symposium.
         PhilipJax

Abstract 411: Oxaliplatin (OX), chronomodulated capecitabine, and UGT1A1 genotype-directed dosing of irinotecan (IR) triplet chemotherapy (OXIRI) in patients (pts) with advanced pancreatic cancer (APC)
          Capecitabine, an oral form of 5FU, was part of the Oxaliplatin (OX) / Irinotecan (IR) regimen used in this Singapore research.  In addition, because Irinotecan (IR) toxicity is dependent upon UGT1A1 genotype status, UGT1A1 was used to determine the IR dose.
          For the 25 mostly-metastatic patients, the Response Rate (RR) was 20% overall, including 1 complete response (a very good, but too rare, event) and 1 unconfirmed partial response.  A 20% RR is fairly good, when one notes that 84% of the patients failed prior non-OX, non-IRI chemotherapy.
          Unfortunately, it is not clear whether the response came from the 21 metastatic patients or the 4 locally advanced patients.  Trial information is here:
http://clinicaltrials.gov/show/NCT02368860 

Abstract 449: Gemcitabine, nab-paclitaxel, cisplatin, and anakinra (AGAP) treatment in patients with localized pancreatic ductal adenocarcinoma (PDAC)
          Anakinra is an interleukin 1 (IL1) receptor antagonist typically used to treat rheumatoid arthritis.
          Sixteen (16) patients with non-metastatic, Locally Advanced PDAC were treated by Texas researchers using the AGAP combo.  The result: 12 patients underwent surgery, all with negative margins (which is very good).
          The researcher report: “No patients had systemic progression while on AGAP chemotherapy.  Eight patients are alive without recurrence at a median follow up of 13 months.”  “Systemic progression” is metastasis.
          The trial has been expanded to take more patients.  See:
https://clinicaltrials.gov/ct2/show/NCT02550327
          Important.  This regimen contains Cisplatin which was shown in Part 4 to produce good results.  The exceptional performance numbers for Cisplatin (which include 2 Complete Responses) are found in this report:
http://jaxelection.altervista.org/pancreatic/AddCisplatinToGem+NabPaclitaxel2017.doc 

Bright light therapy may help fatigued cancer survivors sleep better
          Researchers at US and European institutions sought to learn whether poor sleep efficiency among cancer patients was due to disruption in their internal clocks or circadian rhythms.
          The 44 test subjects, all cancer survivors, were required to sit close to a bright light box for 30 minutes each morning for one month.
          The result: 86% of the patients exposed to bright white light developed normal sleep efficiency, while 79% of the people exposed to dim light had poor sleep efficiency.
          Bright white light was also associated with medium to large improvements in sleep quality, total sleep time and wake time.
          After patients stopped light therapy, sleep improvements disappeared within 3 weeks.
          Researchers suggest: “If patients do not have access to a light box, going outside and getting natural light exposure in the morning or during the day can exert similar effects.”  More information here:
http://jaxelection.altervista.org/pancreatic/Sleep_BrightLig
http://jaxelection.altervista.org/pancreatic/SleepBrightLigh
          Finally, PhilipJax’s drug-free sleep method can be found here:
http://jaxelection.altervista.org/pancreatic/SleepMethod_Phi

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Mon Feb 12, 2018 08:16 PM

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Targeted Therapy – Chasing A Mirage
A plea for personal education & skepticism

          There is much interest in “Targeted Therapy”, also called Molecular Targeted Therapy and Gene Therapy, for Pancreatic Cancer.  For several reasons: (1) the mainstay chemo regimens rarely, if ever, produce a cure; (2) it is being offered by an institution (which may need subjects to fill a trial), and (3) the concept is intellectually appealing and is hyped by the press for OTHER cancer types.
          Reasons 2 and 3 are feeble rationales for pursuing Targeted Therapy.  Yet, patients too often pursue this elusive mirage, even though NO report among hundreds celebrated successful targeting at the 2017 and 2018 Gastrointestinal Cancers Symposia.
          When targeted therapies begin to work for pancreatic adenocarcinoma, they will make media headlines around the world.  Until then, what should the patient do? 
          Answer: Always select therapies based upon the NUMBERS, meaning based upon a regimen’s Response Rate (RR), Progression Free Survival (PFS) and Overall Survival (OS).  Most medical oncologists will NOT research these numbers for you and won’t name the research reports.
          If these numbers don’t exist, you take great risk – you forsake an opportunity (skip a known regimen that may work better), and lose time which can never be recovered.  Meanwhile, the disease progresses.
          Nearly always the NUMBERS are determined by clinical trials, which are how Truth and Falsity are determined in cancer therapy.
          Too often patients ask on various websites: “What do you think of this therapy or that therapy?”  They are too willing to rely on hearsay and don’t want to do the labor themselves.
          Some are lazy and expect the physician to do the work.  A bad idea.  If you neglect personal research, you will not know whether the physician is correct – a fatal error.
          Now, back to the Targeted Therapy NUMBERS.  We will use recent (2018-2016) journal reports (linked below) to uncover those NUMBERS.
          Also, download this free software which easily provides definitions of technical and medical terms.  Just Ctrl Right-Click over a word in any media that you are reading.
http://www.wordweb.info 

Report 1.
          Report 1 (the latest report, dated 2018) describes the targeting of the Epidermal Growth Factor Receptor (EGFR).  Targeting agents, specifically Erlotinib and Cetuximab, were independently tested on large groups, but improved median Overall Survival (OS) and Progression Free Survival (PFS) by no more than 3 months, more often 1 month.
          The targeting of Vascular endothelial growth factor (VEGF) receptor by Bevacizumab produced “no difference in Overall Survival”.  But a small 56-patient trial “showed an improvement in 2-year overall survival, 7.1% for the control arm and 22.9% for the sunitinib arm.”
          The report also describes targeting the RAS signaling pathway, a means to manage the KRAS mutation seen in 90% of pancreatic adenocarcinoma cases.  It was assumed that farnesyltransferase inhibitors (FTIs) were the silver bullet to target KRAS.  Yet, FTI tipifarnib produced no change in OS.
          And, in Table 1 the report describes all other RAS-inhibitors trials (5) which found little or no benefit.
          The targeting of Cancer Stem Cells was also reviewed.  Vismodegib, Saridegib, Demcizumab and Ruxolitinib did not perform well.  However, Napabucasin performed moderately well in a relatively small 71-patient trial, so is being tested in a Phase 3 trial in combination with Gemcitabine plus Nab-Paclitaxel.
          This is a research pattern worth remembering: “Targeted” therapies often do not perform well as mono therapies, so later are combined with mainstay regimens.
          The authors also addressed BRCA mutations, the culprit in 5-10% of pancreatic cancers, mostly due to family origin.  The PARP inhibitors Veliparib and Niraparib were cited.  Niraparib showed a PFS benefit in ovarian cancer patients, among BRCA patients having Homologous Recombination Deficiency (HRD).
          Finally, Report-1 also covered ImmunoTherapy, pointing out that “Checkpoint Inhibitors . . . have proven to be largely unsuccessful.”  However, some “impressive responses” were seen in MSI-H colorectal cancer tumors when the anti–PD-1 checkpoint inhibitor Pembrolizumab was used.  MSI-H means MicroSatellite Instability High.
          Pembrolizumab has received accelerated FDA approval for colorectal cancer which is MSI-H or MMR (mismatch repair).  For pancreatic cancer, oncology leader Tanios Bekaii-Saab, MD, FACP, of Mayo Clinic describes an astonishing MSI-related response to Pembrolizumab in his article:
http://jaxelection.altervista.org/pancreatic/CheckpointInCRC
          The dosages can be found in the relevant trial: KEYNOTE-016, NCT01876511
https://clinicaltrials.gov/ct2/show/NCT01876511
          Finally, the authors also warn of the disease hyperprogression sometimes seen in immunotherapy trials, a condition in which tumors spread 2 to 10 times faster in some patients.
         This is a condensation of 10 pages of text. So, you must read the paper yourself.       

Report 2
          The report provides detailed descriptions of the various forms of gene therapy.  Then, in Table 3 presents the results of clinical trails undertaken from 1999 through 2015.  The table’s footnote explains the table acronyms.
          The report ends with the discouraging observation: “We can conclude from all these trials that the first results are encouraging for most of phase 1 [trials] but remain “fragile” in phase 2, in which the difference between standard treatment and gene therapy did not reach high significance.”
         Although the report was authored by French scientists, the paper covers US and international therapy efforts, much of the same research as Report 1.

Report 3
          This excellent paper covers the topic better than Report 1, but it is older (2016).
          Table 1 gives a list of therapeutic targets for each genetic condition.  Such an excellent table is part of report boilerplate imitated by most testing facilities, to create the appearance of cleverness in their expensive and often-worthless DNA reports.
          The important review of clinical trails begins on page 4.
          The paper does a better job than Report 1 of summarizing each relevant clinical trial.  And most examined trials are probably the same.  However; it is not so recent as Report 1.
          Read each trial summary carefully, looking for the NUMBERS, associated with the terms: Response Rate (RR), median Progression Free Survival (PFS), and median Overall Survival (OS).
          As an example of the detail, the first three trial-summaries review the use of Erlotinib to manage Epidermal Growth Factor Receptor (EGFR), which is over-expressed in pancreatic adenocarcinoma.  OS was increased by approximately one month, unless the patient developed a grade 2 or higher rash.  Typically, the rash foretold an OS of 11 months vs 5 months with no rash.  And, the rash had to occur under standard dose.  Dose-escalation to produce a rash did not produce an OS benefit.
          Important.  The authors warn that the few months of extra survival, seemingly produced by the experimental agents, will be LESS today.  That is because the agents, when tested several years ago, were compared to inferior mainstay chemotherapies.  The researchers state:
          “Most of these trials were compared using gemcitabine with or without the experimental agent as the study group.  Now, with the adoption of FOLFIRINOX or Gem/NabP . . . It would seem improbable that those [targeting] agents, that failed to show efficacy when combined with gemcitabine alone, will demonstrate significant benefit in the setting of newer multimodal cytotoxic regimens [FOLFIRINOX or Gem/NabP].”
         This is a dreadful disease with few options. So, the victim must educate himself thoroughly and act quickly. Scrutinize Report 3 carefully, beginning on page 4, with emphasis on the NUMBERS.

Report 4
          This informative 2016 article explains the role of genetics in pancreatic adenocarcinoma.  But, it is not as thorough as Reports 3 and 1 in detailing the findings of clinical trails – the NUMBERS of supreme importance.
          The article, however, offer some potential therapies, which are offered in the other reports.  Examine, for example, Figure 2.  Locate the cell defined by the Treatment ROW and Germline COLUMN. 
          This cell explains that BRCA mutations might be managed to some extent by Oxaliplatin, PARP inhibitors and Irinotecan dosage.  In the cell to the right, EBFR and MSI-High have existing targeting agents, but the other Somatic conditions do not.
          “Germline” refers to the transport of genetic material from generation to generation, the hereditary genes.  Somatic refers to the other cells of the body, the non-hereditary cells.
          Figures 2 and 3 are the ones testing labs put in their reports to suggest that they have done a lot of work in your case.
          For our purposes, the core of the paper begins on page 7, Implications For Treatment.  However, the critical clinical trial details are more sketchy than those of Reports 3 and 1.
         Finally, although Report 4 has a good chemo-prevention section, that is not our topic as this time.

Immunotherapy
          Immunotherapy is addressed in Report 1, but it is not new.  Twenty years ago, when my brother was dying of pancreatic cancer, I pressed an MD Anderson oncologist to pursue immunotherapy.  He replied: “We must be rational.  Pancreatic cancer has the wrong immune cells.  Possible some day, but difficult.”
          Researcher O’Reilly says the same thing 20 years later: “For pancreatic cancer the immune cells that are present are regulatory or suppressive immune cells, and NOT immune effector T cells.  So there are immune cells present, but they're the wrong immune cells, and the right ones are in small numbers.”  See
http://jaxelection.altervista.org/pancreatic/Interview_Immun
         Immunotherapy is an uphill battle. There has been little progress in the past 20 years – for other cancers yes, but for pancreatic no.

Links To The Reports
http://jaxelection.altervista.org/pancreatic/1_TargetedThera
http://jaxelection.altervista.org/pancreatic/2_GeneTherapy20
http://jaxelection.altervista.org/pancreatic/3_GeneTargeted2
http://jaxelection.altervista.org/pancreatic/4_GeneticTestin
         PhilipJax

RE: nanoknife IRE for pancreatic cancer

by PhilipJax on Mon Feb 12, 2018 08:30 PM

Quote | Reply

PANCAN’s Know Your Tumor
Get hoodwinked for free

          Now, with great dismay, a critique of PANCAN’s Know Your Tumor program, using a sample genetics report (Report 5) produced by Perthera.
http://jaxelection.altervista.org/pancreatic/5_PANCANPerther
          The report leads to therapies which do not work or do not yet exist as viable treatments.  It pushes false hope, without ever telling the desperate patient what works and what doesn’t, or even provide the key NUMBERS (which are Response Rate, Progression Free Survival and Overall Survival).
         Here is a section by section evaluation referring to page numbers:

Page 4.  The vitally important table, “Ranked Therapy Options”, is a modified Delphi scoring method.  It is disconcerting that therapy EFFICACY is not considered independently among the score components – effectiveness, after all, is what matters.
          The result is that the principal table, upon which treatment recommendations are made, is completely unsupportable. But, in the fashion of a snake oil salesman the authors attack their own ranking system by stating: “The scoring . . . is NOT meant to imply that any one option has a greater chance of success.”  (The authors added the emphasis.)
          In addition, the authors reject their product before it leaves the factory.  On page 4, regimens A, B, C, D, E and F are ranked highly.  But, on page 3, a cover letter, therapies A, D and E are shot down as unsuitable or ineffective.  But, they were considered favorably by the ranking system.
          That leaves therapies B and C.  But, a phase 3 trial has since found highly-rated C to be ineffective.  Ruxolitinib’s PFS and OS were worse than the placebo, 43 vs 44 days and 113 vs 124 days, respectively.  If the patient had chosen that recommendation, would time have been spent productively?  The Ruxolitinib NUMBERS can be found the Study Results section here:
ClinicalTrials.gov " target="_blank" rel="nofollow">ClinicalTrials.gov /show/NCT02117479" target="_blank" rel="nofollow">https://ClinicalTrials.gov " target="_blank" rel="nofollow">ClinicalTrials.gov /show/NCT02117479
         That leaves therapy B (MM-398 + 5FU), which is a third line therapy that patients might receive regardless of genetic testing. MM-398 is a form of Irinotecan.

Pages 5 & 6. The “Signaling Implications” and “Comments” on these pages could be obtained from publications like Reports 1-4 (found in the nearby Targeted Therapy post), where they are more understandable.

Page 8. The report repeatedly states that this or that drug “COULD BE OF BENEFIT.” But, the authors (1) never reveal the extent of the benefit in quantitative terms (that is, RR, PFS and OS); (2) never mention that there are frequently no benefits at all, and (3) fail to inform their client that there could be negative consequences because better therapies may be bypassed.

Page 9-11.  The table “Therapy Scoring” offers more detail to the “Ranked Therapy Options” table of page 4.  And, it names the clinical trial being recommended.
          The category “Disease Relevance” contains a guess at performance, since high ratings are assigned to regimens containing mainstay backbones like FOLFIRINOX.
         Nevertheless, relatively unknown agents get a ranking of 3. And, one agent scores a 3 even though it is offered in a Phase 3 trial, where half the subjects do not get the drug at all.

Pages 12-17. These pages could be developed easily by the patient using the Advanced Search feature of ClinicalTrials.gov " target="_blank" rel="nofollow">ClinicalTrials.gov , and entering the genetic target on the Conditions or Interventions line.

Pages 18-20.  This drug information is boilerplate that can be found easily online at Wikipedia or
https://www.cancer.gov/about-cancer/treatment/drugs

Page 21. In their “Therapy Scoring Model” the authors use the hype terms “Clear Evidence” and “Proven Benefit”, but they never explain what those terms mean. Two therapy agents could have “Proven Benefit”, but have very different performance NUMBERS. And, the NUMBERS are what matters.

Pages 22-23. An equivalent References bibliography could be created using the references in Reports 1-4 in the nearby Targeted Therapies post.

Conclusion.  It should be emphasized that nowhere in the report do the authors ever give the performance NUMBERS as seen in Reports 1-4.  Those numbers, which are usually devastatingly poor, may have been omitted because they would have shocked the patient out of the intended euphoria of the report.
          The report is easily proven worthless.  Report recommendations were issued more than 2-1/2 years ago.  None of the recommended experimental agents have been successful enough to find their way into more regular clinical practice – even for patients with the genetic conditions cited.  In addition, one of the highest scoring recommendations proved WORSE than a placebo.  And, at that time MM-398 (Nal-IRI) had already been tested, and performance was assured since it is a microscopic encapsulation of Irinotecan.
          Further, the highly professional NCCN guidelines do not give paramount consideration to these therapies.  Just search the NCCN document (posted on this thread) using genetic targets.
          The report is fattened with dazzle-baffle graphics, tables, clinical trial lists, drug lists and bibliographies to give the impression of thoroughness.  But, those items could be obtained with better comprehension from Reports 1-4 and via the ClinicalTrials.gov " target="_blank" rel="nofollow">ClinicalTrials.gov search system.
          As presented, the report tends to snooker the desperate cancer patient into believing that the recommendations have substance and that they will work.
          It is unfortunate that PANCAN participates in this false-hope scheme.
          It would be far more professional and helpful, if it published regularly updated tables which list genetic targets, therapy performance NUMBERS, the performance sources, and related ongoing/upcoming trials.

Rules To Follow.  It cannot emphasized enough how fast the disease process speeds ahead; how easily the wrong paths are taken, and how frequent opportunities are lost – all because the family fails to educate itself thoroughly and to act quickly.
          Here are the indisputable rules:
1. Study elsewhere in this forum my posting on How To Select Clinical Trials.
2. In all medical matters remember the principal tenet (rule) of science: Skepticism.
3. Study the NCCN guidelines, posted nearby, adhering to the helpful commentary.
4. If the NUMBERS for a specific agent don’t exist, you are squandering an opportunity offered by a NUMBERS-rich therapy.  Most savvy financial investors review the past performance of stocks and funds before investing.  But, when it comes to a life and death issue, they cast away that wisdom.
5. Do NOT base your therapy decision on preclinical (non-human trials).  Every failed human trial, of which there have been hundreds in the past 20 years, began with a successful preclinical study.  Those failed human trials cost many millions and enrolled thousands of patients – most of whom gained nothing.  Select the trial wisely, based on the NUMBERS.
6. Do not be seduced by a researcher’s use of the term “significant”, as in “significant increase” or “significant improvement.”  He is often referring to statistical significance, a technical term in probability theory.  For example, an experimental agent might add 1 week to Overall Survival, the 1-week being “statistically significant”, but not a significantly long time in our quest.
7. Urge PET scans, early and frequently.  In February 2018 NICE, the guidance agency for the UK socialized health care system, began recommending early PET scans.  NICE is the misnamed National Institute for Clinical Excellence.
http://www.dailymail.co.uk/wires/pa/article-5363477/Pancreat
8. Always keep MULTIPLE irons in the fire.  That means: The therapy and site have been found, and the physician contacted.  It does NOT mean: I am thinking about it.
9. Become so well educated about the disease and therapies, that you know in advance what the physician will recommend at the next meeting.  Be ignorant and unprepared, and you will make the wrong decisions.
10. Gather and update all test reports: PET/MRI/CT reports, general condition report, biopsy report, surgery report, blood work, all other test reports.  And, keep them up to date.
11. Study the last 2 years of posts found in this thread.  Those posts will add to the indisputable rules a patient should follow.
         PhilipJax

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