Treating Ascites with Angiogenesis Inhibitors

Malignant ascites are side effects of some cancers (and potentially anti-cancer treatments), characterized by the accumulation of fluid in the abdomen.

Recently, I have received from a friend this article on ascites (from epithelial ovarian cancer), and thought is a good idea to share this here: Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675660/#SD1

According to this article, I understand that effective treatments against the ascites are focused on angiogenesis inhibition addressing the following:

1. VEGF inhibition

2. inhibitors of the tumor-promoting tumor-associated macrophages (TAM) commonly designated as “M2”

Here are some VEGF inhibitors I know (besides the conventional ones): Baicalein, Noscapine, Mebendazole, Albendazole, Celcoxib, Shark Cartilage, Thalidomide, Curcumin

Here is a nice reference for Albendazole:  Albendazole: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation in OVCAR-3 tumor-bearing nude mice.http://www.ncbi.nlm.nih.gov/pubmed/16551879. The only drawback related to Abendazole is the liver toxicity. On the other hand I know a cancer patient who is taking it for a long time with no major issues.

Mebendazole is on the other hand one of my favorites.

Thalidomide is another VEGF inhibitor I specifically like. I intend to write a post on Thalidomide only, but for now here are few words about it: Thalidomide has been shown to be potent in inhibiting tumor necrosis factor (TNF)-α, IL-1, IL-12, and VEGF in addition to IL-6, and can stimulate T cells via its interaction with cereblon 10,11. It has been also demonstrated that thalidomide is capable of decreasing IL-6 levels, lowering C-reactive protein, and, thereby, inducing remission in MCD. Ref:  Thalidomide for tocilizumab-resistant ascites with TAFRO syndrome http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498865/

Regarding the inhibition of M2, I wrote sometime ago an article on my page http://www.cancertreatmentsresearch.com/?p=265

Note:  M2 responses are associated with growth factor production (e.g., VEGF or EGF) http://journal.frontiersin.org/article/10.3389/fimmu.2015.00212/full#F1 so inhibiting growth factor production would have inhibiting impact on M2 response.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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62 thoughts on “Treating Ascites with Angiogenesis Inhibitors

  1. This is helpful Daniel. Always disturbing to see a promising drug, mebendazole discontinued (no reason given) and unavailable in the U.S. The following suggests Albendazole/mebendazole should be explored:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/
    Albendazole or other benzimidazole: There is evidence that the different benzimidazoles vary in their molecular targets and that combining them may improve efficacy and reduce the risks of acquired resistance. While this approach has not been explored in a cancer setting, there is pre-clinical and clinical evidence that the combination of MBZ and albendazole is a more effective treatment in certain hard to treat parasitic conditions [8, 9]. There is also some in vitro and in vivo evidence where albendazole exerts an anti-angiogenic action by down-regulating vascular endothelial growth factor (VEGF), an effect mediated through inhibition of tumoural hypoxia inducible factor (HIF-1α) [10]. As HIF-1α is implicated in multi-drug resistance in cancer, the combination of MBZ and albendazole warrants further investigation in drug-resistant tumours.

  2. Thanks for the very good link Fred. Btw, can you at least order Mebendazole from eBay and be sent in US or there are restrictions on that as well? In Europe is available without prescription. The dose is usually 200mg/day but it has been shown to be safe even up to 1.5g/day administrated during several months. Its bioavailability will increase when administrated with fatty meals. Adding Cimetidine (an anti histamine with aniti mets properties) will further increase Mbendazole absorption. I intend to write an article on Mebendazole on this page and with that will add the required references to my statements above.

  3. I was able to order Thailand Mebendazole in 100mg (Vermox) and 500mg (Benda) packages. The downside is it takes 2 or 3 weeks. I don’t think the shipment will run into import problems but I’ll let you know.

  4. Daniel, both Vermox and Benda came in from Thailand with no delays. We started with Vermox 100 and have moved to Benda 500 (+cimetidine), 1x/day. Is your wife taking it daily or # times per week?

  5. hi hanh

    this is madama

    please contact me thru pm at cancercompass ,my nickname is alternmed there.

    i m trying to post using my nickname madama,but the website is blocking me

    thanks

    1. Thank you, my husband situation was taking a turn for the worse after 1 week on Stivarga. His bilirubin shot up, his tumor marker shot up.
      His oncologist pushing for hospice. I am not confident in self treatment not when his condition is this critical. So we went to an integrative clinic
      Hopefully this doctor can turn thing around. I would ask for your help once his stiuation is stable.
      Thanks,

  6. To Mr Daniel
    The effective treatment of ascites is to use VEGF inhibitors, I think the combination of thalidomide, celecoxib and low dose cytotoxic drug is essential.
    In order to eradicate H.pylori, proton pump inhibitor and antibiotics must be combined.
    It is impossible to eradicate with proton pump inhibitor or antibiotics alone.
    Masato Hada

    Reference ReseachGate
    Report of two cases with pleural effusion and ascites that responded dramatically to the combination of thalidomide, celecoxib, irinotecan, and CDDP infused in thoracic and abdominal cavities.

    1. Thank you Dr. Hada!
      Why do you think H. pylori is relevant in the Ascites case? and
      Why do you think is essential to combine PPIs with antibiotics? What would be the mechanism behind which would otherwise lead to resistance?

  7. To Mr Daniel
    The eradication of H.pylori is nothing to do with the treatment of ascites at all. This is metaphor.
    My expression and English were bad, sorry. I would like to say that PPI only or antibiotics alone could not eradicate H.pylori. Like the eradication of H.pylori , to prevent the accumulation of ascites, cytotoxic dug only or targeted drug alone is not effective. I would like to say that the combination of proper drugs is very important.
    Masato Hada

  8. There is something strange these days

    my mother is improving very fast , but also it looks like ascites is increasing !!!

    I don’t know how something like this could happen , good and bad at the same time

    I contacted prof Vogl , he said that we should treat the cancer to eliminate ascites

    and he didn’t prescribe any drugs to help reduce it

    ——-

    I don’t have thalidomide , I don’t know is it ok to let the ascites increase without using diuretics ? or its better to treat it before it increases even more ?

        1. Avastin works perfect for some patients,i know it is very expensive.
          We talked with Dr Hada about comparison thalidomide and avastin a year ago.
          He said thalidomide has less side effects.
          When i look gene sequencing results of lots of patients,i saw thalidomide is not effective to all.
          Thats why i did not use it.But now i am thinking different.It is a good drug should be think to try.

      1. prof Vogl usually is not interested in something not necessary , but I did ask many doctors locally here , and they said :

        if ascites become annoying .. its better to start with diuretics (Lasix + aldactone) , if nothing goes well then tap it out and give albumin

        her urine output looks like normal , I’m not sure

  9. Recently my mother has Ascites which was increasing day after day , until she felt hard to breath

    but just after 2 days of diuretics , the fluid looks like decreased a lot !!!

    first : is this possible to happen just in less than 2 days ?

    second : how to maintain this response ?

  10. Hi D and other cancer fighters, today I’m here to seek advice for a dear father of a friend who is a late stage liver patient currently battling alcoholic cirrhosis of the liver as well as some tumors present in the liver.( I’m not very clear about the exact diagnosis and the tumor load and I’m only sharing what I have been told).
    apparently liver transplant is not an option even though they are getting second opinion on the matter. from what I understood the challenges include blockage of hepatic and portal vein (pvt?) which has been treated with enoxaparin, (unsuccessful probably)
    patient has gradually lost a lot of weight and mobility since 3 weeks ago and can only travel to the bathroom. (due to Hepatic Encephalopathy?). urine output is good and the patient is getting the standard regimen of diuretics. I’m not informed whether the patient is constipated or not.
    the last Hematology and ascitic fluid markers which is dated a week ago are:
    20 cc of fluid:
    before centrifuge: Color: Bloody appearance: Turbid
    After Centrifuge: color: yellow appearance: clear
    LDH: 86 – Sugar: 115 – Protein: 1.2 g/dl- Albumin 0.8 g/dl
    R.B.C 160000 cell/mm3 – WBC 300 PMN 30 %
    Triglyceride: 44 mg/dl- cholestrol: 28
    ______________________________________________
    Hematology:

    W.B.C: 9.72
    R.B.C: 4.31
    Hemoglobin 12.8
    HCT 34.7
    MCV 80.5
    MCH 29.7
    MCHC 36.9
    PLT 311
    RDW 22.7%
    PDW 13.2
    MPV 10.4
    PLCR 29.7 %
    NEUT 83.7 %
    NEUT value 8.13
    Lymph 10.9 %
    Lymph Value 1.06
    Mono 5
    Mono Value 0.49
    Eosin 0.3 %
    ______________
    this is what I got so far. patient is not under chemotherapy currently and the liver mass has been tread with embolization a year or so ago.
    hope this helps you form an opinion. please let me know what you think/ would do and what are the best possible course of action to take in this tough situation. and if there are any other pieces of info which may help here. let me know so I can ask the family members and share here. thanks in advance.

    1. Hi Pouya, I am sorry to hear about your friend’s father, it sounds like a difficult medical situation. It is hard to tell from what you have posted if this individual is in his condition primarily because of the cirrhosis or the cancer or both? It would also be helpful to see some liver markers or tumor markers. In my experience, a damaged liver can be very responsive to supplements such as milk thistle, SAMe, and NAC, but once someone reaches end-stage cirrhosis there is not so much response because the liver is now mostly scar tissue. Also, supplement choice would depend on the degree of cancer involvement in the liver. Life Extension has a nice protocol on Cirrhosis, but again, I’m not clear on what the situation really is: http://www.lifeextension.com/Protocols/Gastrointestinal/Cirrhosis/Page-01.
      My best to you, -Shanti

      1. thanks for your response Shanti. you are correct, in all honestly I’m not exactly clear whether the condition is mostly due to cancer itself or cirrhosis, based on the treatments they have got, my guess is that it’s mostly cirrhosis.
        I think at this point a serious professional intervention is what they should be looking for since it’s very hard to self treat at this stage, may times it’s hard to tell whether the symptoms one sees is due to cancer, cirrhosis or side effects of therapy.
        I think my real question here is that is anyone aware of a clinic that would accept a patient in such critical condition or has successfully treated one?

        1. this is all I got Alex. I guess we should base our assumptions on the physical condition of the patient which is not good.
          they have been told that liver transplantation is only possible if they can treat portal vein thrombosis successfully. patient is being treated with Enoxaparin currently.
          I’m pretty sure I have come across accounts of liver transplant with PVT present. dunno why this patient should wait in this critical condition.

      1. Hi Pouya,

        A few days ago I activated a function so that every comment needs to be aproved before beeing published. I did this due to the recent wave of unsuitable comments from Ergin. However, I spoke with him on WhatApp to understand why he was doing that. He is taking some strong drugs/medicine that are messing up with his mind. We agreed he will stay away from this website and cancer world for some months. I will now remove the approval required for comments so that you should see your post imidiatly published. I am sorry for that inconvenience.

        Kind regards,
        Daniel

        1. Hi Pouya,

          I am traveling these weeks and my access to internet is limitted. I will asnswer as soon as I can.

          Kind regards,
          Daniel

        2. Daniel, i risk asking for too much. Yet here i am, i feel compelled to ask.
          Please come see my mother and me if possible.
          We hope to hear and see you.

          Thank you so much,
          Alex

        3. Hi Alex, thank you for the invite. As you know, it would be my pleasure to meet you but I will not be able to find the time – i had/have to travel too much from one place to another. Kind regards, Daniel

        4. I don’t know if anyone will even read this, however the story must continue.
          She is in ER now, radiography shows liquid in her thorax, likely generated by the tumor on her spine T2-T4.
          The lung/s are being compressed by this high volume of liquid, she can hardly breathe with oxigen mask, without it she would die quickly.
          They tried draining the liquid, but it’s too thick and full of blood. Signaling a likely perforation by invasion of the tumor of the pleura.
          The doctor there is saying a CT and Surgery is needed. However when my mom first had the surgery, she was able to walk, not paralyzed. I fear she won’t make the trip from hospital to hospital, let alone a surgery.
          So if that’s approved by the doctors, we’ll need to take the risk, as the other option is certain death within a very short time.
          The time for this story’s end may soon come.
          She’s also scheduled for oncologic treatment tomorrow, so she’ll have to be moved from hospital and then back, if surgery is decided to be performed, they will have to move her from local hospital to Bucuresti. A lot that can go wrong.
          Will we beat the odds? One can never know. So… we fight to live and die trying, if we must. 🙁
          I hope to return with good news, but let’s face it, it is very unlikely, she is stable for now, or else i wouldn’t be home online, and she needs sleep, and so do i.

          Thank you very much.
          Alex

        5. Hey Daniel, we’ve beaten the odds and the nightmare medical birocracy.
          She has a drain installed, finally after what? 6 days…. i did all i could and succeeded.
          She is still alive and doing a tiny bit better, had her transfered back to ER…
          About 1,1 Liters of pink fluid was drained thus far.
          She is being monitored and helped within the hospital’s ER room’s abilities. ( i can’t say it’s the best, but it;s better than nothing)
          So many problems i had to deal with, too many, too hard, but we did it. (very long story)
          She had Zometa done, not that it matters much.
          I finally had the chance to see her EGFR testing paper, and the tumor sample, from the surger, presents a 100% genetic mutation for EGFR – Wild Type
          Another oncologist i got in touch with from Bucuresti said, she wouldn’t give Erlotinib for EGFR-WIld type
          So i have more detective work to do.
          WHo knows how many more dice throws we get, maybe not many, maybe a lot.
          But one thing i know, i must carry on and do what i can do, to ensure we get the most of our chances for life.
          Another thing i wish to mention, her blood was acidic, 4.5 and her glucose level was 135, this points me to possible lactic acidosis and The Cori Cycle.

          Best wishes,
          Thank you for everything, i hope you’re having a good time. Have a beer on me, it’s international beer day. (enjoy).
          Alex

        6. Hi Alex,

          Great to hear you succeded to go through this and your mom is better. I had a good holiday indeed but constantly driving from one place to another. I am now going back home. I will start driving soon and should be back tomorrow night. I will have a beer when I get home 🙂

          Kind regards,
          Daniel

        7. @Alex: EGFR Wild type means that the EGFR mutation is NOT present. And the benefit from EGFR inhibitors like Erlotinib is much less in your mother’s case than for patients who do have the EGFR mutation. So all the discussion about overcoming Erlotinib resistance had no potential to help your mother. Maybe someone else will read that and find something useful…

          NSCLC patients with bone metastasis and former smokers usually have the Kras mutation, EGFR is less frequent, and other possibilities are ALK, Her2 and Braf. There are no official targeted therapies against Kras, but there are ways to impede progression. If ALK or Her2 mutations are present, there are targeted therapies available. The oncologist who gave you mother Erlotinib, even if EGFR status was wild type, must have had some reasons that escape me…
          While it may be possible to find some clues about the cancer from an analysis of the circulating cancer cells in the pleural effusion, those are too few for mutation analysis. The oncologist should have asked for a biopsy of the spine metastasis and testing for other mutations months ago, since the EGFR is wild type.

          A pleural effusion can contain some blood, but usually not that much as to impede drainage. I would suspect disruption by the cancer of some blood vessels, which means increased risks for metastasis to brain, liver and kidneys.
          Blood ph 4.5 is very low, very acidic, and could mean kidney failure. Also, if she gets an infection, most antibiotics won’t work because of low ph. And if the blood acidosis translated into increased tumor acidity, then the cancer cells are going to increase proliferation and migration.

        8. Thank you so much Ovidiu, as usual you’re right on the spot.
          I guess we better look for a way to test for ALK, Her2 and Kras mutations then, and after that get the right treatment.
          I don’t have clue why the oncologist gave Erlotinib, given that she had the information, i didn’t.
          I’ll do what i can to address the blood acidity issue.
          I’ll try to gain a sample of the liquid that is being drained, for possible analysis.

          Thank you so much again,
          Have a good weekend there,
          Alex

        9. @Alex: Regarding some practical advice in the dire situation, although I’m uncomfortable giving it, I would suggest the following:
          – first, improve the blood acidity situation, if possible; ZOL treatment could have pushed your mother’s kidneys closer to failure, under high acidity; if the acidosis is because of the cancer, then you might not be able to improve it much, and that would a bad sign;
          – if more blood tests will be performed, try to do the tumor markers you did before; I don’t remember exactly which ones, CEA, CYFRA21-1, NSE, CA125 maybe? While they are going to be higher, it’s possible one of them to have jumped a lot, and that could be a clue regarding the evolution;
          – in the pleural effusion liquid there must be cancer cells; it should be possible to find out how many and how metastatic they are, if they were single cells and alive (anoikis resistant) or spheroids, etc;
          – as for the mutations Kras, Her2, ALK, Braf, these are usually mutually exclusive, but there are exceptions (like 2 mutations); in Romania afaik the only way to get the mutation analysis done is from a biopsy (preferrably fine-needle); I checked the cost for Kras + ALK + Her2 + Braf mutation analysis at Synevo (a lab in Bucharest), and it’s about 1300 euro, so comparable with 1 month of Erlotinib treatment (obviously you want the public health to pay for those); if a biopsy is feasible or not, that you have to discuss with the oncologist, who also has to officially ask for mutations’ analysis;
          – for patients which have the EGFR mutation (not wild type), and don’t have other reasons for resistance, Erlotinib gives about 4 months of regression, followed by several months of stable disease, then indolent or rapid progression; for patients with EGFR wild type, the best you can expect is 2 months of stable disease (no regression), so for these patients Erlotinib shouldn’t be used as mainstay therapy; this has been known for at least 5 years, so the oncologist, even if 2-3-4 years behind the latest research, should have known better; I don’t remember exactly for how long your mother was on Erlotinib, but probably the benefit was limited to the first 2 months, due to the synergy with ZOL and because it was well absorbed (the strong rash); the oncologist should have used the little available time (much less than for mutated EGFR patients) to try to find out which other mutation could be involved; however, you should know that mutation tests are not 100% accurate, and the biopsy could provide an inadequate sample…
          – to get a clearer picture of the targeted therapies for NSCLC, so you’ll understand better what to ask the oncologist, I suggest to download the free PDF of this article:
          Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. PMID: 26620497

        10. @Alex: an addition to the biopsy problem:
          – I understand that it’s a problem (it’s dangerous) to do a biopsy of the spine tumor;
          – it is possible to perform mutation analysis on circulating tumor cells, by first amplifying with PCR (Polymerase chain reaction) the tumor DNA, from blood or pleural fluid, and getting enough material for mutation analysis; but this afaik is not available in Romania; you should still ask the oncologist or other doctor if it’s available;
          – if your mother will get a CT scan, in order to evaluate the progression, the radiologist could identify some spots (other than the spine) from which a biopsy would be doable and useful, like a pleural nodule confirmed metastatic;

        11. @Alex: I checked the LOTUS-MED site for their Onconomics tests, and it seems they can get a lot of useful information from circulating tumor cells too (blood sample, amplified with Oncoquick). But I suppose the price is going to be high. Still, it might be a lot more useful than doing just the mutation tests, since they test for sensitivity to a chemo panel and adjuvants.
          Looking back, it seems your mother has been on Erlotinib for ~8 months, without having the mutation (although EGFR might be over-expressed to some extent). The extra information regarding the cancer should have been gathered months ago, now it may be too late… 🙁

        12. Thank you so much ovidiu,
          I’m trying to get the pleural fluid to be tested by gov insurance.
          I will be doing some private blood tests since nobody else in the medical system appears to be interested.
          I’m thinking about Hydrazine Sulfate. Could help?!
          I didn’t know that the mutation was Wild Type, the information wasn’t presented to me, i didn’t know to ask, all i knew was that my mom had the EGFR mutation and that Erlotinib was aproved for treating my mother. (is what they said)
          It seems to me these people are legal criminals. Only now i’ve been handed the paper, after a big scandal in the doc’s office. They wanted to call in security, because i told them they are criminals, killing people with their ignorance, waiting from one salary to the other, not giving a damn who lives and who dies. Good people, who place their trust in them for the best, only to find, it would have been better not to go to them at all.
          They don’t even talk to me, or other people in similar situations, you’re meant to sign the paper, take the drug and shut up, pray to GOD aka DOC.
          Someone needs to give these people a good beating every now and then. Maybe i am going crazy, or the planet is.
          It has to be one or the other, can’t be both, can it?
          Lotus-Med and their Onconomics tests appear to be the way, and i am happy to see we got something like that in Romania. I’ll give them a call
          My hope and roll of the dice was that by draining the pleural fluid, we would gain time, indeed the time seems to have ended and we are most likely nearing the end, however my mom is now feeling better, able to breathe more freely, and so i hope we still got another roll of the dice, perhaps turning the situation, a last ditch effort, one can never be 100% sure. Had there been no hope, she would have been long dead.
          Doctors are good, drugs are good, but LOVE is the most important. Someone who is sick and has nobody to take care of them is a dead person, but someone who is loved will live longer than expected. (as unscientific as it sounds, i believe it to be the truth).
          Anyway, thank you very much for all the help. You’re awesome.
          Alex

        13. @Alex: I don’t know which tests for pleural fluid are available, so use your wits to ask for useful information out of it.
          The tests for the 4 blood tumor markers (CEA and others) aren’t expensive, about 200 RON in all. Frankly, the public health should pay for those, but if you got into arguments with the oncologist, this is going to be a problem. Look, when I had to deal with my father’s situation, I learned about mutations and markers, the oncologist would just apply the standard treatment, and hope for the best. And he is one of the respected oncologists in Bucharest, was on TV several times. I gave him dozens of printed articles, potentially useful for my father. But the treatment options were even more limited back then. The point is, try to keep a workable relation with the oncologist, he / she will be prescribing the drugs.
          About Hydrazine sulfate, there is nothing on Pubmed about it and bone metastasis. About the addition of Hydrazine sulfate to chemo in NCSLC, there are several clinical trials over 20 years ago, one with a benefit, and two with no benefit.
          Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. PMID: 1688616
          Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. PMID: 8201374
          Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group PMID: 8201372

        14. @Alex: there aren’t many articles on Erlotinib use in patient with wild-type EGFR (not mutated), and I only found two, which are still not freely available, so I copy-paste here the abstracts, quoting:

          Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR. PMID: 26781399
          INTRODUCTION: While epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC.
          AREAS COVERED: This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article.
          EXPERT OPINION: Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.

          Erlotinib for Patients with EGFR Wild-Type Metastatic NSCLC: a Retrospective Biomarkers Analysis. PMID: 29557085
          Erlotinib is approved for the treatment of patients with EGFR mutation positive, metastatic NSCLC. It is also approved as second/third line therapy for EGFR mutation negative patients, but in this setting the benefit of erlotinib is modest and there is no validated biomarker for selecting EGFR wild-type patients who may benefit the most from the treatment. We retrospectively assessed EGFR and K-RAS mutational status, and EGFR, c-MET and IGF1-R expression in tumor samples of 72 patients with metastatic NSCLC treated with erlotinib after at least one prior line of chemotherapy, from 2008 to 2012. We analyzed the association between biomarkers and outcome (RR, PFS, and OS). EGFR mutated patients achieved a better RR (56% vs 8%, p = .002), PFS (10 vs 3 months, HR 0.53, p = 0.48) and OS (20 vs 6 months, HR 0.55, p = .07), compared to EGFR wild-type patients. Among 63 EGFR wild-type patients, those with EGFR high-expression had a better outcome in terms of RR (40% vs 2%, p = .002), PFS (7.5 vs 2 months, HR 0.45, p = .007) and OS (30 vs 5 months, HR 0.34, p < .001) compared to patients with EGFR intermediate or low/negative-expression. IGF1-R expression, c-MET expression and K-RAS mutational status did not significantly affect the outcome; however, no patients with K-RAS mutation or c-MET high-expression achieved an objective response. In patients with metastatic, chemo-refractory EGFR wild-type NSCLC, EGFR high-expression may represent a positive predictor of activity for erlotinib, whereas K-RAS mutation and c-MET high-expression may predict lack of activity. These findings deserve further prospective evaluation.

        15. @Alex: when I got the news that your mother’s cancer progressed (metastasis wasn’t limited to bone anymore) and that she didn’t have the EGFR mutation, I was upset, because the prognosis got significantly worse in such a case; in the mean time, I read some articles, and here is what I believe that should have been done:
          1. I believe the oncologist started with Erlotinib + ZOL before having the result of the EGFR mutation, is this correct?
          2. Then, after receiving the EGFR mutation result, she should have told you it’s WT, and mentioned the limited efficacy of Erlotinib in such cases; however, for some time your mother responded to Erlotinib, so it’s possible the EGFR was and still is over-expressed, to an unknown level; patients with WT EGFR benefit more from Erlotinib, if the cancer is still addicted to EGFR, meaning EGFR is not weakly over-expressed;
          3. A possible alternative, after seeing the WT EGFR result, since there was some benefit from Erlotinib, would have been Afatinib, which binds stronger to WT EGFR, and also Her2 and Her4, but the rash would have been even worse; I looked into the approved compensated drug list, August 2018, and Afatinib is about 2x more expensive than Erlotinib; Osimertinib is about 7x more expensive than Erlotinib, but would be useless for WT EGFR, it’s useful for mutant EGFR with T790M mutation;
          4. besides trying to find out what treatment targets could be available (since EGFR is WT and progression happened during Erlotinib treatment), the progression should have been monitored with tumor marker blood tests, these could have predicted the Erlotinib failure some time ago;

          I looked into options for second or third line treatment of NSCLC with WT EGFR, and last information is that there are 2 relatively good options, immunotherapy or a docetaxel combination (docetaxel alone is almost useless), I’ll post more on those tomorrow;

        16. @Alex: an update on the possible use of Afatinib – considering that Erlotinib exposure was of ~8 months, it is very likely that the resistance to Erlotinib to be caused by mutations or amplifications that would induce resistance to Afatinib too; the only exception would be resistance to Erlotinib by over-expression of Her2, Her3 or Her4, without other resistance causes, in which case Afatinib could help for a while;
          Currently afaik all we know about your mother’s cancer is that it’s lung adenocarcinoma with WT EGFR and spine metastasis, and this is too little information for a targeted therapy;
          At this stage, since getting more detailed information is going to take time, even if you’ll somehow afford to pay for such information from Onconomics, I suggest to ask the oncologist for metronomic chemotherapy, in order to buy time; it should delay the progression, while Erlotinib won’t; However, I don’t know if your mother’s condition allows her to receive any more chemo;
          Metronomic chemo is approved in lung cancer with Vinorelbine, or with Etopside + Cyclophosphamide, both oral low dose, and cheap;
          I’ll post next about the 2 currently most effective treatments, immunotherapy and docetaxel combination, but these are very expensive, and I doubt would be approved for your mother (you have nothing to offer the oncologist);

        17. @Alex: the latest study on treatments for previously treated NSCLC, published just 2 weeks ago, puts the immune checkpoint inhibitor Pembrolizumab (Keytruda) at the top for overall survival in adenocarcinoma, and Nivolumab ( Opdivo) at the top for OS in squamous cell carcinoma. These 2 are available in Romania, but very expensive, about 6x more than Erlotinib. They could be combined with metronomic chemotherapy, targeting the immunosuppressive tumor microenvironment.
          Another option would be Pemetrexed (Alimta), which may synergize with Itraconazole, but you can’t expect a response, just stable disease, and is also very expensive.
          If Abraxane (nab-Paclitaxel) would have been available, I would have recommended it, in combination with Lansoprazole, but it’s still not approved in Romania.
          The Docetaxel combinations are with Ramucirumab (Cyramza), a very expensive VEFGR2 inhibitor, and with Nintedanib (Ofev, Vargatef), a VEGFR, FGFR and PDGFR inhibitor, expensive but not very.
          Unfortunately, the Docetaxel + Ramucirumab combination induces strong immune suppression, so adding Filgrastim is a must. And Nintedanib is approved for pulmonary fibrosis, not for cancer, so the oncologist may be not allowed to prescribe it. However, for Docetaxel, which alone is almost useless, there are several synergy options.
          About the prices, I looked into the latest list of regulated prices, but I’m not sure about the math, since they list the price for an U.T. (unitatea terapeutica), and I’m not sure what dosage they mean. I suggest to download (it’s free PDF) and print this study, and show it to the oncologist.
          Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis. PMID: 30044785

        18. Thank you very much Ovidiu.
          You are always on the spot.
          The oncologist gave Tarceva after the test results, not before.
          By draining the pleural fluid, we managed to buy time. I am worried that by giving medication to her, that the fluid will return.
          Meanwhile i intend to ask the oncologist to perform more genetic testing on the tumor tissue, saved after the surgery, for the genes you suggested. I tried to do that before but she is on leave.
          Blood tests for CEA, CA-19-9, Sugar levels and PH, these we’ll do in private.
          The oncologist suggested yet again we try Gefitinib, but i will try to counter that.
          I still have a bottle in the fridge with the pleural fluid and some tissue in it, a gram at minimum.
          Whatever test they did on the fluid in the lab, showed nothing abnormal.

          I’m thinking of getting more information and then acting on target!?
          What do you make of my plan?

          Mom is feeling better, needs oxigen concentrator an hour a day or less, compared to needing it non-stop.
          However she feels a sorts of paralisys, in her right arm again. I’m guessing this is because she is without treatment of any kind for a good time now.
          She eats more, and drinks more water, get’s more sleep.

          Have a good weekend.
          Thank you, Alex

        19. @Alex: I wasn’t on the spot at all… I assumed the pleural effusion with “lots of blood” was because of the cancer, and it meant progression, and obvious Erlotinib resistance.
          But you wrote now that “whatever test they did on the fluid in the lab, showed nothing abnormal”, and I understand that there were no cancer cells in the pleural fluid, is this correct?
          If not caused by the cancer, the pleural effusion can be caused by an infection or by some drugs. Possible pneumonitis induced by the long exposure to Erlotinib, did the oncologist mention that?
          About Gefitinib, I doubt it would be more effective against the cancer than Erlotinib, based on the common knowledge: Gefitinib binds weaker than Erlotinib to WT EGFR, so it has lower adverse effects (less rash), but it is also less effective against a WT EGFR cancer that over-expresses EGFR. Considering that your mother has seen a benefit from Erlotinb, she is probably one of the ~80% of lung cancer patients which over-express EGFR, while she is also one of the ~80% which have wild type (not mutant) EGFR. And for some one with WT EGFR, the benefit was unusually long.
          About the tumor markers in blood, please do more than 2, especially if there was a long time since you didn’t do any. Please refresh my memory on which you did before, just CEA and CA 19-9?
          About tests on the old tumor tissue, if it still good for tests, check (in order of probabilities) for the Kras mutation first, ALK (rearrangement ) second, and Her2 third. But it would be more relevant to do the test on a biopsy sample of the spine metastasis, the results could be different.
          Did you contact Lotus Med and asked how much does the Onconomics test cost?

        20. ok, so the test they did on the fluid is unclear as to what it looked for.
          it’s written by hand, no values nothing. just a text saying, that no germs were found. ( i don’t trust it)
          Another oncologist i talked about supported the theory that erlotinib could have caused the fluid problem in the first place., as a possiblity.
          The oncologist here is very very difficult as a person, today i made her burst in tears and cry. apparently i somehow insulted her by telling her what test she could do. It’s crazy…she has a deadly pride, and that’s no joke.
          Mom is up for gefitinib, 250mg/day, meanwhile, osteonecrosys and denosumab is not covered by insurrace, so i have been told, but it could be fake information, as the doctor also said that more gene testing is not covered by inssurance, but when i called this other oncologist, she said that indeed the others are not but ALK is, so that’s what i pushed for, and finally got it, after actual tears.
          Won’t do a biopsy i guess. I don’t know what to do with this person anymore, it’s impossible, it’s hard to exchange words with a person who is probabbly suffering from some form of insanity.
          Managed to also get a new CT scan to be schedduled, yey.

          we did CEA, CA 19-9 for the most part but yeah we also did CYFRA21 at one time.
          Lotus med i didn’t call yet, trying to get it done one at a time, as i have too many things to do in a given day, and my energy is dipping into lows, low blood pressure today, dizziness, but pushing forward till i collapse

          Chasing down the doctors lol. they scared of me.
          I found their fear, it’s loss of income, someone gives you a problem, ask them who their boss is, because you suddenly need to have a serious word with “him”. Suddenly you no longer need to worry much, if you feel you are right inside, logic and reasoning tell you things should be your way, it’s probably how things are going to work, this is my experience anway, helped me keep mom alive. People who wanna look smart tell you NO? Ask to talk to their boss. No special gifts to be made anymore, everything is free and sorted. As it should be in a normal society and medical system, because…. you can hurt them, you can curse them, but never threaten the salary 🙂
          In this world there are people, and then there are maggots, sadly many of them are not people, they just wait for month’s end, to get that sweet cash wad, without regard of their success in treating people’s problems, apparently nobody is above them but GOD, but those are just appearances for the average guys, in reality there should be people who inspect their work, it is unfortunate they only do it when someone insists for a closer look, but what can i say, i offered to do it, and so i had things my way.
          They didn’t want to drain my mom’s fluid, they said it would be best if she dies then, they accused me of becoming Dr Mengele for asking that my mom be taken care of and allowed to live more, apparently they decide on who to live and who to die, and when, and how, and they also call it ethical.

          Anyway, i apologize for all this, and i realize you are probably all too aware of what i just said, sadly.
          If this is what i got for getting an alk test, immagine what i will get for immunotherapy….. 🙁

          Thank you Ovidiu, https://youtu.be/0EygqL–RW4
          Alex

        21. @Alex: it’s unfortunate that the analysis of the pleural fluid didn’t reveal anything regarding the possible progression. I would have expected the reporting of some circulating tumor cells, dead or alive, single or in spheroids… We’ll have to wait for the results of the CT-scan to find out about the progression.
          About Gefitinib, your mother would be very lucky to see better results, but the rash should be less. Please watch for hepatic toxicity, it’s a bit worse than Erlotinib for the liver; Denosumab has indeed a higher risk of osteonecrosis, especially after ZOL; but if your mother’s kidneys will get worse because of ZOL, then what?
          If the oncologist decides that a new biopsy is too dangerous, the only way to find out (a lot) more is Onconomics (or similar); in the Onconomics test suite they list 72 tumor related genes, over or under-expressed.
          I know that doctors in general don’t like patients that know too much, but to burst into tears, that’s disturbing. The mutations in lung cancer have been known for many years, only ALK is newer. I understand that they don’t test for Kras, because they don’t have a targeted therapy for it, and don’t test for Her2, because even if it’s over-expressed in about 25% of lung cancers, only 2% have the mutation. So testing for ALK (treated with Crizotinib) is a long-shot, but better than nothing. In case of the Kras mutation, it is possible to treat the cancer by inhibiting the Her (EGFR, Her2, Her3, Her4) family upstream of Ras with Afatinib, and Raf or MEK downstream with Trametinib, Selumetinib, Vemurafenib, but these are very expensive. There is another possibility, against Kras-mutant cancers, which have low levels of catalase, intravenous (high dose) vitamin C could be effective.
          Please remind me of some facts, just to be sure (I could search, but could miss some):
          – your mother’s age;
          – smoking history, light or heavy, for how long;
          – which lines of therapy did she take, and what were the outcomes;
          – Erlotinib was given some time alone, or only together with Zoledronic acid?
          I understand that you are exhausted and angry at the medical staff, but the anger won’t help your mother, and is not good for you either. Try to rest when you have the time, and try to understand that the oncologists don’t care, because if they cared, they’d be depressed all the time, and could not do their job at all.

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