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Knowing the tumor’s size and location, could we target treatment to THE ROI by applying…..

http://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-target-treatment-to-the-roi-by-applying-imaging-guided-intervention/

24 Responses

1. edit this on October 16, 2012 at 10:30 AM | Reply2012pharmaceutical

   GREAT work.

   I’ll read and comment later on

2. edit this on October 17, 2012 at 1:49 PM | Reply2012pharmaceutical

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   Watchful waiting or radical prostatectomy for men with early-stage prostate cancer? What the research suggests.
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   Locally advanced prostate cancer: Will you benefit from radiation and hormones?
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   New warnings about 5-alpha-reductase inhibitors and aggressive prostate cancer.

3. edit this on December 1, 2012 at 6:29 AM | ReplyBB

   Promising technique.

   INCORE pointed out in detail about the general problem judging response and the stil missing quality in standardization:

   http://www.futuremedicine.com/doi/abs/10.2217/fon.12.78?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

   I did research in response evaluation and prediction for about 15y now and being honest: neither the clinical, nor the molecular biological data proved significant benefit in changing a strategy in patient diagnosis and / or treatment. I would state: this brings us back on the ground and not upon the sky. Additionally it means: we have to ´work harder on that and the WHO has to take responsibility: clinicians use a reponse classification without knowing, that this is just related to “ONE” experiment from the 70′s and that this experiment never had been rescrutinized (please read the Editorial I provided – we use a clinical response classification since more than 30 years worldwide (Miller et al. Cancer 1981) but it is useless !

4. edit this on December 1, 2012 at 6:48 AM | Reply2012pharmaceutical

   Dr. BB

   Thank you for your comment.
   Dr. Nir will reply to your comment.
   Regarding the Response Classification in use, it seems that the College of Oncology should champion a task force to revisit the Best Practice in use in this domain and issue a revised version or a new effort for a a new classification system for Clinical Response to treatment in Cancer.

5. edit this on December 2, 2012 at 5:01 PM | Replylarryhbern

   I’m sorry that I was looking for this paper again earlier and didn’t find it. I answered my view on your article earlier.

   This is a method demonstration, but not a proof of concept by any means. It adds to the cacophany of approaches, and in a much larger study would prove to be beneficial in treatment, but not a cure for serious prostate cancer because it is unlikely that it can get beyond the margin, and also because there is overtreatment at the cutoff of PSA at 4.0. There is now a proved prediction model that went to press some 4 months ago. I think that the pathologist has to see the tissue, and the standard in pathology now is for any result that is cancer, two pathologist or a group sitting together should see it. It’s not an easy diagnosis.

   Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital, & Alexander Stojadinovic. Tumor response criteria: are they appropriate? Future Oncol. (2012) 8(8), 903–906. 10.2217/FON.12.78. ISSN 1479-6694.

   ..Tumor heterogeneity is a ubiquitous phemomenon. In particular, there are important differences among the various types of gastrointestinal (GI) cancers in terms of tumor biology, treatment response and prognosis.

   ..This forms the principal basis for targeted therapy directed by tumor-specific testing at either the gene or protein level. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal.

   ..Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment?

   ..In 2000 theNCI with the European Association for Research and Treatment of Cancer, proposed a replacement of 2D measurement with a decrease in the largest tumor diameter by 30% in one dimension. Tumor response as defined would translate into a 50% decrease for a spherical lesion

   ..We must rethink how we may better determine treatment response in a reliable, reproducible way that is aimed at individualizing the therapy of cancer patients.

   ..we must change the tools we use to assess tumor response. The new modality should be based on empirical evidence that translates into relevant and meaningful clinical outcome data.

   ..This becomes a conundrum of sorts in an era of ‘minimally invasive treatment’.

   ..integrated multidisciplinary panel of international experts – not sure that that will do it

   Several years ago i heard Stamey present the totality of his work at Stanford, with great disappointment over hsPSA that they pioneered in. The outcomes were disappointing.

   I had published a review of all of our cases reviewed for 1 year with Marguerite Pinto.
   There’s a reason that the physicians line up outside of her office for her opinion.
   The review showed that a PSA over 24 ng/ml is predictive of bone metastasis. Any result over 10 was as likely to be prostatitis, BPH or cancer.

   I did an ordinal regression in the next study with Gustave Davis using a bivariate ordinal regression to predict lymph node metastasis using the PSA and the Gleason score. It was better than any univariate model, but there was no followup.

   I reviewed a paper for Clin Biochemistry (Elsevier) on a new method for PSA, very different than what we are familiar with. It was the most elegant paper I have seen in the treatment of the data. The model could predict post procedural time to recurrence to 8 years.

   • edit this on December 6, 2012 at 4:29 AM | ReplyDror Nir

     I hope we are in agreement on the fact that imaging guided interventions are needed for better treatment outcome. The point I’m trying to make in this post is that people are investing in developing imaging guided intervention and it is making progress.

     Over diagnosis and over treatment is another issue altogether. I think that many of my other posts are dealing with that.

6. edit this on December 5, 2012 at 2:05 PM | Replylarryhbern

   Tumor response criteria: are they appropriate?
   Future Oncology 2012; 8(8): 903-906 , DOI 10.2217/fon.12.78 (doi:10.2217/fon.12.78)
   Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital & Alexander Stojadinovic
   Tumor heterogeneity is a problematic because of differences among the metabolic variety among types of gastrointestinal (GI) cancers, confounding treatment response and prognosis.
   This is in response to … a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment.
   1. There is a difference between expected response to esophageal or gastric neoplasms both biologically and in expected response, even given variability within a class. The expected time to recurrence is usually longer in the latter case, but the confounders are – age at time of discovery, biological time of detection, presence of lymph node and/or distant metastasis, microscopic vascular invasion.
   2. There is a long latent period in abdominal cancers before discovery, unless a lesion is found incidentally in surgery for another reason.
   3. The undeniable reality is that it is not difficult to identify the main lesion, but it is difficult to identify adjacent epithelium that is at risk (transitional or pretransitional). Pathologists have a very good idea about precancerous cervical neoplasia.

   The heterogeneity rests within each tumor and between the primary and metastatic sites, which is expected to be improved by targeted therapy directed by tumor-specific testing. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal.

   The heterogeneity is a problem that will take at least another decade to unravel because of the number of signaling pathways and the crosstalk that is specifically at issue.

   I must refer back to the work of Frank Dixon, Herschel Sidransky, and others, who did much to develop a concept of neoplasia occurring in several stages – minimal deviation and fast growing. These have differences in growth rates, anaplasia, and biochemical. This resembles the multiple “hit” theory that is described in “systemic inflammatory” disease leading to a final stage, as in sepsis and septic shock.
   In 1920, Otto Warburg received the Nobel Prize for his work on respiration. He postulated that cancer cells become anaerobic compared with their normal counterpart that uses aerobic respiration to meet most energy needs. He attributed this to “mitochondrial dysfunction. In fact, we now think that in response to oxidative stress, the mitochondrion relies on the Lynen Cycle to make more cells and the major source of energy becomes glycolytic, which is at the expense of the lean body mass (muscle), which produces gluconeogenic precursors from muscle proteolysis (cancer cachexia). There is a loss of about 26 ATP ~Ps in the transition.
   The mitochondrial gene expression system includes the mitochondrial genome, mitochondrial ribosomes, and the transcription and translation machinery needed to regulate and conduct gene expression as well as mtDNA replication and repair. Machinery involved in energetics includes the enzymes of the Kreb’s citric acid or TCA (tricarboxylic acid) cycle, some of the enzymes involved in fatty acid catabolism (β-oxidation), and the proteins needed to help regulate these systems. The inner membrane is central to mitochondrial physiology and, as such, contains multiple protein systems of interest. These include the protein complexes involved in the electron transport component of oxidative phosphorylation and proteins involved in substrate and ion transport.
   Mitochondrial roles in, and effects on, cellular homeostasis extend far beyond the production of ATP, but the transformation of energy is central to most mitochondrial functions. Reducing equivalents are also used for anabolic reactions. The energy produced by mitochondria is most commonly thought of to come from the pyruvate that results from glycolysis, but it is important to keep in mind that the chemical energy contained in both fats and amino acids can also be converted into NADH and FADH2 through mitochondrial pathways. The major mechanism for harvesting energy from fats is β-oxidation; the major mechanism for harvesting energy from amino acids and pyruvate is the TCA cycle. Once the chemical energy has been transformed into NADH and FADH2 (also discovered by Warburg and the basis for a second Nobel nomination in 1934), these compounds are fed into the mitochondrial respiratory chain.
   The hydroxyl free radical is extremely reactive. It will react with most, if not all, compounds found in the living cell (including DNA, proteins, lipids and a host of small molecules). The hydroxyl free radical is so aggressive that it will react within 5 (or so) molecular diameters from its site of production. The damage caused by it, therefore, is very site specific. The reactions of the hydroxyl free radical can be classified as hydrogen abstraction, electron transfer, and addition.
   The formation of the hydroxyl free radical can be disastrous for living organisms. Unlike superoxide and hydrogen peroxide, which are mainly controlled enzymatically, the hydroxyl free radical is far too reactive to be restricted in such a way – it will even attack antioxidant enzymes. Instead, biological defenses have evolved that reduce the chance that the hydroxyl free radical will be produced and, as nothing is perfect, to repair damage.
   Currently, some endogenous markers are being proposed as useful measures of total “oxidative stress” e.g., 8-hydroxy-2’deoxyguanosine in urine. The ideal scavenger must be non-toxic, have limited or no biological activity, readily reach the site of hydroxyl free radical production (i.e., pass through barriers such as the blood-brain barrier), react rapidly with the free radical, be specific for this radical, and neither the scavenger nor its product(s) should undergo further metabolism.
   Nitric oxide has a single unpaired electron in its π*2p antibonding orbital and is therefore paramagnetic. This unpaired electron also weakens the overall bonding seen in diatomic nitrogen molecules so that the nitrogen and oxygen atoms are joined by only 2.5 bonds. The structure of nitric oxide is a resonance hybrid of two forms.
   In living organisms nitric oxide is produced enzymatically. Microbes can generate nitric oxide by the reduction of nitrite or oxidation of ammonia. In mammals nitric oxide is produced by stepwise oxidation of L-arginine catalyzed by nitric oxide synthase (NOS). Nitric oxide is formed from the guanidino nitrogen of the L-arginine in a reaction that consumes five electrons and requires flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) tetrahydrobiopterin (BH4), and iron protoporphyrin IX as cofactors. The primary product of NOS activity may be the nitroxyl anion that is then converted to nitric oxide by electron acceptors.
   The thiol-disulfide redox couple is very important to oxidative metabolism. GSH is a reducing cofactor for glutathione peroxidase, an antioxidant enzyme responsible for the destruction of hydrogen peroxide. Thiols and disulfides can readily undergo exchange reactions, forming mixed disulfides. Thiol-disulfide exchange is biologically very important. For example, GSH can react with protein cystine groups and influence the correct folding of proteins, and it GSH may play a direct role in cellular signaling through thiol-disulfide exchange reactions with membrane bound receptor proteins (e.g., the insulin receptor complex), transcription factors (e.g., nuclear factor κB), and regulatory proteins in cells. Conditions that alter the redox status of the cell can have important consequences on cellular function.
   So the complexity of life is not yet unraveled.

   Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment?
   The goal is not just complete response. Histopathological response seems to be related post-treatment histopathological assessment but it is not free from the challenge of accurately determining treatment response, as this method cannot delineate whether or not there are residual cancer cells. Functional imaging to assess metabolic response by 18-fluorodeoxyglucose PET also has its limits, as the results are impacted significantly by several variables:

   • tumor type
   • sizing
   • doubling time
   • anaplasia?
   • extent of tumor necrosis
   • type of antitumor therapy and the time when response was determined.
   The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics, a greater challenge in an era of ‘minimally invasive treatment’.
   This listing suggests that for every cancer the following data has to be collected (except doubling time). If there are five variables, the classification based on these alone would calculate to be very sizable based on Eugene Rypka’s feature extraction and classification. But looking forward, time to remission and disease free survival are additionally important. Treatment for cure is not the endpoint, but the best that can be done is to extend the time of survival to a realistic long term goal and retain a quality of life.

   Brücher BLDM, Piso P, Verwaal V et al. Peritoneal carcinomatosis: overview and basics. Cancer Invest.30(3),209–224 (2012).
   Brücher BLDM, Swisher S, Königsrainer A et al. Response to preoperative therapy in upper gastrointestinal cancers. Ann. Surg. Oncol.16(4),878–886 (2009).
   Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer47(1),207–214 (1981).
   Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst.92(3),205–216 (2000).
   Brücher BLDM, Becker K, Lordick F et al. The clinical impact of histopathological response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer106(10),2119–2127 (2006).

   • edit this on December 5, 2012 at 2:16 PM | Reply2012pharmaceutical

     Dr. Larry,

     Thank you for this comment.

     Please carry it as a stand alone post, Dr. Ritu will refer to it and reference it in her FORTHCOMING pst on Tumor Response which will integrate multiple sources.

     Please execute my instruction

     Thank you

   • edit this on December 6, 2012 at 4:41 AM | ReplyDror Nir

     Thank you Larry for this educating comment. It explains very well why the Canadian investigators did not try to measure therapy response!

     What they have demonstrated is the technological feasibility of coupling a treatment device to an imaging device and use that in order to guide the treatment to the right place.

     the issue of “choice of treatment” to which you are referring is not in the scope of this publication.
     The point is: if one treatment modality can be guided, other can as well! This should encourage others, to try and develop imaging-based treatment guidance systems.

7. edit this on December 5, 2012 at 2:11 PM | Replylarryhbern

   The crux of the matter in terms of capability is that the cancer tissue, adjacent tissue, and the fibrous matrix are all in transition to the cancerous state. It is taught to resect leaving “free margin”, which is better aesthetically, and has had success in breast surgery. The dilemma is that the patient may return, but how soon?

   • edit this on December 6, 2012 at 4:50 AM | ReplyDror Nir

     Correct. The philosophy behind lumpectomy is preserving quality of life. It was Prof. Veronesi (IEO) who introduced this method 30 years ago noticing that in the majority of cases, the patient will die from something else before presenting recurrence of breast cancer..

     It is well established that when the resection margins are declared by a pathologist (as good as he/she could be) as “free of cancer”, the probability of recurrence is much lower than otherwise.

8. edit this on December 5, 2012 at 2:19 PM | Reply2012pharmaceutical

   Dr. Larry,

   To assist Dr. Ritu, PLEASE carry ALL your comments above into a stand alone post and ADD to it your comment on my post on MIS

   Thank you

9. edit this on December 5, 2012 at 2:34 PM | Replysjwilliamspa

   Great post! Dr. Nir, can the ultrasound be used in conjunction with PET scanning as well to determine a spatial and functional map of the tumor. With a disease like serous ovarian cancer we typically see an intraperitoneal carcimatosis and it appears that clinicians are wanting to use fluorogenic probes and fiberoptics to visualize the numerous nodules located within the cavity Also is the technique being used mainy for surgery or image guided radiotherapy or can you use this for detecting response to various chemotherapeutics including immunotherapy.

   • edit this on December 6, 2012 at 4:11 AM | ReplyDror Nir

     Ultrasound can and is actually used in conjunction with PET scanning in many cases. The choice of using ultrasound is always left to the practitioner! Being a non-invasive, low cost procedure makes the use of ultrasound a non-issue. The down-side is that because it is so easy to access and operate, nobody bothers to develop rigorous guidelines about using it and the benefits remains the property of individuals.

     In regards to the possibility of screening for ovarian cancer and characterising pelvic masses using ultrasound I can refer you to scientific work in which I was involved:

     1. VAES (E.), MANCHANDA (R), AUTIER, NIR (R), NIR (D.), BLEIBERG (H.), ROBERT (A.), MENON (U.). Differential diagnosis of adnexal masses: Sequential use of the Risk of Malignancy Index and a novel computer aided diagnostic tool. Published in Ultrasound in Obstetrics & Gynecology. Issue 1 (January). Vol. 39. Page(s): 91-98.

     2. VAES (E.), MANCHANDA (R), NIR (R), NIR (D.), BLEIBERG (H.), AUTIER (P.), MENON (U.), ROBERT (A.). Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using Ovarian HistoScanning. Published in International Journal of Gynecologic Cancer (IJGC). Issue 1. Vol. 21. Page(s): 35-43.

     3. LUCIDARME (0.), AKAKPO (J.-P.), GRANBERG (S.), SIDERI (M.), LEVAVI (H.), SCHNEIDER (A.), AUTIER (P.), NIR (D.), BLEIBERG (H.). A new computer aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: Results of a multicentre validation study. Published in European Radiology. Issue 8. Vol. 20. Page(s): 1822-1830.

     Dror Nir, PhD
     Managing partner

     BE: +32 (0) 473 981896
     UK: +44 (0) 2032392424

     web: http://www.radbee.com/
     blogs: http://radbee.wordpress.com/ ; http://www.MedDevOnIce.com

10. edit this on December 5, 2012 at 2:39 PM | ReplyBB

    totally true and i am very thankfull for these briliant comments.

    Remember: 10years ago: every cancer researcher stated: “look at the tumor cells only – forget the stroma”. The era of laser-captured tumor-cell dissection started. Now , everyone knows: it is a system we are looking at and viewing and analyzing tumor cells only is really not enough.

    So if we would be honest, we would have to declare, that all data, which had been produced 13-8years ago, dealing with laser capture microdissection, that al these data would need a re-scrutinization, cause the influence of the stroma was “forgotten”. I ‘d better not try thinking about the waisted millions of dollars.

    If we keep on being honest: the surgeon looks at the “free margin” in a kind of reductionable model, the pathologist is more the control instance. I personally see the pathologist as “the control instance” of surgical quality. Therefore, not the wish of the surgeon is important, the objective way of looking into problems or challenges. Can a pathologist always state, if a R0-resection had been performed ?

    The use of the Resectability Classification:
    There had been many many surrogate marker analysis – nothing new. BUT never a real substantial well tought through structured analysis had been done: mm by mm by mm by mm and afterwards analyzing that by a ROC analysis. BUt against which goldstandard ? If you perform statistically a ROC analysis – you need a golstandard to compare to. Therefore what is the real R0-resectiòn? It had been not proven. It just had been stated in this or that tumor entity that this or that margin with this margin free mm distance or that mm distance is enough and it had been declared as “the real R0-classification”. In some organs it is very very difficult and we all (surgeons, pathologists, clinicians) that we always get to the limit, if we try interpretating the R-classification within the 3rd dimension. Often it is just declared and stated.

    Otherwise: if lymph nodes are negative it does not mean, lymph nodes are really negative, cause up to 38% for example in upper GI cancers have histological negative lymph nodes, but immunohistochemical positive lymph nodes. And this had been also shown by Stojadinovic at el analyzing the ultrastaging in colorectal cancer. So the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.

    AS we see: cancer has multifactorial reasons and it is necessary taking the challenge performing high sophisticated research by a multifactorial and multidisciplinary manner.

    Again my deep and heartly thanks for that productive and excellent discussion !

    • edit this on December 5, 2012 at 3:23 PM | Reply2012pharmaceutical

      Dr. BB,

      Thank you for your comment.

      Multidisciplinary perspectives have illuminated the discussion on the pages of this Journal.

      Eager to review Dr. Ritu’s forthcoming paper – the topic has a life of its own and is embodied in your statement:

      “the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.”

    • edit this on December 6, 2012 at 5:05 AM | ReplyDror Nir

      Thank you BB for your comment. You have touched the core limitation of healthcare professionals: how do we know that we know!

      Do we have a reference to each of the test we perform?

      Do we have objective and standardise quality measures?

      Do we see what is out-there or are we imagining?

      The good news: Everyday we can “think” that we learned something new. We should be happy with that, even if it is means that we learned that yesterday’s truth is not true any-more and even if we are likely to be wrong again…:)

      But still, in the last decades, lots of progress was made….

11. edit this on December 11, 2012 at 2:34 AM | Replyritusaxena

    Dr. Nir,
    I thoroughly enjoyed reading your post as well as the comments that your post has attracted. There were different points of view and each one has been supported with relevant examples in the literature. Here are my two cents on the discussion:
    The paper that you have discussed had the objective of finding out whether real-time MRI guidance of treatment was even possible and if yes, and also if the treatment could be performed in accurate location of the ROI? The data reveals they were pretty successful in accomplishing their objective and of course that gives hope to the imaging-based targeted therapies.
    Whether the ROI is defined properly and if it accounts for the real tumor cure, is a different question. Role of pathologists and the histological analysis they bring about to the table cannot be ruled out, and the absence of a defined line between the tumor and the stromal region in the vicinity is well documented. However, that cannot rule out the value and scope of imaging-based detection and targeted therapy. After all, it is seminal in guiding minimally invasive surgery. As another arm of personalized medicine-based cure for cancer, molecular biologists at MD Anderson have suggested molecular and genetic profiling of the tumor to determine genetic aberrations on the basis of which matched-therapy could be recommended to patients. When phase I trial was conducted, the results were obtained were encouraging and the survival rate was better in matched-therapy patients compared to unmatched patients. Therefore, everytime there is more to consider when treating a cancer patient and who knows a combination of views of oncologists, pathologists, molecular biologists, geneticists, surgeons would device improvised protocols for diagnosis and treatment. It is always going to be complicated and generalizations would never give an answer. Smart interpretations of therapies – imaging-based or others would always be required!

    Ritu

    • edit this on December 11, 2012 at 6:10 AM | Reply2012pharmaceutical

      Dr. Nir,
      One of your earlier comments, mentioned the non invasiveness of ultrasound, thus, it’s prevalence in use for diagnosis.

      This may be true for other or all areas with the exception of Mammography screening. In this field, an ultrasound is performed only if a suspected area of calcification or a lump has been detected in the routine or patient-initiated request for ad hoc mammography secondery to patient complain of pain or patient report of suspected lump.

      Ultrasound in this field repserents ascalation and two radiologists review.

      It in routine use for Breast biopsy.

    • edit this on December 12, 2012 at 7:11 AM | ReplyDror Nir

      Thanks Ritu for this supporting comment. The worst enemy of finding solutions is doing nothing while using the excuse of looking for the “ultimate solution” . Personally, I believe in combining methods and improving clinical assessment based on information fusion. Being able to predict, and then timely track the response to treatment is a major issue that affects survival and costs!

Judging the ‘Tumor response’-there is more food for thought

http://pharmaceuticalintelligence.com/2012/12/04/judging-the-tumor-response-there-is-more-food-for-thought/

13 Responses

1. edit this on December 4, 2012 at 2:25 PM | Replysjwilliamspa

   Dr. Sanexa
   you have brought up an interesting and very clinically relevant point: what is the best measurement of response and 2) how perspectives among oncologists and other professionals differ on this issues given their expertise in their respective subspecialties (immunologist versus oncologist. The advent of functional measurements of tumors (PET etc.) seems extremely important in the therapeutic use AND in the development of these types of compounds since usually a response presents (in cases of solid tumors) as either a lack of growth of the tumor or tumor shrinkage. Did the authors include an in-depth discussion of the rapidity of onset of resistance with these types of compounds?
   Thanks for the posting.

2. edit this on December 4, 2012 at 4:48 PM | Replyritusaxena

   Dr. Williams,
   Thanks for your comment on the post. The editorial brings to attention a view that although PET and other imaging methods provide vital information on tumor growth, shrinkage in response to a therapy, however, there are more aspects to consider including genetic and molecular characteristics of tumor.
   It was an editorial review and the authors did not include any in-depth discussion on the rapidity of onset of resistance with these types of compounds as the focus was primarily on interpreting tumor response.
   I am glad you found the contents of the write-up informative.
   Thanks again!
   Ritu

3. edit this on December 5, 2012 at 4:40 AM | ReplyBB

   Thank you for your wonderful comment and interpretation. Dr.Sanexa made a brilliant comment.

   May I allow myself putting my finger deeper into this wound ? Cancer patients deserve it.

   It had been already pointed out by international experts from Munich, Tokyo, Hong-Kong and Houston, dealing with upper GI cancer, that the actual response criteria are not appropriate and moreover: the clinical response criteria in use seem rather to function as an alibi, than helping to differentiate and / or discriminate tumor biology (Ann Surg Oncol 2009):

   http://www.ncbi.nlm.nih.gov/pubmed/19194759

   The response data in a phase-II-trial (one tumor entity, one histology, one treatment, one group) revealed: clinical response evaluation according to the WHO-criteria is not appropriate to determine response:

   http://www.ncbi.nlm.nih.gov/pubmed/15498642

   Of course, there was a time, when it seemed to be useful and this also has to be respected.

   There is another challenge: using statistically a ROC and resulting in thresholds. This was, is and always be “a clinical decision only” and not the decision of the statistician. The clinician tells the statistician, what decision, he wants to make – the responsibility is enormous. Getting back to the roots:
   After the main results of the Munich-group had been published 2001 (Ann Surg) and 2004 (J Clin Oncol):

   http://www.ncbi.nlm.nih.gov/pubmed/11224616

   http://www.ncbi.nlm.nih.gov/pubmed/14990646

   the first reaction in the community was: to difficult, can’t be, not re-evaluated, etc.. However, all evaluated cut-offs / thresholds had been later proven to be the real and best ones by the MD Anderson Cancer Center in Houston, Texas. Jaffer Ajani – a great and critical oncologist – pushed that together with Steve Swisher and they found the same results. Than the upper GI stakeholders went an uncommon way in science: they re-scrutinized their findings. Meanwhile the Goldstandard using histopathology as the basis-criterion had been published in Cancer 2006.

   http://www.ncbi.nlm.nih.gov/pubmed/16607651

   Not every author, who was at the authorlist in 2001 and 2004 wanted to be a part of this analysis and publication ! Why ? Everyone should judge that by himself.

   The data of this analysis had been submitted to the New England Journal of Medicine. In the 2nd review stage process, the manuscript was rejected. The Ann Surg Oncol accepted the publication: the re-scrutinized data resulted in another interesting finding: in the future maybe “one PET-scan” might be appropriate predicting the patient’s response.

   Where are we now ?

   The level of evidence using the response criteria is very low: Miller’s (Cancer 1981) publication belonged to ”one single” experiment from Moertel (Cancer 1976). During that time, there was no definition of “experiences” rather than “oncologists”. These terms had not been in use during that time.

   Additionally they resulted in a (scientifically weak) change of the classification, published by Therasse (J Natl Cancer Inst 2000). Targeted therapy did not result in a change so far. In 2009, the international upper GI experts sent their publication of the Ann Surg Oncol 2009 to the WHO but without any kind of reaction.

   Using molecular biological predictive markers within the last 10years all seem to have potential.

   http://www.ncbi.nlm.nih.gov/pubmed/20012971

   http://www.ncbi.nlm.nih.gov/pubmed/18704459

   http://www.ncbi.nlm.nih.gov/pubmed/17940507

   http://www.ncbi.nlm.nih.gov/pubmed/17354029

   But, experts are aware: the real step breaking barriers had not been performed so far. Additionally, it is very important in trying to evaluate and / predict response, that not different tumor entities with different survival and tumor biology are mixed together. Those data are from my perspective not helpful, but maybe that is my own Bias (!) of my view.

   INCORE, the International Consortium of Research Excellence of the Theodor-Billroth-Academy, was invited publishing the Editorial in Future Oncology 2012. The consortium pointed out, that living within an area of ‘prove of principle’ and also trying to work out level of evidence in medicine, it is “the duty and responsibility” of every clinician, but also of the societies and institutions, also of the WHO.

   Complete remission is not the only goal, as experts dealing with ‘response-research’ are aware. It is so frustrating for patients and clinicians: there is a rate of those patients with complete remission, who develop early recurrence ! This reflects, that complete remission cannot function as the only criterion describing response !

   Again, my heartly thanks, that Dr.Sanexa discussed this issue in detail.
   I hope, I found the way explaining the way of development and evaluating response criteria properly and in a differentiated way of view. From the perspective of INCORE:

   “an interdisciplinary initiative with all key stake¬holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prognosis.”

4. edit this on December 5, 2012 at 5:34 AM | Replyritusaxena

   Dr. Brucher,

   First of all thanks for expressing your views on the ‘tumor response’ in a comprehensive way. You are the first author of the editorial review one of the prominent people who has taken part in the process of defining tumor response and I am glad that you decided to write a comment on the writeup.
   The topic has been explained well in an immaculate manner and that it further clarifies the need for the perfect markers that would be able to evaluate and predict tumor response. There are, as you mentioned, some molecular markers available including VEGF, cyclins, that have been brought to focus in the context of squamous cell carcinoma.

   It would be great if you could be the guest author for our blog and we could publish your opinion (comment on this blog post) as a separate post. Please let us know if it is OK with you.

   Thanks again for your comment
   Ritu

5. edit this on December 5, 2012 at 6:34 AM | Reply2012pharmaceutical

   Thank you all to the compelling discussions, above.

   Please review the two sources on the topic I placed at the bottom of the post, above as post on this Scientific Journal,

   All comments made to both entries are part of thisvdiscussion, I am referring to Dr. Nir’s post on size of tumor, to BB comment to Nir’s post, to Larry’ Pathologist view on Tumors and my post on remission and minimally invasive surgery (MIS).

   Great comments by Dr. Williams, BB and wonderful topic exposition by Dr. Ritu.

6. edit this on December 5, 2012 at 6:43 AM | Replyritusaxena

   Aviva,
   Thats a great idea. I will combine all sources referred by you, the post on tumor imaging by Dr. Nir and the comments made on the these posts including Dr. Brucher’s comments in a new posts.
   Thanks
   Ritu

   • edit this on December 5, 2012 at 6:58 AM | Reply2012pharmaceutical

     Great idea, ask Larry, he has written two very long important comments on this topic, one on Nir’s post and another one, ask him where, if it is not on MIS post. GREAT work, Ritu, integration is very important. Dr, Williams is one of our Gems.

   • edit this on December 5, 2012 at 8:37 AM | Replylbretes

     Assessing tumour response it is not an easy task!Because tumours don’t change,but happilly our knowlege(about them) does really change,is everchanging(thans god!).In the past we had the Recist Criteria,then the Modified Recist Criteria,becausa of Gist and other tumors.At this very moment,these are clearly insuficient.We do need more ,new validated facing the reality of nowadays.A great,enormoust post Dr Ritu!Congratulations!