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Posts Tagged ‘free margin’


Couple of days ago I have posted on breast-cancer mammography screening and associated costs; Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA. Treatment of breast-cancer represents much heavier cost-burden. According to the following publication: Variability in Reexcision Following Breast Conservation Surgery made in JAMA: “Failure to achieve appropriate margins at the initial operation will require additional surgery with re-excision rate estimates ranging from 30% to 60%. These additional operations can produce considerable psychological, physical, and economic stress for patients and delay use of recommended adjuvant therapies. A high percentage (10%-36%) of women requiring reexcision undergo total mastectomy. Thus, the effect of reexcision on altering a patient’s initial treatment of choice is significant.”

 Considering that ~70% of the 285,000 new patients diagnosed with breast cancer each year undergoes lumpectomy, this data represents significant cost. Not to mention morbidity, stress and reduce quality of life for the patients. In my post Optical Coherent Tomography – emerging technology in cancer patient management I discussed the potential of OCT in controlling the quality of lumpectomies in-situ. A workflow that represents potential to reduce the costs of repeated lumpectomies.

Last week, Dune Medical Devices, Inc., the company that developed the MarginProbeTM System, an intra-operative tissue assessment device to be used as accessory during lumpectomies of early-stage breast cancer, has received Premarket Approval (PMA) by the United States Food and Drug Administration.

MarginProbe system

marginProbe

FDA approval of the MarginProbe System was based on a 664 patient prospective, multi-center, randomized, double arm study to evaluate the effectiveness of MarginProbe in identifying cancerous tissue along the margins of removed breast tissue during initial lumpectomy procedures. MarginProbe, which uses electromagnetic “signatures” to identify healthy and cancerous tissue, was found to be over three times more effective in finding cancer on the margin during lumpectomy, compared to traditional intra-operative imaging and palpation assessment. This enabled surgeons to significantly reduce the number of patients with positive margins following initial surgery.

The following publication gives an idea on the clinical performance of MarginProbe:

J Surg Res. 2010 May 15;160(2):277-81. doi: 10.1016/j.jss.2009.02.025. Epub 2009 Mar 31.

Diagnostic performance of a novel device for real-time margin assessment in lumpectomy specimens.

Pappo ISpector RSchindel AMorgenstern SSandbank JLeider LTSchneebaum SLelcuk SKarni T.

Source

Department of General Surgery, Assaf Harofeh Medical Center, Zrifin, Israel. pappo@zahav.net.il

Abstract

BACKGROUND:

Margin status in breast lumpectomy procedures is a prognostic factor for local recurrence and the need to obtain clear margins is often a cause for repeated surgical procedures. A recently developed device for real-time intraoperative margin assessment (MarginProbe; Dune Medical Devices, Caesarea, Israel), was clinically tested. The work presented here looks at the diagnostic performance of the device.

METHODS:

The device was applied to freshly excised lumpectomy and mastectomy specimens at specific tissue measurement sites. These measurement sites were accurately marked, cut out, and sent for histopathologic analysis. Device readings (positive or negative) were compared with histology findings (namely malignant, containing any microscopically detected tumor, or nonmalignant) on a per measurement site basis. The sensitivity and specificity of the device was computed for the full dataset and for additional relevant subgroups.

RESULTS:

A total of 869 tissue measurement sites were obtained from 76 patients, 753 were analyzed, of which 165 were cancerous and 588 were nonmalignant. Device performance on relatively homogeneous sites was: sensitivity 1.00 (95% CI: 0.85-1), specificity 0.87 (95% CI: 0.83-0.90). Performance for the full dataset was: sensitivity 0.70 (95% CI: 0.63-0.77), specificity 0.70 (95% CI: 0.67-0.74). Device sensitivity was estimated to change from 56% to 97% as the cancer feature size increased from 0.7 mm to 6.6 mm. Detection rate of samples containing pure DCIS clusters was not different from rates of samples containing IDC.

CONCLUSIONS:

The device has high sensitivity and specificity in distinguishing between normal and cancer tissue even down to small cancer features.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

PMID: 19628225

Imagine how cost effective breast cancer management can be if it will involve systems such as these in addition to the systems I discussed in some of my previous posts, for example: What could transform an underdog into a winner?

Written by: Dror Nir, PhD.

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Author and curator: Ritu Saxena, Ph.D.

This post attempts to integrate three posts and to embed all comments made to all three papers, allowing the reader a critically thought compilation of evidence-based medicine and scientific discourse.

Dr. Dror Nir authored a post on October 16th titled “Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?” The article attracted over 20 comments from readers including researchers and oncologists debating the following issues:

  • imaging technologies in cancer
  • tumor size, and
  • tumor response to treatment.

The debate lead to several new posts authored by:

This post is a compilation of the views of authors representing different specialties including research and medicine. In medicine: Pathology, Oncology Surgery and Medical Imaging, are represented.

Dr. Nir’s post talked about an advanced technique developed by the researchers at Sunnybrook Health Sciences Centre, University of Toronto, Canada for cancer lesions’ detection and image-guided cancer treatment in the specific Region of Interest (ROI). The group was successfully able to show the feasibility and safety of magnetic resonance imaging (MRI) – controlled transurethral ultrasound therapy for prostate cancer in eight patients.

The dilemma of defining the Region of Interest for imaging-based therapy

Dr. Bernstein, one of the authors at Pharmaceuticalintelligence.com, a Fellow of the American College of Pathology, reiterated the objective of the study stating that “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.” He expressed his opinion about the study by bringing into focus a very important issue i.e., given the fact that the part surrounding the cancer tissue is in the transition state, challenge in defining a ROI that could be approached by imaging-based therapy. Regarding the study discussed, he states – “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. I think that the pathologist has to see the tissue, and the standard in pathology now is for any result that is cancer, two pathologists or a group sitting together should see it. It’s not an easy diagnosis.”

“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?” concludes Dr. Larry.

Dr. Nir responded, “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. He explains further, “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!

In this discussion my view is expressed, below.

  • The paper that discusses imaging technique had the objective of finding out whether real-time MRI guidance of treatment was even possible and if yes, whether 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 and what they bring 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 encouraging and the survival rate was better in matched-therapy patients compared to unmatched patients. Therefore, every time 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!

To read additional comments, including those from Dr. Williams, Dr. Lev-Ari, refers to:

Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention? Author and Reporter: Dror Nir, Ph.D.

Dr. Lev-Ari in her paper linked three fields that bear weight in the determination of Tumor Response to Therapy:

  • Personalized Medicine
  • Cancer Cell Biology, and
  • Minimally Invasive Surgery (MIS)

Her objectives were to address research methodology, the heterogeneity innate to Cancer Cell Biology and Treatment choice in the Operating Room — all are related to the topic at hand: How to deliver optimal care with least invasive intervention course.

Any attempt aimed at approaching this desirable result, called Personalized Medicine,  involves engagement in three strategies:

  • prediction of Patient’s reaction to Drug induction
  • design of Clinical Trials to validate drug efficacy on small subset of patients predicted to react favorable to drug regimen, increasing validity and reliability
  • Genetical identification of patients at no need to have a drug administered if non sensitivity to the drug has been predicted

These method are to be applied to a list of 56 leading Cancer types.

While the executive task of the clinician remains to assess the differentiation in Tumor Response to Treatment, pursuit of  individualized histopathology, as well as tumor molecular, genetic and functional characteristics has to take into consideration the “total” individual patients’ characteristics: age, co-morbidities, secondary risks and allergies to drugs.

In Dr. Lev-Ari’s paper Minimally Invasive Treatment (MIT) is compared with Minimally Invasive Surgery (MIS) applied for tumor resection.  In many cases MIS is not the right surgical decision, yet, it is applied for a corollary of patient-centered care considerations. At present, facing the unknown of the future behavior of the tumor as its response to therapeutics bearing uncertainty related to therapy outcomes.

Forget me not – says the ‘Stroma’

Dr. Brücher, the author of review on tumor response criteria, expressed his views on the topic. He remembers that 10 years ago, every cancer researcher stated – “look at the tumor cells only – forget the stroma”. However, the times have changed, “now, everyone knows that it is a system we are looking at, and viewing and analyzing only tumor cells is really not enough.”

He went on to state “if we would be honest, we would have to declare that all data, which had been produced 8-13 years ago, dealing with laser capture microdissection, would need a rescrutinization, because the influence of the stroma was ‘forgotten’.”

He added, “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?”

What is the real RO-resection?

There have been many surrogate marker analysis, says Dr. Brücher, and that a substantially well thought through structured analysis has never been done: mm by mm and afterwards analyzing that by a ROC analysis. For information on genetic markers on cancer, refer to the following post by Dr. Lev-Ari’s: Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

He also stated that there is no gold standard to compare the statistical ROC analysis to. Often it is just declared and stated but it is still not clear what the real RO-resection is?

He added, “in some organs it is very difficult and we all (surgeons, pathologists, clinicians) that we always get to the limit, if we try interpreting the R-classification within the 3rd dimension.”

Dr. Brücher explains regarding resectability classification, “If lymph nodes are negative it does not mean, lymph nodes are really negative. For example, up to 38% upper GI cancers have histological negative lymph nodes, but immunohistochemical positive lymph nodes. And, Stojadinovic et al have also shown similar observations at el 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.”

The discussion regarding the transition state of the tumor surrounding tissue and the ‘free margin’ led to a bigger issue, the heterogeneity of tumors.

Dr. Bernstein quoted a few lines from the review article titled “Tumor response criteria: are they appropriate?, authored by Dr Björn LDM Brücher et al published in Future Oncology in 2012.

  • 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, the NCI 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.

Dr. Bernstein followed up by authoring a separate post on tumor response. His views on tumor response criteria have been quoted in the following paragraphs:

Can tumor response to therapy be predicted?

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 were 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.

For detailed discussion on the topic of tumor response and comments refer to the following posts:

What can we expect of tumor therapeutic response?

Author: Larry H. Bernstein, MD, FCAP

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

Reporter: Ritu Saxena, Ph.D.

Additional Sources:

Research articles:

Brücher BLDM  et al. Tumor response criteria: are they appropriate? Future Oncol. August Vol. 8, No. 8, Pages 903-906 (2012).

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).

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