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Posts Tagged ‘lymph nodes’


Author: Tilda Barliya PhD

Metastasis, the spread of cancer cells from a primary tumour to seed secondary tumours in distant sites, is one of the greatest challenges in cancer treatment today. For many patients, by the time cancer is detected, metastasis  has already occurred. Over 80% of patients diagnosed  with lung cancer, for example, present with metastatic  disease. Few patients with metastatic cancer are cured by surgical intervention, and other treatment modalities are limited. Across all cancer types, only one in five patients diagnosed with metastatic cancer will survive more than 5 years. (1,2).

Metastatic Cancer 

  • Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.
  • Metastatic cancer has the same name and same type of cancer cells as the original cancer.
  • The most common sites of cancer metastasis are the lungs, bones, and liver.
  • Treatment for metastatic cancer usually depends on the type of cancer and the size, location, and number of metastatic tumors.

How do cancer cells spread (3)

  • Local invasion: Cancer cells invade nearby normal tissue.
  • Intravasation: Cancer cells invade and move through the walls of nearby lymph vessels or blood vessels.
  • Circulation: Cancer cells move through the lymphatic system and the bloodstream to other parts of the body.

The ability of a cancer cell to metastasize successfully depends on its individual properties; the properties of the noncancerous cells, including immune system cells, present at the original location; and the properties of the cells it encounters in the lymphatic system or the bloodstream and at the final destination in another part of the body. Not all cancer cells, by themselves, have the ability to metastasize. In addition, the noncancerous cells at the original location may be able to block cancer cell metastasis. Furthermore, successfully reaching another location in the body does not guarantee that a metastatic tumor will form. Metastatic cancer cells can lie dormant (not grow) at a distant site for many years before they begin to grow again, if at all.

Although cancer therapies are improving, many drugs are not reaching the sites of metastases, and doubt  remains over the efficacy of those that do. Methods  that are effective for treating large, well-vascularized tumours may be inadequate when dealing with small clusters of disseminated malignant cells.

We expect that the expanding capabilities of nanotechnology, especially in targeting, detection and particle trafficking, will enable  novel approaches to treat cancers even after metastatic dissemination.

 

Lymph nodes, which are linked by lymphatic vessels, are distributed throughout the body and have an integral role in the immune response. Dissemination of cancer cells through the lymph network is thought to be an important route for metastatic spread. Tumor proximal lymph nodes are often the first site of metastases, and the presence of lymph node metastases signifies further metastatic spread and poor patient survival.

As such, lymph nodes have been targeted using cell-based nanotechnologies

Lymph nodes are small, bean-shaped organs that act as filters along the lymph fluid channels. As lymph fluid leaves the organ (such as breast, lung etc) and eventually goes back into the bloodstream, the lymph nodes try to catch and trap cancer cells before they reach other parts of the body. Having cancer cells in the lymph nodes suggests an increased risk of the cancer spreading. It is thus very important to evaluate the involvement of lymph nodes when choosing the best possible treatment for the patient.

Although current mapping methods are available such as CT and MRI scans, PET scan, Endobronchial Ultrasound, Mediastinoscopy and lymph node biopsy, sentinel lymph node (SLN) mapping and nodal treatment in lung cancer remain inadequate for routine clinical use. 

Certain characteristics are associated with preferential (but not exclusive) nanoparticle trafficking to lymph nodes following intravenous administration.

Targeting is often an indirect process, as receptors on the surface of leukocytes bind nanoparticles and transfer them to lymph nodes as part of a normal immune response. Several strategies have been used to enhance nanoparticle uptake by leukocytes in circulation. Coating iron-oxide nanoparticles with carbohydrates, such as dextran, results in the increased accumulation of these nanoparticles in lymph nodes. Conjugating peptides and antibodies, such as immunoglobulin G (IgG), to the particle surface also increases their accumulation in the lymphatic network. In general, negatively charged particles are taken up at faster rates than positively charged or uncharged particles. Conversely, ‘stealth’ polymers, such as polyethylene glycol (PEG), on the surface of nanoparticles, can inhibit uptake by leukocytes, thereby reducing accumulation in the lymph nodes.

Lymph node targeting may be achieved by other routes of administration. Tsuda and co-workers reported that non-cationic particles with a size range of 6–34nm, when introduced to the lungs (intrapulmonary administration), are trafficked rapidly (<1 hour) to local lymph nodes. Administering particles <80 nm in size subcutaneously also results in trafficking to lymph nodes. Interestingly, some studies have indicated that non-pegylated particles exhibit enhanced accumulation in the lymphatics and that pegylated particles tend to appear in the circulation several hours after administration.

Over the last twenty years, sentinel lymph node (SLN) imaging has revolutionized the treatment of several malignancies, such has melanoma and breast cancer, and has the potential to drastically improve treatment in other malignancies, including lung cancer. Several attempts at developing an easy, reliable, and effective method for SLN mapping in lung cancer have been unsuccessful due to unique difficulties inherent to the lung and to operating in the thoracic cavity.

An inexpensive method offering rapid, intraoperative identification of SLNs, with minimal risk to both patient and provider, would allow for improved staging in patients. This, in turn, would permit better selection of patients for adjuvant therapy, thus reducing morbidity in those patients for whom adjuvant treatment is inappropriate, and ensuring that those who need this added therapy actually receive it. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/)

Current methods for SLN identification involve the use of radioactivity-guided mapping with technetium-99m sulfur colloid and/or visual mapping using vital blue dyes. Unfortunately these methods can be inadequate for SLN mapping in non-small cell lung cancer (NSCLC) The use of vital blue dyes is limited in vivo by poor visibility, particularly in the presence of anthracotic mediastinal nodes, thereby decreasing the signal-to-background ratio (SBR) that enables nodal detection. Similarly, results with technetium-99m sulfur colloid have been mixed when used in the thoracic cavity, where hilar structures and aberrant patterns of lymphatic drainage make detection more difficult.

Although Nomori et al. have reported an 83% nodal identification rate following a preoperative injection of technetium-99 colloid, there is an associated increased risk of pneumothorax and bleeding with this method. Further, the recently completed CALGB 140203 multicenter Phase 2 trial investigating the use of intraoperative technetium-99m colloid found an identification rate of only 51% with this technique.  Clearly a technology with greater accuracy, improved SBR, and less potential risk to surgeon and patient would be welcome in the field of thoracic oncology.

Near-infrared (NIR) fluorescence imaging has the potential to meet this difficult challenge.

Near-Infrared Light

NIR light is defined as that within the wavelength range of 700 to 1000 nm. Although NIR light is invisible to the naked eye, it can be thought of as “redder” than UV and visible light.

  • Absorption, scatter, and autofluorescence are all significantly reduced at redder wavelengths. For instance, Hemoglobin, water, lipids, and other endogenous chromophores, such as melanin, have their lowest absorption within the NIR spectrum, which permits increased photon depth penetration into tissues
  • In addition, imaging can also be affected by photon scatter, which describes the reflection and/or deflection of light when it interacts with tissue. Scatter, on an absolute scale, is often ten-times higher than absorption. However, the two major types of scatter, Mie and Rayleigh, are both reduced in the NIR, making the use of NIR wavelengths especially important for the reduction of photon attenuation.
  • living tissue has extremely high “autofluorescence” in the UV and visible wavelength ranges due to endogenous fluorophores, such as NADH and the porphyrins. Therefore, UV/visible fluorescence imaging of the intestines, bladder, and gallbladder is essentially precluded. However, in the NIR spectrum, autofluorescence is extremely low, providing the black imaging background necessary for optimal detection of a NIR fluorophore within the surgical field
  • Additionally, optical imaging techniques, such as NIR fluorescence, eliminate the need for ionizing radiation. This, combined with the availability of a NIR fluorophore already FDA-approved for other indications and having extremely low toxicity (discussed below), make this a potentially safe imaging modality.

The main disadvantage is that it’s invisible to the human eye, requiring special imaging-systems to “see” the NIR fluorescence.

Currently there are three intraoperative NIR imaging systems in various stages of development:

  • The SPY system (Novadaq, Canada) – utilizes laser light excitation in order to obtain fluorescent images. The Spy system has been studied for imaging patency of vascular anastamoses following CABG and organ transplantation
  • The Photodynamic Eye(Hamamatsu, Japan) – is presently available only in Japan
  • The Fluorescence-Assisted Resection and Exploration (FLARE) system ()- developed by the authors’ laboratory utilizes NIR light-emitting diode (LED) excitation, eliminating the need for a potentially harmful laser. Additionally, the FLAREsystem has the advantage of being able to provide simultaneous color imaging, NIR fluorescence imaging, and color-NIR merged images, allowing the surgeon to simultaneously visualize invisible NIR fluorescence images within the context of surgical anatomy.

Near-Infrared Fluorescent Nanoparticle Contrast Agents

The ideal contrast agent for SLN mapping would be anionic and within 10–50 nm in size in order to facilitate rapid uptake into lymphatic vessels with optimal retention within the SLN.

Due to the lack of endogenous NIR tissue fluorescence, exogenous contrast agents must be administered for in vivo studies. The most important contrast agents that emit within the NIR spectrum are the heptamethine cyanines fluorophores, of which indocyanine green (ICG) is the most widely used, and fluorescent semiconductor nanocrystals, also known as quantum dots (QDs).

  • ICG is an extremely safe NIR fluorophore, with its only known toxicity being rare anaphylaxis. The dye was FDA approved in 1958 for systemic administration for indicator-dilution studies including measurements of cardiac output and hepatic function. Additionally, it is commonly used in ophthalmic angiography. When given intravenously, ICG is rapidly bound to plasma albumin and cleared from the blood via the biliary system. Peak absorption and emission of ICG occur at 780 nm and 830 nm respectively, within the window where in vivo tissue absorption is at its minimum. ICG has a relatively neutral charge, has a hydrodynamic diameter of only 1.2 nm, and is relatively hydrophobic. Unfortunately, this results in rapid transport out of the SLN and relatively low fluorescence yield, thereby decreasing its efficacy in mapping techniques. However, noncovalent adsorption of ICG to human serum albumin (HSA), as occurs within plasma, results in an anionic nanoparticle with a diameter of 7.3 nm and a three-fold increase in fluorescence yield markedly improving its utility in SLN mapping.
  • QDs consist of an inorganic heavy metal core and shell which emit within the NIR spectrum. This structure is then surrounded by a hydrophilic organic coating which facilitates aqeuous solubility and lymphatic distrubtion. QDs have been extensively studied and are ideal for SLN mapping as their hydrodynamic diameter can be customized to the appropriate size within a narrow distribution (15–20 nm), they can be engineered to have an anionic surface charge, and exhibit an extremely high SBRs with significant photostability. Unfortunately, safety concerns due to the presence of heavy metals within the QDs so far have precluded clinical application

Human Clinical Trials and NIR SLN mapping

Several studies have investigated the clinical use of indocyanine green without adsorption to HSA for NIR fluorescence-guided SLN mapping in breast and gastric cancer with good success (9-13).

Kitai et al. first examined this technique in 2005 in breast cancer patients, and was able to identify a SLN node in 17 of 18 patients using NIR fluorescence rather than the visible green color of ICG (9). Sevick-Muraca et al. reported similar results using significantly lower microdoses of ICG (10 – 100 μg), successfully identifying the SLN in 8 of 9 patients (11). Similar to these subcutaneous studies, 56 patients with gastric cancer underwent endoscopic ICG injection into the submucosa around the tumor 1 to 3 days preoperatively or injection directly into the subserosa intraoperatively with identification of the SLN in 54 patients (13).

Recently, Troyan et al. have completed a pilot phase I clinical trial examining the utility of NIR imaging the ICG:HSA nanoparticle fluorophore for SLN mapping/biopsy in breast cancer using the FLAREsystem. In this study, 6 patients received both 99mTc-sulfur colloid lymphoscintigraphy along with ICG:HSA at micromolar doses. SLNs were identified in all patients using both methods. In 4 of 6 patients the SLNs identified were the same, while in the remaining two, lymphoscintigraphy identified an additional node in one patient and ICG:HSA identified an additional SLN in the other. Irrespective, this study demonstrates that NIR SLN mapping with low dose ICG:HSA is a viable method for intraoperative SLN identification.

Nanotechnology and Drug Delivery in Lung cancer

We previously explored Lung cancer and nanotechnology aspects as polymer nanotechnology has been an area of significant research over the past decade as polymer nanoparticle drug delivery systems offer several advantages over traditional methods of chemotherapy delivery

see: (15) https://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/                (16) https://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

As the importance of micrometastatic lymphatic spread of tumor becomes clearer, there has been much interest in the use of nanoparticles for lymphatic drug delivery. The considerable focus on developing an effective method for SLN mapping for lung cancer is indicative of the importance of nodal spread on overall survival.

Our lab is investigating the use of image-guided nanoparticles engineered for lymphatic drug delivery. We have previously described the synthesis of novel, pH-responsive methacrylate nanoparticle systems (14). Following a simple subcutaneous injection of NIR fluorophore-labeled nanoparticles 70 nm in size, we have shown that we can deliver paclitaxel loaded within the particles to regional draining lymph nodes in several organ systems of Yorkshire pigs while simultaneously confirming nodal migration using NIR fluorescent light. Future studies will need to investigate the ability of nanoparticles to treat and prevent nodal metastases in animal cancer models. Additionally, the development of tumor specific nanoparticles will potentially allow for targeting of chemotherapy to small groups of metastatic tumor cells further limiting systemic toxicities by narrowing the delivery of cytotoxic drugs.

Ref:

1. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

2. http://www.nature.com/nrc/focus/metastasis/index.html

3. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic

4. http://www.cancerresearchuk.org/cancer-help/about-cancer/what-is-cancer/body/the-lymphatic-system

5. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphnodessecondary/Secondarycancerlymphnodes.aspx

6. Khullar O, Frangioni JV and Colson YL. Image-Guided Sentinel Lymph Node Mapping and Nanotechnology-Based Nodal Treatment in Lung Cancer using Invisible Near-Infrared Fluorescent Light. Semi Thorac Cardiovasc Surg 2009 :21 (4);  309-315. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/

7. Stacker SA, Achen MG, Jussila L,  Baldwin ME and Alitalo K. Metastasis: Lymphangiogenesis and cancer metastasis.  Nature Reviews Cancer 2002 2, 573-583. http://www.nature.com/nrc/journal/v2/n8/full/nrc863.html

8. Schroeder A., Heller DA., Winslow MM., Dahlman JE., Pratt GW., Langer R., Jacks T and Anderson DG.. Nature Reviews Cancer 2012; 12(1), 39-50. Treating metastatic cancer with nanotechnology. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/full/nrc3180.html

9. Kitai T, Inomoto T, Miwa M, et al. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12:211–215.

10. Ogasawara Y, Ikeda H, Takahashi M, et al. Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World journal of surgery.2008;32:1924–1929.

11. Sevick-Muraca EM, Sharma R, Rasmussen JC, et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology.2008;246:734–741.

12. Miyashiro I, Miyoshi N, Hiratsuka M, et al. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol.2008;15:1640–1643.

13. Tajima Y, Yamazaki K, Masuda Y, et al. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009;249:58–62.

14. Griset AP, Walpole J, Liu R, et al. Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive drug delivery system. J Am Chem Soc. 2009;131:2469–2471

15. https://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

16.  https://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

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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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Non-small Cell Lung Cancer drugs – where does the Future lie?

In focus: Tarceva, Avastin and Dacomitinib

 

UPDATED on July 5, 2013

(from reports published in New England Journal of Medicine on drug, crizotinib)

 

Curator: Ritu Saxena, Ph.D.

 

Introduction

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.

There are three common forms of NSCLC:

  • Adenocarcinomas are often found in an outer area of the lung.
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.

Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.

Treatment

Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.

FDA approved drugs for NSCLC

Abitrexate (Methotrexate)
Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) 
Alimta (Pemetrexed Disodium)
Avastin (Bevacizumab)
Bevacizumab
Carboplatin
Cisplatin
Crizotinib
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gefitinib
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel
Paclitaxel Albumin-stabilized Nanoparticle Formulation
Paraplat (Carboplatin)
Paraplatin (Carboplatin)
Pemetrexed Disodium
Platinol (Cisplatin)
Platinol-AQ (Cisplatin)
Tarceva (Erlotinib Hydrochloride)
Taxol (Paclitaxel)
Xalkori (Crizotinib)

On the basis of target, the drugs have been classified as follows:

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NSCLC Drug Market Analysis

NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020

Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.   

However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.

In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.

Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.

Tarceva (Erlotinib)

Generic Name: Erlotinib, Brand Name: Tarceva

Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781

Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.

Tarceva has been approved for different cancers and several indications have been filed-

  • non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
  • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
  • non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
  • non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease

Sales of Tarceva 

May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.

In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.

It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.

According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Avastin (Bevacizumab)

Generic Name: Avastin, Brand Name: Bevacizumab

Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435

Mechanism of Action

Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.

Targets

Vascular endothelial growth factor (VEGF, VEGF-A, VEGFA)

Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.

Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their tar­gets.

Avastin has been approved for different cancers and several indications have been filed:

  • colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
  • colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
  • renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
  • glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
  • ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
  • ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer

SOURCE:

New medicine Oncology Knowledge Base

Sales of Avastin 

As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.

It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)

Dacomitinib: New promising drug for NSCLC

Generic Name: Dacomitinib

Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804

PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.

Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.

SOURCE:

New medicine Oncology Knowledge base

Dacomitinib bests Erlotinib in advanced NSCLC:  Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.

In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.

SOURCE:

Randomized Phase II Study of Dacomitinib Versus Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer

The results indicated indicated the following:

  • Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
  • Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.

Patients were divided into groups by tumor type and following results were obtained:

  • Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
  • Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
  • PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.

The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.

Although adverse side effects were uncommon in both the groups, certain side effects such as:

  • mouth sores,
  • nailbed infections, and
  • diarrhea

were more common and tended to be more severe with Dacomitinib as compared to Tarceva.

Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.

Current status of Dacomitinib

Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.

SOURCE:

New medicine Oncology Knowledge base

*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.

REFERENCES

Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinib is an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.

  • Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine.  A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).

However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)

Reference: 

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