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Posts Tagged ‘American Cancer Society’


Cancer Screening Programs at Sourasky Medical Center’s Cancer Prevention Center in Tel-Aviv

Author: Ziv Raviv, PhD

Cancer is one of the leading causes of death in the World. Major efforts are devoted for its eradication. There are several strategies to fighting cancer. Considerable research efforts were allocated over the last 50 years to elucidate the genetic factors causing cancer and the molecular mechanisms governing its biology for the purpose of developing anti-cancer treatments. It is important to note that cancer is a disease that environmental and life style factors play crucial role in its development.

It is accepted in the Medical community that the earlier the cancer has being detected, the greater are the odds for better prognosis and often the attainment of complete remission. Thus, it is important that more efforts should be addressed into prevention and early detection programs. Several medical centers and research institutes have set up prevention programs, among them is the integrated cancer prevention center (ICPC) of Tel-Aviv Sourasky medical center (TASMC) directed by Prof. Nadir Arber. A comprehensive cancer screening is applied by specialist physicians aimed at identification of potential cancer patients. The Screening program is supported by an integrated research laboratory, that develops and implements innovative technologies and approaches for early detection and therapy of cancer.

ICPC program is considered to be unique in the World. The Screening involves a comprehensive examination, on the spot, for the early detection of at least 11 different most common cancers taking advantage of up-to-date contemporary as well as innovative tests, which are carried out under the same roof and require a single visit taking only few hours, where results are given within few weeks. That is instead of doing separate examinations for the detection of each cancer type, a process when performed through the ordinary health care pathway could consume much of the patient time and involves several bureaucratic levels.

The cancers being tested for by the center include among others:

  • Skin
  • Colon
  • Breast
  • Lung
  • Ovarian
  • Prostate

Respectively, the screenings performed include careful body and skin examination, imaging, blood tests for cancer markers accompanied with standard clinical tests, as well as personal interview evaluating the family history and risk factors of the client. However, it is important to note that the ICPC is not restricted only to patients with known family history of cancer incidents and/or with high risk factors, rather, ICPC is providing its services to any person whom would like to be examined if having cancer. The goal of ICPC is indeed to create the atmosphere among the general public to give attitude to this screening as it is a standard process of body checkup that should be performed periodically on a regular basis. The visit at ICPC clinic consumes relatively small effort from the patient in terms of time and costs. In addition, the persons arriving to ICPC are receiving dietary as well as life style counseling. If cancer or a pre-cancerous condition is been discovered, the client is being referred for further evaluation of treatment options. Personalized approach is applied that includes performing a personal questionnaire and interview before screening as mentioned above, as well as ongoing documentation and follow-ups that are initiated after the results are obtained and shared with the patient.

The cost of this sequence of checkups and tests is seemingly expensive, and there is an impression that this is a “rich people only clinic”, too expensive for the average pocket. Yet, when thinking carefully the costs are rather low, only few hundreds of American dollars, a price which is definitely low comparing to the costs of some of these tests, and as Prof. Arber stated: “the cost is not higher than that one pays for his annual car service, so why not giving the same attention to your own body as given to your car.” The fees being paid by the patients for the screening and genetic testing are not covering the costs. However, in the long run, it is believed that this approach is worthwhile if taking in consideration the costs benefits of cancer early detection, of reducing hospitalization days and medicines prescription. Therefore, a governmental intervention should take place in the form of subsidizing the costs of the cancer screening. In addition, the various health care insurance plans should cover at least in part the fees required to be paid by the patient for this screening, thus, making the visit to the cancer prevention center affordable to every citizen.

ICPC reported that, around 10 percent of people following the screening protocol, were found to be carrying premature tumors, emphasizing the importance of the existence of such a preventive center. Now it is remained to evaluate if the program is being accepted broadly by the general public. PR is needed in order to support public awareness to this program. It is important to note that aside from rising public responsiveness for the existence of ICPC, overcoming psychological barriers is another issue that requires attention on as many people do not like to “know what the future holds” especially when it comes to diseases.

ICPC, a cancer prevention center located within a major hospital, integrates specialized medical doctors with state of the art facilities, performing comprehensive tests for cancer detection in an intensive one-day visit, is unique and very important for performing a good cancer prevention program. The ICPC and other similar prevention centers (see references) should give example for other medical centers around the globe willing to adopt the approach of cancer prevention in the ongoing battle against cancer. The more centers as such will exist, the greater are the chances for early Cancer detection and increase the potential of significantly reducing the rate of cancer incidences worldwide.

REFERENCES:

http://www.tasmc.org.il/sites/en/internalmed/ICPC/Pages/ICPC.aspx

MD Anderson Cancer Prevention Center

St. Joseph Hospital cancer programs Related article on this Open Access Online Scientific Journal, include the following:

https://pharmaceuticalintelligence.com/2013/03/07/the-importance-of-cancer-prevention-programs-new-perceptions-for-fighting-cancer/

 

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In focus: Melanoma therapeutics

 

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma.  This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment.  It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4).  The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference:

  1. Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36
  2. Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24
  3. Chapman PB, et al, ASCO 2011, Abstract LBA4
  4. Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8
  5. Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89
  6. Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46
  7. Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27
  8. Chudnovsky Y, et al, J Clin Invest, Apr 2005;115(4):813-24.
  9. National Cancer Institute (National Institute of Health)
  10. Clinical Trials reported on the U.S. Institute of Health
  11. New Medicine Oncology KnowledgeBase (nm|OK)

Related articles on Melanoma on this Open Access Online Scientific Journal: 

  1. In focus: Melanoma Genetics Curator- Ritu Saxena, Ph.D.
  2. Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.
  3. A New Therapy for Melanoma  Reporter- Larry H Bernstein, M.D.
  4. Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.
  5. Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

 

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State of the art in oncologic imaging of Colorectal cancers.

Author-Writer: Dror Nir, PhD

This is the fourth post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on colorectal cancer imaging. It reviews current and developing radiologic practices in CRC with respect to screening, preoperative evaluation, surveillance, and post-treatment re-staging.

Colorectal cancer (CRC) is an example to successful imaging-based screening evident by noticeable reduction in mortality rates. The 5-year survival rate of CRC patients diagnosed at an early stage is 90%.1 121 According to this review; “(CRC) is the third most common cancer worldwide and the second most frequent cause of cancer death in the United States. The American Cancer Society estimates that 143,460 new cases of CRC will be diagnosed and 51,690 deaths from CRC will occur in the United States in 2012.120 Because of screening and removal of premalignant polyps, incidence rates have declined over the last 3 decades.

The authors found out that the increased use of CT in CRC screening has the potential of reducing its costs and associated tisks 122 In addition, use of DW-MRI enabled better outcomes of CRC liver metastasis treatment as it enables tailored localized treatment of such lesions.123 124 Finally, the authors found that: “MRI for staging of rectal cancer has become standard practice and, in some instances, is performed in lieu of surgeon-performed endorectal US (ERUS), providing the radiologist with an even greater role in the management of patients with CRC.125 “

 Screening

CRC is a largely preventable disease, as the progression of the adenoma-carcinoma sequence of mutations is slow and leaves ample time to intervene. Nonetheless, approximately 41% of the population (in the USA) eligible for screening remains unscreened. 126 Most screening is performed using non-imaging tests”

Any of these screening strategies will reduce mortality from CRC.126127 

Among imaging tests used for screening, barium enema has seen a continual decline in usage, at least in part due to the landmark study showing that this test detected only 39% of polyps identified at colonoscopy, including only 48% of those > 1 cm in size.131 The recent (and largest, with > 2500 patients) multicenter CT colonography (CTC, also known as virtual colonoscopy) screening study, performed by the American College of Radiology Imaging Network, found that CTC had sensitivity of 90% and similar specificity for polyps > 9 mm, and the number of centers using CTC has increased.122 Widespread deployment of CTC remains hindered, in part, by the 2009 decision of the Center for Medicare and Medicaid Service (CMS) to deny reimbursement based on 1) potential radiation risk, 2) impact of detection of extracolonic findings, and 3) efficacy in the 65 years and older age group of concern to CMS. Data from studies reported after this decision put CTC in a good position to be reconsidered for reimbursement. The median estimated effective dose is currently 5 to 6 mSv, a dose far less than that received from a standard CT exam and even comparable to or lower than that received from a barium enema examination. In fact, the radiation dose from CTC is equivalent to that received from cosmic radiation in a 1-year period.132 Extra-colonic findings occur in 7% to 11% of cases and lead to extra examinations in about 6% with a relevant new diagnosis made in 2.5%, according to the experience of the largest screening center in the United States.133 Furthermore, when detection of extracolonic cancers and aortoiliac aneurysms is included along with CRC screening, CT colonography (CTC) has been shown to be more clinically effective and more cost-effective than optical colonoscopy.134 In an observational study, CTC accuracy was maintained in patients aged 65 to 79 years, who were compared to the overall general population sample. In the older patients, CTC remained a safe and effective modality and program outcome measures, such as colonoscopy referral and extracolonic work-up rates, remained similar to those in other screened groups.135

 Detection and Characterization

Diagnosis and clinical staging of primary colonic adenocarcinoma is most often accomplished by combining colonoscopy with biopsy and performing cross-sectional imaging to detect metastatic disease.

Although CT and MRI are widely used for preoperative whole-body staging, they are not recommended first-line methods for detection of primary lesions. In contradistinction, CTC has matured into an excellent diagnostic method for detection of CRC. Data drawn largely from screening studies tell us that its sensitivity for polyps > 10 mm is 90% or greater, and that it will detect nearly every cancer. In fact, a recent meta-analysis of more than 11,000 patients indicated that CTC had sensitivity of 96.1% (398 of 414) for CRC, and when cathartic cleansing and fecal tagging were used, no cancers were missed (Fig. 16).137 Detection of flat cancers remains a challenge with CTC as compared with endoscopic methods in which mucosal surface details are better appreciated. CTC not only detects CRC, but with its cross-sectional depiction also allows characterization of tumors using the TNM staging system138 with reasonable T- and N-stage accuracies of 83% and 80%, respectively.139 CTC is an operator-dependent technique that has shown great variability between radiologists with different degrees of training. Computer-aided detection (CAD) was developed for this reason and because 10,000 to 15,000 images must be scrutinized for each large adenoma detected. In a screening cohort of 3077 consecutive asymptomatic adults, stand-alone CAD had sensitivities of 97% and 100% for advanced neoplasia and cancer, respectively.140

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

With magnetic resonance colonography (MRC), detection of masses is limited because techniques employing air cause susceptibility artifacts, and those employing dark-lumen techniques with water-filling and intravenous gadolinium are under scrutiny because of concerns about the potential risk of nephrogenic systemic fibrosis. In addition, in the largest screening study, the sensitivity of MRC was only 70% in patients with colorectal lesions more than 10 mm in size.141

Imaging plays a critical role in detecting liver metastases in order to properly stage and treat the patient with colorectal cancer. NCCN guidelines recommend contrast-enhanced CT or MRI.142 “

MRI is the most promising imaging modality for management of rectal cancer.

Staging of this cancer is primarily accomplished with US, typically performed by surgeons. MRI using phased-array coils provides complete visualization of the pelvic anatomy and, especially, the circumferential resection margin, an important landmark for the standard total mesorectal excision.

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

 

 The MERCURY study125established the near equivalence of MRI to histopathology for identification of this margin, an important advantage of MRI over ERUS, with which the margin is not routinely visualized.147 T- and N- stage accuracies of MRI (87% and 74%, respectively) were similar to those of ERUS (82% and 74%, respectively).148 Accurate lymph node identification remains a problem for MRI. Toward this end, a new albumin-bound gadolinium agent has shown some promise, and further results are awaited.149

 Role of Imaging in Assessing Treatment Response

Imaging plays a critical role in 1) determining response to systemic and loco-regional treatment of liver metastases, 2) assessing response to local treatment and restaging rectal cancer primary lesions, and 3) detecting and assessing the treatment response of extra-hepatic metastatic disease. Systemic treatment (and in some centers, hepatic artery infusion) of non-resectable liver metastases with chemotherapy aims at reduction of the metastatic burden, which, occasionally may allow attempts at curative liver resection.

Due to the limitations of CT with regard to soft tissue contrast and fatty liver. MRI has greater sensitivity for remaining (or new) lesions < 1.0 cm due to its superior soft tissue contrast. In a recent meta-analysis of 25 eligible studies, MRI showed higher sensitivity than CT on a per-patient basis (P = .05) and on a per-lesion basis as well (P = .0001). With its 81.1% sensitivity and 97.2% specificity, MRI is thus the preferred modality.151 Nonetheless, under the current NCCN guidelines, CT remains the preferred modality.142 

Loco-regional (“liver-directed”) therapies include radiofrequency, microwave ablation, transarterial chemo- or particle embolization and irreversible electroporation. With these treatments, responding lesions can actually increase in size, and simple size criteria are no longer sufficient to determine response. The European Association for the Study of the Liver has issued new criteria to assess viability of remaining tumor based on enhancing residual volume by multiphase CT or MRI.152 However, the field is rapidly changing and there is no consensus on the optimal imaging strategy following loco-regional therapy.

Recent meta-analyses of randomized controlled trials comparing low-intensity and high-intensity surveillance programs have shown advantages for more intense follow-up in Stages I-III disease;170-173 however, controversies remain regarding the optimal surveillance strategy.

Lymphoma Imaging

To be followed…

Other research papers related to the management of Colorectal cancer were published on this Scientific Web site:

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

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

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State of the art in oncologic imaging of Prostate.

 Author-Writer: Dror Nir, PhD

 

 This is the third post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on prostate cancer imaging.

Prostate Cancer Imaging

Although ultrasound is the most frequently used imaging-device in prostate cancer management the authors did not review the related literature. Instead, they focused their review on MRI and PET imaging. To anyone who wishes to learn about ultrasound-imaging’s state of the art in prostate cancer I can offer reading some of my previous posts that are listed below.

My own interpretation (as stated in my summary-note) to the focus by the authors on MRI and PET imaging is that they were mainly looking to highlight the advances in those imaging modalities which provides tissue characterization! Although, this term is not explicitly mentioned by them.

The authors identifies correctly the main issues in Prostate cancer management:

  1. It’s a frequent disease, but not an aggressive killer
  2. It’s highly heterogeneous, therefore it is difficult to predict the clinical outcomes both before and after treatment.
  3. “Although several predictive methods have been developed,72 the treatment decision-making process is complex and requires balancing clinical benefits, life expectancy, comorbidities and potential treatment-related side effects.”
  4. The disease’s staging and related prognosis are determined during diagnosis based on PSA level and the Gleason score of biopsy’s samples. “Although prostate-specific antigen (PSA) screening hsis as resulted in the diagnosis of prostate cancer at earlier stages and with lower Gleason scores, it has also contributed to concerns about over-diagnosis, overtreatment of clinically insignificant disease, associated treatment-related toxicity, and escalating costs”

The following sections summarizes the latest advances in MRI and PET imaging methods for functional and metabolic assessment of prostate cancer.

Advances in MRI of Prostate Cancer

“MRI is potentially an ideal imaging modality for the local staging of prostate cancer, given its ability to depict the prostate and surrounding structures in exquisite detail. Recently, morphologic imaging with conventional MR imaging sequences has been supplemented by a multiparametric imaging approach using new functional and metabolic methods, namely diffusion waited MRI (DW-MRI); dynamic contrast-enhanced MRI (DCE-MRI), which probes tissue micro-vascular and perfusion properties; and MR spectroscopy (Fig. below).”

Representative images from a 3-T multiparametric MRI examination in a 57-year-old man with PSA level of 9.1 ng/mL and Gleason score 7 (3 + 4) prostate cancer (arrow) located in the right anterior prostate and involving the transition and peripheral zones: (A) transverse T2-weighted image, (B) transverse ADC map generated from DW-MRI images, (C) transverse DCE-MRI image, (D) volume transfer constant (Ktrans) parametric map from DCE-MRI overlaid on T2-weighted image.

Representative images from a 3-T multiparametric MRI examination in a 57-year-old man with PSA level of 9.1 ng/mL and Gleason score 7 (3 + 4) prostate cancer (arrow) located in the right anterior prostate and involving the transition and peripheral zones: (A) transverse T2-weighted image, (B) transverse ADC map generated from DW-MRI images, (C) transverse DCE-MRI image, (D) volume transfer constant (Ktrans) parametric map from DCE-MRI overlaid on T2-weighted image.

Diffusion-Weighted MRI

“Because the diffusion of water molecules within tumors is more restricted than in normal tissue, ADCs calculated with DW-MRI tend to be lower in cancer than in normal tissue. A number of studies, using various image acquisition methods and reference standards, have reported the utility of DW-MRI in prostate cancer detection.74-79. More importantly, studies have indicated that the greatest value of DW-MRI as an addition to conventional MRI might lie in its potential to assess prostate cancer aggressiveness noninvasively, because ADC values have been shown to correlate significantly with tumor Gleason scores.77-79

“However, the clinical value of DW-MRI in predicting the surgical Gleason score needs to be further studied.”

Dynamic Contrast-Enhanced MRI

“DCE-MRI is based on the repeated acquisition of images of a region of interest during the passage of an intravenously administered contrast agent. DCE-MRI allows malignant tissue to be distinguished from benign tissue by exploiting differences in the distribution of the contrast agent between vascular and extravascular spaces over time. 80 Prostate cancer usually shows early, rapid, and intense enhancement with quick washout of contrast compared to noncancerous prostate tissue. Although DCE-MRI has shown potential in assessing prostate cancer in preliminary studies, further research is necessary to establish its clinical value and indications and address technical challenges, such as standardization of acquisition and analysis methods.”

MR Spectroscopy

“Commercially available acquisition and analysis software packages for MR spectroscopic imaging of the prostate produce 3-dimensional spectral data showing the relative concentrations of tissue metabolites within specified volumes of tissue. In the prostate, the metabolites of interest on in vivo MR spectroscopic imaging are citrate, creatine, choline, and polyamines.8788 (choline + creatine)/citrate ratio has traditionally been used to identify prostate cancer on MR spectroscopy. “

“Studies have indicated that MR spectroscopy might have potential for aiding cancer localization, estimating tumor volume, noninvasively assessing prostate cancer aggressiveness and predicting the probability of insignificant cancer.90-92

the authors found that MRI, especially when acquired with multiparametric techniques (DW-MRI, DCE-MRI, and/or MR spectroscopy), has the potential to add value in prostate cancer diagnosis, eg, by guiding biopsy to the most suspicious areas and eventually reduce the number of systematic/random biopsies.108-110 A specific use-case for MRI guided biopsies is men with elevated PSA and negative systematic/random TRUS-guided biopsy where MRI is used for locating suspicious areas for targeted biopsies.111  MRI, “could potentially improve prostate cancer management especially in the intermediate- and high-risk groups.” 112 They also suggest to use MRI, especially when acquired with multiparametric techniques as a tool for choosing and managing active survailance and focal treatment. These two novel methods of treatment have immerged as an answer to unbearable overdiagnosis and overtreatment in prostate cancer management.113 114

About active surveillance: “Given the risks of morbidity associated with radical treatment (eg, radical prostatectomy or radiation therapy), active surveillance (monitoring of PSA levels, periodic imaging and repeat biopsies) is gaining acceptance as an alternative initial management strategy for carefully selected men with low-risk prostate cancer.115 Active surveillance could be a considerably more cost-effective approach than immediate treatment for prostate cancer, as suggested in a theoretical cohort.116 Furthermore, by preserving quality of life and minimizing the harms from radical treatment of low-risk prostate cancer, active surveillance could mitigate the concerns regarding extensive screening, overdiagnosis, and overtreatment of prostate cancer. Ultimately questions about how to best practice active surveillance will need to be addressed in prospective studies. Currently, the main challenges in active surveillance of prostate cancer are adequate characterization of disease at diagnosis and determination of the risk of progression.”

About focal therapy:, sometime referred to as focused therapy. This approach is frequently used in other cancers; e.g. breast lumpectomies. The idea is to treat only the cancer lesion and preserve the rest of the organ. Such treatment has the potential of offering better quality of life for the patients. 117 An open clinical question in respect to focal treatments is related to the fact that prostate cancer is often multifocal. Some studies suggest that it is enough to treat the index tumor (tumor volume > 0.5 mL) in order to control the disease.118 To date, patients’ selection for focal treatment is based on multiparametric MRI techniques and prostate mapping biopsy (trans-perinea template biopsy) 119

Advances in PET Imaging of Prostate Cancer

The main application for [18F]FDG PET is in patients with aggressive, metastatic prostate cancer. For these patients it helps detecting metastasis, and assessment on response to treatment.93-97, The authors of this review did not find support to using it for the majority of prostate cancer patients who are diagnosed at early stage due to its low specificity in this population.

Representative images from 3-T MRI and [18F]FDG PET/CT examinations in a 70-year-old man with PSA level of 8.0 ng/mL and Gleason score of 8 (4 + 4) prostate cancer (arrow) located in the left posterolateral prostate within the peripheral zone: (A) transverse T2-weighted image, (B) transverse fused [18F]FDG PET/CT image, (C) transverse fused [18F]FDG PET/CT image overlaid on T2-weighted MRI.

Representative images from 3-T MRI and [18F]FDG PET/CT examinations in a 70-year-old man with PSA level of 8.0 ng/mL and Gleason score of 8 (4 + 4) prostate cancer (arrow) located in the left posterolateral prostate within the peripheral zone: (A) transverse T2-weighted image, (B) transverse fused [18F]FDG PET/CT image, (C) transverse fused [18F]FDG PET/CT image overlaid on T2-weighted MRI.

Other tracers such as [11C]choline and radiolabeled acetate ([11C]acetate) have recently been evaluated in clinical studies and found to be more promising than [18F]FDG for prostate cancer assessment.939698

“Currently, the major indication for choline PET/CT is the early localization of recurrence in patients with PSA relapse after primary radical treatment. Potentially, this test may also be useful in radiotherapy planning.99100 Acetate participates in cytoplasmic lipid synthesis, and an increased fatty acid synthesis is thought to occur in prostate cancer.101 Similarly to [11C]choline, radiolabeled acetate ([11C]acetate) appears to be more useful than [18F]FDG in the assessment of prostate cancer before and after treatment.102103 “

“In summary, the role of PET imaging in prostate cancer is still evolving, as new and promising tracers are under investigation. Rigorous clinical trials using these new tracers in specific clinical scenarios will be needed before they can be employed routinely.”

On expectations from future screening, diagnosis and pre-treatment staging the authors summarizes:  “An imaging modality that could reliably assess prostate cancer would be of great help in selecting from the wide range of management options now available.” and;

“there is a pressing need to improve not only anatomical imaging for tumor detection, localization and staging, but also functional and metabolic imaging for characterization of tumor biology. “

In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”

My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!

Colorectal Cancers Imaging

To be followed…

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

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State of the art in oncologic imaging of lungs.

Author-Writer: Dror Nir, PhD

 This is the second post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on lung cancer imaging.

Lung Cancer Imaging

“Lung cancer remains the most common cause of death from cancer worldwide, having resulted in 1.38 million deaths (18.2% of all cancer deaths) in 2008.48 It also represents the leading cause of death in smokers and the leading cause of cancer mortality in men and women in the United States. In 2012, it was estimated that 226,160 new cases of lung cancer would be diagnosed (accounting for about 14% of cancer diagnoses) and that lung cancer would cause 160,340 deaths (about 29% of cancer deaths in men and 26% of cancer deaths in women) in the United States.1 The 1-year relative survival rate for the disease increased from 35% to 43% from 1975 through 1979 to 2003 through 2006.49 The 5-year survival rate is 53% for disease that is localized when first detected, but only 15% of lung cancers are diagnosed at this early stage.”

For cancer with such poor survival rates removal of the primary lesion by surgery at an early-stage disease is the best option. The current perception in regards to lung cancr is that patients may have subclinical disease for years before presentation. It is also known that early lung cancer lesions; adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are slow-growing, doubling time which can exceed 2 years.52 But, since at present, no lung cancer early-detection biomarker is clinically available, the diagnosis of this disease is primarily based on symptoms, and detection often occurs after curative intervention and when it’s already too late – see: Update on biomarkers for the detection of lung cancer and also Diagnosing lung cancer in exhaled breath using gold nanoparticles. Until biomarker is found, the burden of screening for this disease is on imaging.

“AIS and MIA generally appear as a single peripheral ground-glass nodule on CT. A small solid component may be present if areas of alveolar collapse or fibroblastic proliferation are present,5051 but any solid component should raise concern for a more invasive lesion (Fig. 8). Growth over time on imaging can often be difficult to assess due to the long doubling time of these AIS and MIA, which can exceed 2 years.52 However, indicators other than growth, such as air bronchograms, increasing density, and pleural retraction within a ground-glass nodule are suggestive of AIS or MIA.

CT image shows a ground glass nodule, which is the typical appearance of AIS, in the right upper lobe.

CT image shows a ground glass nodule, which is the typical appearance of AIS, in the right upper lobe.

 

CT (A) demonstrated extensive consolidation with air bronchograms in the left upper lobe, which at surgical resection were found to represent adenocarcinoma of mixed subtype with predominate (70%) mucinous bronchioloalveolar subtype. PET imaging in the same patient (B) demonstrated uptake in the lingula higher than expected for bronchioloalveolar carcinoma and probably due to secondary inflammation/infection. CT (C) obtained 3 years after images (A) and (B) demonstrated biopsy-proven recurrent soft-tissue mass near surgical site. Fused FDG/PET images (D) demonstrate no uptake in the area. This finding is consistent with the decreased uptake usually seen in tumors of bronchioloalveolar histology (new terminology of MIA).

CT (A) demonstrated extensive consolidation with air bronchograms in the left upper lobe, which at surgical resection were found to represent adenocarcinoma of mixed subtype with predominate (70%) mucinous bronchioloalveolar subtype. PET imaging in the same patient (B) demonstrated uptake in the lingula higher than expected for bronchioloalveolar carcinoma and probably due to secondary inflammation/infection. CT (C) obtained 3 years after images (A) and (B) demonstrated biopsy-proven recurrent soft-tissue mass near surgical site. Fused FDG/PET images (D) demonstrate no uptake in the area. This finding is consistent with the decreased uptake usually seen in tumors of bronchioloalveolar histology (new terminology of MIA).

In August 2011 the results of the “National Lung Screening Trial “ which was funded by the National Cancer Institute (NCI) were published in NEJM; Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. This randomized study results showed that with low-dose CT screening of high-risk persons, there was a significant reduction of 20% in the mortality rate from lung cancer as compared to chest radiographs screening.

Based on these results one can find the following information regarding Lung Cancer Screening on the NCI web-site:

Three screening tests have been studied to see if they decrease the risk of dying from lung cancer.

The following screening tests have been studied to see if they decrease the risk of dying from lung cancer:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Sputum cytology: Sputum cytology is a procedure in which a sample of sputum (mucus that is coughed up from the lungs) is viewed under a microscope to check for cancer cells.
  • Low-dose spiral CT scan (LDCT scan): A procedure that uses low-dose radiation to make a series of very detailed pictures of areas inside the body. It uses an x-ray machine that scans the body in a spiral path. The pictures are made by a computer linked to the x-ray machine. This procedure is also called a low-dose helical CT scan.

Screening with low-dose spiral CT scans has been shown to decrease the risk of dying from lung cancer in heavy smokers.

A lung cancer screening trial studied people aged 55 years to 74 years who had smoked at least 1 pack of cigarettes per day for 30 years or more. Heavy smokers who had quit smoking within the past 15 years were also studied. The trial used chest x-rays or low-dose spiral CT scans (LDCT) scans to check for signs of lung cancer.

LDCT scans were better than chest x-rays at finding early-stage lung cancer. Screening with LDCT also decreased the risk of dying from lung cancer in current and former heavy smokers.

Guide is available for patients and doctors to learn more about the benefits and harms of low-dose helical CT screening for lung cancer.

Screening with chest x-rays or sputum cytology does not decrease the risk of dying from lung cancer.

Chest x-ray and sputum cytology are two screening tests that have been used to check for signs of lung cancer. Screening with chest x-ray, sputum cytology, or both of these tests does not decrease the risk of dying from lung cancer.

The authors of Advances in oncologic imaging found out that for pre-treatment staging and post treatment follow-up of lung cancer patients mainly involves CT (preferably contrast enhanced, FDG PET and PET/CT. “Integrated PET/CT has been found to be more accurate than PET alone, CT alone, or visual correlation of PET and CT for staging NSCLC (Non-small-cell lung carcinoma).59 “

The standard treatment of choice for localized disease remains surgical resection with or without chemo-radiation therapy (stage dependant). “The current recommendations for routine follow-up after complete resection of NSCLC are as follows: for 2 years following surgery a contrast-enhanced chest CT scan every 4 to 6 months and then yearly non-contrast chest CT scans.62 Detection of recurrence on CT is the primary goal in the initial years, and therefore, optimally, a contrast-enhanced scan should be obtained to evaluate the mediastinum. In subsequent years, when identifying an early second primary lung cancer becomes of more clinical importance, a non-contrast CT chest scan suffices to evaluate the lung parenchyma.

CT (A) of 78-year-old male who was status post–left lobe lobectomy and left upper lobe wedge resection shows recurrent nodule at the surgical resection site. Fused PET/CT (B) demonstrates increased [18F]FDG uptake in the corresponding nodule at the surgical resection site consistent with recurrent tumor.

CT (A) of 78-year-old male who was status post–left lobe lobectomy and left upper lobe wedge resection shows recurrent nodule at the surgical resection site. Fused PET/CT (B) demonstrates increased [18F]FDG uptake in the corresponding nodule at the surgical resection site consistent with recurrent tumor.

In patients undergoing chemotherapies: “ [18F]FDG PET response correlates with histologic response.63 [18F]FDG PET scan data can provide an early readout of response to chemotherapy in patients with advanced-stage lung cancer.64

In patients treated by recently developed “Targeted Therapies” such as Radiofrequency ablation (RFA) the authors found out that PET/CT is the preferred imaging modality for post treatment follow-up.

“ Most patients treated with pulmonary ablation will have had a pre-procedure CT or a fusion PET/CT scan, which allows more precise anatomic localization of abnormalities seen on PET. Generally, either CT or PET/CT is performed within a few weeks of the procedure to provide a new baseline to which future images can be compared to assess for changes in size, degree of enhancement or [18F]FDG avidity.67

CT (A) demonstrates new left upper lobe mass representing new primary NSCLC in a patient who had a status post–right pneumonectomy for a prior NSCLC. CT (B) obtained in the same patient 2 weeks after radiofrequency ablation (RFA) demonstrates the postablation density in the left upper lobe. Fused PET/CT (C) obtained 4 months after RFA demonstrates mild [18F]FDG uptake at RFA site in the left upper lobe consistent with posttreatment inflammation. Fused PET/CT (D) obtained 7 months after RFA demonstrates new focal [18F]FDG uptake at post-RFA-opacity consistent with recurrent tumor.

CT (A) demonstrates new left upper lobe mass representing new primary NSCLC in a patient who had a status post–right pneumonectomy for a prior NSCLC. CT (B) obtained in the same patient 2 weeks after radiofrequency ablation (RFA) demonstrates the postablation density in the left upper lobe. Fused PET/CT (C) obtained 4 months after RFA demonstrates mild [18F]FDG uptake at RFA site in the left upper lobe consistent with posttreatment inflammation. Fused PET/CT (D) obtained 7 months after RFA demonstrates new focal [18F]FDG uptake at post-RFA-opacity consistent with recurrent tumor.

Prostate Cancer Imaging

To be followed…

Other research papers related to the management of Lung cancer were published on this Scientific Web site:

Diagnosing lung cancer in exhaled breath using gold nanoparticles

Lung Cancer (NSCLC), drug administration and nanotechnology

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

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Read Full Post »


Curator: Aviva Lev-Ari, PhD, RN

This is our own representation of Experts on our Team expressing Scientific Opinions and Comments on their Peers’ Scientific work

presented from our Research Category on 

Interviews with Scientific Leaders

here are our members of the Team on Cancer Biology

Scientific Leaders @ http://pharmaceuticalintelligence.com

 

 

Dr. Ritu Saxena –  On Personalized Medicine gearing up to tackle cancer

According to the American Cancer Society, the probability that an individual will develop or die from cancer over the course of a lifetime (lifetime risk) in the United States is less than a 1 in 2 for men; and a little more than 1 in 3 for women. Thanks to passionate and committed researchers like Dr. Tsimberidou, personalized medicine-based cancer treatments might take us a few steps closer to curing the disease.  Dr. Tsimberidou concludes, “We have to develop innovative treatment protocols and to offer the best treatment possible for each of our patients”.

In:

Personalized medicine gearing up to tackle cancer

https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

 

Dr. Tilda BarlyiaOn James Watson’s Examination of The “Cancer establishments”

In reply to cancer biologist Robert Weinberg of MIT

I would like to add something regarding this comment and I quote “the main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. If one biochemical pathway to growth and proliferation is blocked by a drug such as AstraZeneca‘s Iressa or Genentech’s Tarceva for non-small-cell lung cancer, said cancer biologist Robert Weinberg of MIT, the cancer cells activate a different, equally effective pathway”

“I think this is why some researching are aiming to find a drug that targets a common denominator of multiple pathways rather that “just” a specific pathway as many cancer cells activate a different equal pathway.”

In:

The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

 

Dr. Stephen WilliamsOn James Watson’s Examination of The “Cancer establishments”

I remember back in the 90s when big pharmas were talking about developing farnesyltransferase inhibitors (the enzyme that puts the modification on ras) as well as myc inhibitors as a sliver bullet for cancer therapy but I have not heard much else.

And as far as personlized medicine, yes personalized medicine does have a role to play and can be very effective but remember we are only talking about  maybe 10% of cases for a tumor type.

Kudos to both Watson and Weinstein for stating we really need to delve into tumor biology to determine functional pathways (like metabolism) which are a common feature of the malignant state

In:

The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

 

 

Pierluigi Scalia MD, PhD  — On Molecular Pathology and Personalized Medicine

Commissioned Comment by Dr. Aviva Lev-Ari

The nanotechnology field certainly provides plenty of opportunity in the field of personalized cancer treatments (Rx). One comment I wanted to make due to the high relevance and implication is in the definition of Personalized Medicine” at large. I believe you are correct to define it as a “movement” within modern medicine as it has been so far. However, I believe we have all the multidisciplinary knowledge we need to move that concept to a real science and a specific operating system in the way we do think and apply medical knowledge.

Even though your definition is definitely correct, I would provide an operating version which I believe can help many to understand WHAT are the minimum requirements to classify a Cancer treatment as part of a “personalized” cancer treatment.
My take on that (which i have expressed elsewhere) is that:

“Personalized Cancer Medicine is that field of medicine using a next-generation diagnostic procedure (or a minimum cancer gene-drivers screening panel) in order to define a key number of cancer abnormalities in each patient clinical specimen for which a targeted therapy or smart integrated approach provides a definite survival advantage versus current conventional medicine”.

This operational definition anticipates the concept of applied pharmacogenomics that is currently more of a research area rather than a clinically mature field.

On the other hand, it leads us to that limiting factor towards the adoption of personalized treatments which is the evolution in molecular pathology with full adoption of genomics as the routine way to screen for a patient Oncotype as part of the routine diagnostic process.

The fact of using nanotechnology in order to target and treat abnormal cancer cells and tissues adds a powerful weapon towards eradicating the disease in the foreseeable future. However, focusing on weapons when we still have not found a reliable way to build that personalized “shooting target” (Cancer Fingerprinting) still constitutes, in my opinion, the single most relevant barrier to the adoption of Personalized treatments.

In:

Nanotechnology, personalized medicine and DNA sequencing

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

 

 

Larry Bernstein, MD – On  Modern Techniques of Molecular Pathology

A look at clinical laboratory science and its expected progress over the next decade

 

In Response to Dr. Scalia’s Comment on Molecular Pathology

In:

Nanotechnology, personalized medicine and DNA sequencing

Commissioned Post by Dr. Aviva Lev-Ari

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

Promising forecasts have been made projecting great expectations for medical sciences in the year 2013 and beyond. These predictions follow a decade after completion of the Human Genome Project, and are accompanied by immense breakthroughs in computational and applied mathematics.  In my view, they are:

  • Genomic and allied “OMICs-technology”
  • Innovation in mathematical classification (complexity)
  • Nanotechnology
  • Synthetic chemistry from physics, organic and inorganic chemistry

It is not my intention to go deeply into the exponential group of these advanced and integrative sciences; rather, I want raise awareness of an emerging new world that will open to the clinical laboratory scientist, and signal the need in the next generation of laboratory personnel to embrace knowledge domains that will be critical for their careers.

All of these breakthroughs are tied together by a search for personalized and integrative medicine.  These breakthroughs will reinvent nutritional and pharmaceutical medicine as well as medical devices and restructure clinical laboratory and imaging applications to cardiology, oncology, radiology and anatomical pathology.

Metabolomics

What does metabolomics and metabolic profiling have to do with this? Metabolomics is the measurement of small molecules that interact with membrane receptors1 that are involved with regulation of genomic transcription and cellular regulation and upregulation or downregulation of metabolic processes essential to health. As well, these small molecules may provide targets for disease treatments, and as they are investigated, also provide further “analytes for diagnosis and, moreover, prediction of short-term or long-term outcomes.”2

As a result, the laboratory will become a more significant factor in measuring health and disease and in guiding health or disease maintenance.  As our population has reached increased age limits, the laboratory has been a contributor in the public health sphere, and will have a greater role as a result of

  • Improved tie in with provision of information to not only the healthcare workers, but also the patient.
  • Achieve turnaround times for critical results through better workflow
  • Greater control and access to a next generation of point-of-care technology integrated with the laboratory database, and a restructured electronic health record.
  • Despite the hype about the BIG DATA revolution, this is achievable in the system here proposed because there is a published model to achieve this(2)

Familiar Methods

Either individually or grouped as a profile, metabolites are detected by either nuclear magnetic resonance spectroscopy or mass spectrometry, providing a basis for uses of metabolome findings extended to the early detection and diagnosis of cancer and as both a predictive and pharmacodynamics marker of drug effect. We can expect it to become the link between the laboratory and the clinic. The methods used in genomics are microarrays, and for proteomics they are the already familiar chromatographic principles that species migrate at different rates through a column matrix based on their volatility, or carries out a separation as the molecules differ by their adsorption to and elution from a solid matrix, dependent on the binding to the matrix and solubility in the solvent eluate, modified by ph, ionic concentration, and specific conditions needed for recovery.  Powerful mathematical tools are used to analyze the data.3

Cardiovascular Disease

Although coronary thrombosis is the final event in acute coronary syndromes, there is increasing evidence that inflammation also plays a key role in development of atherosclerosis and its clinical manifestations, such as myocardial infarction, stroke and peripheral vascular disease. The inflammatory component was indicated by epidemiological studies of elevated serum levels of high sensitivity C-reactive protein. That eventually led to the demonstration of a benefit from reduction of CRP in individuals without characteristic lipidemia in a major clinical trial, which drew a relationship between diabetes, obesity and disordered inflammatory response in the causation of coronary artery disease, aortic valve and artery disease, carotid artery and peripheral vascular disease.

Cancer

Because cancer cells are known to possess a highly unique metabolic phenotype, development of specific biomarkers in oncology is possible and might be used in identifying fingerprints, profiles or signatures to detect the presence of cancer, determine prognosis and/or assess the pharmacodynamic effects of therapy.4

HDM2, a negative regulator of the tumor suppressor p53, is over-expressed in many cancers that retain wild-type p53. Consequently, the effectiveness of chemotherapies that induce p53 might be limited, and inhibitors of the HDM2–p53 interaction are being sought as tumor-selective drugs.5

Coagulation

Blood coagulation plays a key role among numerous mediating systems activated in inflammation. Receptors of the PAR family serve as sensors of serine proteinases of the blood clotting system in the target cells involved in inflammation. Activation of PAR_1 by thrombin and of PAR_2 by factor Xa leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade.

The details of evolving methods are avoided in order to build the argument that a very rapid expansion of discovery has been evolving depicting disease, disease mechanisms, disease associations, metabolic biomarkers, study of effects of diet and diet modification, and opportunities for targeted drug development.

Dr. Bernstein is CEO of Triplex Medical Science, and CSO of Leaders in Pharmaceutical Intelligence http://pharmaceuticalintelligence.com. He has been involved in writing,  reviewing, and a collaborative project on reducing  the noise that exists in complex data, and developing a primary evidence-based classification since retiring from a career in pathology spanning 4 decades.

References

1. Bernstein LH. Metabolomics, metabonomics and functional nutrition: The next step in nutritional metabolism and biotherapeutics. Journal of Pharmacy and Nutrition Sciences, 2012, 2, (xxx).

2. David G, Bernstein LH, and Coifman RR. Generating evidence-based interpretation of hematology screens via anomaly characterization. The Open Clinical Chemistry Journal 2011;4: 10-16.

3. Grainger DJ. Megavariate statistics meets high data-density analytical methods: The future of medical diagnostics? IRTL Reviews 2003;1:1-6.

4. Spratlin JL, Serkova NJ, and Eckhardt SG. Clinical applications of metabolomics in oncology: A review. Clin Cancer Res 2009;15; 15(2): 431–440.

5. Fischer PM, Lane DP. Small molecule inhibitors of thep53 suppressor HDM2: Have protein-protein interactions come of age as drug targets? Trends in Pharm Sci 2004;25(7):343-346.

Other Articles on this Open Access Online Scientific Journal:

Bernstein LH. Assessing Cardiovascular Disease with Biomarkers. http://pharmaceuticalintelligence.com

Bernstein LH. Predicting Tumor Response, Progression, and Time to Recurrence. http://pharmaceticalintelligence.com

Bernstein LH. Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment. http://pharmaceuticalintelligence.com

Comment in Response to Dr. Scalia’s Comment In:

Nanotechnology, personalized medicine and DNA sequencing

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

 

 

Dr. Tilda Barlyia – On Quality control (QC) of DNA sequencing

In response to Larry Bernstein, MD comment on 

Nanotechnology, personalized medicine and DNA sequencing

Quality control (QC) of DNA sequencing is of major challenge especially when sequencing long DNA strands. This is also probably one of the reasons why these nanopore DNA sequencers devices haven’t made it to the market yet. Some of the challenges that these sequencing technique have encountered are: (a) high velocity in which the DNA segment passes through the pores and which needs to be slowed down, (b) the need for high spatial resolutions and orientation of the nucleotide in the gap, (c) complex algorithms as well as error-prone DNA conversion steps (from dsDNA to ssDNA). I believe that there’s a long way before we see these devices on the shelf but it’s definitely inspiring to see how scientists vision these techniques and creatively finds ways to solve the problem.

In:

Nanotechnology, personalized medicine and DNA sequencing

January 9, 2013

https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

Read Full Post »


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:

Image

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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