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Posts Tagged ‘Bevacizumab’


Author Tilda Barliya PhD

Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem. The liver is the dominant metastatic site for patients with CRC, and although two-thirds of affected patients have extrahepatic spread, some have disease that is isolated to the liver. For patients with isolated liver metastases, regional treatment approaches may be considered as an alternative to systemic chemotherapy (1).

Metastases from CRC most commonly develop within 2 years of resection of the primary tumor and are usually asymptomatic; rarely, patients may complain of vague upper abdominal pain. Hepatic metastases associated with CRC may occur regardless of the initial stage of the primary tumor although nodepositive primary lesions are more likely to precede hepatic metastasis (2).

The available regional treatments for hepatic metastases from CRC include (1):

  • Surgical resection
  • Local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions
  • Radiofrequency ablation [RFA])
  • Regional hepatic intraarterial chemotherapy or chemoembolization
  • Radiation therapy (RT)

**Among these treatments, only surgery is associated with a survival plateau.

Screening for Hepatic metastasis (3):

  • A biopsy may be indicated to confirm the diagnosis, depending upon the clinical picture. However, fine needle aspiration cytology has not been advocated as a screening test, because of its high risk of complications. It has been shown that the incidence of needle tract metastases is 0.4%-5.1% after fine needle aspiration and use of the procedure in abdominal tumors is fatal in 0.006%-0.031% of cases.  Most deaths are due to hemorrhage of liver tumors (3).
  • Laparoscopy has not been advocated as a screening test for colorectal liver metastases due to its invasiveness.
  • Imaging modalities, such as contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography CT (PET-CT), may establish the diagnosis of liver metastasis of colorectal cancer. However, it is more difficult to make the clinical diagnosis of early liver metastases of colorectal cancer due to the absence of typical symptoms or signs.
  • Serological examination including tumor and biochemical markers for liver function evaluation is routinely performed, though its accuracy is not high.  In that aspect, carcinoembryonic antigen (CEA) levels is elevated in 63% of patients, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is increased in about 30% of patients with liver metastases of colorectal cancer.

Surgical Resection (1)

Resection offers the greatest likelihood of cure for patients with liver-isolated CRC. In surgical case series, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent and surgical mortality rates are generally <5 percent (1). It’s worth noted that subgroups with advanced age, comorbid disease, and synchronous hepatic and colon resection may have higher procedure-related mortality and worse long-term outcomes.

The five-year survival rate was only 25 percent, Even so, five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 percent, only about one-fifth of whom have a sustained disease remission. More so, approximately one-third of five-year survivors suffer a cancer-related death, while those who survive 10 years appear to be cured (4).

Because of its clear survival impact, surgical resection is the treatment of choice when feasible. Unfortunately, no more than 20 percent of patients with isolated hepatic metastases are amenable to potentially curative resection. Most are not surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.

Patient candidates for resection – The criteria for resectability differ among individual liver surgeons regarding borderline cases, from center to center and from country to country. One consensus statement defined absolute unresectability as nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (1,2).  Patients are evaluaed using preoperative liver MRI and intraoperative ultrasound which offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures.

Modern multidisciplinary consensus for resectable CRC liver metastases:

  • Tumors that can be resected completely (leaving an adequate liver remnant)
  • No  involvement of the hepatic artery, major bile ducts, main portal vein, orceliac/paraaortic lymph nodes
  • Adequate predicted functional hepatic reserve postresection

Criteria for unresectable liver metastases (5):

  • Pateitns with more than three lesions, those
  • Patients with bilobar distribution (ie, tumor involving any segments of the left and right hemi-liver),
  • Patients in whom it was not possible to achieve 1 cm margins,
  • Patients with portal lymph node or other extrahepatic metastases, and
  • Patients with liver metastases from cancers other than colorectal tumors

Some of these exclusion criteria have been challenged.

  • Better and safer surgical techniques are now more suitable for patients with multiple, even bilobar tumors.
  • A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases
  • Achieving wide margins doesn’t increase the 5-year survival. **** Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate.
  • Presence of portal lymph node metastases – still been challenged and results are controversy.
  • A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases.  The presence of portal node metastases is not inevitably associated with distant metastases.  Outcome was more favorable if nodal involvement was limited to the porta as compared to along the common hepatic artery.
  • The presence of other sites of limited extrahepatic metastases (particularly lung) should not be considered a contraindication to resection as long as the disease is amenable to complete extirpation. However, outcomes in this group are not as favorable, particularly when there are >6 liver metastases.

Diagnostic Laparoscopy

In modern treatment paradigms, laparoscopy is infrequently performed, particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor. Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease.

A growing number of authors report that staging laparoscopy (including laparoscopic US) performed under general anesthesia just prior to planned resection will identify 16 to 64 percent of patients with unresectable disease.

This approach is particularly useful in identifying small peritoneal metastases, additional hepatic metastases, and unsuspected cirrhosis. Laparoscopy in this setting is less likely to identify lymph node metastases, vascular compromise, and extensive biliary involvement that might render a patient unresectable (2,6).

Neoadjuvant chemotherapy

The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection.  It may  be considered as a means of “downsizing” liver metastases prior to resection to lessen the complexity of hepatic metastasectomy or for initially unresectable metastatic disease (1). Chemotherapy, has many side effects including liver toxicity such as:  steatosis (chemotherapy-associated steatohepatitis, CASH), vascular injury, and nodular regenerative hyperplasia in the livers.

Due to high number of patients with liver toxicity and morbidity, these instructions have been suggested:

  • For low-risk (medically fit, four or fewer lesions), potentially resectable patients, initial surgery rather than neoadjuvant chemotherapy should be chosen, followed by postoperative chemotherapy.
  • For patients who have higher risk, borderline resectable or unresectable disease, neoadjuvant chemotherapy is the preferred approach.

Neoadjuvant Chemotherapy Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following:

  • FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
  • FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) or
  • FOLFOXIRI alone

Bevacizumab – Its addition to traditional chemotherapy results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab. However, these benefits have come at the cost of significant treatment-related toxicity. Such as: such as stroke and arterial thromboembolic events, bowel perforation and bleeding.  Data regarding the need and timing of use of bevacizumab is somewhat conflicting.

Cetuximab (if K-ras wild type) and panitumumab (if K-ras wild type) are also suggested as part of the  chemotherapy regimen in certain clinics are regional dependent.

Intraarterial (HIA) chemotherapy – The administration of chemotherapy into the hepatic artery. The benefit of this approach is remains unclear. A combined approach of HIA floxuridine plus systemic chemotherapy (oxaliplatin plus irinotecan) was explored in a single institution study of 49 patients with initially unresectable CRC liver metastases. Overall, 92 percent had either a complete or partial response rate to chemotherapy, and 23 (43 percent) were able to undergo a later resection, 19 with negative margins. The median overall survival from pump placement for the entire cohort was 40 months (1, 7).  Another approach is HIA oxaliplatin combined with systemic 5-FU and leucovorin for patients with initially unresectable but isolated hepatic CRC metastasis.

It should be noted that this approach is not used by many clinicians outside of New York City. The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial.

Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis, administration into the portal vein has been explored as an alternative. hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply. Like HIA infusion, portal vein infusion (PVI) carries with it a significant regional exposure advantage.

The potential benefit of adjuvant PVI with FUDR after resection or ablation of isolated hepatic metastases was evaluated in two trials conducted at the City of Hope Medical Center (1, 8).  The benefit of this approach was somewhat lower than has been reported with HIA FUDR and systemic 5-FU. Therefore, the use of this approach is limited.

Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy through the use of yttrium-labeled microspheres.  Radiation therapy (RT) has traditionally had a limited role in the treatment of liver tumors, primarily because of the low whole-organ tolerance of the liver to radiation (9).   When radiation is applied to the entire liver, RT doses of 30 to 33 Gy carry about a 5% risk of radiation-induced liver disease (RILD). The risk rises rapidly, such that by 40 Gy, the risk is approximately 50%.  Considering that most solid tumors require RT doses higher than 60 Gy to provide a reasonable chance for local control, it is not surprising that wholeorgan liver RT provides only a modest palliative benefit rather than durable tumor control. Hepatic dysfunction after RT is a very frequent event.

Summary:

Liver metastasis are a very tough disease to battle and the outcome is not encouraging. Currently, surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer. For appropriately selected patients with four or fewer metastases, five-year relapse-free survival rates average 30 percent.  Diagnostic laparoscopy is suggested only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging and for selected other cases at high risk for intraperitoneal metastatic disease. The optimal chemotherapy regimen is still not fully established but some suggestions have been made and the benefits of using HIA is still not clear.

Standardization of scoring, timing, surgical techniques , results from clinical trials and advanced research will offer better hope for these patients, who now, have a very bad prognosis and survival rates.

Reference:

1.  Venook AP and Curley SA. Management of potentially resectable colorectal cancer liver metastases. UpToDate Jun 2013. http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases

2. Smith AJ., DeMatteo RP., Fong Y and Blumgart LH.  Metastatic Liver Cancer.  HEPATOBILIARY CANCER. http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/Hepatobiliary%20Cancer/DOCS/Ch4.pdf

3. Wu XZ., Ma F., and Wang XL. Serological diagnostic factors for liver metastasis in patients with colorectal cancer. World J Gastroenterol. 2010 August 28; 16(32): 4084–4088. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928464/

4. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575. http://www.ncbi.nlm.nih.gov/pubmed?term=17925551

5. Tanabe KK. Palliative liver resections. J Surg Oncol. 2002;80(2):69. http://onlinelibrary.wiley.com/doi/10.1002/jso.10108/abstract;jsessionid=F19964733A4A1A2708A0BA0E274CF586.d01t03

6.  Ravikumar TS. Laparoscopic staging and intraoperative ultrasonography for liver tumor management. Surg Oncol Clin N Am 1996;5:271–282. http://www.ncbi.nlm.nih.gov/pubmed/9019351

7, Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, Jarnagin WR, Patel D, D’Angelica M.  Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646304/

8.  Faynsod M, Wagman LD, Longmate J, Carroll M, Leong LA. Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.J Clin Oncol. 2005;23(22):4876. http://www.ncbi.nlm.nih.gov/pubmed?term=16009960

9. I. Frank Ciernik and Theodore S. Lawrence. Radiation Therapy for Liver Tumors. Book: Systemic and Regional Therapies. Chapter 7.  http://www.jblearning.com/samples/0763718572/Chapter_07.pdf

Other articles from our open journal access

I.  By: Dr. Sudipta Saha PhD . Treatment for Endocrine Tumors and Side Effects. https://pharmaceuticalintelligence.com/2013/06/24/treatment-for-endocrine-tumors-and-side-effects/

II. By: Dr. Stephen J. Williams PhD. Differentiation Therapy – Epigenetics Tackles Solid Tumors. https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

III. By: Dr.  Ritu Saxena, PhD. In focus: Circulating Tumor Cells. https://pharmaceuticalintelligence.com/2013/06/24/in-focus-circulating-tumor-cells/

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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:

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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Reporter: Aviva Lev-Ari, PhD, RN

In researching Intracanalicular Meningiomas, Vestibular Schwannomas — we presented on 10/15/2012 the following article:

Facial Nerve, Intracanalicular Meningiomas, Vestibular Schwannomas: Surgical Planning

https://pharmaceuticalintelligence.com/2012/10/15/facial-nerve-intracanalicular-meningiomas-vestibular-schwannomas-surgical-planning/

Our research continues by tracing all Clinical Trials – active for Schwannoma

1 Recruiting Intraarterial Cerebral Infusion of Avastin for Vestibular Schwannoma (Acoustic Neuroma)

Condition: Vestibular Schwannoma
Intervention: Drug: Bevacizumab (Avastin)
2 Active, not recruiting Bevacizumab for Symptomatic Vestibular Schwannoma in Neurofibromatosis Type 2 (NF2)

Conditions: Neurofibromatosis 2;   Vestibular Schwannoma;   Acoustic Neuroma
Intervention: Drug: bevacizumab
3 Active, not recruiting Stereotactic Radiation in Vestibular Schwannoma

Condition: Vestibular Schwannoma
Interventions: Radiation: stereotactic radiotherapy;   Radiation: stereotactic radiosurgery
4 Not yet recruiting Study of RAD001 for Treatment of NF2-related Vestibular Schwannoma

Conditions: Neurofibromatosis Type 2;   Neuroma, Acoustic
Intervention: Drug: RAD001, everolimus
5 Active, not recruiting Efficacy and Safety Study of RAD001 in the Growth of the Vestibular Schwannoma(s) in Neurofibromatosis 2 (NF2) Patients

Condition: Neurofibromatosis 2
Intervention: Drug: RAD001
6 Recruiting Concentration and Activity of Lapatinib in Vestibular Schwannomas

Conditions: Vestibular Schwannoma;   NF2;   Neurofibromatosis 2;   Acoustic Neuroma;   Auditory Tumor
Intervention: Drug: lapatinib
7 Recruiting Hearing Outcomes Using Fractionated Proton Radiation Therapy for Vestibular Schwannoma

Conditions: Vestibular Schwannoma;   Acoustic Neuroma
Intervention: Radiation: Fractionated proton radiation
8 Recruiting A Study of Nilotinib in Growing Vestibular Schwannomas

Conditions: Volumetric Tumor Response and Lack of Tumor Progression;   Quality of Life of Patients on Nilotinib Versus Not
Intervention: Drug: Nilotinib
9 Active, not recruiting Lapatinib Study for Children and Adults With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors

Conditions: Neurofibromatosis 2;   Vestibular Schwannoma
Intervention: Drug: Lapatinib
10 Recruiting Stereotactic Body Radiotherapy for Spine Tumors

Conditions: Spinal Metastases;   Vertebral Metastases;   Benign Spinal Tumors;   Chordoma;   Meningioma;   Schwannoma;   Neurofibroma;   Paragangliomas;   Arteriovenous Malformations
Intervention: Radiation: stereotactic body radiotherapy
11 Recruiting Natural History Study of Patients With Neurofibromatosis Type 2

Conditions: Spinal Cord Disease;   Intracranial Central Nervous System Disorder;   Neurologic Disorders;   Brain Neoplasms
Intervention:
12 Recruiting Using Positron Emission Tomography to Predict Intracranial Tumor Growth in Neurofibromatosis Type II Patients

Conditions: Neoplasms;   Nervous System Disease;   Vestibular Disease
Intervention:
13 Unknown  Hippocampal Radiation Exposure and Memory

Conditions: Arteriovenous Malformation;   Schwannoma;   Trigeminal Neuralgia
Intervention:
14 Completed Recovery of Visual Acuity in People With Vestibular Deficits

Conditions: Vestibular Neuronitis;   Vestibular Neuronitis, Bilateral;   Vestibular Schwannoma
Interventions: Other: Control exercises;   Other: gaze stabilization exercises
15 Recruiting Bevacizumab in Treating Patients With Recurrent or Progressive Meningiomas

Conditions: Acoustic Schwannoma;   Adult Anaplastic Meningioma;   Adult Ependymoma;   Adult Grade I Meningioma;   Adult Grade II Meningioma;   Adult Meningeal Hemangiopericytoma;   Adult Papillary Meningioma;   Neurofibromatosis Type 1;   Neurofibromatosis Type 2;   Recurrent Adult Brain Tumor
Intervention: Biological: bevacizumab
16 Unknown  NF2 Natural History Consortium

Conditions: Schwannoma, Vestibular;   Neurofibromatosis 2;   Meningioma
Intervention:
17 Completed Analysis of NF2 Mutations in Radiation-Related Neural Tumors

Condition: Neural Tumors
Intervention:
18 Completed Corticosteroids in Prevention of Facial Palsy After Cranial Base Surgery

Condition: Facial Palsy
Intervention: Drug: methylprednisolone
19 Recruiting Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2

Condition: Neurofibromatosis Type II
Intervention: Drug: Everolimus (RAD001) , Afinitor®
20 Completed Phase II Study of Imatinib Mesylate in Patients With Life Threatening Malignant Rare Diseases

Condition: Life Threatening Diseases
Intervention: Drug: Imatinib mesylate
21 Recruiting Taste Disorders in Middle Ear Disease and After Middle Ear Surgery

Condition: Taste Disturbance
Interventions: Other: taste measurement;   Other: Symptom questionnaire;   Behavioral: Quality of life questionnaire;   Other: Nerve sample
22 Completed Vasopressin and V2 Receptor in Meniere’s Disease

Condition: Meniere Disease
Intervention: Genetic: vasopressin, V2 receptor and cyclic AMP
23 Recruiting Gemcitabine and Docetaxel in Combination With Pazopanib (Gem/Doce/Pzb) for the Neoadjuvant Treatment of Soft Tissue Sarcoma (STS)

Conditions: Sarcoma;   Leiomyosarcoma;   Malignant Peripheral Nerve Sheath Tumor;   Malignant Fibrous;   Histiocytoma/Undifferentiated Pleomorphic Sarcoma
Intervention: Drug: Gemcitabine and Docetaxel in Combination with Pazopanib
24 Recruiting Pazopanib Hydrochloride Followed By Chemotherapy and Surgery in Treating Patients With Soft Tissue Sarcoma

Conditions: Adult Alveolar Soft-part Sarcoma;   Adult Angiosarcoma;   Adult Desmoplastic Small Round Cell Tumor;   Adult Epithelioid Hemangioendothelioma;   Adult Epithelioid Sarcoma;   Adult Extraskeletal Chondrosarcoma;   Adult Fibrosarcoma;   Adult Leiomyosarcoma;   Adult Liposarcoma;   Adult Malignant Fibrous Histiocytoma;   Adult Malignant Hemangiopericytoma;   Adult Malignant Mesenchymoma;   Adult Neurofibrosarcoma;   Adult Synovial Sarcoma;   Dermatofibrosarcoma Protuberans;   Stage IIA Adult Soft Tissue Sarcoma;   Stage III Adult Soft Tissue Sarcoma;   Stage IV Adult Soft Tissue Sarcoma
Interventions: Drug: pazopanib hydrochloride;   Drug: doxorubicin hydrochloride;   Drug: ifosfamide;   Other: placebo;   Procedure: therapeutic conventional surgery;   Radiation: external beam radiation therapy;   Other: pharmacological study;   Other: laboratory biomarker analysis
25 Active, not recruiting Trial of Dasatinib in Advanced Sarcomas

Conditions: Rhabdomyosarcoma;   Malignant Peripheral Nerve Sheath Tumors;   Chondrosarcoma;   Sarcoma, Ewing’s;   Sarcoma, Alveolar Soft Part;   Chordoma;   Epithelioid Sarcoma;   Giant Cell Tumor of Bone;   Hemangiopericytoma;   Gastrointestinal Stromal Tumor (GIST)
Intervention: Drug: Dasatinib
26 Active, not recruiting Sorafenib and Dacarbazine in Soft Tissue Sarcoma

Conditions: Sarcoma;   Synovial Sarcoma;   Leiomyosarcoma;   Malignant Peripheral Nerve Sheath Tumor
Intervention: Drug: Sorafenib and Dacarbazine
27 Recruiting Safety Study of PLX108-01 in Patients With Solid Tumors

Conditions: Solid Tumors;   Mucoepidermal Carcinoma (MEC) of the Salivary Gland;   Pigmented Villo-nodular Synovitis (PVNS);   Gastrointestinal Stromal Tumors (GIST);   Anaplastic Thyroid Carcinoma (ATC);   Solid Tumors With Documented Malignant Pleural or Peritoneal Effusions;   Malignant Peripheral Nerve Sheath Tumor (MPNST);   Neurofibromatosis Type I (NF-1);   Melanoma
Intervention: Drug: PLX3397
28 Active, not recruiting Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma

Conditions: Adult Alveolar Soft-part Sarcoma;   Adult Angiosarcoma;   Adult Epithelioid Sarcoma;   Adult Extraskeletal Chondrosarcoma;   Adult Extraskeletal Osteosarcoma;   Adult Fibrosarcoma;   Adult Leiomyosarcoma;   Adult Liposarcoma;   Adult Malignant Fibrous Histiocytoma;   Adult Malignant Hemangiopericytoma;   Adult Malignant Mesenchymoma;   Adult Neurofibrosarcoma;   Adult Rhabdomyosarcoma;   Adult Synovial Sarcoma;   Gastrointestinal Stromal Tumor;   Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor;   Recurrent Adult Soft Tissue Sarcoma;   Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor;   Stage III Adult Soft Tissue Sarcoma;   Stage IV Adult Soft Tissue Sarcoma
Intervention: Drug: romidepsin
29 Completed S0330 Erlotinib in Treating Patients With Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumor

Condition: Sarcoma
Intervention: Drug: erlotinib hydrochloride
30 Recruiting IMC-A12 and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma

Conditions: Adult Angiosarcoma;   Adult Desmoplastic Small Round Cell Tumor;   Adult Epithelioid Sarcoma;   Adult Extraskeletal Chondrosarcoma;   Adult Extraskeletal Osteosarcoma;   Adult Fibrosarcoma;   Adult Leiomyosarcoma;   Adult Liposarcoma;   Adult Malignant Fibrous Histiocytoma of Bone;   Adult Malignant Hemangiopericytoma;   Adult Malignant Mesenchymoma;   Adult Neurofibrosarcoma;   Adult Rhabdomyosarcoma;   Adult Synovial Sarcoma;   Childhood Angiosarcoma;   Childhood Desmoplastic Small Round Cell Tumor;   Childhood Epithelioid Sarcoma;   Childhood Fibrosarcoma;   Childhood Leiomyosarcoma;   Childhood Liposarcoma;   Childhood Malignant Hemangiopericytoma;   Childhood Malignant Mesenchymoma;   Childhood Neurofibrosarcoma;   Childhood Synovial Sarcoma;   Dermatofibrosarcoma Protuberans;   Metastatic Childhood Soft Tissue Sarcoma;   Mixed Childhood Rhabdomyosarcoma;   Pleomorphic Childhood Rhabdomyosarcoma;   Previously Treated Childhood Rhabdomyosarcoma;   Previously Untreated Childhood Rhabdomyosarcoma;   Recurrent Adult Soft Tissue Sarcoma;   Recurrent Childhood Rhabdomyosarcoma;   Recurrent Childhood Soft Tissue Sarcoma;   Stage III Adult Soft Tissue Sarcoma;   Stage IV Adult Soft Tissue Sarcoma
Interventions: Biological: cixutumumab;   Drug: doxorubicin hydrochloride;   Other: laboratory biomarker analysis
31 Active, not recruiting Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors

Conditions: Neurofibromatosis Type 1;   Sarcoma
Interventions: Biological: filgrastim;   Drug: doxorubicin hydrochloride;   Drug: etoposide;   Drug: ifosfamide;   Procedure: conventional surgery;   Radiation: radiation therapy
32 Terminated Imatinib Mesylate Treatment of Patients With Malignant Peripheral Nerve Sheath Tumors

Condition: Malignant Peripheral Nerve Sheath Tumors
Intervention: Drug: imatinib mesylate
33 Recruiting Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors

Conditions: Malignant Peripheral Nerve Sheath Tumors;   MPNST;   Sarcoma
Interventions: Drug: everolimus;   Drug: bevacizumab
34 Recruiting Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma

Conditions: Adult Alveolar Soft-part Sarcoma;   Adult Angiosarcoma;   Adult Desmoplastic Small Round Cell Tumor;   Adult Epithelioid Hemangioendothelioma;   Adult Epithelioid Sarcoma;   Adult Extraskeletal Chondrosarcoma;   Adult Extraskeletal Osteosarcoma;   Adult Fibrosarcoma;   Adult Leiomyosarcoma;   Adult Liposarcoma;   Adult Malignant Fibrous Histiocytoma;   Adult Malignant Hemangiopericytoma;   Adult Malignant Mesenchymoma;   Adult Neurofibrosarcoma;   Adult Rhabdomyosarcoma;   Adult Synovial Sarcoma;   Childhood Alveolar Soft-part Sarcoma;   Childhood Angiosarcoma;   Childhood Desmoplastic Small Round Cell Tumor;   Childhood Epithelioid Hemangioendothelioma;   Childhood Epithelioid Sarcoma;   Childhood Fibrosarcoma;   Childhood Leiomyosarcoma;   Childhood Liposarcoma;   Childhood Malignant Hemangiopericytoma;   Childhood Malignant Mesenchymoma;   Childhood Neurofibrosarcoma;   Childhood Synovial Sarcoma;   Dermatofibrosarcoma Protuberans;   Metastatic Childhood Soft Tissue Sarcoma;   Nonmetastatic Childhood Soft Tissue Sarcoma;   Recurrent Adult Soft Tissue Sarcoma;   Recurrent Childhood Soft Tissue Sarcoma;   Stage III Adult Soft Tissue Sarcoma;   Stage IV Adult Soft Tissue Sarcoma
Interventions: Drug: gemcitabine hydrochloride;   Drug: pazopanib hydrochloride;   Other: placebo;   Other: laboratory biomarker analysis
35 Recruiting Proton Therapy for Spinal Tumors

Conditions: Malignant Peripheral Nerve Sheath Tumors of the Spine;   Neurofibroma
Intervention: Radiation: Proton Therapy
36 Recruiting Natural History Study of Patients With Neurofibromatosis Type I

Conditions: Neurofibromatosis Type 1;   Malignant Peripheral Nerve Sheath Tumor;   Plexiform Neurofibroma;   Optic Glioma;   Neurofibroma
Intervention:
37 Completed Phase II Study of the Multichannel Auditory Brain Stem Implant for Deafness Following Surgery for Neurofibromatosis 2

Condition: Neurofibromatosis 2
Intervention: Device: Multichannel Auditory Brain Stem Implant
38 Completed An Implant for Hearing Loss Due to Removal of Neurofibromatosis 2 Tumors

Condition: Neurofibromatosis 2
Intervention: Device: Penetrating auditory brainstem implant
39 Suspended PTC299 for Treatment of Neurofibromatosis Type 2

Condition: Neurofibromatosis 2
Intervention: Drug: PTC299
40 Unknown  Sunitinib in Treating Patients With Recurrent or Unresectable Meningioma, Intracranial Hemangiopericytoma, or Intracranial Hemangioblastoma

Conditions: Brain and Central Nervous System Tumors;   Neurofibromatosis Type 1;   Neurofibromatosis Type 2;   Precancerous Condition
Intervention: Drug: sunitinib malate

SOURCE:

http://clinicaltrials.gov/ct2/results?term=schwannoma&pg=1

http://clinicaltrials.gov/ct2/results?term=schwannoma&pg=2

Benign Intracranial Tumors Radiosurgery Treatment

Points to remember

  • Radiosurgery is focused delivery of radiation to an image-defined target performed in 1 to 5 sessions.
  • When used as an alternative to or in conjunction with open neurosurgical techniques, radiosurgery is an effective, less invasive option for treating many benign intracranial tumors, including meningiomas, vestibular schwannomas, and pituitary adenomas.

The challenge

Benign intracranial tumors occur about as often as primary malignant brain tumors. Most benign tumors are noninvasive, well defined and well visualized on MRI, and have a slow rate of progression. Each of these features makes them good candidates for radiosurgery.

Radiosurgery can deliver a destructive dose of radiation to the target with little or no radiation effects on adjacent structures. Proper patient selection for this procedure is critical.

Defining selection criteria

With 2 decades of experience performing radiosurgery, Mayo Clinic neurosurgeons have accumulated a depth of expertise and a vast database that includes patient characteristics, radiosurgical dosimetry, and outcomes.

After reviewing more than 1,400 cases of meningiomas, vestibular schwannomas, and pituitary adenomas, Mayo clinicians observe that radiosurgery is an excellent choice when these types of benign tumors are small, occur in critical locations, or have recurred following previous surgery.

Radiosurgery is also well tolerated and of particular utility in elderly patients with medical conditions that put them at risk for an open procedure. Additionally, radiosurgery does not preclude an open procedure, should that be necessary at a later time.

Radiosurgery for meningiomas

The rate of recurrence for a surgically removed meningioma is about 18% to 25% at 10 years. For this reason, Mayo neurosurgeons recommend maintaining extended surveillance of meningiomas. In contrast, radiosurgery has been found to reduce the risk of recurrence or progression.

Tumor progression outside the field of radiation and tumor histology can affect both long- and short-term outcomes. Tumors that can be clearly imaged and those that are benign and without atypical histology have a far greater rate of 5-year progression-free survival.

Radiosurgery is also an effective therapy for cavernous sinus meningiomas, except when there is symptomatic mass effect, an unusual clinical presentation, or nontypical features on imaging.

Radiosurgery is typically not recommended for convexity and parasagittal meningiomas.

Radiosurgery for vestibular schwannomas

Several studies report that radiosurgery for small to moderate-sized vestibular schwannomas is associated with higher rates of hearing preservation and improved facial nerve outcomes when compared to surgical removal. This conclusion was supported by a Mayo Clinic study comparing surgical resection and radiosurgery for vestibular schwannomas with an average diameter of less than 3 cm. These Mayo investigators also found that the radiosurgical patients experienced less postprocedure dizziness.

Image of MRI of patient's brain with parathyroid carcinoma before radiosurgery

MRI of patient’s brain with parathyroid carcinoma before radiosurgery

Enlarge

Image of MRI of patient's brain with parathyroid carcinoma 12 years after radiosurgery

MRI of patient’s brain with parathyroid carcinoma 12 years after radiosurgery

Enlarge

Radiosurgery for pituitary adenomas

Radiosurgery is considered safe and effective for hormone-secreting pituitary adenomas. When compared with radiotherapy, radiosurgery appears to shorten by more than half the time required to achieve biochemical remission and normal hormone levels.

Controversy remains over whether pituitary-suppressive medications at the time of surgery have a negative impact on tumor control. Several studies, however, including a series of 46 acromegaly cases at Mayo Clinic, found that patients were more than 4 times as likely to reach normal hormone levels if they were taken off such medications before surgery.

At Mayo Clinic, patients with oversecretion of growth hormone or adrenocorticotropic hormone and patients who experience new or progressing visual field deficits are referred for surgical resection. Patients with tumors that extend into the cavernous sinuses and patients with recurrent tumors after prior surgery, however, are generally treated with radiosurgery if the tumor does not directly involve the optic nerves and chiasm.

Across Mayo Clinic’s 3 sites in Arizona, Florida, and Minnesota, patients are seen by neurosurgeons with expertise in both open procedures and radiosurgery. When used as an alternative to or in conjunction with traditional neurosurgery, radiosurgery is an effective, noninvasive option for treating benign intracranial tumors.

Source:

http://www.mayoclinic.org/medicalprofs/radiosurgery-for-benign-intracranial-tumors.html

http://www.mayoclinic.org/mcitems/mc2000-mc2099/mc2024-0410.pdf

Radiosurgery Treatment is  Radiotherapy in following versions:

  • single-session stereotactic radiosurgery,
  • fractionated conventional radiotherapy,
  • fractionated stereotactic radiotherapy, and
  • proton beam therapy.

Radiotherapy for vestibular schwannomas: a critical review.

Murphy ESSuh JH.

Source

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA. murphye3@ccf.org

Abstract

Vestibular schwannomas are slow-growing tumors of the myelin-forming cells that cover cranial nerve VIII. The treatment options for patients with vestibular schwannoma include active observation, surgical management, and radiotherapy. However, the optimal treatment choice remains controversial. We have reviewed the available data and summarized the radiotherapeutic options, including single-session stereotactic radiosurgery, fractionated conventional radiotherapy, fractionated stereotactic radiotherapy, and proton beam therapy. The comparisons of the various radiotherapy modalities have been based on single-institution experiences, which have shown excellent tumor control rates of 91-100%. Both stereotactic radiosurgery and fractionated stereotactic radiotherapy have successfully improved cranial nerve V and VII preservation to >95%. The mixed data regarding the ideal hearing preservation therapy, inherent biases in patient selection, and differences in outcome analysis have made the comparison across radiotherapeutic modalities difficult. Early experience using proton therapy for vestibular schwannoma treatment demonstrated local control rates of 84-100% but disappointing hearing preservation rates of 33-42%. Efforts to improve radiotherapy delivery will focus on refined dosimetry with the goal of reducing the dose to the critical structures. As future randomized trials are unlikely, we suggest regimented pre- and post-treatment assessments, including validated evaluations of cranial nerves V, VII, and VIII, and quality of life assessments with long-term prospective follow-up. The results from such trials will enhance the understanding of therapy outcomes and improve our ability to inform patients.

SOURCE:

Below, seminal papers on the subject

Meningioma of the internal auditory canal.

Laudadio PCanani FBCunsolo E.

Source

Department of Otolaryngology–Head and Neck Surgery, Maggiore Hospital, Bologna, Italy.

Abstract

A comprehensive literature search identified only 14 well-documented cases of intracanalicular meningioma. A case is presented of meningioma confined to the internal auditory canal which was excised using a sub-occipital retrosigmoid approach. Preoperative MRI and CT scans were suggestive of intracanalicular vestibular schwannoma. Only the intraoperative findings, which were confirmed by the histological data, revealed that the tumor was a meningioma. We review the literature and discuss the diagnostic and therapeuticissues relating to these tumors.

Facial nerve paralysis and meningioma of the internal auditory canal.

Hilton MPKaplan DMAng LChen JM.

Source

Department of Otorhinolaryngology, Sunnybrook and Women’s College Health Science Centre, University of Toronto, Canada. malcolmhilton@hotmail.com

Abstract

Pathological lesions confined to the internal auditory canal (IAC) commonly present with cochleovestibular symptoms; sensorineural hearing loss, tinnitus and balance disturbance. The commonest lesion of the IAC is vestibular schwannoma. Other lesions include meningioma, facial neuroma, cavernous haemangioma, lipoma and arachnoid cyst. Presentation with facial palsy and an intracanalicular lesion is suggestive of pathology other than acoustic neuroma. Magnetic resonance imaging (MRI) cannot reliably distinguish intracanalicular vestibular schwannomas from meningiomas. Particular care is required for surgery of these lesions: the facial nerve typically does not lie in a protected anterior position within the IAC.

Meningiomas of the internal auditory canal.

Nakamura MRoser FMirzai SMatthies CVorkapic PSamii M.

Source

Department of Neurosurgery, Nordstadt Hospital, Teaching Hospital Hannover Medical School, Hannover, Germany. mnakamura@web.de

Abstract

OBJECTIVE:

Meningiomas arising primarily within the internal auditory canal (IAC) are notably rare. By far the most common tumors that are encountered in this region are neuromas. We report a series of eight patients with meningiomas of the IAC, analyzing the clinical presentations, surgical management strategies, and clinical outcomes.

METHODS:

The charts of the patients, including histories and audiograms, imaging studies, surgical records, discharge letters, histological records, and follow-up records, were reviewed.

RESULTS:

One thousand eight hundred meningiomas were operated on between 1978 and 2002 at the Neurosurgical Department of Nordstadt Hospital. Among them, there were 421 cerebellopontine angle meningiomas; 7 of these (1.7% of cerebellopontine angle meningiomas) were limited to the IAC. One additional patient underwent surgery at the Neurosurgical Department of the International Neuroscience Institute, where a total of 21 cerebellopontine angle meningiomas were treated surgically from 2001 to 2003. As a comparison, the incidence of intrameatal vestibular schwannomas during the same period, 1978 to 2002, was 168 of 2400 (7%). There were five women and three men, and the mean age was 49.3 years (range, 27-59 yr). Most patients had signs and symptoms of vestibulocochlear nerve disturbance at presentation. One patient had sought treatment previously for total hearing loss before surgery. No patient had a facial paresis at presentation. The neuroradiological workup revealed a homogeneously contrast-enhancing tumor on magnetic resonance imaging in all patients with hypointense or isointense signal intensity on T1- and T2-weighted images. Some intrameatal meningiomas showed broad attachment, and some showed a dural tail at the porus. In all patients, the tumor was removed through the lateral suboccipital retrosigmoid approach with drilling of the posterior wall of the IAC. Total removal was achieved in all cases. Severe infiltration of the facial and vestibulocochlear nerve was encountered in two patients. There was no operative mortality. Hearing was preserved in five of seven patients; one patient was deaf before surgery. Postoperative facial weakness was encountered temporarily in one patient.

CONCLUSION:

Although intrameatal meningiomas are quite rare, they must be considered in the differential diagnosis of intrameatal mass lesions. The clinical symptoms are very similar to those of vestibular schwannomas. A radiological differentiation from vestibular schwannomas is not always possible. Surgical removal of intrameatal meningiomas should aim at wide excision, including involved dura and bone, to prevent recurrences. The variation in the anatomy of the faciocochlear nerve bundle in relation to the tumor has to be kept in mind, and preservation of these structures should be the goal in every case.

Surgical management of jugular foramen schwannomas with hearing and facial nerve function preservation: a series of 23 cases and review of the literature.

Sanna MBacciu AFalcioni MTaibah A.

Source

Gruppo Otologico, Piacenza-Rome, Rome, Italy. mario.sanna@gruppotologico.it

Abstract

OBJECTIVE:

Schwannomas of the jugular foramen are rare lesions and controversy regarding their management still exists. The objective of this retrospective study was to analyze the management and outcome in a series of 23 cases collected at a single center.

SETTING:

This study was conducted at a quaternary private otology and skull base center.

METHODS:

Charts belonging to patients with a diagnosis of jugular foramen schwannoma attending our center between May 1988 and April 2006 were examined retrospectively.

RESULTS:

The study group consisted of 23 patients. One patient (a 73-year-old woman) with normal lower cranial nerves function was managed with watchful expectancy and regular clinical and radiologic follow ups. The infratemporal fossa approach-type A (IFTA-A) was performed in 3 cases. One patient underwent a transcochlear-transjugular approach. Of the 22 patients surgically treated, 12 patients were operated on by the petrooccipital transsigmoid approach (POTS). In one patient with a preoperative dead ear, a combined POTS-translabyrinthine approach was adopted. Two patients were operated on through the POTS approach combined with the transotic approach. In another case (a 67-year-old woman), a subtotal tumor removal through a transcervical approach was planned to resect a 10-cm mass in the neck. One patient underwent a first-stage combined transcervical-subtotal petrosectomy approach to remove a huge tumor in the neck; the second-stage intradural removal of the tumor was accomplished through a translabyrinthine-transsigmoid-transjugular approach. The last patient underwent a first-stage combined transcervical-subtotal petrosectomy approach to remove the neck tumor component; this patient is now waiting for the second-stage intradural removal of the tumor. Complete tumor removal was accomplished in 21 cases and in one case, a residual schwannoma was left in place in the area of the jugular foramen. The 3 patients who were operated on by IFTA-A underwent permanent anterior transposition of the facial nerve. At 1-year follow up, 2 of these patients had House-Brackmann grade I and 1 reached grade IV. The patient who underwent a transcochlear-transjugular approach had a permanent posterior transposition of the facial nerve. At 1-year follow up, he had grade III facial nerve function. Postoperative facial nerve function was normal (House-Brackmann grade I) in all patients operated on by the POTS approach. Twelve patients had hearing-preserving surgery using the POTS approach. Good hearing was preserved in 10 cases (83.3%), the majority of whom (58.3%) maintained their preoperative hearing level. There was no perioperative mortality. One patient (4.5%) experienced a postoperative cerebrospinal fluid leak. After surgery, all patients did not recover the function of the preoperatively paralyzed lower cranial nerves. A new deficit of one or more of the lower cranial nerves was recorded in 50% of cases. So far, no patient has experienced recurrence during the follow-up period as ascertained by computed tomography or magnetic resonance imaging.

CONCLUSIONS:

Surgical resection is the treatment of choice for jugular foramen schwannomas. The POTS approach allowed single-stage, total tumor removal with preservation of the facial nerve and of the middle and inner ear functions in the majority of cases. Despite the advances in skull base surgery, new postoperative lower cranial nerve deficits still represent a challenge.

Meningiomas and schwannomas: molecular subgroup classification found by expression arrays.

Martinez-Glez VFranco-Hernandez CAlvarez LDe Campos JMIsla AVaquero JLassaletta LCasartelli CRey JA.

Source

Unidad de Investigación, Hospital Universitario La Paz, 28046 Madrid, Spain. vmartinezg.hulp@salud.madrid.org

Abstract

Microarray gene expression profiling is a high-throughput system used to identify differentially expressed genes and regulation patterns, and to discover new tumor markers. As the molecular pathogenesis of meningiomas and schwannomas, characterized by NF2 gene alterations, remains unclear and suitable molecular targets need to be identified, we used low density cDNA microarrays to establish expression patterns of 96 cancer-related genes on 23 schwannomas, 42 meningiomas and 3 normal cerebral meninges. We also performed a mutational analysis of the NF2 gene (PCR, dHPLC, Sequencing and MLPA), a search for 22q LOH and an analysis of gene silencing by promoter hypermethylation (MS-MLPA). Results showed a high frequency of NF2 gene mutations (40%), increased 22q LOH as aggressiveness increased, frequent losses and gains by MLPA in benign meningiomas, and gene expression silencing by hypermethylation. Array analysis showed decreased expression of 7 genes in meningiomas. Unsupervised analyses identified 2 molecular subgroups for both meningiomas and schwannomas showing 38 and 20 differentially expressed genes, respectively, and 19 genes differentially expressed between the two tumor types. These findings provide a molecular subgroup classification for meningiomas and schwannomas with possible implications for clinical practice.

Histological classification and molecular genetics of meningiomas.

Riemenschneider MJPerry AReifenberger G.

Source

Department of Neuropathology, Heinrich-Heine-University, Duesseldorf, Germany.

Abstract

Meningiomas account for up to 30% of all primary intracranial tumours. They are histologically classified according to the World Health Organization (WHO) classification of tumours of the nervous system. Most meningiomas are benign lesions of WHO grade I, whereas some meningioma variants correspond with WHO grades II and III and are associated with a higher risk of recurrence and shorter survival times. Mutations in the NF2 gene and loss of chromosome 22q are the most common genetic alterations associated with the initiation of meningiomas. With increase in tumour grade, additional progression-associated molecular aberrations can be found; however, most of the relevant genes are yet to be identified. High-throughput techniques of global genome and transcriptome analyses and new meningioma models provide increasing insight into meningioma biology and will help to identify common pathogenic pathways that may be targeted by new therapeutic approaches.

The neurofibromatosis type 2 gene is inactivated in schwannomas.

Twist ECRuttledge MHRousseau MSanson MPapi LMerel PDelattre OThomas GRouleau GA.

Source

Centre for Research in Neuroscience, McGill University, Montreal, Canada.

Abstract

Schwannomas are tumors arising from schwann cells surrounding peripheral nerves. Although most schwannomas are sporadic, they are seen in approximately 90% of individuals with neurofibromatosis type 2 (NF2), an autosomal dominantly inherited disease with an incidence of 1:40000 live births. The NF2 gene has recently been isolated on chromosome 22 and encodes a putative membrane organizing protein named schwannomin. It is believed to act as a tumor suppressor gene based on the high frequency of loss of heterozygosity (LOH) on this autosome in both sporadic and NF2 associated schwannomas and meningiomas and the identification of inactivating mutation in NF2 patients. In this study we examined 61 schwannomas including 48 sporadic schwannomas (46 of which are vestibular schwannomas) and 12 schwannomas obtained from NF2 patients, for mutations in 10 of the 16 coding exons of the NF2 gene. Twelve inactivating mutations were identified, 8 in sporadic tumours and 4 in tumors from people with NF2. These results support the hypothesis that loss of function of schwannomin is a frequent and fundamental event in the genesis of schwannomas.

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