Arbor Pharmaceuticals Slide Deck Outline
ICD-10-CM PCS Coordination and Maintenance Committee

Slide 1

Henry Brem MD
Harvey Cushing Professor 
Neurosurgery, Ophthalmology, Oncology & Biomedical Engineering
Chairman - Department of Neurosurgery
Johns Hopkins University

ICD-10-CM PCS Coordination and Maintenance Committee 
Wednesday, March 19, 2014
CMS Headquarters
Baltimore, Maryland

Slide 2

Presentation Content
* About Malignant Glioma
* About Gliadel® Wafer
* Gliadel® Wafer in Malignant Glioma Management
* Malignant Glioma Case Presentation
* Rationale for new ICD 10 PCS Code
* Questions and Answers
Slide 3

Incidence/Mortality
* An estimated 24,620 new cases of primary malignant brain and CNS tumors were predicted in 2013
* This represents 1.47% of all cancers
* An estimated 13,700 deaths in 2013 were attributed to primary malignant brain tumors
* Age of onset is between 45 and 70; median age is 45 for grade III and 60 for grade IV tumors

Central Brain Tumor Registry of the United States (CBTRUS) Fact Sheet 2013.
American Cancer Society: Facts & Figures 2014.
American Association of Neurological Surgeons: Patient Information 2012
Narayanan et al., ACNR 12 (4): 24-29, 2012

Slide 4

Brain Tumors
• In 1984 – many systemic treatments had been tried with no benefit.  
• The FDA had not approved any new therapy in over 20 years.



Slide 5

Glioblastoma: Treatment Outcome
The graph illustrates the median survival in months vs. treatment method
Surgery Only: median survival is 4 months
Surgery + Radiotherapy: Median Survival is 9.25 months
Surgery + Radiotherapy + Chemotherapy: Median Survival is 10 months

McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds.  Principles of Neurosurgery.  
St Louis, MO: Mosby-Wolfe; 1994: chap 26.

Slide 6

Problem: Clinical effectiveness of new cancer therapies
Hypothesis: Better delivery of agents to target sites would improve outcome
Solution: Targeted controlled delivery (polymers)

Slide 7

Rationale for Local Therapy
• Primary brain  tumors usually recur within approximately 2cm of original tumor site
• Bypass the limitations of the blood-brain barrier
 Delivers high local concentrations chemotherapy 
 Continuously releases chemotherapy over several days to weeks
• Limits systemic circulation
• Part of a multimodal management strategy for aggressive tumor types with high mortality rates and few available therapies 

Slide 8

Gliadel Wafer (carmustine Implant)

The image on the slide illustrates the configuration of the Gliadel Wafer implant
* Small white circular implant 
* Approximately the size of a dime
* Diameter of 14 mm
* Thickness of 1.3 mm
* Impregnated with 7.7 mg of carmustine (BCNU)

Slide 9

The image on the slide illustrates the mechanism of wafer release 
* Released via surface erosion
* Hydrophobic monomers permit surface erosion for slow release & protect active agent from hydrolysis
* Copolymer degradation of 70% by 2-3 weeks

Brem H, Langer R: Polymer-Based Drug Delivery to the Brain. Science & Medicine. 1996;3(4):2-11. 

Slide 10

Image showing that concept of maximally resecting the tumor.

Up to eight polymer implants line a tumor resection cavity, where the loaded drug is gradually released as they dissolve.  The inset shows conceptually how drug molecules diffuse away from these implants.

Brem and Langer, Scientific American: Science and Medicine 3:2-11, 1996

Slide 11

The Lancet
Placebo-controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas
* A Pivotal Study conducted by Dr. Brem and colleagues.
* first done in patients who failed all therapies
* 27 medical centers
* 222 patients
* Equally divided (half received wafers with chemotherapy, half received empty polymers and otherwise best available therapy).
* Study demonstrated statistically significant improve in survival in those patients who received the Gliadel wafer as compared to the control group.

Lancet 345:1008-12, 1995

Slide 12 

Neuro-Oncology
A Phase 3 Trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel® Wafers) in patients with primary malignant glioma
* An European study conducted by Dr. Westphal and colleagues.
* 240 patients
* Used the same trial design as Lancet, but used Gliadel as the initial therapy in combination with radiation therapy.
* They were able to demonstrate statistically significant improvement and survival.

Neuro-Oncology  Vol 5, Issue 2: April 2003

Slide 13

* This slide demonstrates the three pivotal studies (two in Europe and one in the United States) for Gliadel and the outcomes of improvement and survival in each of them, compared to the other newly diagnosed drug for malignant Gliomas, Temozolomide, which shows similar improvement and survival.
o Increased median survival of newly diagnosed patients
o Increased number of long term survivors


Slide 14

Current United States FDA-Approved Indications for Gliadel® Wafer (carmustine implant)
* In September of 1996, FDA gave approval to the Gliadel Wafer for patients with recurrent glioblastoma multiforme as an adjunct to surgery.
* In February of 2003, FDA gave approval to the Gliadel Wafer for patients with newly diagnosed high grade malignant glioma as an adjunct to surgery and radiation.

Slide 15

Important Safety Information

Indications
* Patients with newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation
* Patients with recurrent glioblastoma multiforme as an adjunct to surgery.

Important Safety Information
Use of this treatment is complex and there is some very important safety information that is involved.

* Can cause fetal harm when administered to a pregnant women
* Recommended patients receiving Gliadel discontinue nursing
* Female patients of reproductive potential should receive counseling on pregnancy planning and prevention
* Males should be advised of the potential for infertility and should be advised to seek counseling on fertility and family planning options prior to implantation.

Slide 16

Warnings and Precautions

The following may occur when Gliadel Wafer is used
* Seizures: 54% of patients treated with Gliadel wafers in the recurrent disease trial experienced new or worsened seizures within the first five post-operative days. Optimize anti-seizure therapy prior to surgery.
* Intracranial Hypertension: Brain edema occurred in 23% of patients treated with Gliadel wafers in the initial surgery trial.  Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection.
* Impaired Neurological Wound Healing: In the initial disease trial, 16% of Gliadel wafer-treated patients experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks.  In the recurrent disease trial, 14% of Gliadel wafer-treated patients experienced wound healing abnormalities.
* Meningitis: Meningitis occurred in 4% of patients receiving Gliadel wafers in the recurrent disease trial.
* Wafer Migration: Close any communication larger than the diameter of a wafer between the surgical resection cavity and the ventricular system prior to wafer implantation to reduce the risk of wafer migration.

These can be managed medically, but lead to very complex surgical decisions that must be made by the surgeon.

Adverse Reactions
* The most common adverse reactions in Newly-Diagnosed High Grade Malignant Glioma patients are cerebral edema, asthenia, nausea, vomiting, constipation, wound healing abnormalities and depression.
* The most common adverse reactions in Recurrent Glioblastoma Multiforme patients are urinary tract infection, wound healing abnormalities and fever.

Slide 17

Lessons from Clinical Experience with Gliadel Wafer
• Gliadel® Wafer is safe and effective at initial presentation and recurrence 
•  Maximize debulking prior to inserting polymers wafer
•  Small opening of ventricle does not preclude use
•  Watertight closure of dura to eliminate CSF leaks and decrease infections

Slide 18 

Lessons from Clinical Experience with Gliadel Wafer
• Preoperative anticonvulsant medication
•  Post-operative AIR is routine on imaging studies
•  High dose steroids (dexamethasone up to 20mg q4h) if post-op neurological compromise
•  Steroids for at least 2 weeks post-op (during “chemotherapy”)
Slide 19
The Diagram shows current optimal therapy utilized at John’s Hopkins
Phase One
* Surgery (maximally resect tumor) and Gliadel
Phase Two (2 – 3 weeks after surgery)
* Temodar(oral chemotherapy) + Radiation Therapy 

Slide 20

Standard of Care Systemic Chemotherapy: Temozolomide (TMZ)
• lipid soluble
• has modest toxicity
• active against melanoma, lymphomas, and primary brain tumors
• spontaneously chemically converted to its active methylating metabolite, the methyldizaonium ion, via hydrolysis

While systemic chemotherapy was included as part of a multimodal regimen in the pivotal trials involving Gliadel® Wafer, TMZ was not available at the time and therefore not included in the studies.  
Slide 21

Gliadel Implantable BCNU Wafers: Similar Survival to Temozolomide (TMZ)

TMZ Overall Survival
Median overall survival:  14.6
Gliadel Overall Survival
Median overall survival:  13.1

Slide 22

French Clinical Study looking at implanting Gliadel, using radiation therapy and combining it with TMZ and seeing a better survival rate that has ever been achieved historically with this disease.
* A multi-center study conducted in 17 French centers by Dr. Duntze and colleagues.
* 92 patients
* Treated with craniotomy, Gliadel, Temozolomide
* RT Progression free Survival 10.5 months, median
* 18.8 month overall survival, median

Annals of Surgical Oncology, 20: 2065-2072, 2013

Slide 23

Some of the adverse events that they saw with this combined surgery, radiation, TMZ and Gliadel include:
* Alopecia
* Exhaustion
* Epilepsy
* Digestive Disorders
* Hematological Disorders
* Neurological Aggravation

Table four shows the survival benefit of this combined approach.  A survival rate of 17 – 20 months was consistently reported in various reports when using the combined approach of surgery, radiation, TMZ and Gliadel.

Slide 24

Case Presentation
* 52 year old male
* Presented with several week history of severe headaches
* He saw his primary care physician, who obtained an MRI.  
* The MRI revealed a ring enhancing mass

Slide 25 

Image of Initial MRI taken 09/18/2005
* Revealed ring enhancing mass

Slide 26

Operated on patient and resected the tumor and placed 8 Gliadel wafers.
Image of Post Op Scan 9/29/2005 




Slide 27

• XRT + Temodar (temozolamide/TMX) 
– IMRT 6000cGy 10/13/05-11/23/2005
– Concomitant TMZ (75 mg/m˛ body surface area) was given 7 days per week during radiotherapy 
– Adjuvant TMX 150 mg/m˛ 
o Stupp Regimen:5 days on 23 days off times 6 cycles completed 08/2006
– Watchful monitoring
o Excellent quality of life (QOL) with return to work (RTW)

Slide 28

Image of follow up scans 6/29/06 and 9/14/06
9 and 12 months out from Gliadel/XRT/TMZ
This scan shows return to normal with some scar tissue left from operation.

Slide 29

Image of follow up scan 11/09/2006
14 months from initial dx and treatment
Normal scan

Slide 30

Routine 2 year follow up scan 9/2007
Scan shows recurrence in right temporal lobe
Radiographic progression

Slide 31 

10/2007 brought to the operating room, tumor was removed and Gliadel was placed for the second time.

Scan shows post op crani #2 + Gliadel #2

Slide 32

Case Summary
* Diagnosed with Glioblastoma at age 54 in September 2005
* Two craniotomies with Gliadel
* Survived 34 months

Note: This patient case is not representative of all GBM cases or treatment courses.  Clinical presentation of GBM, management approaches and outcomes will vary.

Slide 33

Image of surgical procedure
* Patient’s head placed in clamp 
* Neuro-navigational localization of mass
* Incision made
* Burr holes made, bone flap removed

Slide 34

Image of surgical procedure
* Field irrigated and hemostasis achieved
* Cruciate incision of dura is made

Slide 35

Image of surgical procedure
* Dura placed under tension & kept moist with telfa

Slide 36

Image of surgical procedure
* Maximize resection of the tumor
* Send tumor specimens to the pathologist to confirm the diagnosis
* Achieve absolute hemostasis

Slide 37

Image of surgical procedure
* Gliadel® Wafers are placed along the surface of the brain from which the tumor arose

Slide 38

Image of surgical procedure
* Gliadel® Wafers should be packed to cover as much of the cavity as possible
* Slight overlapping of the wafers is acceptable
* Wafers broken in half may be used, but wafers broken in more than 2 pieces should be discarded in a biohazard container

Slide 39

Image of surgical procedure
* Surgicel® may be used to anchor the Gliadel® Wafers
* The wound should then be irrigated with artificial CSF or saline to remove air from the cavity
* The dura should be closed in a watertight fashion



Slide 40

Image of surgical procedure
* Closing of the dura
* Done in a very meticulous manner, when the chemotherapy drug is being released.

Slide 41

Image of surgical procedure
* 4 triangles re-apposed
*  Sutures placed 1-2 mm apart

Slide 42

Image of surgical procedure
* Water tight closure 
* Crucial to prevent infection wound healing problems
* Consider dural substitutes or grafts

Slide 43

Image of surgical procedure
* Gelfoam placed over dura and secured in placed with tenting sutures
* Tenting suture carried up through bone

Slide 44

Image of surgical procedure
* Burr hole covers, plates and screws are used to secure the bone plate
* Skin closed

Slide 45

Summary
* In the management of patients with high-grade malignant glioma (HGG), it is essential to consider every treatment with a proven survival advantage. 
*  GLIADEL Wafer (carmustine implant) is the first and currently the only FDA-approved treatment that delivers an antineoplastic agent directly to the resected tumor environment while sparing the patient from systemic exposure to that agent.



Slide 46

Intra-operative Carmustine Wafer (Gliadel) Guidelines for Anaplastic Gliomas and Glioblastoma

AANS/CNS Treatment Guidelines for Newly Diagnosed High Grade Gliomas: 
• BCNU-impregnated biodegradable polymers are recommended in patients for whom craniotomy is indicated, on the basis of evidence taken from 2 well-designed comparative clinical studies:
• Westphal M, et al. Neurooncol. 2003;5(2):79-88.
• Valtonen S, et al. Neurosurgery. 1997;41(1):44-48.

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®)*
• BCNU wafer recommended for patients where maximal safe resection is feasible and frozen-section diagnosis supports high-grade glioma (category 2B)

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.2.2013. © National Comprehensive Cancer Network, Inc 2013.  All rights reserved.  Accessed  February 27, 2014.  To view the most recent and complete version of the guideline, go online to www.nccn.org.  NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Slide 47

NCCN Guidelines
Recommendation is after maximal safe resection, carmustine wafer is a reasonable therapy, followed by other adjuvant therapies.

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for  Central Nervous System Cancers V.2.2013.  © 2013 National Comprehensive Cancer Network, Inc.  All rights reserved.  The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.  To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.  NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Slide 48 

NCCN Guidelines
This diagram demonstrates adjuvant therapies that are available depending on the pathology of the tumors.  These include fractionated external beam radiation therapy, PCV chemotherapy, and temozolomide chemotherapy; used alone or in combination, 

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for  Central Nervous System Cancers V.2.2013.  © 2013 National Comprehensive Cancer Network, Inc.  All rights reserved.  The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.  To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.  NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Slide 49

NCCN Guidelines
Demonstrates if patient is doing well, continue with follow up and monitor with MRI 2-6 weeks after radiation therapy, and again every 2-4 months for the next 2-3 years.

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for  Central Nervous System Cancers V.2.2013.  © 2013 National Comprehensive Cancer Network, Inc.  All rights reserved.  The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.  To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.  NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
Slide 50

NCCN Guidelines
If there is recurrence the recommendation is to resect the tumor and if possible carmustine wafers implanted as well.

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for  Central Nervous System Cancers V.2.2013.  © 2013 National Comprehensive Cancer Network, Inc.  All rights reserved.  The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.  To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.  NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Slide 51

Rationale for New ICD-10-PCS Code

The ICD-9-PCS code 00.10, Implantation of chemotherapeutic agent, did not transition to a unique ICD-10-PCS code.

Currently, under ICD-10-PCS there is not a unique procedure code that captures the procedure to insert chemotherapeutic wafer(s) into cranial cavity following open craniotomy for tumor excision.

Request: Create new code 3E0Q00_, effective 10/1/2014

*Approach:
Open approach (not percutaneous) is essential to capture surgical approach
Percutaneous approach as interim coding recommendation will create coding confusion and inconsistencies 
*Qualifier
Add qualifier for chemotherapeutic wafer so that utilization, costs and outcomes can be captured, 
Qualifier will differentiate for other types of antineoplastic agents 

Slide 52

Discussion & Questions

