Patrick Y. Wen, MD Director, Center for Neuro-Oncology Dana-Farber Cancer Institute Director, Division of Neuro-Oncology Brigham and Women’s Hospital Professor

Patrick Y. Wen, MDDirector, Center for Neuro-OncologyDana-Farber Cancer InstituteDirector, Division of Neuro-OncologyBrigham and Women’s HospitalProfessor of Neurology Harvard Medical SchoolBoston, Massachusetts

Patient Assessment, Supportive Care and Managing Adverse Events

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clinicaloptions.com/oncologyPatient Assessment, Supportive Care and Managing Adverse Events

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Faculty Disclosure

Patrick Y. Wen, MD, has disclosed that he has received consulting fees from Merck, Novartis, and Stemline; fees for non-CME services from Merck; and contracted research from Amgen, AstraZeneca, Eisai, Exelixis, Genentech, Merck, Novartis, MedImmune, sanofi-aventis, and Vascular Biogenics.


Overview

Patient Assessment, including determination of response Supportive Care

– Antinausea medications

– Seizure prophylaxis

– Treatment of peritumoral edema

Management of Adverse Events– Steroid-induced complications

– Chemotherapy-induced cytopenias

– DVT/PE and anticoagulation

– Radiation necrosis

– Bevacizumab-related adverse events

Patient Assessment


Patient Assessment and Determination of Benefit Clinical/neurologic function

Performance score

Corticosteroid use

Neuropsychologic function

Quality of life

– FACT-Br, EORTC QLQ-C30, MDASI-BT

Radiographic response


Why Determine Response?

Accurate response assessment important for

– Clinicians and patients

– Continue beneficial treatments

– Stop unhelpful treatments

– Avoid unnecessary toxicity and cost

– Evaluation of new brain tumor treatments

– Identify promising new treatments

– Abandon evaluation of inactive treatments


Macdonald’s Criteria

Tumor size

– Maximum cross-sectional area of contrast-enhancing tumor on CT or MRI scan

Neurological function

Steroid dose

Macdonald DR, et al. J Clin Oncol. 1990;8:1277-1280.


Macdonald’s Criteria

Limitations

– Measures enhancing component only

– Does not address nonenhancing tumors

– Pseudoprogression

– Antiangiogenic treatments

– Pseudoresponse

– Nonenhancing progression

van den Bent MJ, et al. J Clin Oncol. 2009;27:2905-2908.


Before RT4 wks after RT

8 wks after RT

6 mos later

Pseudoprogression

Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.


Pseudoresponse

Cediranib

XL814





General Principles

Product of the maximal cross-sectional enhancing diameters will be used to determine the size of the contrast-enhancing lesions

Enhancing and nonenhancing tumor areas evaluated

Response (CR, PR) requires confirmatory scan (≥ 4 wks)

Steroid dose and clinical status must be recorded



Measureable and Nonmeasurable Disease for Contrast-Enhancing Lesions Measurable disease

– Bidimensionally contrast-enhancing lesions with clearly defined margins, a minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at least 5 mm apart with 0 mm skip

Nonmeasurable disease

– Unidimensionally measurable lesions, masses with margins not clearly defined, or lesions with maximal perpendicular diameters < 1 cm



Criteria for Entry Into Clinical Trials for Recurrent High-Grade Glioma Currently, no minimum criteria for entry into trials, except

that it has to be “worse”

25% increase in the sum of the products of perpendicular diameters of the contrast-enhancing lesions on stable or increasing doses of corticosteroids

Worsening of nonenhancing disease if patients have received previous antiangiogenic therapy



Determining Progression by Time From Initial Radiochemotherapy Definition of PD less than 12 wks from completion of

radiochemotherapy

– New enhancing lesion outside of the radiation field (beyond the 80% isodose line)

or

– Unequivocal evidence of viable tumor on histopathology sampling (ie, 70% tumor cell nuclei in areas, high or progressive increase in MIB-1 proliferation index compared with previous biopsy, or evidence for histologic progression or increased anaplasia in tumor)



Courtesy of Jan Drappatz, DFCI


RANO Criteria Summary

Criterion CR PR SD PD

T1-Gd+ 0* ≥ 50% * < 50% < 25%

≥ 25% †

T2/FLAIR Stable or Stable or Stable or Stable or †

New lesion 0 0 0 Present†

Steroids 0 Stable or Stable or NA†

Clinical Stable or Stable or Stable or †

All All All Any†

*Sustained for at least 4 wks.†Progression occurs when criterion is present.



RANO Response Criteria for High-Grade Gliomas Progressive disease

– ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over baseline or best response scan)

and/or

– Significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response following initiation of therapy, not due to comorbid events

– Ideally this would be quantified like contrast-enhancing lesions

– Difficult

– Left to investigator’s discretionWen PY, et al. J Clin Oncol. 2010;28:1963-1972.


RANO Criteria

Proposed new criteria are a work in progress Implementation and validation in clinical trials is important Future revisions to include

– Volumetric imaging

– Advanced MRI

– DCE, DSC, diffusion/ADC, MRS

– PET (FLT, amino acid)

– Neurocognitive status and HRQOL

– Corticosteroids

RANO criteria for brain metastases, meningioma, and pediatric brain tumors (RAPNO)


Patient With Increasing Subnormal ADC

Low ADC

Gerstner ER, et al. Neuro Oncol. 2010;12:466-472.

Supportive Care


Supportive Care

Antiemetic therapy

Seizure prophylaxis

Treatment of peritumoral edema

Other issues


Antiemetic Therapy

Concomitant temozolomide

– None, metoclopramide, or serotonin 5-HT3 antagonist (eg, ondansetron, granisetron)

Adjuvant temozolomide

– 5-HT3 antagonist for up to 7 days

– ± lorazepam

– ± H2-blocker or proton pump inhibitor

– ± corticosteroids

– Neurokinin 1 antagonist (eg, aprepitant, fosaprepitant)

Adapted from 2011 NCCN guidelines


Seizure Prophylaxis

Patients with seizures

– Should be treated with standard AED

– Preference for cytochrome P450-enzyme non-EIAED

– EEG usually not necessary


Non-EIAED

EIAED

Wen PY, et al. Clin Cancer Res. 2006;12:4899-4907.

North American Brain Tumor Consortium Study 99-08

Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas

160,000

140,000

120,000

100,000

80,000

60,000

40,000

20,000

0400 600 800 1000 1200

Dose (mg/day)

Group AGroup B

AU

C (

ng

*hr/

mL

)

Imatinib


EIAEDs and Non-EIAEDs

EIAEDsCarbamazepine

Oxcarbazepine

Phenytoin

Fosphenytoin

Phenobarbital

Primidone

Non-EIAEDsValproic acid

Gabapentin

Lamotrigine

Topiramate

Tiagabine

Zonisamide

Levetiracetam

Clonazepam

Clonozam

Pregabalin

Lacosamide


EORTC/NCIC Temozolomide Trial

175 patients (30.5%) were AED free, 277 (48.3%) were receiving EIAEDs, and 135 (23.4%) were receiving non-EIAEDs

97 patients receiving valproic acid alone had increased survival from treatment with RT and TMZ

– Valproic acid median survival: 17.3 mos

– EIAED only median survival: 14.4 mos

– No AED median survival: 14.0 mos

Patients receiving valproic acid only had more grade 3/4 thrombocytopenia and leukopenia

Weller M, et al. Neurology. 2011;77:1156-1164.


EORTC/NCIC Temozolomide Trial

Weller M, et al. Neurology. 2011;77:1156-1164.

*95% CI everywhere

Test for heterogeneityChi square = 3.73, df = 2: P > .1

AED Status

No AED

VPA only

EIAED only

Total

90/103

41/49

105/113

236/265(89.1%)

71/72

47/48

134/139

252/259(97.3%)

-15.7

-16.6

-21.1

-53.4

35.5

18.7

56.8

111.2

0.64 (0.46-0.89)

0.41 (0.26-0.65)

0.69 (0.53-0.89)

0.62 (0.51-0.74)

Events/Patients Statistics HR & CI*

TMZ/RT RT (O-E) Var. (TMZ/RT: RT) HR (95% CI)

0.25 0.5 1.0 2.0 4.0

TMZ/RTBetter

RTBetter

Treatment effect; P < .00000


Prophylactic Anticonvulsants

No definite evidence that patients who have not had seizures benefit from prophylactic AED

Recommend tapering AED 1 wk after surgeryGlantz MJ, et al. Neurology. 2000;54:1886-1893.


Placebo-Controlled Phase III Trial of Prophylactic AED in High-Grade Gliomas

Primary objective

– Time to first seizure

Secondary objectives

– 1-yr risk of first seizure

– Patient-reported symptoms

Patients with newly diagnosed high-

grade glioma(planned N = 302)

Lacosamide

Placebo

Taper any prestudy anticonvulsant

Stratified byperioperative

anticonvulsant use

ClinicalTrials.gov. NCT01432171.


Peritumoral Edema

Glucocorticoids preferred

Twice daily dosing adequate

Use as little as possible


Novel Treatments for Peritumoral Edema

COX-2 inhibitors[1]

Corticorelin acetate (corticotrophin-releasing factor)[2,3]

VEGF inhibitors (eg, bevacizumab, aflibercept)

VEGFR inhibitors

1. Portnow J, et al. Neuro Oncol. 2002;4:22-25. 2. Shapiro WR, et al. ASCO 2009. Abstract 2080. 3. Recht LD, et al. ASCO 2010. Abstract 2078.


Cediranib: VEGFR Inhibitor


Responders are colored in orange

Patient Index

% C

han

ge

Fro

m B

asel

ine

Percent Change of Lowest Corticosteroid Dose From Baseline

Friedman HS, et al. J Clin Oncol. 2009;27:4733-4740.

50

0

-50

-1000 5 10 15 20 25 30 35 40 45

Bevacizumab(n = 43)

Patient Index

% C

han

ge

Fro

m B

asel

ine

50

0

-50

-1000 5 10 15 20 25 30 35 40 45

Bevacizumab + Irinotecan (n = 43)


Cabozantinib: Effects on Pts Receiving Corticosteroids at Baseline (N = 76)

Wen PY, et al. ASCO 2010. Abstract 2006.

Dex

amet

has

on

e E

qu

ival

ent

Do

se (

mg

)/D

ay 61% experienced ≥ 50% reduction in dose of corticosteroids46% experienced a 100% reduction in dose of corticosteroids

8

7

6

5

4

3

2

1

00 2 4 6 8 10 12 14 16 18 20 22

Wks

Median25th and 75th percentiles

n = 76 n = 76

n = 73

n = 57n = 51

n = 41n = 33 n = 28

n = 26 n = 17 n = 14n = 7


Other Issues

Abulia, inattention (methylphenidate)[1]

Fatigue (modafinil, armodafinil, methylphenidate)[2,3]

Memory

– Donepezil[4]

– Memantine

Depression (often underdiagnosed)

1. Myers CA, et al. J Clin Oncol. 1998;16:2522-2527. 2. Kaleita TA, et al. ASCO 2006. Abstract. 1503. 3. Gerard ME, et al. SNO 2011. Abstract QL-18. 4. Shaw EG, et al. J Clin Oncol. 2006;24:1415-1420.

Management of Adverse Events


Management of Adverse Events

Steroid-induced complications

Chemotherapy-induced cytopenias

DVT/PE and anticoagulation

Radiation necrosis

Bevacizumab-related adverse events


Neurologic Complications of Corticosteroids Common

– Myopathy

– Behavioral changes

– Visual blurring

– Tremor

– Insomnia

– Reduced taste and olfaction

– Cerebral atrophy

Uncommon

– Psychosis

– Hallucinations

– Hiccups

– Dementia

– Seizures

– Dependence

– Epidural lipomatosis


Pneumocystis Jerovecii (Carinii) Pneumonia

Mahindra AK, et al. J Neurooncol. 2003;63:263-270.


Osteoporosis and Compression Fractures


Osteoporosis

Patients receiving chronic corticosteroid therapy should probably be given

– Calcium supplements with vitamin D 800 IU/day or

– An activated form of vitamin D (eg, alfacalcidiol 1 µg/day) or

– Calcitriol 0.5 µg/day

– Bisphosphonates such as etidronate, alendronate, risedronate, and zoledronate

Kyphoplasty: unclear benefit for compression fractures[1]

– 2 negative trials have been reported

1. Muijs SP, et al. J Bone Joint Surg Br. 2011;93:1149-1153.


Association Between Hyperglycemia and Survival in Newly Diagnosed GBM N = 191 newly diagnosed patients with GBM and with

good baseline KPS

Hyperglycemia was associated with shorter survival, after controlling for glucocorticoid dose and other confounders

Effect of intensive management of glucocorticoid-related hyperglycemia on survival deserves additional study

Derr RL, et al. J Clin Oncol. 2009;27:1082-1086.


OS in GBM by Quartiles of Time-Weighted Glucose

Derr RL, et al. J Clin Oncol. 2009;27:1082-1086.

Quartile 1Quartile 2Quartile 3Quartile 4

P for trend = .041

Mos

Pro

bab

ilit

y o

f O

S

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30 35 40 45


Focal RT daily—30 x 200 cGy; total dose: 60 Gy

TMZ 75 mg/m2 PO QD for 6 wks, then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles

Concomitant TMZ + RT Adjuvant TMZ

Wks6 10 14 18 22 26 30

RT Alone

R0

Chemotherapy-Induced Cytopenias

Stupp R, et al. N Engl J Med. 2006;352:987-996.


Adverse Event Grade 2 Grade 3 Grade 4

Arm 1 Arm 2 Arm 1 Arm 2 Arm 1 Arm 2

Anemia* 17 21 4 4 0 0

Leukopenia 52 69 13 33 7 3

Neutropenia 25 31 16 29 8 7

Lymphopenia 52 26 41 76 10 31

Thrombocytopenia 24 26 20 18 13 8

Fatigue 85 109 12 33 0 0

Nausea/vomiting 43 51 5 8 0 0*1 grade 5 toxicity.Grade 3-5 adverse events were more common in arm 2 vs arm 1 (194 vs 120; P < .0001); mostly lymphopenia (107 vs 51) and fatigue (33 vs 12).

Chemotherapy-Induced Cytopenias in RTOG Study of Adjuvant TemozolomideRTOG 0525: Adjuvant TMZ (arm 1, standard dose = 351; arm 2, dose-dense = 369)

Gilbert M, et al. ASCO 2011. Abstract 2006.


Immunosuppression in High-Grade Gliomas Treated With RT and TMZ N = 96

Median CD4+ cell count before RT and TMZ: 664 cells/mm3

CD4+ cell count nadir occurred 2 mos after initiating therapy; 73% had CD4+ cell counts < 300 cells/mm3, 40% had < 200 cells/mm3

CD4+ cell counts remained low throughout the yr of follow-up

Infection risk low (2.5% rate of death from infection)

Grossman SA, et al. Clin Cancer Res. 2011;17:5473-5480.

Outlier90th percentile75th percentile25th percentile10 percentileOutlier

24002200200018001600140012001000

8006040

2000

Ab

solu

te C

D4

+ C

ell

Co

un

t

Baseline 121 2 3 4 5 6 7 9 10 118Mo of Follow-up


Grossman SA, et al. Clin Cancer Res. 2011;17:5473-5480.

OS With RT + TMZ by CD4+ Cell Count at Month 2

CD4+ cell count ≥ 200 cells/mm3

CD4+ cell count < 200 cells/mm3

Pro

bab

ilit

y o

f S

urv

ival

Mos

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54


Pulmonary Angiogram Showing Intraluminal Filling Defects


Venous Thromboembolic Disease

Common

Highest incidence among cancers, comparable to pancreatic and gynecologic malignancies

Majority occur in postoperative period

> 40% occur outside postoperative period

21% rate at 12 mos; 32% at 24 mos

Gerber DE, et al. J Clin Oncol. 2005;24:1310-1318.


Intracranial Hemorrhage Following Anticoagulation


Complications of Inferior Vena Cava Filter

Levin JM, et al[1]

– 42 brain tumor patients who had IVC filters placed

– 12% experienced recurrent PE

– 57% developed either IVC or filter thrombosis, recurrent DVT, or postphlebitic syndrome

Schiff D, et al[2]

– 42 patients with brain metastases and VTE who received anticoagulation

– 3 (7%) experienced cerebral hemorrhage, 2 with supratherapeutic anticoagulation

– 10 patients who received an IVC filter, 4 (40%) developed recurrent VTE requiring anticoagulation

Filter complications also occur frequently in patients with other neoplasms if concomitant anticoagulation is not used

1. Levin JM, et al. Neurology. 1993;43:1111-1114. 2. Schiff D, et al. Cancer 1994;73:493-498.


Risks of Anticoagulation

Ruff RL, et al[1]

– 2/103 (1.9%) with VTE, who were anticoaglated, experienced ICH

– 6/272 (2.2%) with VTE had spontaneous hemorrhage

Choucair AK, et al[2]

– 0/22 experienced ICH

Olin JW, et al[3]

– 1/25 experienced ICH

1. Ruff RL, et al. Ann Neurol. 1983;13:334-336. 2. Choucair AK, et al. J Neurosurg. 1987;66:357-358. 3. Olin JW, et al. Arch Intern Med. 1987;147:2177-2179.


Algorithm for VTE Treatment in Patients With Brain Tumors

Wen PY, et al. J Neurooncol. 2006;80:313-3332.

Diagnosis of VTE IVC filter

PE ± DVT

DVT with no significant PE

LMWH or LMWH/ warfarin ± IVC filter

IV heparin without bolus ± IVC filter

IV heparin with mini or full bolus ± IVC filter

Severe

Mild When stable

Recent bleeding

No recent bleeding

Nonenhanced CT scan

No contraindication to anticoagulation

Contraindication to anticoagulation, recent surgery (within 1-2 wks),hemorrhagic tumorsMelanomaChoriocarcinomaThyroid carcinomaRenal carcinomaOther contraindications to anticoagulation


Safety of Anticoagulation Use and Bevacizumab in Patients With Glioma N = 21 patients treated for mean of 72 days

No lobar hemorrhages

3 small parenchymal hemorrhages

– 1 symptomatic

– 2 petechial hemorrhages

Nghiemphu PL, et al. Neuro Oncol. 2008;10:355-360.


Safety of Concurrent Bevacizumab and Anticoagulation in High-Grade Gliomas 64 patients with glioma treated with bevacizumab and

anticoagulation

7 (10.9%) experienced intracranial hemorrhage

– Grade 4: 2 (3.1%)

– Grade 1: 5 (7.8%)

Among 218 patients who did not receive anticoagulants, there were 2 (0.9%) serious hemorrhages (both grade 4 intracranial hemorrhages)

Serious hemorrhage rate was higher in patients who received anticoagulants (P = .025), but the rate was low

Norden AD, et al. J Neurooncol. 2011;[E-pub ahead of print].


Lee AY, et al. N Engl J Med. 2003:349:146-153.

LMWH (Dalteparin) ± Coumarin for VTE Prophylaxis: Risk of Recurrence

Cancer patients with VTE randomized to dalteparin ± coumarin derivative

6-mo VTE rates

– Dalteparin: 27/336 (9%)

– Coumarin: 53/336 (17%)

– HR: 0.48; P = .002

– No difference in bleeding or death

25

20

15

10

5

00 30 60 90 120 150 180 210

Days After Randomization

Pro

bab

ilit

y o

f R

ecu

rren

t V

eno

us

Th

rom

bo

emb

oli

sm (

%)

P = .002

Oral anticoagulant

Dalteparin

Pts at Risk, nDalteparinOral anticoagulant

336336

301280

264242

235221

227200

210194

164154


Prophylactic Anticoagulation

Role of long-term prophylactic anticoagulation unknown

PRODIGE: randomized phase III trial of daily dalteparin vs placebo in patients with newly diagnosed malignant glioma

– Terminated prematurely

– Dalteparin associated with trend toward decreased VTE and increased bleeding

Perry JR, et al. J Thromb Haemost. 2010;8:1959-1965.


Complications of Radiation Therapy on the Nervous System Direct effects on neural structures within radiation portal

– Acute reaction (hrs or days)

– Early delayed reaction (2 wks to 4 mos)

– Late delayed reaction (4 mos to several yrs)

Indirect effects

– Vascular injury (cerebral infarction and hemorrhages)

– Secondary neoplasms

– Endocrinopathies


Treatment of Radiation Necrosis

Corticosteroids

Surgery

Pentoxifylline?

Anticoagulation?

Hyperbaric oxygen?

Bevacizumab


Gonzalez J, et al. Int J Radiat Oncol Biol Phys. 2007;67:323-326.

Radiation Necrosis


Gonzalez J, et al. Int J Radiat Oncol Biol Phys. 2007;67:323-326.


Bevacizumab vs Placebo in Patients With Radiation Necrosis N = 14 patients with radiation necrosis randomized

placebo or bevacizumab (7.5 mg/kg every 3 wks)

Response

– 0/7 placebo

– 7/7 bevacizumab

Levin VA, et al. Int J Radiat Oncol Biol Phys. 2011;79:1487-1495.


Complications of Anti-VEGF Therapies

Hypertension

Fatigue

Proteinuria

Impaired wound healing

Hemorrhage

Cerebral infarction

Venous thromboembolism

Bowel perforation


Hypertension

Treat if SBP > 140/90 mm Hg; treat to goal of < 140/80 mm Hg

Treatment

– First line: ACE inhibitors (eg, lisinopril) or calcium channel blockers (eg, amlodipine)

– Many patients will require 2 agents; some need more

– Titrate dose rapidly; every 3-5 days, not every month, as needed

– Patients should keep home BP log

– Second-line agents include hydrochlorothiazide 25 mg/day

– Beta-blockers seem to be less effective, with the exception of labetalol, which also has alpha-blockade properties

– In some cases, clonidine can be very effective (need to titrate)


Proteinuria

Risks

– Preexisting proteinuric kidney disease, ? DM

Definitions

– Urine protein:creatinine ratio (UPC) > 0.2 mg/dL

Urine protein:creatinine ratio = Protein concentration (mg/dL)(normal: < 0.2 mg/dL) Creatinine concentration (mg/dL)

Detection

– Check UA before starting therapy

– Monitor UA every 2-3 mos on therapy

– If UA shows ≥ 2+ protein on therapy, quantitate with spot urine protein and spot urine creatinine ratio

– 24-hr urine collection to detect proteinuria is NOT REQUIRED (UPC is just as accurate)


Proteinuria: Treatment

If UPC ≥ 0.2

– Start an ACE inhibitor (angiotensin receptor blockers are alternatives) for antiproteinuric effect

– Control BP to < 130/80 mm Hg (HTN and proteinuria synergize)

– Follow UPC every 2-4 wks

If UPC ≥ 3.5, stop therapy

If UPC is stably below 3.5, there are few data on long-term safety

– Monitor closely

– Consider nephrology referral

If Cr rises out of normal range consistently, either stop therapy or further evaluation


Cerebral Ischemia

64-yr-old man with recurrent GBM admitted with increased left-sided weakness


Conclusions

The RANO criteria is an attempt to improve response assessment in high-grade gliomas

It is a work in progress and will eventually require modification

Optimizing supportive care is critical in improving the quality of life of patients with brain tumors

Many of the treatments for patients with brain tumors are associated with complications

It is important to be aware of these and to treat them aggressively

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Patrick Y. Wen, MD Director, Center for Neuro-Oncology Dana-Farber Cancer Institute Director, Division of Neuro-Oncology Brigham and Women’s Hospital Professor