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Challenging Cases in
Select Gastrointestinal Cancers
Oncologist and Nurse Investigators
Consult on Actual Patients from the
Practices of the Invited Faculty
Saturday, May 3, 2014
12:00 PM – 1:30 PM
Faculty
Tanios Bekaii-Saab, MD
Charles S Fuchs, MD, MPH
Jessica Mitchell, RN, CNP, MPH
Yahna T Smith, MSN, CNP
Moderator
Neil Love, MD
Oncology 6-Part Case Series: Key Themes
• Mechanisms of action of novel agents and tissue
assays to predict response
• Side effects and toxicities of novel agents; dose
adjustments
• Assessment and management of adherence
• Specific goals of therapy and likely outcomes;
sequencing of agents in advanced disease
• Local and systemic complications of cancer: Fatigue,
pain, CNS involvement
• Care of older, frail patients and those with comorbidities
Oncology 6-Part Case Series: Key Themes
• Clinical trials as a means to access new treatments earlier
• Management of anxiety and depression
• Key determinants of patient satisfaction: What do people
with cancer want and need?
• Quality, value and cost: Investing resources optimally
• End-of-life care and planning
• Impact of the cancer experience on family and loved
ones, including minor children
• Impact of the oncology experience on oncology health
professionals
Agenda
A Patient with Chronic Alcoholism and Metastatic
Hepatocellular Carcinoma (HCC)
• 48 yo man with stable disease on sorafenib whose
adherence to treatments is challenged by his alcoholism
(Ms Mitchell)
Two Patients with Metastatic Gastroesophageal (GE)
Cancer
• 68 yo man with HER2-positive, metastatic gastric cancer
(Ms Smith)
• 38 yo mother of 3 young children diagnosed with recurrent
metastatic disease 9 months after gastrectomy
(Ms Mitchell)
Agenda
A Patient with Rectal Cancer and Metastases Confined
to the Liver
• A 55-year-old man diagnosed with Stage III
adenocarcinoma of the rectum (Ms Smith)
A Patient with Disease Progression on Multiple Lines of
Therapy; A Patient Rendered Disease Free with
Stereotactic Body Radiation Therapy
• A 56-year-old woman with BRAF-mutant colon cancer
metastatic to the liver (Ms Mitchell)
• An 82-year-old woman with a history of congestive heart
failure who presented with colon cancer that was
surgically resected (Ms Smith)
Case 1 (from the practice of Ms Mitchell)
• A 48-year-old man with a history of alcohol-related
cirrhosis (Child-Pugh A) was diagnosed in 2012 with
extensive intrahepatic HCC and small metastases to the
skin of the abdominal wall that were biopsy proven
• The patient has received sorafenib intermittently
– When a full dose was administered, he developed
moderate hand-foot syndrome, anorexia and
mucositis
– With dose reduction the patient was better able to
tolerate the drug and has experienced stable
disease to date
• The patient has been in and out of alcohol rehabilitation
and continues to binge drink
• Adherence to his oncologic medications has been
problematic
Pre-sorafenib
Post-sorafenib
Stable disease
Discussion Point
Clinical manifestations of HCC:
Sites of metastases and biologic
characteristics
HCC-Related Symptoms
• Pain
• Fatigue
• Weight loss
• Ascites
• Jaundice
Discussion Point
Diagnosis and interdisciplinary care of
HCC; the challenge of coexisting liver
disease
Risk Factors for HCC
A study of SEER-Medicare, 1994-2010 (≥68 years old)
Risk factors
HCC cases
(N = 6,991)
HCV
22.9%
HBV
6.9%
Alcohol-related disease
31.2%
Rare metabolic disorder
4.5%
Diabetes
59.6%
Obesity
8.8%
Diabetes and/or obesity
61.5%
Welzel TM et al. Am J Gastroenterol 2013;108:1314-21.
Discussion Point
Local treatment of HCC for palliation
and cure (organ transplant, TACE,
radiofrequency ablation)
Discussion Point
Risks, benefits and approach to dosing
of sorafenib
N Engl J Med 2008;359:378-90.
SHARP: Sorafenib in Advanced HCC
(Child-Pugh A)
Sorafenib
(n = 299)
Placebo
(n = 303)
p-value
Median overall survival
10.7 mo
7.9 mo
<0.001
One-year survival rate
44%
33%
0.009
Time to symptomatic progression
4.1 mo
4.9 mo
0.77
Time to radiologic progression
5.5 mo
2.8 mo
<0.001
43%
32%
0.002
Outcome
Disease control rate
Grade ≥3 Adverse Events
Hand-foot syndrome
Diarrhea
Llovet JM et al. N Engl J Med 2008;359(4):378-90.
Sorafenib
8%
8%
Placebo
<1%
2%
Discussion Point
Prevention and management of
hand-foot syndrome
Getting a Handle on Hand-Foot Syndrome
Topicals
Inflammation
(Tenderness, edema,
erythema)
Hyperkeratosis
(Thickening, peeling,
cracking)
Courtesy of M Lacouture.
Urea/Lactic acid
Orals
Pyridoxine
Celecoxib
Topicals
Urea 40% cream
Salicylic acid cream
Clobetasol 0.05% cream
Discussion Point
Ongoing Phase III trials in HCC
Investigational Agents for HCC
• Brivanib
• Tivantinib (ARQ 197)
• Lenvatinib (E7080)
• Cabozantinib
• Ramucirumab
• Regorafenib
REACH Phase III Study Design
Eligibility
• Advanced HCC
• Child-Pugh A cirrhosis
• Progression or
intolerance to 1st-line
sorafenib
Ramucirumab +
best supportive care (BSC)
R
(N = 565)
Primary endpoint: Overall survival
Estimated primary completion: March 2014
www.clinicaltrials.gov, Accessed March 12, 2014 (NCT01140347)
Placebo + BSC
RESORCE Phase III Study Design
The study is ongoing and currently recruiting participants.
Eligibility
• Advanced HCC
• Child-Pugh A cirrhosis
• Progression or
intolerance to 1st-line
sorafenib
Regorafenib +
best supportive care (BSC)
R
2:1 (N = 530)
Placebo + BSC
Primary endpoint: Overall survival
Estimated primary completion: October 2015
www.clinicaltrials.gov, Accessed March 12, 2014 (NCT01774344)
Two Patients with Metastatic Gastroesophageal
(GE) Cancer
• 68 yo man with HER2-positive, metastatic gastric
cancer (Ms Smith)
• 38 yo mother of 3 young children diagnosed with
recurrent metastatic disease 9 months after
gastrectomy (Ms Mitchell)
Case 2 (from the practice of Ms Smith)
• A 68-year-old man with HER2-positive metastatic
gastric adenocarcinoma received first-line therapy
with FOLFOX and trastuzumab, which resulted in a
complete response
• Treatment was then stopped for 6 months, at which
time disease progression was documented
• The patient was then restarted on treatment
Pretreatment
2 months into treatment
Discussion Point
Comparison of HER2 testing in breast
and gastric/GEJ cancers
Bang YJ et al. Lancet 2010;376(9742):687-97.
ToGA: Median Overall Survival
Median OS
(months)
HR
p-value
Trastuzumab plus
chemotherapy
13.8
0.74
0.0046
Chemotherapy alone
11.1
Bang YJ et al. Lancet 2010;376(9742):687-97.
ToGA: Cardiac Safety of Trastuzumab +
Chemotherapy versus Chemotherapy Alone
FC
FC + T
Cardiac adverse events (AEs)
(All grades)
6%
6%
Cardiac AEs
(Grade 3/4)
3%
1%
Cardiac failure
<1%
<1%
Cardiac dysfunction
(≥10% drop in LVEF to an
absolute value <50%)
1%
5%
Bang YJ et al. Lancet 2010;376(9742):687-97.
Ongoing Phase III Clinical Trials
Primary
Endpoint
Phase Disease Setting
N
Regimen
II/III
Metastatic gastric
and GEJ, 2nd line
412
Arm A: T-DM1 3.6 mg/kg q3wk
Arm B: T-DM1 2.4 mg/kg weekly
Arm C: Standard taxane
OS
III
Metastatic gastric
and GEJ, 1st line
780
Arm A: Pertuz + T/Cis/FP
Arm B: Placebo + T/Cis/FP
OS
III
Metastatic gastric
and GEJ, 1st line
400
Arm A: T 6 mg q3wk + Cape/Cis
Arm B: T 10 mg q3wk +
Cape/Cis
OS
III
Esophagus and
GEJ, Neoadjuvant
480
Arm A: RT with Carbo/Pac/T
Arm B: RT with Carbo/Pac
DFS
III
Previously untreated
resectable
Esophagogastric
1,140
Arm A: Lapatinib + chemo
Arm B: Bevacizumab + chemo
Arm C: Chemo
Safety,
OS
T = Trastuzumab
www.clinicaltrials.gov, May 2014
Case 3 (from the practice of Ms Mitchell)
• A 38-year-old married woman and mother of 3 young children
presented with metastatic gastric cancer in 2010 and received
DCF followed by resection:
– She developed significant mucositis in response to DCF
and experienced a difficult postoperative course, including
bacteremia and severe depression.
• Nine months later she complained of persistent abdominal
pain and was placed on FOLFOX, which she tolerated poorly.
• Her pain, now diffuse, worsened and her disease ultimately
progressed in the peritoneum and bone.
• The patient worked as an ultrasound technician in the
oncology clinic along with her husband who is an IT
professional there.
• They both struggled with her diagnosis and how to discuss
her disease and the possibility of her death with their young
children.
2010: Thickened GEJ and gastric wall at diagnosis
Preferred Regimens for Metastatic or Locally
Advanced Gastric Cancer
Two-drug regimens preferred due to lower toxicity
Three-drug regimens should be reserved for medically fit patients with good PS
and access to frequent toxicity evaluation
•
Docetaxel, cisplatin, fluorouracil (DCF)
•
DCF modifications
– Docetaxel, oxaliplatin, fluorouracil
– Docetaxel, carboplatin, fluorouracil
•
Epirubicin, cisplatin, fluorouracil (ECF)
•
ECF modifications
– Epirubicin, oxaliplatin, fluorouracil
– Epirubicin, cisplatin, capecitabine
– Epirubicin, oxaliplatin, capecitabine
•
Fluoropyrimidine and cisplatin
•
Fluoropyrimidine and oxaliplatin
•
Fluoropyrimidine and irinotecan
NCCN Guidelines, Gastric Cancer, v2.2013.
Discussion Point
Ramucirumab: Mechanism of action
and available research data as a
single agent or in combination with
chemotherapy
Agents Targeting the VEGF Pathway
Anti-VEGF
antibody
(bevacizumab)
Anti-VEGFR2
antibody
(ramucirumab)
VEGF-A
Soluble VEGF
receptor
(Ziv-aflibercept)
VEGFR-1
P
P
P
P
VEGFR-2
P
P
P
P
VEGFR-3
P
P
P
P
Endothelial cell
Small-molecule inhibitors of VEGFR
(regorafenib, PTK-787, AZD2171, motesanib,
sunitinib, sorafenib, pazopanib, axitinib, etc)
REGARD Phase III Study in Gastric or GEJ
Adenocarcinoma
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
2:1
Ramucirumab 8 mg/kg
q2wk
+
BSC (n = 238)
Placebo q2wk
+
BSC (n = 117)
Treatment
until disease
progression
or
intolerable
toxicity
N = 355
BSC = best supportive care; GEJ = gastroesophageal junction
Overall survival: 5.2 vs 3.8 months
Progression-free survival: 2.1 vs 1.3 months
All grade/Grade ≥3 hypertension: 16%/8% vs 8%/3%
Fuchs CS et al. Lancet 2014;383(9911):31-9.
Tumor
assessment,
survival,
and safety
follow-up
RAINBOW: Phase III Study of Paclitaxel ±
Ramucirumab in Second-Line Gastric Cancer
665 patients after failure of FU or platinum-based therapy
R
A
N
Weekly Paclitaxel +
Ramucirumab
(n = 330)
D
O
M
I
Z
Weekly Paclitaxel +
Placebo
(n = 335)
E
Overall survival: 9.6 vs 7.4 months
Progression-free survival: 4.4 vs 2.9 months
Wilke H et al. Gastrointestinal Cancers Symposium 2014;Abstract LBA7.
RAINBOW: Efficacy Summary
Ramucirumab +
Paclitaxel
Placebo +
Paclitaxel
p-value
Response rate
28%
16%
0.0001
Disease control rate
80%
64%
<0.0001
Median PFS
4.40 mo
2.86 mo
<0.0001
Median OS
9.63 mo
7.36 mo
0.0169
Efficacy Parameter
Wilke H et al. Gastrointestinal Cancers Symposium 2014;Abstract LBA7.
FDA News Release (April 21, 2014)
• The U.S. FDA approved ramucirumab to treat patients
with advanced gastric cancer or gastroesophageal
junction (GEJ) adenocarcinoma.
• Single-agent ramucirumab is FDA approved for
patients with unresectable or metastatic gastric or
GEJ cancer after being treated with a fluoropyrimidineor platinum-containing therapy.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394107.htm
Possible Side Effects Associated with
Ramucirumab
• Hypertension
• Fatigue
• Abdominal pain
• Anemia
• Decreased appetite
• Vomiting
• Bleeding or hemorrhage
• Dysphagia
• Dyspnea
Fuchs CS et al. Lancet 2014;383(9911):31-9.
Case 4 (from the practice of Ms Smith)
• A 55-year-old man was diagnosed with Stage III
adenocarcinoma of the rectum and received
neoadjuvant chemoradiation therapy followed by
surgical resection
• He was noted on restaging images to have liver
metastases
• He received FOLFOX with bevacizumab and went
on to surgical removal of the hepatic metastases
• He is currently without evidence of disease a year
and a half later
March 2012:
Bilobular liver mets
November 2013:
After resection of
liver mets and RFA
Postresection
Post-radiofrequency ablation
Discussion Point
Clinical approach to patients with liveronly metastases; role of neoadjuvant
and adjuvant systemic treatment
Colorectal Liver Metastases
• Hepatic metastases occur in approximately 50% of
CRC patients and account for at least two thirds of
all CRC deaths
• 25% of CRC patients present with hepatic
metastases
• 30% to 60% of patients develop hepatic
metastases
Abdalla et al. Annals of Surgical Oncology 2006;13(10):1271-80;
Donadon et al. Gastrointest Cancer Res 2007;1:20-7.
Contraindications to Resection
Relative
Absolute
Extrahepatic metastases
Peritoneal carcinomatosis
Colonic recurrence
Multiple extrahepatic metastases
Solitary resectable
peritoneal metastasis
Inability to perform hepatic
R0 resection
Hilar lymph node metastases
—
Donadon et al. Gastrointest Cancer Res 2007;1:20-7.
Discussion Point
Role of up-front systemic therapy
for patients presenting with a
primary tumor and simultaneous
metastatic disease
Phase III TRIBE Study Schema
INDUCTION
MAINTENANCE
FOLFIRI +
Bevacizumab
(Up to 12 cycles)
Eligibility
• Untreated metastatic
colorectal cancer
• Unresectable
R
5-FU/LV
+ Bev
(N = 508)
FOLFOXIRI +
Bevacizumab
(Up to 12 cycles)
5-FU/LV
+ Bev
Maintenance until disease progression
PFS:
OS:
Response rate:
R0 resection rate:
9.7 vs 12.1 mo
25.8 vs 31.0 mo
53% vs 65%
12% vs 15%
Falcone A et al. Proc ASCO 2013;Abstract 3505.
Possible Side Effects Associated with
Bevacizumab
Common Side Effects
• Nosebleeds
• Rhinitis
• Headache
• Hypertension
• Proteinuria
• Lacrimation disorder
Serious Side Effects
• Hemorrhage
• Thromboembolism
• GI perforation
• Wound-healing
complications
• Reversible posterior
leukoencephalopathy
syndrome (RPLS)
Phase III randomized, placebo (PL)-controlled,
double-blind study of intravenous
calcium/magnesium (CaMg) to prevent
oxaliplatin-induced sensory neurotoxicity
(sNT), N08CB: An alliance for clinical trials in
oncology study
Loprinzi CL et al. Proc ASCO 2013;Abstract 3501.
Discussion Point
Second-line treatment for patients
with disease progression on first-line
therapy with bevacizumab/chemotherapy
TML (ML18147): Phase III Study of Bevacizumab
Beyond First Disease Progression
Progression on
bevacizumab +
standard first-line CT
(either oxaliplatin or
irinotecan-based)
(n = 820)
Standard
second-line CT
(n = 411)
R
CT switch:
Oxaliplatin  Irinotecan
Irinotecan  Oxaliplatin
Bevacizumab +
standard
second-line CT
(n = 409)
Median survival: 9.8 vs 11.2 months
Bennouna J et al. Lancet Oncol 2013;14(1):29-37.
VELOUR: A Phase III Randomized Study with
Ziv-Aflibercept versus Placebo in Combination
with FOLFIRI in Second-Line mCRC
Patients with mCRC
after failure of an
oxaliplatin-based
regimen in first line
(n = 1,226)
Placebo +
FOLFIRI
(n = 614)
R
Ziv-Aflibercept +
FOLFIRI (n = 612)
Median survival: 12.1 vs 13.5 months
Van Cutsem E et al. J Clin Oncol 2012;30(28):3499-506.
Case 5 (from the practice of Ms Mitchell)
• A 56-year-old woman with Gilbert syndrome presented
with KRAS wild-type, BRAF-mutant colon cancer
metastatic to the liver
• The patient initially received FOLFOX/bevacizumab
followed by FOLFIRI/bevacizumab and is currently
receiving regorafenib
– Aside from an ongoing problem with hand-foot skin
reaction, the patient is otherwise tolerating the drug
now in the third cycle
• She is married and the mother of 3 children
• She has an analytical personality and has anxiety about
the future
• She and her family are struggling with the acceptance
of her diagnosis
2012: Liver disease at diagnosis
2014: Liver disease at beginning of regorafenib
Grothey A et al. Lancet 2013;381(9863):303-12.
CORRECT: Study Design and Survival Outcome
Patients with refractory
metastatic CRC
(n = 760)
2:1
Regorafenib + BSC
(n = 505)
R
Placebo + BSC
(n = 255)
Median survival: 6.4 vs 5.0 months
Grothey A et al. Lancet 2013;381(9863):303-12.
Discussion Point
Considerations for initial dosing of
regorafenib: Importance of careful
follow-up in the first month of
treatment
Possible Side Effects Associated with
Regorafenib
•
•
•
•
•
Hand-foot skin reaction
Fatigue
Diarrhea
Hypertension
Rash or desquamation
Grothey A et al. Lancet 2013;381(9863):303-12.
Hand-Foot Syndrome
• “Palmoplantar erythrodysesthesia”
• Most clinically significant dermatologic adverse event
associated with multikinase inhibitors, with all-grade
incidences of:
– Sorafenib = 60%
– Sunitinib = 30%
– Regorafenib = 46%
• May affect palms, soles and other areas exposed to
friction or trauma
• Reaction usually appears within first 6 weeks of therapy
Lacouture M. ASCO Post 2012;3(18). www.ascopost.com.
Possible Side Effects Associated with
Regorafenib — Hepatotoxicity
“Severe and sometimes fatal hepatotoxicity has
been observed in clinical trials. Monitor hepatic
function prior to and during treatment. Interrupt
and then reduce or discontinue regorafenib for
hepatotoxicity as manifested by elevated liver
function tests or hepatocellular necrosis,
depending upon severity and persistence.”
Regorafenib Full Prescribing Information, Issued 9/2012