When Cancer Comes Back, Sarah Adams, MD

Recurrent Ovarian Cancer
Ovarian Cancer Research Fund Alliance
2016 Conference
Sarah Adams, MD

Disclosures
• Clinical trial support from Astra Zeneca
• Research support
Ovarian Cancer Research Fund
American Cancer Society
American Society of Clinical Oncology
Oxnard Foundation
Phi Beta Psi Foundation
Ovarian Cancer SPORE
University of Pennsylvania Research Foundation
National Institutes of Health
Sandy Rollman Foundation
Kaleidoscope of Hope Foundation
Gynecologic Cancer Foundation

Outline
1. What are the chances that ovarian cancer will
return after initial treatment?
2. What symptoms might suggest recurrent
disease?
3. How is a recurrence diagnosed or confirmed?
4. What treatment options are available and what
factors affect decisions about which to choose?
5. Are there benefits to enrolling in a clinical trial?

Ovarian cancer subtypes
• Most ovarian cancers arise from
the lining of the ovary –the
epithelial layer
• Cancers arising from germ cells
(eggs) or stromal cells are less
common
• In this presentation, I will focus on
epithelial cancers (ovarian, tubal,
peritoneal)

Ovarian cancer subtypes
• Accumulating data indicates
that serous ovarian cancers
may actually develop in the
fallopian tubes and then
spread to the ovary.

Initial treatment: curative intent
Primary treatment:
– Debulking or cytoreductive surgery
– Chemotherapy
• Neo-adjuvant chemotherapy (chemotherapy before surgery)
• Primary adjuvant chemotherapy (chemotherapy after surgery)

Primary treatment:
– Chemotherapy
[Maintenance therapy: ongoing chemotherapy to reduce the risk
of recurrence]

Primary treatment:
– Chemotherapy
[Maintenance therapy: ongoing chemotherapy to reduce the risk
of recurrence]
Cancer surveillance:
• 3-month intervals for two years
• 4-month intervals for the third year
• 6-month intervals for up to 10 years

What are the chances that ovarian cancer will return
after initial treatment?

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
Approximate Percentage of Recurrence
Stage I
Stage II
Stage III
(optimal)
Stage III
(suboptimal)
Stage IV
Ovarian cancer recurrence

What symptoms might suggest recurrent disease?

Symptoms associated with ovarian cancer
recurrence
• Bloating, abdominal fullness, increased girth, indigestion
• Pelvic pain
• Change in bowel or bladder habits
• Early satiety
• Vaginal discharge or bleeding
• Pain with intercourse
• Lymphedema / leg swelling
• Shortness of breath
• Nausea, vomiting
*Any new or persistent symptoms should be reported to your
oncologist

How is a recurrence diagnosed or confirmed?

Physical exam
• Physical exam
– Evaluation of lymph nodes
– Chest exam for pleural fluid
– Abdominal exam for masses, fullness, fluid accumulation, pain
– Pelvic exam for masses or nodularity
– Extremities for swelling, tenderness, range of motion
• 35% who presented with symptoms had a normal physical
exam

CA125
• 61% of women are diagnosed with recurrence based on
an elevated CA125 level
– Rises in CA125 may precede symptomatic relapse by a median of 4.5
months (range 0.5-29.5 months)
– Doubling of CA125 has a sensitivity of 86% and a specificity of 91% for
detecting progression.
– A second confirmatory value reduces the false-negative rate to <2%.
– Even a rise within the normal range is associated with a high risk of
relapse.

Imaging
• CT or MRI scan can be used to evaluate for recurrence
– Imaging is indicated in response to new symptoms or a rise in CA125
– Sensitivity ranges from 40-93%
– It may be difficult to detect peritoneal or serosal disease
• PET sensitivity of 88-90%
• Directed biopsy may be performed to confirm recurrence

What treatment options are available and what
factors affect decisions about which to choose?

Treatment goals for recurrent disease
• Recurrent ovarian cancer is unlikely to be cured with
currently available chemotherapeutics, radiation or
surgery.
Goal of treatment in the setting of recurrent disease is to
prolong disease-free and overall survival and to palliate
symptoms
• Options include surgery, chemotherapy, targeted
therapeutics, immune therapy, hormones, radiation,
observation

Surgery
• Secondary (or tertiary) debulking surgery
– Rationale is based on benefit seen with primary debulking
– Studies of secondary surgery are limited by patient selection
Generally, surgery is reserved for women with:
• Platinum-sensitive disease
• Limited sites of recurrence
• Long treatment-free intervals (>24 mos)
• Absence of ascites
• Good performance status
• As with primary surgery, the best outcomes are seen in patients
who can be optimally debulked
• Minimally invasive options (robotic or laparoscopic surgery) may
reduce morbidity for eligible women

Chemotherapy
• Most patients respond to second-line chemotherapy
• Response to second-line chemotherapy predicted by:
– Tumor type, size, and number of disease sites
– Duration of response to previous platinum-based regimen,
platinum-free interval and TFI (most important)
• TFI <12 mos: Response Rate 24-35%
• TFI >12 mos: Response Rate 52-62%

Platinum sensitivity
Most women with ovarian cancer receive a platinum drug (carboplatin,
cisplatin, oxaloplatin) as part of their primary chemotherapy regimen.
The time to recurrence after platinum treatment determines “platinum
sensitivity”
Response to
platinum
Likely secondary
treatment
Examples
Platinum sensitive >6 months without
recurrence
Another platinum-
based regimen
Carboplatin alone
or in combination
with another drug
Platinum resistant < 6 months until
recurrence
A non-platinum
drug
Doxil, Taxol,
Gemzar, Topotecan
Platinum refractory Failure to achieve
remission
A non-platinum
drug
Doxil, Taxol,
Gemzar, Topotecan

Platinum sensitivity
Most women with ovarian cancer receive a platinum drug (carboplatin,
cisplatin, oxaloplatin) as part of their primary chemotherapy regimen.
The time to recurrence after platinum treatment determines “platinum
sensitivity”
Response to
platinum
Likely secondary
treatment
Examples
Platinum sensitive >6 months without
recurrence
Another platinum-
based regimen
Carboplatin, often
in combination with
another drug
Platinum resistant < 6 months until
recurrence
A non-platinum
drug
Doxil, Taxol,
Gemzar, Topotecan
Platinum refractory Failure to achieve
remission
A non-platinum
drug
Doxil, Taxol,
Gemzar, Topotecan

Study
(number of
patients)
Agents Response
Rate (%)
Median progression
free survival
(months)
Median overall
survival (months)
ICON 4 (802) Carboplatin
Carboplatin + Taxol
54%
66%
9
12*
24
29*
AGO (366) Carboplatin
Carboplatin + Gemcitabine
31%
47%
5.8
8.6*
17.3
18
CALYPSO (976) Carboplatin + Taxol
Carboplatin + Doxil
9.4
11.3*
31.5
OCEANS (484) Carboplatin + Gemcitabine
Carbo+Gem+Avastin
57%
79%
8.4
12.4*
35.2
33.3
Clinical trials in platinum-sensitive patients with recurrent
ovarian cancer
Coleman R, et al. Nat Rev Clin Oncol 5 Feb 2013
Response rates to second-line treatment are high among women with platinum –
sensitive disease.

Study
(number of
patients)
Agents Response
Rate (%)
Median progression
free survival
(months)
Median overall
survival (months)
ICON 4 (802) Carboplatin
Carboplatin + Taxol
54%
66%
9
12*
24
29*
AGO (366) Carboplatin
Carboplatin + Gemcitabine
31%
47%
5.8
8.6*
17.3
18
CALYPSO (976) Carboplatin + Taxol
Carboplatin + Doxil
9.4
11.3*
31.5
OCEANS (484) Carboplatin + Gemcitabine
Carbo+Gem+Avastin
57%
79%
8.4
12.4*
35.2
33.3
Clinical trials in platinum-sensitive patients with recurrent ovarian cancer
Platinum-sensitive patients are usually treated with another platinum-containing
regimen – often carboplatin in combination with a second drug.

Agent Response
Rate (%)
Median
progression
free survival
(months)
Median overall
survival
(months)
Side effects
Doxil 10-20% 3-4 10-12 Hand-foot syndrome, mucositis
Topotecan 12-18% 3-4 10-12 Myelosuppression
Taxotere 22% 3.5 12.7 Myelosuppression
Gemzar 15% 4-5 11.8-12.7 Myelosuppression
Etoposide 6-27% 4-5 10-11 Myelosuppression
Taxol 10-30% 4-6 13 Myelosuppression, neuropthy
Avastin 21% 4.7 17 Hypertension, blood clots
Most-frequently used agents in platinum-resistant disease
Because of the more limited prognosis associated with platinum-resistant disease,
reducing toxicity becomes a primary goal, and typically single agent protocols are used.

Targeted agents
• Advantages:
– Different (often more limited) toxicity profile
– May be active in chemotherapy resistant disease
– Better understood mechanism of action
• Bevacizumab (Avastin):
– blocks blood vessel formation in tumors
– Also has immune modulatory effects
– response rate greater than 20% (6 mo PFS 28-40%)
• PARP-inhibitors:
– block single-stranded DNA repair
– best response is among women with BRCA gene mutations
– response rates as high as 33% in recurrent EOC

Hormone therapy
• Advantages:
– Lower toxicity
– Oral administration
• Tamoxifen:
– Response rate of 17-20% among women with recurrent ovarian cancer
• Fulvestrant (selective estrogen receptor modulator)
– Maintained disease stability in 50-64% of patients, 30% at 90 days
• Aromatase Inhibitors
– Modest objective RR of 8-15%, stability in 19-24%
– Evidence for efficacy in low grade serous cancers

Radiotherapy
• Whole abdominal radiation therapy is associated with
significant toxicity and has limited efficacy in the treatment of
recurrent disease
• Localized radiation may be effective
– Good for symptom control
– Best for deposits in the pelvis, at the vaginal vault, on the abdominal
wall.
– Median remission of 4.8 months.

Immune therapy
• Advantages:
– Toxicity profile is different than cytotoxic chemotherapy
– Adaptive effects and potential for long-term benefit
• Currently available primarily through clinical trials
• Examples:
– Cancer vaccines
– T cell therapy
– Immune checkpoint blockade antibodies

A model for the induction of an anti-tumor T cell
response

response
APC
T cell

response
APC
T cell
T cell

The goal of immune therapy is to amplify the
anti-tumor T cell response
APC T cell APC

T cellAPC T cell
The goal of immune therapy is to amplify the
anti-tumor T cell response

Types of immune therapy
• Tumor vaccines
• T cell therapy
• Cytokines
• Immune checkpoint blockade
• (Chemotherapy)

Goals of immune therapy
• Elicit or boost an adaptive anti-tumor immune
response
• Induce immune memory for protection
against cancer recurrence

Observation -
When should treatment be initiated?
• Many oncologists believe that early diagnosis and treatment of
recurrent disease improves outcomes for women with ovarian
cancer
– Better surgical outcomes
– Smaller tumors are more susceptible to chemotherapeutics
– Better symptom control

Observation -
• Many oncologists believe that early diagnosis and treatment of
recurrent disease improves outcomes for women with ovarian
cancer
– Better surgical outcomes
– Smaller tumors are more susceptible to chemotherapeutics
– Better symptom control
Rustin GJ,et al, Lancet 2010
• 2010 European study: Does earlier treatment improve survival?

1442 women with ovarian cancer
• complete remission
• normal CA125 levels
• platinum-based primary chemotherapy.
Underwent CA125 testing every 3 months
529 experienced a doubling in CA125 and were randomized
265 assigned to the “early treatment” group
• Clinicians and patients notified of the rise in
CA125
• Treatment initiated
264 assigned to “delayed treatment” group
• Clinicians and patients blinded to CA125 levels
• Treatment initiated when symptoms or clinical
findings suggested recurrence
Evaluated for the length of treatment-free intervals, overall survival, and quality of life
2010 European study: Does earlier treatment improve survival?

• No difference in overall survival
• Women in the early treatment group underwent more courses of chemotherapy
• Delayed treatment was associated with better quality of life scores.
Results:

Are there benefits to enrolling in a clinical trial?

Standard health care vs. clinical trials
• Standard health care: interventions designed solely to
enhance the well-being of the patient that have a
reasonable expectation of success
• Research (Clinical trial): an activity designed to test a
hypothesis, permit conclusions to be drawn, develop
or contribute to generalizable knowledge

Clinical Trials
• Oversight and protection of subjects
– Institutional Review Boards (IRB)
• Protect the rights and welfare of research subjects
• Include members of the community
– Informed consent
• Benefits, risks and discomforts
• Alternatives to participation
• Must be voluntary and un-coerced
• Strategies to optimize results
– Randomization
• Process by which participants are assigned to treatment groups
• Placebo control is optimal to evaluate new treatments
– Blinding
• Single-blind: treating physician knows but patient doesn’t
• Double-blind: neither the treating physician nor the patient knows

Goals of clinical trials
Phase I Trials:
– Safety and tolerability
– Uncontrolled, unblinded
– Not randomized

Phase I Trials:
– Not randomized
Phase II Trials:
– Dose finding; dose-dependent efficacy
– Controlled or uncontrolled; may be blinded or unblinded
– Randomized or not randomized

Phase I Trials:
– Not randomized
Phase II Trials:
– Dose-finding; dose-dependent efficacy
Phase III Trials:
– Therapeutic ratio (and continued safety) (Drug x compared to drug y)
– Control is placebo or standard of care.
– Blinded
– Randomized

Phase I Trials:
– Not randomized
Phase II Trials:
– Dose-finding; dose-dependent efficacy
Phase III Trials:
– Therapeutic ratio (and continued safety) (Drug x compared to drug y)
– Control is placebo or standard of care.
– Blinded
– Randomized
Phase IV Trials: post-marketing surveillance (safety)

Benefits of clinical trials
• Additional benefits:
– Oversight by a team of physicians, nurses, study personnel – both
locally and often at a national level
– Expanded options for treatment
– Benefit to other women with ovarian cancer by advancing our
understanding of treatment options and cancer biology
Advantages Disadvantages
Phase I
trials
Access to newest therapeutic agents Dose escalation may mean that a lower
dose is given to early participants
Usually not randomized or blinded Primary outcome is safety and
tolerability
Smaller studies, results may be
available sooner
May or may not be given with known
active agents
Phase III
trials
Protocol already tested in prior phase
I/II with evidence of efficacy
Often randomized
Often blinded
Often given with active agents; control
arm is usually standard treatment
Large scale studies – may take years to
learn results

Questions to ask if you are considering
enrolling in a clinical trial:
• What is the scientific rationale for conducting the trial?
• What are the objectives of the trial?
• In what phase is the trial? How many participants will there be?
• What are the eligibility requirements?
• What is the intervention, and what is its duration and schedule?
• What are the possible risks, side effects and benefits?
• What medical tests and follow-up tests will participants undergo?
How often?
• What are the endpoints (measurable outcomes that indicate an
intervention’s effectiveness)?
• Who is sponsoring the trial?
• What is the contact information to inquire about the trial?

There are many options available to
manage ovarian cancer recurrence
• Several factors affect choice of treatment including
the presence of symptoms, response to prior
treatment, availability of a clinical trial, patient
preference
• Goal of treatment is to optimize quality of life and to
prolong remission
• For more information about available clinical trials:
www.ocrf.org/clinicaltrials

When Cancer Comes Back, Sarah Adams, MD

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