Recurrence Management

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Recurrence Management
Hal Hirte Medical Oncologist Juravinski Cancer
Centre Hamilton, Ontario
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The Boulevard of Broken Dreams
I walk a lonely road The only one that I have
ever known Dont know where it goes But its home
to me and I walk alone I walk this empty
street On the Boulevard of Broken Dreams Where
the city sleeps And Im the only one and I walk
alone My shadows the only one that walks beside
me My shallow hearts the only thing thats
beating Sometimes I wish someone out there will
find me Til then I walk alone
Green Day
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Outline

• Recurrent ovarian cancer
• Survival after treatment
• How is recurrence detected?
• Treatment options
• The role of clinical trials

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Ovarian Cancer Survival After Treatment
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Survival by stage
Ozols RF, et al. Cancer Principles Practice of
Oncology. 6th ed. 20011597-1632.
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Recurrent Ovarian CancerMagnitude of the
Clinical Problem

• Stage I/II
• Essentially all patients will achieve a clinical
  CR after surgery and chemotherapy
• 20 to 25 will relapse
• Optimal stage III
• 90 will achieve a clinical CR
• 75 will recur
• Suboptimal stage III and IV
• 50 will achieve a clinical CR
• 90 will recur

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Recurrent Ovarian Cancer Magnitude of the
Clinical Problem

• Long-term control of disease not achieved in most
  patients
• Overall, 62 of patients will have either
  recurrent or persistent disease
• Candidates for further therapy

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Recurrent Disease

• 95 of recurrences will occur in the first 3
  years after completion of initial therapy
• 99 of recurrences will occur in the first 5
  years

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Survival From Time of Recurrence
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Treatment Group Alive Dead
Total Cisplatin/paclitaxel 85 214 299 Carboplatin
/paclitaxel 87 191 278
80
60
Proportion Surviving ()
40
20
0
24
36
60
0
12
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Months From Progression
Originally published by the American Society of
Clinical Oncology. Ozols RF, et al. J Clin Oncol.
2003213194-3200.
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How is recurrence detected?

• Symptoms
• Abdominal bloating
• Abdominal pain, cramping
• Change in bladder/bowel function
• Signs on examination
• Abdominal/pelvic mass
• Ascites
• Lab Investigations
• Rising CA-125 level
• Imaging

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Management of a Rising CA-125 in a Patient Who Is
Clinically Disease Free

• Rising CA-125 is highly predictive of a clinical
  relapse
• Median time of 4-6 months before symptoms develop
  and/or a clinical recurrence (physical exam or
  imaging studies) is documented1,2
• Patient/physician preference about instituting
  chemotherapy is similar ( 50)
• No evidence that delaying chemotherapy until
  clinical relapse is detrimental
• Randomized trial in progress in Europe

1. Niloff JM, et al. Am J Obstet Gynecol.
198615556-60. 2. Vergote IB, et al. Tumour
Biol. 199213168-174.
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Patterns of Recurrence

• Serologic relapse
• Rising CA-125 only evidence of disease
• Localized recurrence
• Disseminated intraperitoneal disease
• Extraperitoneal metastases
• Recurrences can be symptomatic or asymptomatic

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Treatment of Recurrent Disease
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Treatment of Recurrent Disease

• Palliative in intent
• Must balance benefits in improvements in symptoms
  versus side-effects of treatment

Cancer Care Ontario Practice Guideline Original
September 25, 2001 Update August
2006 http//www.ccopebc.ca/guidelines/gyn/es4_3f.h
tml
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Balance
Side Effects of Treatment
Benefits of Treatment
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Treatment Options in Recurrent Disease

• Surgery
• Radiation
• Systemic Therapy
• Supportive Treatment
• Role of Clinical Trials

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Therapeutic Goals in Recurrent Ovarian Cancer

• Manage symptoms
• Response to treatment
• Delay progression of disease
• Increase survival
• Maintain quality of life

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Considerations After Recurrence/Progression

• Treatment-free interval (TFI)
• Existing residual toxicity from first-line
  therapy
• Performance status
• Volume of disease at time of relapse
• Serologic relapse (CA-125)

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Treatment-Free Interval (TFI)

• Chemosensitive disease
• Response to front-line therapy
• Significant TFI
• Chemoresistant disease
• Progression on front-line therapy
• Best response stable disease
• Short TFI

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Treatment of Recurrent Ovarian Cancer
Platinumsensitive
Platinum refractory/resistant
6 months
Platinum retreatment
Non-platinum treatment
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Chemosensitive Disease TFI
Blackledge G, et al. Br J Cancer.
198959650-653.Thigpen JT, personal
communication.
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How to choose a treatment?

• Efficacy
• Toxicity
• Ease of Adminstration
• Cost

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Chemosensitivity Testing

• Oncotech Extreme Drug Resistance assay
• Requires fresh tumour tissue
• Able to predict which drugs the tumour is
  resistant too, rather than which drugs the tumour
  will be sensitive to
• Remains investigational

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Platinum-Sensitive Recurrence
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Treatment of Platinum-Sensitive Disease

• ICON-4/AGO-OVAR-2.2
• Randomization
• Platinum vs paclitaxel/carboplatin
• AGO, NCIC-EORTC
• Randomization
• Carboplatin vs gemcitabine/carboplatin
• Ongoing trial AGO-OVAR 2.9 (CALYPSO trial)
• Randomization
• Carboplatin PLD vs carboplatin paclitaxel

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Benefit of Platinum-Doublets
Parmar MK, et al. Lancet. 20033612099-2106.Pfis
terer J, et al. J Clin Oncol. 2006244699-4707.
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Toxicity Comparison of Regimens in
Platinum-Sensitive Ovarian Cancer
Complications of increased myelosuppression
manageable.
Parmar MK, et al. Lancet. 20033612099-2106.Pfis
terer J, et al. J Clin Oncol. 2006244699-4707.
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Chemosensitive Disease Conclusions

• Platinum regimens superior to nonplatinum
  regimens tested to date
• Paclitaxel/carboplatin yields superior PFS and OS
  compared with carboplatin
• Gemcitabine/carboplatin produces superior
  response and PFS compared with carboplatin
• PLD/carboplatin produces excellent response, PFS,
  and OS

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Chemosensitive Disease Principles

• Retreat with same or similar regimen
• Carboplatin doublet regimen of choice
• Treatment to progression, unacceptable toxicity,
  clinical complete remission (vs defined treatment
  duration)
• Repeat platinum doublet on further relapse for
  patients with clinical CR and TFI 6 mos

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Treatment of Platinum-resistant Disease
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Chemotherapeutic Agents for Relapsed
Platinum-Resistant Disease

• oral etoposide
• pegylated liposomal doxorubicin
• topotecan
• paclitaxel, docetaxel
• melphelan
• gemcitabine

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How to choose a treatment?

• Efficacy
• Toxicity
• Ease of Adminstration
• Cost

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Trial Results in Platinum-Resistant Disease

• PLD vs topotecan1
• RCT, which included patients with
  platinum-sensitive and platinum-resistant
  disease, showed improved OS with PLD
• Subset analysis showed no difference in OS for
  platinum-resistant disease
• PLD vs gemcitabine2
• No difference in PFS or OS in 2 RCTs (improved
  QoL with PLD in one trial)

1. Gordon AN, et al. Gynecol Oncol. 2004951-8.
2. Ferrandina G, et al. J Clin Oncol.
200826890896.
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Strategies to Improve Outcomes in
Platinum-Resistant Disease

• No evidence that combinations of cytotoxic agents
  superior to single agents
• No randomized studies of in vitro
  sensitivity/resistance assays have shown
  improvement over empirical therapy
• Targeted agents
• Anti-angiogenic agents
• ? single agent or in combination with chemotherapy

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How Long to Treat Patients With Recurrent Disease?

• Only a minority of patients will achieve a
  clinical CR with chemotherapy
• In platinum-sensitive disease 6 to 15
• In platinum-resistant disease 2 to 3
• The majority of patients will have residual
  disease after 6 cycles of chemotherapy
• What to do?
• Continue with same chemotherapy if patient is
  asymptomatic?
• Stop after 6 cycles (drug holiday) if patient
  is asymptomatic?
• Switch to another chemotherapy?

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Answers?

• No RCTs in recurrent disease directly address
  this issue
• In previously untreated patients, RCTs have
  failed to show any benefit for either continuing
  with the same chemotherapy or switching to a
  noncross-resistant regimen
• In recurrent disease, the same could be expected
• Currently, this is a personal choice issue with
  patient/physician
• Toxicity is key
• Some patients will choose more therapy as long as
  there is evidence they are not in a
  remissionpsychochemotherapy
• Benefit of drug holidays

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Role of Clinical Trials
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What Proportion of Cancer Patients in North
America Enter a Clinical Trial?

• 1
• 3
• 10
• 25
• 50

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What Proportion of Cancer Patients in North
America Enter a Clinical Trial?

• 3!

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Clinical Trials as a Beacon
Give me your tired, your poor, Your huddled
masses yearning to breathe free, The wretched
refuse of your teeming shore, Send these, the
homeless, tempest-tost to me I lift my lamp
beside the golden door.
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Hope
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Studies for Recurrent Ovarian Cancer
Juravinski Cancer Centre (August 2008)
no
yes

• Eligible for EPO-906?
• (epothilone B)
• Consider after 2nd or 3rd line platinum-based
  chemo
• if recurrence less than 6 months from prior
  therapy

EPO-906 (patupilone vs caelyx) Reid
First Recurrence?
yes
no
NCIC OV.18 (taxol/carbo /- AZD2171) Harris
yes

Platinum-sensitive disease? - May have had 1
prior chemo
yes
Sunesis (SNS-595) Anderson

• Eligible for Sunesis?
• Platinum-resistant disease
• No more than 1 platinum-based and 1
• non-platinum-based chemo given for recurrence

no
no
Eligible for EPO-906? (epothilone B)
EPO-906 (patupilone vs caelyx) Reid
yes
yes
Does patient have ascites?
VEGF-Trap Anderson
no
no
yes
yes

• Eligible for Sunesis?
• Platinum-resistant disease
• No more than 1 platinum-based and 1
• non-platinum-based chemo given for recurrence

Sunesis (SNS-595) Anderson
Phase I List Iacobucci/Turner
Candidate for Phase I Study?
no
Best standard care
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Role of Supportive Therapy
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The Fork in the Road
Active Therapy
Symptom Control
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Conclusions

• Recurrent ovarian cancer remains a major clinical
  challenge
• Most controversies have not been addressed in
  RCTs
• Clinical trials with novel approaches, including
  biologic agents, are needed

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Hope
"Dreams are made if people only try.I believe in
miracles.I have to...Because somewhere the
hurting must stop.I just wish people would
realize that anythings possible if you
try. Terry Fox July 28, 1952 - June 28, 1981
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Thanks for Your Attention