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Very Rare Tumors: How Should They Be Studied?
David Gershenson Nicoletta Colombo
Gabriele Elser Mark Brady
Very Rare Tumors
• No universal definition of “rare,” much less “very rare”
• Examples of very rare gynecologic cancers: – Poorly differentiated Sertoli Leydig Cell Tumors – Ovarian ependymoma – Transitional cell carcinoma of the ovary – Squamous cell carcinoma of the endometrium – Adenoid basal carcinoma of the cervix – Small cell carcinoma of the ovary
Very Rare Tumors: Mechanisms for Study
• Case Reports and Small Series • Survey • Registry/Registry Trial
– Retrospective – Prospective – Concomitant
• Phase II Trial • Randomized Phase II Trial • Randomized Phase III Trial
Survey Study
Goals
• Establish registry to study rare tumors – Collect clinical information to assess feasibility
and direction of future studies – Include quality control
• Collect tissue for molecular studies • Correlate clinical and molecular data • Develop clinical trials • Improve cure rate through therapeutic
advances
Mechanism
• Consensus: Registry Study – Retrospective (particularly for genomics, etc.) – Prospective
• Patient-driven and/or Provider-driven • GCIG will need to select specific database • Requires multidisciplinary approach
– Scientists working in the area – Pathologists – Pediatric oncologists
Rare Cancer Registries
REDCap
REDCap
Database Elements
• Clinical information – Focused – Iterative
• ? Limit to small cell carcinoma of ovary or broader categorization
• Central pathology review by country via international coordinating group
• Digital imaging
Database Elements • Tissue collection: Fresh frozen, FFPE, blood (plasma,
buffy coat, serum), normal tissue, urine – Genomics – Proteomics – Metabolomics – Return of information to provider – SOPs – Opportunities for serial samples
• Governance (Steering Committee) • Consumers/Advocates involvement • Outcomes
Focused Questions
• Prognostic markers • Defining standard therapy (personalized
therapy) – Current – Future
• Response to therapy • Identification of actionable mutations,
outcomes of targeted therapies • Comparison with other neuroendocrine tumors • Identification of hereditary syndromes
Barriers and Challenges • Confidentiality/Privacy: Informed Consent • Biostatistical support • Transfer of tissue between countries • Governance • Ethics • Geography • Funding • Incentives • Maintaining awareness/motivation • Continuous follow-up
Funding Priorities
• Establish database • Identification of past cases • Identification of archival tissue • Identification of high-quality cell lines • Bioinformatics support • Translational research
Summary
• Establish standard database for rare gynecologic malignancies
• Early focus on small cell carcinoma of ovary • Convene steering committee (ruthless) • Develop database elements • Survey existing tumor repositories • Generate proof of principle genomics (e.g., 2-3
cases) • Address barriers • Secure grant funding
Very Rare Tumors
• Chair: David Gershenson
• Co-Chair: Nicoletta Colombo
• Stats Representative: Mark Brady
• Ops Representative: Gabriele Elser
Rare Cancer Registries
Rare Cancer Registries
Rare Cancer Registries
Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
Randomized Registry Trial
Very Rare Tumors: Clinical Trials?
• Type of Trials – Phase II – Randomized Phase II – Randomized Phase III
• Challenges – Rarity of cancer leading to slow accrual – Adequate funding
Prospective Multicenter Observational Cohort Study
Recommendations for Study of Small Cell Carcinoma of Ovary
• Survey has already been conducted • Consider concomitant retrospective and
prospective registry study • REDCap or similar database/registry could be
utilized – Secure web application – Allows users to build online surveys and
databases – Translated into multiple languages
© Colombo IEO 2013
Small cell Carcinoma of the ovary
Nicoletta Colombo University Milan Bicocca
European Institute of Oncology Milan, Italy
© Colombo IEO 2013
Small cell Carcinoma of the ovary
To identify specific objectives to be addressed by cooperative trials
© Colombo IEO 2013
Small cell carcinoma of pulmonary type
(SCCOPT)
Small cell carcinoma of the ovary of
hypercalcemic type (SCCOHT)
Non-small cell, a neuroendocrine carcinoma
(large cell variant)
Carcinoid tumors primary or metastatic
Small cell carcinoma of the ovary Small cell carcinoma of the ovary
© Colombo IEO 2013
Rare and aggressive , closely resembles SCC of the lung
17 reported cases Mean age 59 years ( older age than SCCOHT) Bilateral in about half of reported cases Stage III more frequent Paraneoplastic syndrome less common than in SCC of
the lung Surgery + chemotherapy , but poor prognosis So rare that no specific treatment recommendations can
be made
Small cell carcinoma of the ovary SCCOPT
© Colombo IEO 2013
Which trial??
Small cell carcinoma of the ovary SCCOPT
© Colombo IEO 2013
Highly aggressive. 2/3 associated with hypercalcemia Most patients die within 2 years of diagnosis Young women , mean age 24 y Unilateral The origin remains unclear 400 cases reported to date Mostly at advanced stage at diagnosis Young’s review of 150 cases (1994) 14/42 stage Ia alive 18/20 stage Ic alive 1/8 stage stage II alive 3/52 stage III alive
Small cell carcinoma of the ovary SCCOHT
© Colombo IEO 2013
Surgery is a critical component of successful management
Maximal debulking if extensive disease 2 possible questions about surgery to be
addressed: 1. Fertility-preserving surgery 2. Role of neoadjuvant chemotherapy
Small cell carcinoma of the ovary SCCOHT : Surgery
© Colombo IEO 2013
Young noted that stage IA patients who underwent bilateral salpingo-oophorectomy fared better in survival than those who underwent unilateral salpingo-oophorectomy ( retrospective finding in 1994)
Rationale for FPS in stage I: Young patients, tumor mostly unilateral, prognosis influenced by extraovarian disease
Few reports on FPS even in stage III Poor survival may justify less aggressive initial
approach 2 successful case reports of FPS followed by
aggressive chemotherapy.
Small cell carcinoma of the ovary SCCOHT : Fertility preserving Surgery
© Colombo IEO 2013
Which study to address the role of fertility preserving surgery ??
Small cell carcinoma of the ovary SCCOHT : Fertility preserving Surgery
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : Adjuvant treatment When ? Which? Chemotherapy Radiotherapy Both?
Chemotherapy: which and for how long? Radiotherapy after chemotherapy? Cranial irradiation to prevent brain mets?
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : Adjuvant treatment
Potential prognostic factors
Stage Age >30 years Normal pre-operative calcium level Tumor size <10 cm Absence of large cells Surgical resection
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : Adjuvant treatment
Challenges for clinical trials
20-25% stage I ( extremely rare) Very young patients treated by
pediatricians ( which are not part of our network) Most ( all) patients treated with adjuvant
chemotherapy, given the highly aggressive behaviour of this tumor
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : adjuvant radiotherapy
Young: 4/5 long term stage IA survivors received radiation
Harrison: 5/6 stage I patients who received radiation were
alive. Radiation was given to pelvis+aortic nodes or to pelvis+abdomen
1/4 not receiving radiation was alive The single surviving advanced stage received
radiation Isolated reports of successfully treated pediatric
patients did not cite the use of radiation.
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : chemotherapy
Platinum-based regimens that include etoposide have been cited in successful cases
Several retrospective reviews, a single prospective study and a relative abundance of isolated case reports seem to support intensive multiagent chemotherapy regimens.
Some reports have included high-dose chemotherapy with stem cell rescue.
Harrison and Distalmaier suggested that carboplatin/paclitaxel is poorly effective
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : chemotherapy
Retrospective reviews and case reports
Platinum/etoposide Platinum/etoposide+ bleomycin Platinum/etoposide+ ifosfamide Carboplatin, etoposide, vincristine, actinomycin,
ifosfamide and doxorubicin +/- HD-SCR Cisplatin, vinblastine, cyclophosphamide,
bleomycin, doxorubicin and etoposide ( VPCBAE) +/- HD-SCR
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : chemotherapy
Prospective multicenter study Cisplatin, adriamycin, etoposide,
cyclophosphamide + GCSF support x 6cycles 27 patients: 18 CR
10/18 treated with HD-SCR: 7CR1 , 1 CR2 8/18 not treated with HD-SCR: 3 CR, 2 CR2 All 5 stage I patients are alive 4 pelvic relapses after CR ( 3 after HD-SCR)
argue in favor of pelvic radiation Pautier et al.,Annals of Oncology, 2007
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : High dose chemotherapy
Pautier and 2 pediatric reports indicate some possible success even in advanced stages, after CR with conventional chemotherapy
The potential toxicity of HD-SCR in heavily
pretreated patients is substantial
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : targeted therapy
Pressey reported on a 6-year-old girl treated with: VPCBAE x 6 Surgeries HD-SCR ( carboplatin, etoposide and
melphalan) Pelvis and abdomen radiotherapy Maintenance bevacizumab x 6 months
Alive at 30 months
© Colombo IEO 2013
Small cell carcinoma of the ovary SCCOHT : biology Biology is poorly understood cKIT demonstrated in a single case leading to the use of
imatinib with success Wide scale genomic and/or expression studies urgently
needed Finding of potential therapeutic targets may lead to
prospective phase II studies Inherited cancer predisposition syndrome may play a
role in the genesis of SCCOHT. Sibling pairs and mother-dauther pair have been reported. Some of the affected families demonstrated an increased frequency of breast cancers. ( BRCA ???)
© Colombo IEO 2013
Fertility preserving surgery Adjuvant treatment in early stages When? Which? Chemo ? RT? For how long: 4 vs 6 cycles Cranial irradiation to prevent brain metastases ?
Type of chemotherapy Cisplatin vs carboplatin + etoposide Intensive multi-agent chemotherapy High dose Targeted agents
Small cell carcinoma of the ovary Area of research
© Colombo IEO 2013
Extremely rare: phase III almost impossible Need carefull pathology review to differentiate from
highly malignant germ cell tumors, granulosa cell tumor, small cell carcinoma of the pulmonary type, neuroendocrine carcinoma, metastases from pulmonary small cell tumor.
Most plausible design: prospective and retrospective registry
Phase II study possible only with strong committment and cooperation
Biology and translational studies higly warranted (SCCOHT tumor bank)
Small cell carcinoma of the ovary Considerations for clinical design
© Colombo IEO 2013
Very Rare Tumors Harmonization issues
Gabriele Elser AGO Study Group
London 16 November 2013
© Colombo IEO 2013
Barriers to overcome Financial issues – very low patient numbers but trial costs high start up efforts, prolonged recruitment time
and long administrative trial maintenance as per site accrual low
Need of continent comprehensive responsibility multinational regulations need to be identified & followed share tasks between groups, share especially knowlegde for trial conduct
© Colombo IEO 2013
Specific barriers
o Confidentiality/Privacy issues
o Indemnification/Insurance issues (eg. Ph II/III trials)
o Biostatistical support
o Data collection systems
o Conduct of central pathology review eg. remote visual vs. one center confirmation vs. expert panel; crossborders or country based; or other options?
o International tissue specimen transport Identify and characterize capabilities of GCIG associated laboratories for future trials
Tumorspecimen banking
© Colombo IEO 2013
List of tasks to work on (taken from the main presentation of Bénédicte)
Share some tasks between groups Adapt the SOPs (use +++ the existing GCIG harmonization documents)
Simplify the protocol and CRF Adapt the monitoring Reduce the administrative tasks Build efficient processes for patient referral
At least, seek collaboration/network also with ENGOT groups who
are not represented in GCIG!
© Colombo IEO 2013
Very Rare Cancers Getting Started
Mark F. Brady RTwg Brainstorming London, UK Nov 15, 2013
© Colombo IEO 2013
Definition of Very Rare Cancer
• Example: Small cell cancer of the ovary. • My working definition:
Very little is know for sure about the disease and feasibility of any research study is questionable.
© Colombo IEO 2013
Primary Objectives of a Registry Study 1. Assess feasibility of conducting future clinically relevant research studies. 2. Characterize the target patient population. 3. Provide a background and rationale for future studies. 4. Survey current treatment patterns.
© Colombo IEO 2013
Prospective vs Retrospective Observations Retrospective • Investigators identify all cases that were seen in
their clinics over a pre-specified time interval (eg past 5 years)
• Advantage: Relatively quick. • Challenge: Observations are “catch-as-catch-can”. Prospective • Provides an opportunity of standardize pre-treatment
clinical workup. • Provides an opportunity to standardize the
longitudinal disease assessments (methods and schedule).
© Colombo IEO 2013
Questions • Is a single patient population definable ?
• Pulmonary vs hypercalcemic types (lumpers vs splitters). • Distinguishable from look-alike malignancies ?
• Granulosa cell tumors , Lymphomas , Neuroectodermal tumors , • What are the standards of care ?
• Similar vs widely varied ? • Can a single standard of care be agreed upon ? • Is treatment randomization possible (fertility preservation)
• What are the important patient/disease factors • For disease outcome ? • For treatment recommendation ?
• Any targets for treatment ? • How may patients are available annually for future studies ?
© Colombo IEO 2013
Challenges for Future Studies in Small Cell Ca. Ov. • Study Objectives:
• Fertility-sparing surgery – Early stage (25%) only? Randomize? Age a risk factor?
• Unilateral vs bilateral salpingo-oopherectomy (noninferiority)
• Neo-adjuvant treatment: • Yes vs no (non-randomized study confounded?). • Variety of platinum regimens (large differences
expected?) • Identify potential mutations for future targeted therapies. • Time-dependent risk of recurrence.
© Colombo IEO 2013
Is there a role for single-arm phase II trials in small cell ovarian cancer?
© Colombo IEO 2013
Proportion of patients with Mucinous adenocarcinoma in GCIG Trials
GCIG Group
Study
Total N of patients
% with Mucinous
AGO OVAR3 705 4.7 AGO/GINECO OVAR5 1136 4.7 AGO/GINECO OVAR7 1170 4.4 GOG/ANZGOG GOG-182 3882 1.5 MRC/Mango/IMN/NSGO ICON3 567 5.6 MRC/IMN ICON5 363 3.0 SGCTG SCOTROC-1 881 2.8
Total Number 8704 3.0
© Colombo IEO 2013
OS Hazard Ratios by GCIG Study Mucinous vs Serous adenocarcinoma of Ovary
Estimated relative hazard is adjusted for residual disease, stage and age.
© Colombo IEO 2013
By Study ID (Sample Size > 24)Pr
opor
tion
surv
iving
0.00.10.20.30.40.50.60.70.80.91.0
Months on Study0 12 24 36 48 60 72 84 96
Study Alive DiedTotal GOG182 16 41 57
Alive DiedTotal ICON3 9 23 32
Alive DiedTotal
OVAR3 6 27 33
Alive DiedTotal
OVAR5 15 39 54
Alive DiedTotal
OVAR7 14 38 52
Alive DiedTotal
SCOTROC1 9 16 25
Overall Survival by GCIG Study Mucinous adenocarcinoma of Ovary
© Colombo IEO 2013
Thank you
