Transcript Slayt 1

NEOADJUVANT CHEMOTHERAPY
IN EPITHELIAL OVARIAN CANCER
Ateş KARATEKE MD.
ZEYNEP KAMIL HOSPITAL
ISTANBUL
Diagnosed at advanced stages
• Ovarian cancer is the leading cause of death
among women with gynecological
malignancies
• A majority of patients are diagnosed at
advanced stages of the disease, for which the
prognosis is generally poor
[1] Høgdall CK, Taaning L, Nielsen MLS. Annual report 2011, The Danish Gynecological Cancer Database; 2012
[2] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
Extensive and aggressive surgery
improve survival
• The traditional treatment has consisted of PDS
and adjuvant chemotherapy
• The most important factor regarding survival is
the presence of a residual tumor after surgery
• Extensive and aggressive surgery an effective
method to achieve complete tumor resection and
improve survival
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the
platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59.
[du BA Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a
combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials. Cancer 2009;115:1234–44.
Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian
cancer. Obstet Gynecol 2006;107:77–85.
Surgery-related morbidity
• This approach may not be beneficial for a
subgroup of patients for whom surgeryrelated morbidity outweighs the benefit of a
smaller residual tumor
Aletti GD, Eisenhauer EL, Santillan A, Axtell A, Aletti G, Holschneider C, et al. Identification of patient groups at highest risk from
traditional approach to ovarian cancer treatment. Gynecol Oncol 2011;120:23–8.
NACT-IDS
• The use of neoadjuvant chemotherapy followed
by interval debulking surgery has been suggested
as an alternative first-line treatment
• The potential benefit of NACT–IDS
– the debulking is more feasible
– better tolerated by patients than PDS
• poor medical condition
• advanced age
• extensive tumor load
– preoperative diagnostics suggest an inadequate surgical outcome
NACT-IDS
Shorter hospital stay lengths
Less intraoperative blood loss
Less invasive surgery
Fewer complications
Better surgical outcomes with regard to residual tumor
after NACT-IDS compared with PDS
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Giannopoulos T, Butler-Manuel S, Taylor A, Ngeh N, Thomas H. Clinical outcomes of neoadjuvant chemotherapy and primary debulking surgery in advanced ovarian carcinoma. Eur J
Gynaecol Oncol 2006;27:25–8.
[Glasgow MA, Yu H, Rutherford TJ, Azodi M, Silasi DA, Santin AD, et al. Neoadjuvant chemotherapy (NACT) is an effective way of managing elderly women with advanced stage ovarian
cancer (FIGO Stage IIIC and IV). J Surg Oncol 2013;107:195–200
Milam MR, Tao X, Coleman RL, Harrell R, Bassett R, Dos RR, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced
epithelial ovarian cancer. Int J Gynecol Cancer 2011;21:66–71.
Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Neoadjuvant chemotherapy in the Medicare cohort with advanced ovarian cancer. Gynecol Oncol 2011;123:461–6.
Worley Jr MJ, Guseh SH, Rauh-Hain JA, Williams KA, Muto MG, Feltmate CM, et al. Does neoadjuvant chemotherapy decrease the risk of hospital readmission following debulking
surgery? Gynecol Oncol 2013;129:69–73.
Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 1999;72:93–9.
NACT-IDS
• Several studies have shown that NACT–IDS
does not impair survival
– in particular if the population is older or has stage
IV disease
Conflicting results
• Other studies have demonstrated that PDS is a
superior treatment strategy compared with
NACT–IDS
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[1-Luyckx M, Leblanc E, Filleron T, Morice P, Darai E, Classe JM, et al. Maximal cytoreduction in patientswith FIGO stage IIIC to stage IV ovarian, fallopian, and
peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study. Int J Gynecol Cancer 2012;22:1337–43.
[2] Taskin S, Gungor M, Ortac F, Oztuna D. Neoadjuvant chemotherapy equalizes the optimal cytoreduction rate to primary surgery without improving survival in
advanced ovarian cancer. Arch Gynecol Obstet Dec. 2013;288(6):1399–403.
[3] Vergote I, DeWever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian
carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71:431–6.
EORCT 99571
• In 2010, Vergote et al.
published data from
EORCT trial comparing
survival for women with
bulky stage IIIC or IV
disease treated with PDS
or NACT-IDS
Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T,
Johnson N, et al. Neoadjuvant chemotherapy or
primary surgery in stage IIIC or IV ovarian cancer. N
Engl J Med 2010;363:943–53.
• Eligible patients had
biopsy-proven stage IIIC
or IV invasive epithelial
ovarian carcinoma,
primary peritoneal
carcinoma, or fallopiantube carcinoma.
• If a biopsy specimen was
not available, a fineneedle aspirate showing
an adenocarcinoma
• Neoadjuvant chemotherapy is
not inferior to primary
cytoreductive surgery for
patients with stage IIIC or IV
ovarian carcinoma.
• No significant advantages of
neoadjuvant therapy or
primary debulking surgery
were observed with respect to
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–
–
–
survival
adverse effects
quality of life
postoperative morbidity or
mortality
• Patients with metastatic tumors that were <5
cm in diameter at randomization, overall
survival was slightly longer in the PDS group
than in the NACT-IDS group
(hazard ratio, 0.64; 95% CI, 0.45 to 0.93)
• Of the 1677 women eligible for the study,
– 990 (59%)
– 515 (31%)
• 335 (65%)
• 180 (35%)
– 172 (10%)
treated with PDS (Group I)
referred to NACT (Group II)
IDS (Group IIa)
did not have IDS (Group IIb)
palliative treatment (Group III)
• Among the five centers, the use of PDS varied
from 44% to 74% (p < 0.001)
• A total of 352 women (21%) had no debulking
surgery at any time during their treatment
• In Group IIa
– shorter median operation time
– less estimated blood loss
– fewer peroperative complications compared with
patients treated with PDS
– significantly larger fraction of patients without
residual tumor after surgery
• In Group I
– Extensive surgical procedures
• because more patients received large bowel and unspecified
bowel resections
• NACT–IDS was associated
with better surgical
outcomes
– increased risk of death after
two years of follow-up
• Patients without residual
tumor after surgery had
better survival when
treated with PDS
• Stage IV disease and
patients with residual tumor
– no difference in survival
between PDS and NACT-IDS
Referring patients to PDS whenever
this is possible
• Patients without residual tumor after PDS had a
MOS that was 18.8 months longer than for
patients without residual tumor after NACT–IDS
• Patients without residual tumor by stage and
found the difference in MOS
– 25.6 months for stage IIIC patients (p = 0.006)
– 11.3 months for stage IV patients (p = 0.250)
• The importance of referring patients to PDS
whenever this is possible.
• Larger proportion of NACT–IDS patients
without residual tumor after surgery
compared with PDS patients, but this did not
translate into better survival.
• Additional positive effect of PDS may be the
immediate removal of a cancer stem cell
reservoir that might develop platinum resistance
if exposed to chemotherapy
• NACT induces chemotherapy resistance in
colonies of cancer stem cells that are difficult to
detect and therefore to remove at IDS
• The removal of bulks of tumor with poor blood
supply and hence low response to chemotherapy.
• The visual evaluation of tumor spread was more
precise if patients were not treated with
chemotherapy prior to debulking surgery
• Lower sensitivity for identifying malignant sites
after NACT
– indicating the increased risk of leaving tumor colonies
– over estimating the rate of complete tumor removal
at IDS compared with PDS.
• This could account for some of the discrepancy in
better surgical outcome without improved
survival for patients treated with NACT–IDS.
NACT-IDS/PDS
• Retrospective data have also suggested that
NACT-IDS compared to primary surgery may
increase the risk of developing platinumresistant disease and less sensitive recurrent
disease
•
Rauh-Hain JA, Nitschmann CC, Worley Jr MJ, Bradford LS, Berkowitz RS, Schorge JO, et al. Platinum resistance after neoadjuvant
chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma. Gynecol Oncol 2013;129:63–8.
NACT-IDS
Optimal surgical timing and selection criteria for
NACT-IDS remain controversial in clinical
practice
How many cycles of NACT
• Who will benefit from primary surgery or NACT-IDS remain
controversial
• How many cycles of NACT should be given prior to IDS,
ranging from three to six or more
• For advanced or unresectable disease, some authors have
recently proposed to increase the number of NACT cycles with
the aim of improving the rate of complete resection [1]
• IDS could be delayed after 6 or more cycles without
detrimental consequences for long term survival [2-3]
1- Stoeckle E, Boubli B, Floquet A, Brouste V, SireM, Croce S, et al. Optimal timing of interval debulking surgery in advanced ovarian
cancer: yet to be defined? Eur J Obstet Gynecol Reprod Biol 2011;159:407–12.
[2] Stoeckle E, Bourdarias L, Guyon F, Croce S, Brouste V, Thomas L, et al. Progress in survival outcomes in patients with advanced
ovarian cancer treated by neo-adjuvant platinum/taxane-based chemotherapy and late interval debulking surgery. Ann Surg Oncol
2014;21:629–36.
[3] da CostaMiranda V, de Souza Fede AB, Dos Anjos CH, da Silva JR, Sanchez FB, da Silva Bessa LR, et al. Neoadjuvant chemotherapy
with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients unsuitable for primary surgery: safety and
effectiveness. Gynecol Oncol 2014;132:287–91.
• Group A
PDS
• Group B
NACT-IDS
• Group B was divided according to the number
of NACT cycles
– group B1 received 4 or less cycles
– group B2 received more than 4 cycles
• An inverse relationship was observed between
prognosis and the number of NACT cycles:
– patients receiving late IDS had worse survival
compared to patients treated by primary surgery
or early IDS
• This result was observed despite higher rates
of complete resection in the late IDS group
• IDS should be
performed as early as
possible
• Unresectable diseases
should be reevaluated
regularly during NACT
for potential surgery
and complete resection
• Group B2 possibly encompasses patients with
– more extended carcinomatosis at diagnosis
– less chemosensitive tumors
• Explain increased NACT cycles with delayed
IDS and finally a worse outcome
The number of NACT cycles
• In 2006, Bristow et al. published a large metaanalysis derived from 22 cohorts and including
834 stage IIIC–IV EOC patients treated by NACTIDS
• An inverse relationship was observed between
survival and the number of NACT cycles:
– each additional chemotherapy cycle (between 3 and 6
cycles) was associated with a 4-month decrease in
overall survival.
BristowRE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for
advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006; 103:1070–6.
The number of NACT cycles
The results of Bristow and Chi's meta-analysis
• Treated with IDS and receiving more than 3
cycles
– more extended diseases that could explain worse
prognosis.
• A report from a high-volume center
– IDS could be delayed beyond 6 or more cycles
without detrimental consequences on survival
Stoeckle E, Bourdarias L, Guyon F, Croce S, Brouste V, Thomas L, et al. Progress in survival outcomes in patients with advanced ovarian
cancer treated by neo-adjuvant platinum/taxane-based chemotherapy and late interval debulking surgery. Ann Surg Oncol
2014;21:629–36.
The number of NACT cycles
• The meta-analysis by Kang in 2009 showed
that the number of NACT cycles did not
influence survival of EOC patients receiving
NACT in their review of 21 studies published
between 1989 and 2008
Kang S, Nam BH. Does neoadjuvant chemotherapy increase optimal cytoreduction rate in advanced ovarian cancer? Meta-analysis of 21
studies. Ann Surg Oncol 2009;16:2315–20.
The number of NACT cycles
• Patients with advanced EOC receiving NACT
should be evaluated regularly
• IDS should be attempted as soon as possible,
preferably after 4 or less cycles in order to
reserve the maximum number of
chemotherapy cycles on microscopic RD after
IDS.
EORTC 55971 trial
• Survival was similar after PDS and NACT-IDS
• Patients with stage IIIC and less extensive
metastatic tumours had a better survival after
PDS
• Patients with stage IV disease and large
metastatic tumours had a better survival after
NACT-IDS
• Clinical stage before initiation of treatment could
be informative for selecting patients for PDS or
NACT-IDS
Selecting patients with resectable
tumours
• For patients who do not meet these criteria,
and have an intermediate risk, treatment is
debatable.
– diagnostic laparoscopy, could help to distinguish
which patients in this group would benefit most
from different treatments.
Selecting patients with resectable
tumours
• PET–CT
• whole body diffusion magnetic resonance
imaging
Rutten MJ, Gaarenstroom KN, Van Gorp T, et al. Laparoscopy to predict the result of primary cytoreductive surgery in
advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study. BMC Cancer 2012;12:31.
Unresectable disease
• Diffuse and/or deep infiltration of the small
bowel mesentery.
• Diffuse carcinomatosis involving the
stomach and/or large parts of the small or large
bowel
• Infiltration of the duodenum and/or parts of the
pancreas (not limited to the pancreatic tail)
• Involvement of the large vessels of the
hepatoduodenal ligament, celiac trunk or behind
the porta hepatis
• Involvement of the liver parenchyma
Initial CA125 levels >2000 U/ml
• Kang et al. demonstrated that in a sub cohort
of patients with initial CA125 levels >2000
U/ml, the patients treated with NACT had
superior progression-free survival compared
with patients treated with PDS
Kang S, Kim TJ, Seo SS, Kim BG, Bae DS, Park SY. Interaction between preoperative CA-125 level and survival benefit of
neoadjuvant chemotherapy in advanced epithelial ovarian cancer. Gynecol Oncol 2011;120:18–22.
Cochrane review
• NACT is a reasonable alternative to primary
surgery particularly in bulky disease.
• The authors of this review did not specify the
size of main tumour or metastases that defines a
bulky disease.
• Clinicians should take into account resectability,
age, histology, stage and performance status of
the patients in deciding who will benefit from
neoadjuvant chemotherapy.
Morrison J, Haldar K, Kehoe S, et al. Chemotherapy versus surgery for initial treatment in advanced ovarian
epithelial cancer. Cochrane Database Syst Rev. 2012;8:CD005343.
CONCLUSION
• Patients without residual tumor after surgery had
better survival when treated with PDS
• Stage IV disease and patients with residual tumor
– no difference in survival between PDS and NACT-IDS
• The potential benefit of NACT–IDS
– the debulking is more feasible
– better tolerated by patients than PDS
• Patients with advanced EOC receiving NACT
should be evaluated regularly and IDS should be
attempted as soon as possible
Thank you