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Neo-adjuvant chemotherapy in stage IIIC potentially resectable epithelial ovarian cancer
20 November 2016
Open Access - Commentary:
I
would like to comment on the recently (October 2016 issue of
Gynecologic Oncology) published guideline for neoadjuvant chemotherapy
(NACT) in newly diagnosed ovarian cancer and specifically with regards
to potentially resectable disease (Recommendation 3.1) (Wright et al., 2016).
The decision to proceed with NACT or primary surgery (PCS) in newly
diagnosed stage IIIC disease should not be confused with the decision of
whether surgery is at all appropriate in a given patient because of her
general condition or comorbidities. This should be clarified first and
be distinct from the decision of timing of cytoreductive surgery. The
appropriateness of surgery may of course be modified if there is a
progression during NACT (as Recommendation 7 of the guideline advocates)
or conversely if an unexpected improvement of the clinical condition of
the patient is obtained during palliative chemotherapy. Availability of
the NACT option should not be an “excuse” for not operating on a
potentially resectable patient because of other comorbidities that would
increase her surgical complication risk or because of concerns of
inexperienced surgeons that a primary debulking surgery would be more
difficult. Instead the general status of the patient should weight in
the decision of proceeding with NACT only if it is believed to be
related to the burden of the cancer and patients that are expected to be
technically more difficult should be referred to more experienced
centers.
In the case of
surgery deemed appropriate the main factor that should be considered in
the decision for the timing of surgery and tip the balance towards or
away from PCS is the stage and bulk of the disease. Patients who could
be considered for NACT are those that meet the criteria used in the
EORTC/NCIC trial (FIGO IIIC and IV) (Vergote et al., 2010)
except for patients in the lower range of FIGO IIIC staging (major
tumor masses of 2–5 cm) as these patients appear to have better outcomes
with PCS (van Meurs et al., 2013).
It is noteworthy that in both trials of PCS versus NACT, that have
survival data available at present, the complete response rate is more
than double in the NACT arm, nevertheless survival outcomes are similar (Vergote et al., 2010 and Kehoe et al., 2015). On the other hand the bulk of residual disease after primary surgery is known to be the best predictor of survival outcomes (Bristow et al., 2002).
This may imply that microscopic residual disease post-NACT is more
extensive and difficult to visually identify than microscopic disease at
presentation (Hynninen et al., 2013).
A possible cause of this could be that chemotherapy is able to kill the
bulk of cells in the diffuse peritoneal nodules but stem or tumor
initiating cells resistant to treatment remain and repopulate the tumors
(Chang, 2016).
In other tumor types such as triple negative breast cancers where
neo-adjuvant chemotherapy is used and tumors respond well, radiopaque
coils are placed pre-NACT to guide excision of the residual if
macroscopically invisible (Pinder et al., 2015).
This is obviously impractical in ovarian cancers but in fact is a
strong theoretical disadvantage of NACT in these tumors. Thus, both
available data and theoretical considerations support primary radical
surgery over NACT in patients with potentially resectable stage IIIC and
certainly those stage IIIC patients with smaller tumor masses of less
than 5 cm in major diameter. NACT should remain a second best option in
these patients and should be reserved as first option for patients with
stage IV disease, patients with a high risk for perioperative
complications clearly due to tumor-related factors (where reducing tumor
load may improve surgical risks), or for patients that are unlikely to
receive optimal cytoreduction even with a meticulous surgical effort.
Both PCS and especially NACT will benefit from better methods for
identification of microscopic disease in the future (Cocco et al., 2015).
References
- Bristow et al., 2002
- Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis
- J. Clin. Oncol., 20 (2002), pp. 1248–1259
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- Chang, 2016
- Cancer stem cells role in tumor growth, recurrence, metastasis, and treatment resistance
- Medicine, 95 (2016), pp. S20–S25
- |
- Cocco et al., 2015
- Clostridium perfringens enterotoxin C-terminal domain labeled for fluorescent dyes for in vivo visualization of micrometastatic chemotherapy-resistant ovarian cancer
- Int. J. Cancer, 137 (2015), pp. 2618–2629
- | |
- Hynninen et al., 2013
- Is perioperative visual estimation of intra-abdominal tumor spread reliable in ovarian cancer surgery after neo-adjuvant chemotherapy?
- Gynecol. Oncol., 128 (2013), pp. 229–232
- | | |
- Kehoe et al., 2015
- Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomized, controlled, non-inferiority trial
- Lancet, 386 (2015), pp. 249–257
- | | |
- Pinder et al., 2015
- Macroscopic handling and reporting of breast cancer specimens pre- and post-neoadjuvant chemotherapy treatment: review of pathological issues and suggested approaches
- Histopathology, 67 (2015), pp. 279–293
- | |
- van Meurs et al., 2013
- Which patients benefit most from primary surgery or neoadjuvant chemotherapy in stage IIIC or IV ovarian cancer? An exploratory analysis of the European Organisation for Research and Treatment of Cancer 55971 randomised trial
- Eur. J. Cancer, 49 (2013), pp. 3191–3201
- | | |
- Vergote et al., 2010
- Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer
- N. Engl. J. Med., 363 (2010), pp. 943–953
- | |
- Wright et al., 2016
- Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline
- Gynecol. Oncol., 143 (2016), pp. 3–15
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© 2016 The Author(s). Published by Elsevier Inc.
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