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New windows of surgical opportunity for gynecological cancers in the era of targeted therapies
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  1. Inge Peters1,2,
  2. Claudia Marchetti1,2,
  3. Giovanni Scambia1,2 and
  4. Anna Fagotti1,2
  1. 1 Department of Woman’s and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
  2. 2 Catholic University of the Sacred Heart, Rome, Italy
  1. Correspondence to Dr Anna Fagotti, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; anna.fagotti{at}policlinicogemelli.it

Abstract

Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting.

  • Carcinoma, Ovarian Epithelial
  • Endometrial Neoplasms
  • Cervical Cancer
  • Gynecologic Surgical Procedures

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Embedded ImageINTRODUCTION

The advent of precision medicine has revolutionized the treatment of solid tumors by the development of innovative drugs that target molecular pathways independently of histology.1 In addition, therapeutic agents have lately been introduced that scrupulously modulate the tumor microenvironment by targeting its vascular or immune compartments.2 3 With respect to cancers originating from the female genital tract, the prognostic effects of these newly-engineered therapies have been thoroughly studied. Yet, less is known about their implications for surgical management. These include, for instance, enhancement of complete surgical resection or even omission of surgical treatment, reduction of surgical morbidity, prolongation of the platinum-free interval to augment the number of eligible patients for secondary cytoreductive surgery, and an increased application of the minimally invasive approach. In this review, we will shed light onto the wide-ranging opportunities these molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and the recurrent setting.

EPITHELIAL OVARIAN CANCER

Poly(ADP-ribose) Polymerase Inhibitors (PARPi)

Primary Setting

In patients with newly-diagnosed advanced-stage epithelial ovarian cancer (EOC), the combination of cytoreductive surgery and platinum-based chemotherapy has been the cornerstone of treatment for decades now. Since the completeness of surgery—defined as the resection of all macroscopically visible lesions—repeatedly turned out to be independently associated with survival,4 the likelihood of achieving complete gross resection serves, until today, as an essential premise in current treatment algorithms. As such, patients in whom complete resection of tumor burden seems feasible will be triaged to primary cytoreductive surgery, whereas neoadjuvant chemotherapy followed by interval cytoreductive surgery (NACT/ICS) is reserved for patients in whom complete gross resection is not deemed a viable option, due to either the extent of the disease and/or a poor performance status that precludes these patients from undergoing major surgery.5–7

Now that we have increasing access to molecular profiling, the question arises to what extent these longstanding fundamentals of surgical management remain valid. The vast majority of EOCs are represented by high-grade serous ovarian cancers (HGSOCs). The Cancer Genome Atlas revealed that approximately half of these HGSOCs show defects in the homologous recombination repair pathway, of which up to 30% are attributable to distinctive germline or somatic mutations, such as BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, and BARD1.8 9

The presence of a BRCA gene mutation has been shown to impact disease presentation. During laparoscopic assessment, patients with a deleterious BRCA germline mutation presented with a higher tumor load in terms of diffuse peritoneal dissemination (laparoscopic predictive index value >8) and bulky lymph nodes as compared with those who lack a BRCA mutant genotype.10 Interestingly, a unique BRCA mutant phenotype could also be discerned on pre-operative CT scans. In a retrospective observational study conducted by Nougaret and co-workers, two radiologists independently examined pre-operative CT images from patients diagnosed with BRCA mutant and BRCA wild-type HGSOCs.11 They concluded that BRCA-driven HGSOCs more often presented with a nodular peritoneal disease pattern and tumor deposits located on the gastrohepatic ligament, while mesentery involvement as well as enlarged supradiaphragmatic lymph nodes were less frequently observed as compared with their BRCA wild-type counterparts. Furthermore, at a microscopic level, BRCA mutated HGSOCs have been shown to exhibit typical histopathological features, classified as either pushing/circumscribed metastatic patterns that are often accompanied by a solid, pseudo-endometrioid and transitional cell architecture (so-called ‘SET architecture’), or infiltrative metastases exclusively composed of micropapillae.12 By contrast, BRCA wild-type HGSOCs manifested with miscellaneous tumor architectures.

Whether the absence or presence of specific BRCA-associated features has an impact on surgical management and clinical outcome of patients diagnosed with HGSOCs has been the subject of several studies. With respect to patients with BRCA wild-type HGSOCs, more favorable progression-free survival rates were found when patients directly proceeded to primary cytoreductive surgery.10 13 14 On the contrary, the same studies unequivocally demonstrated that patients with BRCA mutant HGSOCs equally benefited from primary cytoreductive surgery versus NACT/ICS, which has been primarily ascribed to their high chemosensitivity. After all, both BRCA1 and BRCA2 are tumor suppressor genes and their corresponding functioning proteins play a vital role in DNA double-strand break repair through the aforementioned homologous recombination repair pathway. In the absence of these BRCA1/2 genes, HGSOCs display unstable genomes that are deficient in this pathway, thereby rendering these entities highly susceptible to DNA-damaging chemotherapeutic agents. On the basis of this mechanism, these tumors also appear exquisitely sensitive to treatment with poly(ADP-ribose) polymerase inhibitors (PARPi).15

Notoriously, the introduction of PARPi maintenance therapy has impressively changed the treatment paradigm of EOC. According to the current guidelines, these agents can now be offered to patients with International Federation for Obstetrics and Gynecology (FIGO) stage III–IV high-grade serous and endometrioid EOC who have a complete or partial response to first-line platinum-based chemotherapy.16 17 While each of the six randomized double-blind phase III trials conducted in the primary disease setting principally aimed at demonstrating the effect of PARPi maintenance therapy on progression-free survival in these patients,18–23 subgroup analyses now reveal the significance of these agents on surgical outcome. Considering the timing of surgery, a subgroup analysis of the SOLO1 trial showed that patients with BRCA somatic or germline mutations who received olaparib experienced substantially longer progression-free survival when undergoing upfront surgery than when being subjected to NACT/ICS (progression-free survival not reached vs 33.6 months).24 These data meticulously illustrate that targeted therapy with PARPi may considerably influence surgical management: where patients with BRCA mutant tumors prior to the PARPi era had similar progression-free survival outcomes following either primary cytoreductive surgery or NACT/ICS,10 13 14 these patients nowadays seem more likely to benefit from primary cytoreductive surgery when they are expected to receive PARPi maintenance therapy.24

Of further interest in this context is the value of PARPi in the neoadjuvant setting. The NOW trial, a phase I feasibility study, revealed that patients who received olaparib as a single agent for up to two cycles before surgery had an incredible response rate (NCT03943173).25 Thirteen out of a total of 15 patients (86%) proceeded to ICS without any need of additional chemotherapy. Moreover, in 86% of these patients, complete gross resection was achieved. Several other phase I-II trials are still ongoing (Table 1). Should the administration of PARPi in the neoadjuvant setting result in a lower tumor burden and normalization of cancer antigen 125 (CA125) values, then the outcomes of the currently ongoing LANCE trial might be of even greater importance. This trial aims to compare the progression-free survival outcomes following minimally invasive surgery versus open laparotomy in patients with good clinical treatment response after 3–4 cycles of NACT (NCT04575935).26

Table 1

Clinical trials evaluating PARPi in the neoadjuvant setting in newly-diagnosed advanced EOC

The foregoing triggers the question to what extent PARPi maintenance therapy may affect intra-operative decision-making. Specifically, one may inquire whether the encouraging survival outcomes related to PARPi maintenance therapy may justify less radical surgery in patients in whom major surgical morbidity following complete gross resection cannot be ruled out. In an attempt to formulate a response to this issue, we recently performed a systematic review and meta-analysis.27 This analysis comprised all randomized double-blind phase III trials on first-line PARPi maintenance therapy (ie, SOLO 1,18 PAOLA 1,19 PRIMA,20 PRIME,21 ATHENA-MONO,22 and VELIA).23 Within these trials, the percentage of residual disease following cytoreductive surgery was around 30%. An overview of the effect of PARPi on progression-free survival by residual disease status is shown in Table 2. Regarding the progression-free survival rates, the magnitude of PARPi maintenance therapy in comparison to placebo appeared to be almost equivalent between patients with macroscopic residual disease and patients in whom complete gross resection was achieved (pooled HR 0.55, 95% CI 0.44 to 0.68, vs pooled HR 0.53, 95% CI 0.41 to 0.67, respectively).27 Hence, patients with residual disease following cytoreductive surgery benefit to the same extent from PARPi maintenance therapy as those with complete gross resection. Yet, with the exception of the ATHENA-MONO trial, which reported a higher magnitude of benefit for rucaparib as compared with placebo in the group with macroscopic residual disease treated with bevacizumab,22 all studies demonstrated that PARPi maintenance therapy elicited best survival rates in patients in whom complete gross resection was accomplished. Obviously, the heterogeneity in inclusion criteria and study designs of these trials should not be disregarded when interpreting these results. Nevertheless, it is abundantly clear that also in the PARPi era, the ultimate goal remains to ascertain the absence of any macroscopically visible lesions upon completion of surgery.

Table 2

Effect of PARPi maintenance on progression-free survival by surgical residual tumor status in newly-diagnosed advanced EOC

Recurrent Setting

With respect to the recurrent disease setting, both the SOC-1 and DESKTOP III trial have recently shown that secondary cytoreductive surgery might significantly prolong progression-free survival in patients with platinum-sensitive relapsed EOC.28 29 Especially in the DESKTOP III trial, the eligibility criteria for the identification of patients who mostly benefit from secondary cytoreductive surgery were well defined. These criteria are based on a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, consisting of an Eastern Cooperative Oncology Group (ECOG) performance score of 0, ascites of <500 mL, and complete resection at initial surgery. Although this AGO score led to a fairly adequate patient selection, as complete secondary cytoreductive surgery could be achieved in 75.5% of patients,29 there is still room for some improvement. Indeed, also a negative AGO score occasionally resulted in complete secondary cytoreduction.30 In pursuit of optimizing patient selection for secondary cytoreductive surgery, some researchers therefore endeavored to elucidate the role of BRCA mutational status in this setting. Glajzer and co-workers conducted a large retrospective international multicenter study, in which they found that in patients with BRCA mutant recurrent HGSOCs complete secondary cytoreduction was more often achieved than in patients with BRCA wild-type recurrent HGSOCs (82.1% vs 56.4%, p=0.004).31 This difference was even more pronounced in the second/third relapse setting (75.0% vs 26.8%, p=0.005) and the presence of a BRCA mutation was found to be a significant predictive factor for complete secondary resection (OR 0.214, 95% CI 0.078 to 0.587, p=0.003). These figures were likewise reflected in a significantly longer progression-free survival following secondary resection in BRCA mutant patients as compared with their BRCA wild-type counterparts (22 vs 15 months, p=0.025). Remarkably enough, no differences in peritoneal involvement were observed between these groups. These data are in line with a publication from Gallotta et al, in which the authors described the impact of BRCA mutational status on the outcomes of patients with a platinum-sensitive relapse with liver involvement. Notwithstanding the fact that in this study no differences in disease presentation between the study cohorts were found, patients with BRCA mutant recurrent HGSOC showed significantly better progression-free survival rates at 3 years following hepatic resection than those with BRCA wild-type recurrent HGSOC (81.0% vs 15.2%, p=0.001).32 These results may contribute to the selection of patients for secondary cytoreductive surgery requiring liver resection. Strikingly, in patients with isolated lymph node recurrence, on the other hand, the presence of a BRCA gene mutation had no prognostic impact and has therefore no place in the selection of patients for salvage lymphadenectomy.33 Incidentally, although the presence of a BRCA gene mutation mostly resulted in higher progression-free survival rates, it does not necessarily indicate that patients not harboring a BRCA germline mutation may not benefit from secondary cytoreductive surgery.34

The implementation of PARPi maintenance therapy not only results in a prolongation of the disease-free interval, it also seems to alter the manifestation of disease recurrence. A secondary analysis of the PRIMA trial showed that >75% of patients diagnosed with a relapse under niraparib presented with oligometastatic disease.35 Although stereotactic radiotherapy might be an efficacious treatment option for these patients,36 cytoreductive surgery using a minimally invasive approach needs to be considered. This approach is particularly suitable for patients who present with either single or oligometastatic disease (ie, 2–3 separate nodules) and those being exposed to NACT in the first line setting.37 The oncological outcomes following this approach were found to be roughly equivalent as compared with open laparotomy (3-year recurrence free-survival of 76.0% vs 84.1%, respectively, p=not significant). Besides, the risk of peri-operative complications was considerably lower—33.3% in patients undergoing minimally invasive surgery versus 10.3% in patients who underwent open laparotomy (p=0.004). While this potential advantage of reduced peri-operative complications did not emerge from the study performed by Eriksson et al, their results confirmed that a minimally invasive approach is non-inferior to the open technique in terms of survival outcomes.38 To enable the performance of this minimally invasive approach, a timely diagnosis of recurrent disease is absolutely necessary. Thorough follow-up of these patients is thus warranted, as the monitoring of only CA125 serum levels was found to be insufficient for early detection of disease progression.39 Moreover, research is needed to comprehensively revise the current selection criteria for secondary cytoreductive surgery, as the trials from which these criteria originated were largely performed prior to the PARPi era. The SOCCER-P trial, a randomized phase II study on secondary cytoreductive surgery in patients with relapsed ovarian cancer who have progressed on PARPi maintenance (NCT05704621), is a first step in that direction. Further unraveling of the role of BRCA mutational status within this recurrent disease setting should also definitely be a key point to focus on.

Bevacizumab

Primary Setting

Apart from targeted therapy with PARPi, bevacizumab has also conquered a place in the treatment of advanced-stage EOC, although several years earlier. This humanized monoclonal antibody, that is directed against the vascular endothelial growth factor (VEGF) thereby inhibiting the tumor’s angiogenic capacity, has been examined in the ICON-740 and GOG-21841 trials. Based on these two randomized phase III trials, the European Medicines Agency approved the concurrent use of bevacizumab with adjuvant platinum-based chemotherapy and its continuation thereafter as a maintenance therapy in patients diagnosed with FIGO stage IIIB–IV EOC, irrespective of histological subtype. Although this bevacizumab-throughout treatment schedule resulted in statistically significant and clinically meaningful improvements in progression-free survival, particularly in patients with >1 cm residual disease,40 a significant treatment difference with respect to overall survival was not forthcoming.42

The feasibility and outcome of the use of bevacizumab in chemo-naive patients was investigated at a second instance. The GEICO1205/NOVA trial was a phase II randomized, open, multicenter trial that explored NACT with or without bevacizumab in patients with unresectable FIGO stage III–IV EOC and ECOG performance status 0–2.43 The authors did not observe any differences in the complete macroscopic response rate (ie, a peritoneal index score of 0) between the NACT-bevacizumab group and the NACT only group. Surgical operability, however, which was defined as the proportion of patients in whom ICS could be carried out, was significantly higher in patients who concomitantly received bevacizumab (89% in the NACT-bevacizumab cohort vs 67% in the NACT only group, p=0.029). Nevertheless, adding three to four cycles of bevacizumab to NACT did not exert a higher complete cytoreduction rate. A subanalysis of the MITO16A-MaNGO OV2A trial revealed that 86.5% of patients who received NACT in combination with bevacizumab had residual disease of <1 cm on ICS.44 Although this percentage is relatively high, no further conclusions could be drawn as this analysis was unforeseen and beyond the original scope of the study. The ANTALYA trial, instead, aimed at examining the complete resection rate at ICS in patients in whom bevacizumab was added to NACT.45 In this cohort, a complete resection rate of 59% was obtained following bevacizumab-NACT/ICS, which was significantly higher than the historical reference rate of 45% based on patients who were exposed to conventional NACT/ICS. Moreover, in 69% of the study population ICS appeared feasible. Nonetheless, due to the non-comparative character of this study, the effect of bevacizumab on surgical operability could not be established. Thus, to briefly summarize the results of the studies hitherto conducted, the introduction of bevacizumab in the neoadjuvant setting may lead to a higher surgical operability and possibly a higher complete cytoreduction rate, but data are yet too limited to permit a firm conclusion.

Recurrent Setting

With respect to the recurrent setting, data delineating recurrent disease patterns following exposure to bevacizumab in the first-line setting are markedly scarce. Rauh-Jain et al described a significantly higher incidence of distant metastases following treatment with bevacizumab, predominantly manifesting as pulmonary and pleural disease recurrences.46 The number of intra-abdominally located recurrences was found to be considerably lower in this patient population. Nonetheless, the purity of these data might be jeopardized by the fact that the majority of these patients also received intraperitoneal chemotherapy at primary diagnosis. These data are supported by the results of Petrillo et al, describing the recurrent disease pattern after first-line bevacizumab maintenance in patients who were not exposed to intraperitoneal chemotherapy.47 Their retrospective case-control study demonstrated that in cases who were treated with bevacizumab, recurrent disease was more often spread over multiple anatomical locations as compared with controls who did not receive bevacizumab (51.3% vs 31.9%, respectively, p=0.035). Furthermore, peritoneal recurrence occurred more frequently as diffuse disease in cases than in controls (96.8% vs 82.2%, respectively, p=0.046). As a consequence, complete secondary cytoreduction was less frequently achieved in the former group (10.0% in cases vs 53.5% in controls, p=0.016). Hence, first-line maintenance therapy with bevacizumab seems to provide fewer surgical opportunities for recurrent disease than conventional platinum-based chemotherapeutic regimens. Second-line systemic treatment is therefore presumably more appropriate in this setting.

Immunotherapy

The utilization of immune-checkpoint inhibitors in the neoadjuvant setting is currently being investigated (Table 3). In the recurrent setting, its application as a single agent has largely been disappointing, eliciting limited clinical efficacy in patients with platinum-resistant or refractory EOC.48 Nonetheless, combination with other agents, such as PARPi, may potentially result in more survival benefit and numerous phase II-III studies are now ongoing to demonstrate this.49 The outcomes of these studies should be awaited to eventually determine whether combination therapy can make a difference in surgical management.

Table 3

Clinical trials evaluating immune-checkpoint inhibitors in the neoadjuvant setting in newly-diagnosed advanced EOC

Miscellaneous Targeted Therapies

For patients diagnosed with relatively rare carcinomas that respond poorly to platinum-based chemotherapy, investigators have been eagerly searching for novel targeted therapies. Considering low-grade serous ovarian cancer, bevacizumab has been shown to significantly improve survival outcomes with most beneficial survival rates following complete gross resection.50 Conversely, in accordance with the ICON-7 trial,40 the largest benefit was observed in patients having macroscopic residual disease. No conclusions can be drawn with respect to its use in the neoadjuvant setting due to the small sample size in this study. Furthermore, patients diagnosed with low-grade serous ovarian cancer may also significantly benefit from letrozole.51 Here, the absence or presence of residual disease on cytoreductive surgery had no influence on progression-free survival or overall survival. These results are yet to be corroborated in secondary analyses of the currently ongoing randomized phase III trials, that is, the MATAO (NCT04111978), LEPRE (NCT05601700), and NRG-GY019 (NCT04095364) trials. The mitogen-activated protein kinase (MEK) inhibitor trametinib provided encouraging survival outcomes in patients with recurrent low-grade serous ovarian cancer.52 Yet, although measurable disease was required for patient participation, no data were provided on the performance of secondary cytoreductive surgery. With respect to clear cell and mucinous EOC, a variety of targeted therapies are being researched,53–55 but these results are too preliminary yet to determine surgical opportunities.

ENDOMETRIAL CANCER

Driven by a transition from a purely morphological classification towards a fully integrated morphological and molecular-based system, the diagnosis and treatment of endometrial cancer is going through an unprecedented change. On publication of the molecular classification system by the Cancer Genome Atlas,56 a diagnostic algorithm has been introduced that is based on the four distinct molecular subgroups: POLE-ultramutated (POLEmut; characterized by a pathological mutation in the exonuclease domain of the DNA polymerase epsilon), MMR deficient (MMRd; composed of tumors that lack expression of at least one of the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6), p53-abnormal (p53-abn; diagnosed on the basis of an immunohistochemically p53 mutant expression pattern or a TP53 mutation established through sequencing), and a remaining group having no specific molecular profile, simply abbreviated as NSMP. Within the latter, a further distinction was lately added that relies on the expression of the estrogen receptor.57 Following integration into the clinical practice guidelines of the 2021 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP)58 and the European Society of Medical Oncology (ESMO),59 this molecular classification has provoked a complete overhaul of the FIGO staging system.60

Now that these guidelines have drastically been modified according to this molecular classification system, time has come to move on to the next phase: to determine its implications for surgical management and to explore whether targeted therapy directed at these molecular subgroups will result in better disease outcomes. With regard to the first aspect, the EUGENIE trial is currently recruiting.61 This prospective trial aims to examine to what extent molecular classification will guide surgical staging. The primary endpoint is set as the number and site of metastasis in each molecular subgroup, whereas secondary endpoints include time to recurrence and overall survival. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively. Concerning medical treatment, the RAINBO clinical trial program has been launched.62 This represents an umbrella trial encompassing four international clinical trials in which recurrence-free survival at 3 years following molecular-directed treatment strategies after surgical resection will be explored. In brief, these include the de-escalation of adjuvant treatment in POLEmut endometrial cancer (POLEmut-BLUE trial), the supplementation of the immune-checkpoint inhibitor durvalumab to adjuvant radiotherapy in MMRd endometrial cancer (MMRd-GREEN trial), treatment de-escalation with radiotherapy followed by progestin in NSMP endometrial cancer (NSMP-ORANGE trial), and, lastly, the addition of olaparib to adjuvant chemoradiation in p53-abn endometrial cancer (p53-RED trial). It obviously still remains to be seen what the EUGENIE and RAINBO trials will ultimately lead to, but it is beyond any doubt that they will transform current surgical staging and treatment strategies to some extent. Considering the latter, these molecular-directed treatments may possibly come with novel surgical opportunities for subsequent treatment of disease recurrence.

Regarding treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor in combination with platinum-based chemotherapy, two recently published randomized controlled phase III trials heralded highly anticipated breakthroughs in patients with primary advanced FIGO stage III–IV or first recurrent endometrial cancer. The RUBY trial demonstrated that the supplementation of dostarlimab was associated with a 72% lower risk of progression or death in the mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) population (HR 0.28, 95% CI 0.16 to 0.50, p<0.001).63 In the overall population, the risk of progression or death was reduced by 36% (HR 0.64, 95% CI 0.51 to 0.80, p<0.001). A subgroup analysis on the effect of dostarlimab in the overall population having no residual disease at baseline conferred a progression-free survival benefit that was in favor of placebo with platinum-based chemotherapy (HR 1.16, 95% CI 0.52 to 2.59). Yet, this subanalysis concerned only 63 out of the 494 patients (12.8%) being included in the intention-to-treat-analysis. With respect to the MMRd-MSI-H population, no calculation could be executed because of low patient numbers. The NRG-GY018 trial, on the other hand, showed a significant progression-free survival benefit following administration of pembrolizumab in the entire cohort, with a higher magnitude in patients with MMRd-MSI-H endometrial cancer than mismatch repair proficient, microsatellite stability-low (MMRp-MSI-L) endometrial cancer (HR 0.30, 95% CI 0.19 to 0.48, vs HR 0.54, 95% CI 0.41 to 0.71, respectively).64 No secondary analyses on the effect of pembrolizumab in relation to residual disease have been reported. Unfortunately, details on the pattern of recurrent disease following treatment with immune-checkpoint inhibitors are presently lacking.

CERVICAL CANCER

The significance of adding pembrolizumab to NACT in patients with locally-advanced cervical cancer has recently been investigated in the MITO CERV 3 trial (NCT04238988). In this phase II trial, a total of 45 patients with FIGO stage IB2–IIB cervical cancer received three cycles of platinum-based NACT with concomitant administration of pembrolizumab every 3 weeks. If disease progression was absent, patients subsequently underwent radical surgery. Primary endpoints included, among others, clinical and pathological response rate following surgery. Results of this trial are expected shortly.

Regarding the addition of bevacizumab to NACT, good clinical responses were yielded,65 even in patients with FIGO stage IVB disease.66 Nonetheless, no superior effect on the pathological response rate was observed.

Considering patients with recurrent/metastatic cervical cancer, the GOG-240 trial, a randomized controlled, open label, phase III trial, revealed improved progression-free survival and overall survival rates when bevacizumab was added to platinum-based chemotherapy.67 Additionally, owing to the tremendous survival improvements released from the KEYNOTE-826 trial,68 both the US Food and Drug Administration and the European Medicines Agency approved the use of pembrolizumab added to platinum-based chemotherapy plus or minus bevacizumab for patients with recurrent/metastatic cervical cancer whose tumors show a PD-L1 combined positive score >1. No data are available on subsequent treatment or surgery in patients who were exposed to bevacizumab, pembrolizumab, or a combination of these regimens. Hence, no conclusions can be drawn on any surgical opportunities in these patients.

TUMOR-TARGETED FLUORESCENCE-GUIDED SURGERY

A field certainly worth mentioning in the context of surgical opportunities in the era of targeted therapies is tumor-targeted fluorescence-guided surgery. This technique aims to augment the accuracy of conventional surgery by enhancing tumor visualization. Following administration of fluorescently labeled agents that specifically bind to or interact with proteins associated with a cancer hallmark, the cancerous tissues of interest can be illuminated using a sophisticated imaging system.69 Over the past decade, tumor-targeted fluorescence-guided surgery has shown potential in guiding surgeons in radical and safe resection of a variety of tumors.70

Although data are yet preliminary, some studies reported on the use of fluorescent PARPi imaging agents. Kossats et al studied the feasibility of optical imaging with PARPi imaging agents in a mouse xenograft model of esophageal adenocarcinomas.71 Following topical application of the fluorescent PARP1 binding imaging agent PARPi-FL, the authors found an adequate tumor-to-background ratio between tumor and normal esophagus tissue in both high and low PARP1-expressing tumors. A subsequent phase I/II study in patients with oral squamous cell carcinomas is currently ongoing (NCT03085147). Should the imaging findings of PARPi-FL correspond to the histopathological findings in the surgically resected specimens in this study, it might be interesting to examine its use in advanced-stage BRCA mutant HGSOCs and advanced metastatic p53-abn endometrial cancers. Yet, topical application of PARPi-FL to the entire peritoneum seems hardly practicable. Nevertheless, one might hypothesize that this application will be predominantly opportune for situations in which, in some regions, differentiation between clearly pathological and visually dubious peritoneal tumor lesions proves challenging, for instance, due to exposure to NACT.72 Alternatively, a fluorescent PARP1/2-targeted agent could be developed that can be used for intravenous administration. To effectively deliver a fluorescent agent to the target via the intravenous route, however, many barriers in the human body need to be passed.73 Given the intranuclear localization of PARP1 and PARP2, this requires fluorescent PARP1/2-targeted agents that not only pass the blood vessel walls, but can also freely cross both the cell membrane and the nuclear envelope.74

With respect to bevacizumab, various clinical feasibility trials have examined the use of the near-infrared labeled bevacizumab-IRDye800CW in tumors that overexpress VEGF.70 A phase I trial that investigated its feasibility for the detection of peritoneal carcinomatosis in colorectal carcinomas revealed that in two out of seven patients (29%) additional tumor tissue was detected that was initially missed by the surgeons.75 Nevertheless, back-table imaging of fresh surgical specimens demonstrated that tumor tissue was detected in solely 27 out of 51 fluorescent areas, resulting in a false-positive rate of 53%. This is in line with a preclinical study from De Muynck et al, who observed positive immunohistochemical staining for VEGF-A of endothelial cells in tumor-negative peritoneal and omental tissues derived from EOC patients.76 In view of this high background staining, the authors decided to exclude VEGF as a potentially suitable target for fluorescence-guided detection of peritoneal metastases in EOC. Targeting the folate receptor α by injection of pafolacianine (OTL38) might be more promising for real-time EOC detection.77

CONCLUSION

Molecular profiling has evolved notably over the past decade. Although there yet remains much to explore, it has become clear that our view on the disease characterization of epithelial ovarian, endometrial, and cervical cancers has essentially changed. While this has first and foremost led to the emergence of new systemic treatment options for these entities, this review has highlighted that it ultimately may also resonate throughout their surgical management. In fact, this novel perspective brings us on the verge of embarking on a completely new path that will further advance treatment innovations. To chart what surgical opportunities and challenges these treatment innovations entail, it is crucial that future studies continue devoting attention to surgical resectability following NACT as well as the effect of adjuvant treatment in relation to the proportion of residual disease and its impact on the dissemination pattern of recurrent disease. This will enable surgeons to move along with these modern developments and to optimally leverage surgical opportunities in this new era.

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References

Footnotes

  • Twitter @annafagottimd

  • Contributors IP: conception and design, manuscript preparation, final approval; CM: manuscript revision, final approval; GS: manuscript revision, final approval; AF: conception and design, manuscript revision, final approval.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.