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1st Evidence-based Italian consensus conference on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis from ovarian cancer

Abstract

Ovarian cancer (OC) remains relatively rare, although it is among the top 4 causes of cancer death for women younger than 50. The aggressive nature of the disease and its often late diagnosis with peritoneal involvement have an impact on prognosis. The current scientific literature presents ambiguous or uncertain indications for management of peritoneal carcinosis (PC) from OC, both owing to the lack of sufficient scientific data and their heterogeneity or lack of consistency. Therefore, the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology, the Italian Association of Hospital Obstetricians and Gynaecologists, and the Italian Association of Medical Oncology conducted a multidisciplinary consensus conference (CC) on management of advanced OC presenting with PC during the SICO annual meeting in Naples, Italy, on September 10-11, 2015. An expert committee developed questions on diagnosis and staging work-up, indications, and procedural aspects for peritonectomy, systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy for PC from OC. These questions were provided to 6 invited speakers who answered with an evidence-based report. Each report was submitted to a jury panel, representative of Italian experts in the fields of surgical oncology, gynecology, and medical oncology. The jury panel revised the reports before and after the open discussion during the CC. This article is the final document containing the clinical evidence reports and statements, revised and approved by all the authors before submission.

Post author correction

Article Type: REVIEW

DOI:10.5301/tj.5000623

Authors

Davide Cavaliere, Roberto Cirocchi, Federico Coccolini, Anna Fagotti, Massimiliano Fambrini, Orietta Federici, Domenica Lorusso, Marco Vaira, Marco Ceresoli, Paolo Delrio, Alfredo Garofalo, Sandro Pignata, Paolo Scollo, Vito Trojano, Andrea Amadori, Luca Ansaloni, Giuseppe Cariti, Franco De Cian, Pierandrea De Iaco, Michele De Simone, Marcello Deraco, Annibale Donini, Giammaria Fiorentini, Luigi Frigerio, Stefano Greggi, Antonio Macrì, Enrico Maria Pasqual, Franco Roviello, Paolo Sammartino, Cinzia Sassaroli, Giovanni Scambia, Carlo Staudacher, Patrizia Vici, Enrico Vizza, Mario Valle, On behalf of the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology (SIGO), the Italian Association of Hospital Obstetricians and Gynaecologists (AOGOI), and the Italian Association of Medical Oncology (AIOM)

Article History

Disclosures

Financial support: The Authors received no financial support for this review.
Conflict of interest: The Authors declares that there is no conflict of interest regarding the pubblication ofthis review.

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Introduction

According to the latest AIRTUM report (2014), ovarian cancer (OC) remains relatively rare, as it ranks tenth based on incidence among tumors affecting women (3% of all cases), and it represents 30% of all cases of malignant tumors of the female genital apparatus: in 2014, there were around 4,900 diagnoses in Italy and, according to estimations, 1 out of every 74 women will develop an ovarian carcinoma in the course of her life. It is among the top 5 causes of death for tumor in women younger than 50 (it ranks fourth, accounting for 6% of the total number of deaths). It has an increased prevalence in women aged 60 to 74 years (310/100,000) (1).

The aggressive nature of the disease and its often late diagnosis (International Federation of Gynecology and Obstetrics [FIGO] stage IIIB or IV with peritoneal involvement or distant metastasis) have an impact on prognosis (2).

Due to the complexity of its treatment, the current scientific literature presents ambiguous or uncertain indications, both because of the lack of sufficient scientific data and because of their heterogeneity or lack of consistency.

The authors of this article chose the format of a consensus conference (CC). The aim of the CC was to find answers to the current clinical questions regarding the treatment of peritoneal carcinosis (PC) of ovarian origin. This format, to a larger extent than the format of guidelines, focuses both on scientific data and discussions among experts from relevant fields. The experts drew conclusions from the international scientific data that were available and tailored it to the national context.

Due to the richness of the existing scientific literature, this CC offers clinical recommendations that are based on the most up-to-date scientific data. This was tailored to the Italian context, owing to the insight of a multidisciplinary panel, which represented all the different approaches and different types of expertise on this topic. When the available scientific data were sufficient, or when the experts unanimously agreed, recommendations were made. These recommendations include an overview of the areas that are unclear or unreliable, which should be explored further in the future.

This article contains information that can improve the management of patients with PC from OC in a variety of complex clinical contexts.

Methodology

The CC was carried out according to the standards prescribed by the Consensus Development Program of the US National Institutes of Health (3). The guidelines of the methodology employed by the CC can be found in the “Come organizzare una conferenza di consenso” manual of the Italian national health system (4).

Different entities were involved in the promotion, organization, and development of the CC. Their roles are described in this section. The Promoting Committee was formed by representatives of the scientific communities involved in the project: The Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology (SIGO), the Italian Association of Hospital Obstetricians and Gynaecologists (AOGOI), and the Italian Association of Medical Oncology (AIOM). The Promoting Committee was in charge of promoting the conference, organizing its several stages, choosing the members of the jury panel and the experts, developing the questions for the experts, and offering them guidance and support for the preparation of the evidence-based statements for each topic. These were presented to the jury panel during the CC. The topics debated by the experts are as follows:

Topic 1: What preoperative staging is required for PC in advanced OC?

Topic 2: How can one assess the risks connected to surgery for a patient who is a candidate for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for PC from OC?

Topic 3: What is the impact of HIPEC on the onset of postoperative complications?

Topic 4: Peritonectomy: total or locoregional?

Topic 5: Is there room for a second look (SL) after CRS + HIPEC?

Topic 6: What is the best timing as far as results are concerned for CRS + HIPEC?

Topic 7: Is it right from an ethical point of view to subject patients to CRS + HIPEC in view of an incomplete cytoreduction?

The jury panel’s role was that of revising the reports prepared by the experts, attending the presentation and debate during the CC, compiling and approving the draft consensus document that was presented at the end of the CC, and compiling and approving the final version of the document by including the recommendations. The 6 experts compiled the summarized reports based on the available scientific evidence for each assigned topic. These topics were assigned around a month before the conference, revised according with the jury panel’s observations, and subsequently presented during the CC. The reports were written after the experts employed a systematic review of the current scientific literature.

The experts converted the clinical evidence report into a statement by assigning a level of evidence, following the 2011 Oxford scale (5). These levels were modified or approved by the jury panel during the CC. The participants at the CC subsequently assigned a grade of recommendation according to the following indications:

High recommendation, if supported by high levels of evidence (Level I)

Moderate recommendation, if supported by average levels of evidence (Level II)

Low recommendation, if supported by low levels of evidence (Levels III-V)

The conference lasted 2 days (September 10-11, 2015). The experts presented their own evidence-based reviews to the jury, prior to an open debate. At the end of the presentations, the jury gathered behind closed doors to compile and approve a draft with the recommendations. This was based on procedures that had been approved previously by the regulations. The conclusions of the conference were presented the following day. In the following months, the final consensus document, which contains the relevant recommendations and observations, was written.

Topic 1: What preoperative staging is required for PC in advanced OC?

Markers

The oncologic serum markers that are most commonly used for diagnosis and follow-up in ovarian neoplasms are CEA, CA-125, and CA-19-9. For several years, HE4 has been suggested alongside CA-125 for evaluating the risk of malignancy, as it has proven useful in distinguishing among OC, benign masses, and endometrial carcinomas.

CA-125 has a high sensitivity in ovarian neoplasms but it has a specificity of 40%, as its increase is also linked to benign conditions, such as endometriosis. HE4 is indicated as a marker with a higher specificity compared to CA-125, but it is less available and widespread. In ovarian neoplasms with a mucinous histotype, high levels of CA-19-9 can be identified. Evaluating CA-125, HE4, and CA-19-9 values in relationship with the age of the patient allows for differentiation between a benign condition and ovarian neoplasms (6-7-8-9). CA-125/CEA serum ratio greater than 25 resulted in the highest discriminative power with specificity of 100% and sensitivity of 91% resulting in an overall test accuracy of 94% in the preoperative differential diagnosis between adenocarcinomas of ovarian and colorectal origin. (Level II evidence).

Serum dosages of CA-125, HE4, and CA-19-9 are recommended for the initial evaluation and for monitoring during chemotherapy for verified ovarian neoplasms. (Low recommendation).

Endoscopy

The CC unanimously identified that a gastroenteric endoscopic procedure (esophagogastroduodenoscopy and pancolonoscopy) is recommended in cases that do not unequivocally suggest an ovarian root of the carcinosis, allowing to rule out a gastric or colic-originated carcinosis. (No level of evidence available) (Low recommendation).

Radiologic staging

The chance of identifying peritoneal nodular lesions with a computed tomography (CT) scan varies in relationship with the anatomical area on which they develop and the size of the implants. Smaller nodules (<5 mm) are more easily identified on the surfaces of solid organs, such as the liver or spleen. Viewing images on different levels than axial acquisition (sagittal, coronal, oblique multiplanar reconstructions) can prove useful in observing implants on curved surfaces, such as the diaphragm, paracolic gutters, and intestinal loops. Ascites is present in over 70% of carcinosis cases and can be free or encysted. This can be found on the CT scan if it amounts to more than 50 mL.

Computed tomography scan can rule out treatment for patients who have distant metastasis. In the clinical staging of the Peritoneal Cancer Index (PCI; see below), the accuracy, specificity, and sensitivity of the procedure appear different in the current scientific literature depending on the size of the peritoneal lesions. For lesions larger than 5 cm, the specificity of the CT scan in all the abdominal regions is 100% with a sensitivity of 94%. For lesions smaller than 5 cm, sensitivity ranges from 88% with a specificity of 60% to a sensitivity of 11%. The CT scan has a lower sensitivity in the small intestine (8%-17%) and it is 11% for lesions larger than 5 mm and smaller than 5 cm in areas (9-10-11-12). Consequently, the clinical PCI is significantly underestimated for small lesions or for miliary dissemination, with an incidence of false-negatives for the small intestine and mesentery of 35% (9-10-11-12). (Level I evidence).

The CT scan is an essential test for staging PC from OC, as it allows for patient stratification, excluding patients with synchronous distant metastasis from surgery. (High recommendation).

Whole body magnetic resonance imaging with diffusion-weighted sequence (WB-DWI/MRI) demonstrates high accuracy (94%) and 100% sensitivity for characterizing a primary tumor. With PC, it reaches 91% accuracy and a sensitivity that varies from a maximum of 100% on the parietal peritoneum to a minimum of 50% on the serosa of the small intestine. In distant metastasis (mediastinal lymph nodes, suprarenal lymph nodes) it can be used alongside the 18F-FDG-positron emission tomography (PET)/CT. All the studies analyzed, however, highlight how WB-DWI/MRI is not an independent agent and none of the studies takes into account a total number of cases greater than 40 (13-14-15). (Level II evidence).

The MRI test remains optional and supplementary but it is not an alternative test to other radiologic diagnostic procedures, if these can be carried out. (Moderate recommendation).

Positron emission tomography/CT: The PET scan alone undervalues the PC while the 18F-FDG-PET/CT reaches up to 70% sensitivity and 100% preoperative specificity for II and III degree cases but undervalues I degree lesions for nodules smaller than 5 mm in all quadrants (16, 17). (Level II evidence).

Positron emission tomography/CT is recommended in the oncologic follow-up in the case of a relapse as a second-line examination for selecting patients for surgery. The PET/CT scan’s main aim is staging, with the possibility of excluding patients with a high PCI or extraregional disease from surgery. (Moderate recommendation).

None of the noninvasive (nonsurgical) procedures can lead to a reliable prognosis of the PCI and the cytoreduction index (13, 1418). (Level II evidence).

An accurate surgical staging is recommended for all patients who are candidates for resection surgery with the aim of curing the disease. (Moderate recommendation).

Surgical staging

There are several methods of classification and surgical staging for PC. The most common ones are Sugarbaker’s PCI score for PC and, more specifically, Fagotti’s Predictive Index (PI) for PC from OC.

The Sugarbaker score remains the most widespread and comparable staging system for PC, capable even of providing prognostic indications. It calculates a score for each abdominal and intestinal region, in relationship with the size of the disease. The sum of the scores provides the PCI. The score was initially created for an exclusively laparotomic use and it has been applied in several laparoscopy centers with good results both for evaluating the PCI and for obtaining predictive information on resectability (cytoreduction index) (19-20-21). (Level II evidence).

From the 1,134 cases analyzed from existing studies, the laparoscopic method has a null mortality rate and low morbidity (0%-0.35%), and a low degree of understaging (1%) and nonfeasibility (0.35%-3.2%).

A series of studies undertaken by the Department of Gynaecological Oncology at the Cattolica University in Rome have shown that laparoscopy is an adequate procedure for evaluating the possibility to surgically achieve an optimal cytoreduction (residual tumor <1 cm) in patients with advanced OC by evaluating some parameters of intraperitoneal diffusion of the disease. These parameters are the presence of an omental cake, peritoneal and diaphragmatic carcinosis, retraction of the middle section of the small intestine, infiltration to the stomach and intestine, and superficial metastasis of the liver and/or spleen.

Based on a statistical calculation, each of these parameters is assigned a score of 2. The sum provides a laparoscopic score, which is unique for each patient. This is the PI, which represents the likelihood of optimal cytoreduction in percentages (22). (Level II evidence).

The laparoscopic PI and the laparotomic or laparoscopic PCI have proven to be valid and reproducible instruments for selecting patients with advanced OC (23-24-25-26). (Level II evidence).

Therefore, they are recommended for cytoreductive surgery. (Moderate recommendation).

Regardless of the staging score that is employed, videolaparoscopic staging makes it possible to assess the mesentery (superficial lesions and retractions) and the presence of visceral lesions on the antimesenteric border, and to observe the retrocavity, the pelvic cavity, the diaphragm, and the wall. With the mini-invasive approach, it is possible to calculate the PCI as with a laparotomy, to perform the peritoneal washing and potential biopsies to establish the type of the primitive tumor. In addition, it allows for a predictive evaluation of the cytoreduction index and for giving a definite indication on the feasibility and the cost/benefit relationship of the CRS (20-21-22-23-24-25-26). (Level II evidence).

The staging laparoscopy is recommended in the following cases: the staging of PC that have already been diagnosed with uncertain imaging tests (CT/MR), staging of PC of uncertain origin (peritoneal washing, type biopsy), restaging after neoadjuvant chemotherapy, and restaging during follow-up with uncertain or unreliable imaging. (Moderate recommendation).

In Figure 1, the diagnostic algorithm proposed by the CC members at every time point of surgery (upfront, interval, recurrence, or salvage) is shown.

Diagnostic and staging algorithm for peritoneal carcinomatosis from ovarian cancer. *Cutoff 16/22. **Residual small bowel length after resection >2 meters; excision or electrocauterization of mesotenual lesions ≤5 mm. CRS = cytoreductive surgery; CT = computed tomography; HIPEC = hyperthermic intraperitoneal chemotherapy; MRI = magnetic resonance imaging; PCI = Peritoneal Cancer Index; PET = positron emission tomography; VLS = videolaparoscopic staging.

Topic 2: How can one assess the risks connected to surgery for a patient who is a candidate for CRS and HIPEC for PC from OC?

Since there are no randomized trials, we do not have any Level I evidence studies with a high grade of recommendation.

The literature deals with carefully selected patients younger than 70, American Society of Anesthesiologists 1 and 2, Karnofsky >80%. There are no studies focusing solely on OC. Any conclusions are derived from heterogeneous studies that focus, more generally, on patients who are candidates for PC and HIPEC. Therefore, the conclusions are generic and they derive from the variety of scientific literature studies, without focusing on any study in particular. All the CRS + HIPEC procedures found in the current literature are carried out on patients who are in good general physical condition. Thus, the surgical risk is linked to the extension of the disease and, consequently, to the necessary surgical destruction that would lead to virtually no microscopic residual disease (no specific bibliography, observation based on common clinical practices). Some more detailed risk factors have been evaluated for acute renal dysfunction and stoma creation. Aside from assessing the patient’s health condition and the expertise of the center, the main instrument for evaluating the preoperative surgical risk is counting the clinical PCI. This is because this value helps to define the scope of the surgery, the nature of the CRS, and any potential visceral resections (27).

The minimum preoperative study recommended to determine the overall condition of the patient involves evaluating the cardiologic condition with an ECG, pulmonary compliance through a spirometry test, and the serum dosage of the hematochemical basal parameters. (Low recommendation).

Topic 3: What is the impact of HIPEC on the onset of postoperative complications?

The rates of complications reported in maximal CRS with HIPEC in primitive or relapse OC are varied and heterogeneous when analyzing single cases and they range between 0% and 65.2% (28-29-30-31-32-33-34-35-36-37-38-39-40-41-42-43-44-45-46-47-48-49-50-51-52-53-54). A recent meta-analysis has proven that the rate of severe complications due to first-line treatment for OC was confirmed at 31.3% (range 1.8%-55.6%) while that for the treatment of relapse OC was 26.2% (range 1.8%-55.6%) (55). (Level I evidence).

If patients older than 75 years are taken into account, the available data show that the absolute rate of complications (I-IV degree) is higher (78% vs 35%, p<0.05%). The same difference is noticeable for III-IV degree complications (56% vs 16%, p<0.05%) (30).

The most frequent complications linked to surgery are anastomotic dehiscence, intestinal perforations, intraperitoneal haemorrhage, and evisceration. The multivariate studies with a larger sample show that the extent of the PC, the radicality of the CRS, the length of the surgical procedure, and the number of anastomoses are independent risk factors linked to the onset of complications (29). All of these factors are foreseeable through the preoperative calculation of the PCI. However, none of the published studies takes into account the functional reserves of patients who are candidates for CRS with HIPEC. Generally, they are patients in a good overall condition and the preoperative workup mainly consists of routine checks. More in-depth checks, aimed at identifying the renal and bone marrow functional reserves, are not carried out. Serious renal and bone marrow complications are the most common. They are usually attributed to the direct toxicity of the intraperitoneal administered drugs and their presumed high hematic dosage. However, some studies have proven that the hematic dosage toxicity threshold for intraperitoneal administered drugs is not reached even with high dosages (56).

A recent study published in the British Journal of Cancer has proven that during the 90 minutes of HIPEC, the hematic dosage toxicity threshold is never exceeded, even when the dual intraperitoneal drug is administered (cisplatin and paclitaxel). Additionally, the rate of complications is in line with what the existing literature reports regarding single drug intraperitoneal administration (56). (Level III evidence).

Another recent cohort study on patients who underwent CRS with HIPEC evaluated the inflammatory markers linked to hemodynamic and metabolic changes and proved that the hyperthermic phase is essentially comparable to a septic state. Since this is foreseeable and temporary, it is possible to reduce the rate of complications by reducing to the minimum the hemodynamic changes, temperature, and physiopathologic changes, which are accompanied by a similar fluctuation of the interleukin-6 and procalcitonin values. This check can be carried out through a careful examination of the temperature before, during, and after the hyperthermic state. The temperature check significantly reduces the variations in proinflammatory cytokines production, thus reducing metabolic stress and overloading or alterations of the function of several organs and systems. This could lead to a reduction of the rate of complications (57). (Level III evidence).

Further studies are required to obtain more data. The existing literature does not allow us to deduce to what extent the postoperative morbidity is directly linked to HIPEC or to what extent it is linked to the surgical and oncologic medical procedures, which have a significant impact on the individual, and are carried out within a short period of time. Thus, it is not possible to define to what extent this increase in morbidity is directly linked to HIPEC or, instead, to the depleted functional reserves (27). (Level III evidence).

Hyperthermic intraperitoneal chemotherapy seems to increase postoperative complications after maximal CRS in OC, especially in patients over 75. Therefore, it cannot be recommended for patients above the aforementioned age limit. (Low recommendation).

The use of a combination of intraperitoneal administered drugs does not appear to increase the complications. (Low recommendation).

Constant and thorough check and evaluation of the patient’s temperature during the hyperthermic phase is recommended. (Low recommendation).

Topic 4: Peritonectomy: total or locoregional?

The most common OC is high-grade serous OC. Its origin appears to be monoclonal, predominantly from the fimbriae of the ovarian tube, and, less frequently, from the ovaries (58, 59). Due to gravity’s pull, the exfoliated tumoral cells from these organs move to the peritoneal cavity and they are easily dislodged in specific areas of the abdomen, due to a multistep process, formed by anatomical, physiologic, and biological factors. Therefore, the origin of OC should not be considered as a coelomatic one, but as a transcoelomatic one (60). This simple statement leads to serious clinical implications and important therapeutic choices, including that of the extent of the peritonectomy.

The role of first-line surgery in advanced OC is upheld by international guidelines (61, 62) on the basis of data from existing studies, which are mainly retrospective, and from single series of prospective studies, as well as systematic reviews (63-64-65-66-67-68-69-70). It should be carried out by an oncologic gynecologist (71). (Level II evidence).

The CC score should always be specified at the end of surgery (65, 72-73-74). (Level I evidence) (High recommendation).

The desirable surgical outcome is a complete (optimal) CRS with no tumor residue (CC0). (High recommendation).

During the surgical procedure, CRS should be seen as a procedure aiming at having no RT.

The removal of organs or systems that are not involved in the disease is not recommended since it is not supported by data from the literature. (Level V evidence).

In the case of carcinosis that exclusively affects certain quadrants, organs, and/or abdominal apparatuses, a selective peritonectomy is sufficient. (Low recommendation).

Through randomized trials, the idea of interval debulking surgery after neoadjuvant chemotherapy is slowly becoming established for patients with very advanced tumors (75-76-77-78). However, the type of surgery that should be carried out in this setting is not clear at the moment. Pending clearer indications from the scientific literature, the surgical outcome that should be sought even after neoadjuvant chemotherapy is the same as in the case of primary surgery. This outcome is a CC-0 score (73-74-75, 79). (Level I evidence) (High recommendation).

Selective peritonectomy in the case of suspected residual PC after chemotherapy in organs and/or abdominal apparatuses is recommended, although its outcome is uncertain. What is also uncertain is the outcome of peritonectomy of the regions involved in the diagnosis but that had responded to chemotherapy (75). (Low recommendation).

Topic 5: Is there room for a SL after CRS + HIPEC?

During therapy, carrying out a SL on a patient with advanced OC does not modify the survival rate and has no impact on the prognosis (80-81-82). (Level II evidence).

Studies using HIPEC with primary CRS do not describe the SL in patients with clinical-instrumental remission of the disease (27, 41, 42, 48, 83, 84). The SL should be considered when designing these studies since it is the best instrument to establish the efficiency of a first-line treatment that differs from the standard one.

In retrospective studies, using consolidation HIPEC on patients with clinical-instrumental remission of the disease and a negative SL has proven useful for prognosis (43, 85, 86). (Level III evidence).

Pending confirmation from desirable prospective randomized studies, consolidation HIPEC in patients with clinical-instrumental remission of the disease and negative SL is recommended in selected patients. (Low recommendation).

In retrospective studies (27, 42, 47, 49, 83, 87-88-89-90) and in a prospective randomized study (91), using HIPEC with a second-line CRS has proven useful for the prognosis in the case of relapse in the SL setting. (Level III evidence).

The randomized studies that are currently underway will provide clearer indications and a greater evidence level (II) on HIPEC with second-line CRS in peritoneal relapses of OC (92-93-94-95).

Currently, the use of HIPEC with second-line CRS in relapse at the SL is recommended only in selected cases. (Low recommendation).

It is essential to study the prognostic factors to identify a subgroup of patients at high risk of relapse after the primary treatment, who should undergo a routine SL with consolidation HIPEC or relapse treatment (96, 97).

Topic 6: What is the best timing as far as results are concerned for CRS + HIPEC?

Only well-designed and properly carried out randomized trials involving the different settings of the disease will identify whether or not HIPEC has a role in the treatment of PC from OC, and what that role may be.

Although studies on HIPEC in the treatment of OC date back 20 years, they remain at Level III of evidence.

Retrospective studies focusing on the different settings in which HIPEC has been performed (upfront, interval debulking surgery, secondary surgery, platinum-resistant/sensitive) have shown contrasting results in the treatment of OC (36, 98, 99).

Additionally, none of the existing studies differentiate between OC patients according to the histology of disease. We currently recognize that OC is not a single disease but at least 5 different tumors with different biology, ways of spreading, clinical behaviors, prognoses, and chemosensitivities. Intraperitoneal chemotherapy could have a greater impact, therefore, in serous and high-grade endometrioid tumors, histotypes defined as moderately chemosensitive, but might not have impact on chemoresistant histotypes (clear cells, mucinous, and low-grade serum tumors).

The only randomized study published on this topic (91) has biases and can be criticized due to the absence of a well-defined statistical hypothesis; the low number of patients, which does not enable the identification of significant differences in the 2 arms of treatment; and the absence of differences in the clinical outcome between sensitive and resistant patients not just in the experimental sample, but also in the control sample. The last issue in particular invalidates the assumptions that form the basis of 20 years of medical studies on OC. These are based on the proof that there is a specific biological character of the disease, defined as chemoresistance, that medical and surgical innovation and even biological medications and immunotherapy can improve, but not eradicate. This is valid for both OC and all other types of tumors. Additionally, in the aforementioned study, there are no differences in survival rates according to the different stages of the disease when it is well-known that staging is an independent prognostic factor in OC.

Therefore, we need well-designed control trials, which are adequately monitored in terms of efficiency and toxicity, in order to understand whether or not HIPEC plays a role in the treatment of OC, and properly understand what that role might be.

Hyperthermic intraperitoneal chemotherapy is recommended alongside secondary surgery in platinum-sensitive relapses with no RD in clinical trials. (Low recommendation).

This is because according to prospective nonrandomized studies, hyperthermic intraperitoneal chemotherapy appears associated with longer average survival rates than those obtained after chemotherapy alone and comparable to those obtained after secondary surgery followed by chemotherapy (100). (Level III evidence).

A recent review of the existing studies shows that the highest current levels of evidence for HIPEC are for the treatment of relapsed platinum-sensitive diseases in combination with cytoreductive surgery in optimally debulked patients (35). (Level II evidence).

The review focuses on the last 10 years of scientific literature and refers to 143 publications involving 1,450 patients with OC treated with HIPEC. A total of 493 of them received hyperthermic chemotherapy as a primary treatment while 957 received it following a relapse. Among these, 499 patients from 8 studies have homogenous clinical characteristics and represent the most homogenous population, on which conclusions can be drawn with a higher level of interest. In this population, the median overall survival is 37.3 months (range 27-78), the median disease-free survival is 14.4 months (range 12-30), and the median 5-year overall survival is 40% (range 28-71).

These data suggest that platinum-sensitive relapse is the setting in which clinical trials should be developed to evaluate the impact of HIPEC in the treatment of OC in order to understand if HIPEC improves survival rates compared to secondary surgery alone. (Low recommendation).

In the treatment of OC, secondary surgery at relapse without HIPEC appears to have a significant role in increasing survival for platinum-sensitive patients. Despite being biased due to their retrospective nature and the nonhomogenous nature of the participating population, all the existing studies show a survival advantage of 60 months in platinum-sensitive cases in which surgery is able to remove all the visible disease (RT = 0). The DESKTOP studies in particular have shown that the DESKTOP score (PS 0-1, absence of residual tumor from the primary surgery, or FIGO stage I-II and absence of ascites) is a tool able to predict complete cytoreduction in 76% of patients undergoing secondary surgery for relapse. DESKTOP 3 and GOG 213 are 2 prospective randomized trials that will address the role of secondary surgery in relapsed, platinum-sensitive OC. The studies have recently closed recruitment and their results will be available later in 2017 (101-102-103-104-105-106).

The evaluation of toxicity (106), the quality of life of patients (32), and the cost of treatment should be crucial elements in the decision-making process, especially after the introduction of antiangiogenic drugs as the new standard treatment for ovarian tumors. Bevacizumab combined with chemotherapy is currently indicated for the treatment of the first relapse in platinum-sensitive OC for patients who have not been previously treated with this drug, on the basis of an increase in the progression-free survival rate with hazard ratio 0.48 (107). The European regulating authorities and the Gynaecological Cancer Intergroup (GCIC) currently perceive progression-free survival as the preferred endpoint in studies on ovarian tumors where the long postprogression survival (currently around 36 months for the platinum-sensitive recurrent population) and the number of subsequent chemotherapies that the patients receive after the first progression make overall survival an unattainable endpoint.

Moreover, studies on colon cancer report a 3 to 4 times greater risk of perforations and fistulae in patients who received HIPEC in combination with bevacizumab and a doubled mortality rate even when the time interval between the administration of bevacizumab and the surgical procedure follows the safety indications (6-7 weeks) (108). Even preclinical trials report a significant increase in morbidity in mice when hyperthermia and bevacizumab are combined (109). At present, it is difficult to deprive a patient from a treatment based on Level I evidence suggesting an alternative therapeutic strategy that is not universally accepted because of the lack of irrefutable evidence.

Furthermore, from a cost-effectiveness point of view, several drugs licensed owing to phase III randomized trials are not considered cost-effective (i.e., bevacizumab and olaparib) and physicians might face the impossibility of prescribing them in the future. From the same point of view, we should consider this therapeutic strategy taking into account that the cost of the procedure is not covered by diagnosis-related group (DRG) refunds. Although it is reasonably plausible that most of the cost is related to the secondary surgery and not to the HIPEC itself, the lack of specific DRG for this procedure and the rate of complications (reported G3-4 morbidity: 25% in the primary setting and 19% at relapse [35]) make this procedure not cost-effective for the time being. In the Lombardy region, the overall DRG of the procedure is about €8,000, compared to an average cost of €22,000 per patient (110). Finally, the treatment complications might significantly delay the start of the subsequent chemotherapy: in the first-line setting, the timing of starting adjuvant postoperative chemotherapy has a prognostic role in patients who underwent optimal surgery and postoperative complications often prevent or stop the possibility of starting chemotherapy within 19-21 days, which is the identified period for improving the patient’s prognosis.

The evaluation of toxicity and the cost of treatment are recommended as crucial elements in the decision-making process, particularly after the introduction of antiangiogenic drugs as the new standard treatment for OC. (Low recommendation).

A study (84) reports that a delay in administering adjuvant chemotherapy (average 46 days, range 29-75 days) in patients treated with primary cytoreduction and HIPEC does not lead to a worsening of the prognosis for patients with a newly diagnosed OC. Nonetheless, this study only involved 26 patients; therefore, its conclusions should be investigated on a larger scale and in a randomized trial.

Topic 7: Is it right from an ethical point of view to subject patients to CRS + HIPEC in view of an incomplete cytoreduction

No studies with Level I evidence are available.

The data referring to the treatment of epithelial OC through CRS + HIPEC were extracted from the analyzed studies. From this, it can be inferred that reasonable results in terms of prognosis, in relation to the morbidity and mortality of the treatment, can be obtained only in patients who had an optimal CRS, defined by a CC-0 or CC-1 score (111).

It is recommended to use the definition of optimal cytoreduction in the case of complete cytoreductions (CC-0) and when the residual macroscopic residue of the disease is <2.5 mm (CC1). (Level II evidence) (Moderate recommendation).

In the case of patients with advanced OC (FIGO stage III/IV), who are treated with systemic, platinum-based chemotherapy, the completeness of the surgery is one of the most relevant positive prognosis factors (74, 112-113-114-115-116-117). (Level I evidence).

Additionally, due to the features of advanced OC both at the time of its first manifestation and during relapse, PC is considered the ideal way of administering locoregional chemotherapy drugs, first at a normal temperature (118-119-120), and subsequently in hyperthermia (121-122-123-124-125-126). The intraperitoneal administration of chemotherapy drugs allows for the optimal concentration and distribution of these substances, with lower systemic toxic effects compared to an intravenous method. The efficiency of this approach is greater in patients who had an optimal cytoreduction since the medication’s ability to penetrate tissues is limited (5 mm) (111).

However, the association of CRS, which includes techniques of peritonectomy, intraperitoneal chemotherapy, and hyperthermia (CRS + HIPEC), tends to have higher perioperative morbidity and mortality rates as opposed to standard surgery in association with adjuvant systemic chemotherapy (100, 127-128-129).

This procedure can even be considered in the case of macroscopic residues, as long as the CC score is not above CC-1 (macroscopic residue <2.5 mm). Nonetheless, cytoreduction is complete when there is no macroscopic residue and the best prognosis results can be found in patients with no postoperative residue. For the time being, this procedure is considered suitable in prospective randomized trials that would define the actual impact of HIPEC compared to that of cytoreductive surgery alone in the case of relapses and, even more so, when the disease first manifests.

It is not considered ethical or advisable to recommend CRS + HIPEC in the presence of macroscopic residue with a CC-2 or CC-3 score (greater than 2.5 mm) for the first manifestation of advanced OC (FIGO stage III/IV) or for peritoneal relapses (27, 50, 52, 58, 95, 129). (Low recommendation).

Disclosures

Financial support: The Authors received no financial support for this review.
Conflict of interest: The Authors declares that there is no conflict of interest regarding the pubblication ofthis review.
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Authors

Affiliations

  • General Surgery and Surgical Oncology, Morgagni-Pierantoni Hospital, Forlì - Italy
  • General and Oncological Surgery, University of Perugia, Terni - Italy
  • General, Emergency and Trauma Surgery Department, Papa Giovanni XXIII Hospital, Bergamo - Italy
  • Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome - Italy
  • Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence - Italy
  • Department of Digestive Surgery, Regina Elena National Cancer Institute, IRCCS-IFO, Rome - Italy
  • Gynecologic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milan - Italy
  • Surgical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin) - Italy
  • Abdominal Oncology Department, Fondazione Giovanni Pascale, IRCCS, Naples - Italy
  • Department of Gynecologic and Urologic Oncology, Fondazione Giovanni Pascale, IRCCS, Naples - Italy
  • Division of Gynecology and Obstetrics, Maternal and Child Department, Cannizzaro Hospital, Catania - Italy
  • Division of Gynaecologic Oncology, Istituto Tumori Giovanni Paolo II, IRCCS, Bari - Italy
  • Department of Maternity and Childhood, Morgagni-Pierantoni Hospital, Forlì - Italy
  • Department of Surgical Science and Integrated Diagnostics, IRCCS AOU San Martino-IST, Genoa - Italy
  • Department of Obstetrics and Gynecology, St. Orsola Hospital, University of Bologna, Bologna - Italy
  • Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milan - Italy
  • General and Emergency Surgery, Santa Maria della Misericordia Hospital, University of Perugia, Perugia - Italy
  • Department of Oncology-Hematology, San Salvatore Hospital, Pesaro - Italy
  • Division of Gynecology and Obstetrics, Papa Giovanni XXIII Hospital, Bergamo - Italy
  • Department of Human Pathology, University of Messina, Messina - Italy
  • Department of Surgery, AOU Santa Maria della Misericordia, Udine - Italy
  • Department of Medical, Surgical and Neuroscience, University of Siena, Siena - Italy
  • Department of Surgery Pietro Valdoni, Sapienza University of Rome, Rome - Italy
  • Department of Surgery, San Raffaele Scientific Institute, Milan - Italy
  • Division of Medical Oncology B, Regina Elena National Cancer Institute, IRCCS-IFO, Rome - Italy
  • Gynecology Oncology Unit, Department of Oncological Surgery, Regina Elena National Cancer Institute, IRCCS-IFO, Rome - Italy

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