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Review

Management of positive peritoneal cytology gastric cancer patients

Current evidence

Lianos, Georgios D.a,*; Bali, Christina D.a; Schizas, Dimitriosb; Mitsis, Michaila; Galli, Federicac; Rausei, Stefanoc

Author Information
Il Giornale di Chirurgia – Journal of the Italian Surgical Association: October 2022 - Volume 42 - Issue 3 - p e06
doi: 10.1097/IA9.0000000000000005
  • Open

Abstract

Introduction

Gastric cancer (GC) represents undoubtedly one of the most common causes of cancer death worldwide.1 Despite important advances in the management of the disease, it seems that up to date the only treatment with potential curative intent is the surgical approach as part of a multimodal “regimen” of therapy.1,2 Moreover, different biological behavior between tumors from East and West makes this “enigmatic” type of cancer more complex.1–3 It has also to be highlighted that recent protocols, including systemic chemotherapy, radiotherapy, surgical approach, immunotherapy, and individualized targeted therapy are effective in the management of this aggressive disease.1–3 In this way, a multidisciplinary and personalized treatment is of great importance for GC patients.1–3

However, latest evidence suggests that patients’ prognosis with advanced GC remains not so satisfactory even after a completed multimodal treatment.4

In fact, GC, is unfortunately diagnosed at stage IV in more than one-third of cases in the West and the median disease specific survival of stage IV patients is reported to be dismal (approximately 10 months)5 for an overall 5-year survival rate at a dramatic level of 3% to 5%.5,6

However, recently, there is an intense scientific interest and debate for stage IV GC patients and especially for the subgroup of patients with positive peritoneal cytology (PPC) representing a real “gray” zone in the management of advanced disease.

In fact, although according to last UICC TNM editions7 just the presence of tumors cells in the peritoneal cavity induces to classify a GC as a metastatic tumor, this finding is not always detectable either by staging procedures or by surgery. With the exception of a surgical staging approach (preferably laparoscopic), in cases of upfront chemotherapy, it remains a “post-hoc” finding, influencing prognosis but not always treatment decisions.6,8–10 What is more, when dealing with advanced GC with PPC, this might remain not “evident” due to low accuracy of diagnostic methods.6,8–10 Thus, how can we define (and treat) these patients? How to overcome this “gray” zone? To our knowledge, there is no consensus up to date for the “ideal” management of PPC GC patients.6,8–10

In this article, we summarize the current evidence and we provide the latest scientific information regarding stage IV PPC GC.

Search Strategy

This is a narrative review. We have searched Medline and Embase for works published until June 2021 to identify relevant articles using the following keywords: gastric cancer, peritoneal cytology, stage IV, staging laparoscopy, and preoperative therapy.

Stage IV Gastric Cancer

Stage IV GC represents a group of patients with dramatically poor prognosis6,8; for these patients surgical treatment options are very limited and extensively under discussion.6,8,9

Nowadays, in some high-volume surgical departments a subgroup of patients with stage IV GC, undergoes surgical treatment. Surprisingly, it is reported that unexpectedly high long-term survival rates have been obtained which is an interesting issue to explore and analyze.9

In detail, according to the revision by Yoshida et al10 stage IV GC is currently classified into the 2 large subgroups with different potential treatment options. The first group is represented by patients without macroscopic peritoneal “disease” (including PPC status). Nowadays, in these cases surgery could be considered with an upfront approach or after preoperative chemotherapy.9,10

The second group is represented by GC patients with macroscopic peritoneal involvement and the surgical treatment should be a potential option only in carefully selected patients with cytoreduction or palliation goal.10

What is more, robust evidence supports that the first step in advanced GC patients should be to obtain a peritoneal fluid sample for cytology in all cases of potentially resectable disease.11 Recently, it was reported that the potential impact of a PPC on prognosis of GC patients is actually unclear and under debate.12

Hence, what is the real prognostic effect of peritoneal cytology in GC? First, it should be emphasized that PPC in GC patients without surgical treatment have unfortunately a very poor prognosis. On the other hand, as demonstrated in a study published several years ago, unfortunately in all GC patients with PPC, the recurrence occurred even after radical gastrectomy.13

Actually, more recently for the same patient population some studies reported an unexpected 5-year overall survival rate up to 20% after gastrectomy.14,15

Similarly, other experiences even support that radical surgery improved significantly the mean survival rates up to 1.5 years in patients with only PPC.16,17 In this way, is there a space for radical surgery in GC patients with PPC and no evidence of macroscopic distant lesions? Probably the answer lies in the new drugs efficacy and in an improved (and to be further improved) patients selection. Paradoxically, some researchers also have described the possibility to radically treat GC patients with minimal peritoneal involvement, preferable after15 “negativization” of peritoneal disease by effective conversion strategy.17

The Role of Staging Laparoscopy and Diagnostic Methods

In the era of tailored and patient-friendly treatment the basis of “ideal” therapies is the accurate evaluation of tumor spread and exact staging of GC. Nowadays, several imaging tests are used in order to stage GC; however, the accuracy of CT-MRI modalities for peritoneal metastatic disease is still considered low. Hence, staging laparoscopy is considered pivotal to select the correct therapeutic strategy according to peritoneal involvement.18,19 Additionally, laparoscopy allows to obtain a sample of peritoneal fluid (if present) or lavage.18,19 In fact after visual inspection of peritoneal surface for occult disease, peritoneal fluid, if any present, is aspirated and otherwise the peritoneal cavity is irrigated with saline. The aspirated fluid is then prepared for classic cytology examination and stained according to Papanicolaou method to identify free cancer cells, based on qualitative morphological features.18,19 It has been reported that macroscopic peritoneal spread is identified in approximately 20% of patients without imaging evidence of peritoneal involvement. Again, PPC alone is identified in another approximately 10% of patients after cytological exam.18,19

With this regard, another relevant issue to be highlighted is that the sensitivity of peritoneal lavage with conventional cytology in detecting viable cancer cells is unfortunately highly variable (11%–80%).11 Probably, this is responsible for the 49% of isolated disease recurrence to the peritoneum.11 Other diagnostic methods utilized currently in the identification of free cancer cells in lavage fluid are immunohistochemistry (IHC) using antibodies against antigens on cancer cell surface, immunoenzymatic method measuring CEA levels in the supernatant after centrifugation of lavage fluid and molecular methods identifying cancer cell genes by RT-PCR, either single-gene, multigene of limited microarrays.11–21

Although the evidence is still very low, it seems that the accuracy and sensitivity are significantly improved by combining different diagnostic methods.11–21 Therefore, some researchers focus on the need of more accurate methods to examine the peritoneal fluid.22–24

Management of Positive Peritoneal Cytology Gastric Cancer Patients: What Is the Evidence?

Based on the current staging system, GC patients with PPC are considered stage IV and thereafter non eligible on a biological basis for surgical resection. The prognosis of patients with either overt or microscopically peritoneal dissemination has always been considered dismal.25 Thus, traditionally, the treatment guidelines on M1 GC recommend only best supportive care.26,27

However, during the last 2 decades several researchers have focused on the issue of peritoneal carcinomatosis in GC. A distinct group of these patients has only PPC, which is detected by peritoneal lavage during either staging laparoscopy or gastrectomy. Whether this population should be treated radically or palliatively has been an issue for debate up to date.

Kodera et al conducted a phase II trial, enrolling 48 GC patients with PPC, who underwent a D2 gastrectomy followed by adjuvant chemotherapy (S-1). They reported survival advantage in their study group compared with surgery alone (2-year survival rate 46% vs 13.3%, respectively), which persisted for a long time (5-year survival rate 26%).28,29 Shim et al, several years later, reported similar results in a retrospective study, including 88 PPC patients. The median and overall survival in the adjuvant chemotherapy group was superior to D2 surgery alone, 25.5 versus 12.1 months and 88.7% versus 50%, respectively.30 In this way, it seems that adjuvant chemotherapy following a radical operation could modify the prognosis of PPC patients. However, most of the patients eventually will develop recurrence in the peritoneal surface, which emphasizes the need for more intense treatments to eradicate free peritoneal cells.

Toward this goal, different strategies have been used including neoadjuvant chemotherapy, systemic (NAC) or intraperitoneal (NIPS) and HIPEC. Neoadjuvant systemic chemotherapy has several potential benefits including the early treatment of micrometastases, higher dose intensity of delivered chemotherapy, increased R0 resection rates and significantly improved progression-free and overall survival.31 Several studies have reported the efficacy of NAC in conversion of PPC to negative.32–40 Although there were differences regarding the method of retrieval of the peritoneal fluid and the administrated type and cycles of NAC, their results are very encouraging. The median conversion rate to negative peritoneal cytology (NPC) was 58.5% (range 37%–80%). These patients were offered an intention to treat surgery, which had a median R0 resection rate of 62% (range 20.5%–78%). Most of the studies reported survival benefits for the patients, who converted to NPC, with median survival ranging from 26.5 to 37.9 months compared with 12.8 to 24 months survival of PPC patients. Although chemotherapy seems to improve the prognosis by eliminating the cancerous peritoneal cells, the role of gastrectomy was still undefined. Mezhir et al, in a large series of 300 PPC cases, compared the patients who converted to NPC and either had gastrectomy or not, did not find any difference in disease specific survival (2.5 vs 2.3 years).35 But, in most studies, the patients who received a R0 resection had an even better prognosis with a median survival time of 74.7 months (range 41–108.5 months). Particularly, Yasufuku et al reported in their group of converted to NPC and R0 patients the amazing 3-year survival of 76.9% compared to 10.5% and 0% of the palliation chemotherapy or gastrectomy groups, respectively.40 All these details are summarized in Table 1.

Table 1 - Studies dealing with positive peritoneal cytology (PPC) gastric cancer patients
Staging method Chemotherapy Cytology method Total PTS Cyt (+) PTS Convert to cyt (–) R0 Median survival cyt (+) Median survival cyt (–) Survival Survival R0 NAC survival Author
SL—laparotomy NIPS NA 61 39 56% 23% 14.4 months 1 year 67% 20 months (vs 9.9 months in non surgery group) Yonemura et al 42
SL—PL NAC NA 100 61% 78% Nakagawa et al 32
SL—PL NAC PAP staining 381 64 NA 20.5% 12.8 month 3y S 12% (vs 0% in palliation) Badgwell et al 33
SL—PL NAC NA 41 30 70% 70% 43.2 months (vs 10.2 months in R1 or palliation) Okabe et al 34
SL—PL NAC pap staining 1241 300 56% DSS 1.4 years DSS 2.4 years Mezhir et al 35
SL—PL NAC IHC 61 19 37% 54% 13.3 months 37.9 months Lorenzen et al 36
SL or PL (local anesthesia) NIPS ΝΑ 25 56% 88% 9.6 months 27.1 months 16.7 months Fugiwara et al 43
SL or PL (local anesthesia) NIPS NA 18 18 78% 78% 24.6 months Fugiwara et al 44
PL (local anesthesia) NIPS Pap+ IHC 96 68 69% 50% 14.4 month (surgery group) 20 months (vs 9 months in palliation group) Yonemura et al 45
SL—PL NAC pap staining 47 47 49% 49% median survival: 20.4 months
3-year l (OS): 35% 5-year OS: 25.0 %
median survival: 30.4 months
5-year OS: 34.6 %
Aizawa et al 37
PL NAC Pap and
Giemsa staining
23 23 80% 13.6 months 26.5 months 15% in both groups Yamamoto et al 38
SL NIPS Pap staining 95 73 93.2% 55.80% 19.1 months 32.5 months Emoto et al 46
SL—PL NAC Pap staining 115 66% 41 months (vs 11months in palliation group) Nakamura et al 39
SL NAC -LapHIPEC NA 44 14 25% Newhook et al 49
SL NAC NA 214 32 40% 77% 24.1 months 108.5 months 3-year 76.9% Yasufuku et al 40
SL—PL NIPS NA 419 273 53.8% 63.5% 16.8 months 10y: 6.8%. 20.5 months 5y: 14.3% 10y: 8.3% (vs 12 months in R+ 5 y: 1.8% 10y:0% Yonemura et al 50
SL, laparotomy NAC- Lap HIPEC NA 52 48% 28% 24.7 months 21.3 months 25.3 months Blumenthaler et al 51
SL NAC- Lap HIPEC NA 20 85% 22.1 months Badgwell et al 52
SL NAC- HIPEC 88 4 90.9% 21.2 months Manzanedo et al 48
Intraoperative PL Surgery (D2) vs adjuvant chemo ΝΑ 285 24
64
12.1 months 25.5 months 50%
88.7%
Shim et al 30
DSS, disease stable survival; Lap HIPEC, laparoscopic hyperthermic intraperitoneal chemotherapy; NAC, neoadjuvant chemotherapy; NIPS, neoadjuvant intraperitoneal chemotherapy; PL, peritoneal lavage; SL, staging laparoscopy.

The rationale of combination systemic and intraperitoneal chemotherapy (NIPS) seemed very attractive to some researchers, since systemic chemotherapy, either as neoadjuvant or adjuvant, could not prevent recurrence of peritoneal carcinomatosis.34,36,38 NIPS has several advantages comparing to systemic chemotherapy including the direct action in both peritoneal surface and free cancer cells due to higher concentration and lower absorption from the peritoneal cavity.41 Most of NIPS studies come from Far East and are characterized by small number of patients, differences in methodology and also in chemotherapy regimens that have been administered. All studies included patients with PPC and/or limited peritoneal metastasis.42–46 In 3 studies, patients following NIPS, if they converted to NPC without macroscopic disease, they underwent gastrectomy.43,44,46 In the other 2 studies, a more radical operation was performed including gastrectomy plus peritonectomy, if NPC or partial response of peritoneal disease was found in restaging.42,45 The results in these studies showed a median conversion to NPC in 69% (range 56%–93%) of patients, which consequently led to a median R0 resection rate of 56% (range 23%–88%). Median survival time of those who achieved NPC was significantly longer than that of those who did not and the authors proposed the necessity of adjuvant chemotherapy.43,44,46 Yomemura et al reported better survival in R0 patients, comparing to nonsurgery group (20 vs 9 months) and focused on the need of better patient selection to avoid incomplete cytoreduction, which does not add anything to survival.42,45 Based on these data, Jamel et al proposed to reconsider the presence of persistent PPC as an absolute indication of palliative care and suggested an algorithm which includes gastrectomy only in the management for converted to NPC patients.47

Currently, hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreduction surgery (CRS) is the standard treatment for primary peritoneal tumors, and in selected cases of peritoneal dissemination from colorectal cancer.48 The addition of hyperthermia is supposed to have direct cytotoxic effects on the peritoneum surface, resulting in an increase of the effects of some chemotherapeutic agents. In previous studies, the addition of HIPEC to gastrectomy increased the risk of significant complications, with reported morbidity rates of 15% to 53% and mortality 0% to 7%.49 The most recent literature from specialized centers around the globe highlights the possibility of beneficial effects of HIPEC and cytoreduction in well selected patients with minimal peritoneal disease, including PPC.48–52

Newhook et al showed a safer profile of HIPEC, when it is administered laparoscopically, since the clinically significant grade 3 or 4 toxicity occurred in a minority of patients.49 In 2 studies, HIPEC was responsible for conversion to NPC in almost half of the patients.50,51 Additionally, the reported median R0 resection rate in patients treated by HIPEC and cytoreduction was 63.5% (range 25%–90%).48–52 However, surgery was followed by 30% grade II/III surgical morbidity and mortality up to 3.4%.48–52 Regarding survival in HIPEC patients, Yonemura et al reported a significant difference only for the patients that converted to NPC, and for those that R0 resection was achieved.50 Blumenthaler et al have not found a significance in survival in HIPEC group compared to standard care and also any benefit of the subsequent surgical resection.51 This effect over survival is probably explained by Badgwell et al, which reported peritoneal recurrence in 50% of patients after HIPEC and cytoreduction.52

In contrast to cytotoxic therapies, extensive intraperitoneal lavage (EIPL) was introduced as a less invasive method to eliminate free peritoneal cancer cells and consequently minimize the peritoneal dissemination. The rationale behind this method lies in the mechanical wash out of the abdominal cavity with saline during the gastrectomy. Hundeyin and Strong commented recently on the EXPEL trial and reviewed the literature on this issue.53 Previous studies have provided conflicting evidence regarding the effectiveness of EIPL in reducing the rate of peritoneal carcinomatosis and improving survival. EXPEL is a randomized multicenter trial, comparing surgery to surgery plus EIPL, that is designed to clarify the role of EIPL. The study showed no difference in survival and recurrence and contrariwise an increase in morbidity and mortality in the EIPL group. The major drawback in this study is that only a small percentage (5%) of the locally advanced GC patients had PPC, which could have overturned the effectiveness in EIPL in this patient group.

Conclusions and Future Perspectives

It is out of doubt that the “standardization” of surgical treatment in accordance with patient’s personal medical status is of paramount importance for an improved survival outcome of GC patients.54 It has to be admitted that, unfortunately, one-third of patients in Western countries are diagnosed with stage IV GC. Given the increased efficacy of new drugs and the improvement in patients selection (at least clinical selection), recent guidelines suggest a multidisciplinary approach to therapeutic algorithm for patients with GC and especially for patients with stage IV disease.55

Stage IV GC patients have undoubtedly a very poor prognosis, but in the subgroup of GC patients with only PPC the discussion of surgical treatment, based on current evidence, is now “opened” by the scientific community. In a well-defined multimodal setting, gastrectomy and lymphadenectomy could be a potential treatment option with, sometimes, surprising results of survival rates. In fact, recent evidence (although weakly) suggests that, in this subgroup of patients, the addition of intraperitoneal chemotherapy to surgical treatment is more than feasible and could add important benefits in terms of survival. Actually, when these patients from PPC are converted to NPC, the survival rates are more than encouraging. However, on the other hand, the potential high rates of postoperative morbidity and mortality should be taken into consideration in the treatment plan of GC patients with PPC.56

In conclusion, the management of PPC GC patients is very challenging although the evidence is yet scarce.56–59

However, future well-conducted clinical trials with a large number of this heterogeneous group of patients are much needed on this topic in order to reach safe conclusions. This topic is still highly under discussion in the current literature, whereas the most challenging issue is to clarify how to biologically select those patients who will gain a potential benefit from surgery. It is more than clear that the major hope is to give GC patients with PPC the possibility of long-term survival. It seems paradoxical but to overlook a positive peritoneal cytology may become an option in the near future for advanced gastric cancer patients treated in the multimodality setting.

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Keywords:

gastric cancer; peritoneal cytology; stage IV; staging laparoscopy; preoperative therapy

Copyright © 2022 The Authors. Published on behalf of the Associazione Chirurghi Ospedalieri Italiani and Wolters Kluwer.