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Annals of Surgical Oncology

, Volume 24, Issue 4, pp 983–989 | Cite as

Prognostic Significance of Basing Treatment Strategy on the Results of Photodynamic Diagnosis in Advanced Gastric Cancer

  • Yuki Ushimaru
  • Yoshiyuki Fujiwara
  • Kentaro Kishi
  • Keijiro Sugimura
  • Takeshi Omori
  • Jeong-Ho Moon
  • Yoshitomo Yanagimoto
  • Masayuki Ohue
  • Masayoshi Yasui
  • Hidenori Takahashi
  • Shogo Kobayashi
  • Hirofumi Akita
  • Norikatsu Miyoshi
  • Akira Tomokuni
  • Masato Sakon
  • Masahiko Yano
Gastrointestinal Oncology

Abstract

Background

We have previously reported that use of a staging laparoscopy (SL) combined with photodynamic diagnosis using 5-aminolevulinic acid (ALA-SL) improves sensitivity in detecting peritoneal dissemination in gastric cancer (GC). The purpose of this study was to examine the clinical significance of basing treatment strategies on the results of ALA-SL in patients with advanced GC.

Patients and Methods

ALA-SL was performed on 113 patients with advanced GC prior to determination of their first course of treatment. According to the results of ALA-SL, patients were divided into four groups, including those classified as P0 (45%), ALA-P (12%), P1 plus P2 (23%), and P3 (20%). Patients with peritoneal metastases were subjected to chemotherapy. In addition, drug responders also received a gastrectomy. Treatment outcomes and patient characteristics stratified upon the results of ALA-SL were then analyzed.

Results

The 3-year survival rates for patients in the P0, ALA-P, P1-2, and P3 groups were 73, 72, 49, and 6%, respectively. The survival estimates of patients classified as ALA-P via ALA-SL were very similar to those of P0 patients and were significantly better than those of P1-2 and P3 patients. Moreover, the false negative rate for ALA-SL-mediated detection of peritoneal metastasis at exploration was minimal (1/40, 2.5%), possibly due to the use of ALA.

Conclusions

ALA-SL may enhance the accuracy of diagnosis and contribute to therapeutic advantages in advanced GC. It should be introduced for advanced GC patients, especially females, as well as for individuals with high-stage tumors and/or tumors with diffuse-type histology.

Keywords

Gastric Cancer Gastric Cancer Patient Advanced Gastric Cancer Peritoneal Metastasis Peritoneal Dissemination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Peritoneal dissemination is the most common type of recurrence in advanced gastric cancer (GC), even after curative resection, particularly in patients with high T-stage and pathologic-grade tumors, as well as in tumors that invade the serosa.1 3 Therefore, precise diagnosis of peritoneal metastasis is critical for guiding advanced GC treatment. However, diagnosis of peritoneal metastasis with imaging modalities such as ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT is limited and is complicated further by the limitations of a surgeon’s gross inspection.4 Therefore, development of a new and accurate diagnostic method is imperative. Staging laparoscopy (SL) before the onset of treatment has recently been introduced for patients with advanced GC to detect small peritoneal metastases and to avoid unnecessary surgical exploration. Although the introduction of SL has improved detection sensitivity by 31.1–45.2%, particularly for peritoneal dissemination, a false negative rate of 6.2–16.9% has also been reported for conventional SL.5 11

Oral 5-aminolevulinic acid (ALA) is an approved optical imaging agent for enhancing the intraoperative detection of surgical margins in malignant glioma and occult bladder cancer during cystoscopy and radical prostatectomy.12 15 ALA is a naturally occurring metabolite that is a precursor to porphyrin in heme biosynthesis. Exogenous ALA leads to the accumulation of the potent photosensitizer protoporphyrin IX (PpIX) in mitochondria. PpIX is known to accumulate more in malignant and proliferating tissues than in normal tissues. After stimulation with blue light (400 nm), PpIX emits red fluorescent light, a feature that allows PpIX to be used as a detection marker for occult cancer. We have previously introduced photodynamic diagnosis (PDD) with ALA into SL (ALA-SL) for detection of peritoneal micrometastases in GC patients,16 and have demonstrated that ALA-SL enhances the detection sensitivity for peritoneal micrometastases.17

In this study, we used ALA-SL to guide treatment strategies in a cohort of GC patients, evaluated the advantages and prognostic significance of this procedure, and assessed treatment outcomes. We also assessed the predictive factors for peritoneal metastasis in this cohort and examined the indications for ALA-SL in advanced GC.

Materials and Methods

Patients

A total of 146 GC patients received ALA-SL at the Osaka Medical Center for Cancer and Cardiovascular Diseases between April 2011 and June 2015. Of these, 113 patients diagnosed with treatment-naive advanced GC, a type 4 or large type 3 tumor, the presence of pelvic ascites, or extensive lymph node (LN) metastasis (para-aortic LN or bulky LN) on the basis of prior imaging modalities were enrolled in this study. The clinicopathological features were assessed using the Japanese Classification of Gastric Carcinoma (JCGC) guidelines.18 Peritoneal metastasis was classified according to the JCGC, 12th edition, as follows: P0, no peritoneal metastasis; P1, implantation of peritoneal metastasis adjacent to the stomach and above the transverse colon; P2, scattered implantation within the abdomen but not of great number; and P3, numerous implantations throughout the abdomen and pelvis. Furthermore, we defined peritoneal metastasis detected via ALA observation only as ALA-P. This study protocol was approved by the Institutional Review Board of the Osaka Medical Center for Cancer and Cardiovascular Diseases. All patients provided written informed consent for their samples to be used in research.

Staging Laparoscopy with Photodynamic Detection with 5-Aminolevulinic Acid (ALA-SL)

ALA-SL was performed under general anesthesia for the 113 advanced GC patients enrolled in this study. An incision was made at the umbilicus and a 12-mm trocar was inserted into the abdomen as a scope port. The second and third trocars were 5 mm in diameter and were inserted into the right and/or left lateral abdomen as working ports. Sequential observation by switching from white light (WL) to ALA was performed to examine the entire peritoneum. The subphrenic space, liver surface, omentum, surface of the stomach, wall-side peritoneum, pelvic floor, and surface of the entire bowel were examined by switching from WL to ALA. If necessary, the omental bursa was opened to examine the posterior wall of the stomach and the surface of the pancreas. Nodules detected under WL and/or ALA were biopsied and subjected to pathological examination. After laparoscopic observation, peritoneal lavage fluids were obtained from the pelvic cavity and subjected to cytological examination.

ALA-SL procedures were performed as previously described.16,17 In brief, 1 g of ALA was administered orally to each patient 3–5 h prior to the SL, according to recommendations from a previous clinical study of Japanese patients.19,20 This dose was equivalent to approximately 15–25 mg/kg, the reported dose for detection of gastrointestinal tumors.21,22 Sequential observation with WL and ALA was performed by using the D-LIGHT System (Karl Storz, Tuttlingen, Germany).

Treatment Strategy

All patients with peritoneal metastasis and/or positive cytology diagnosed via ALA-SL were subjected to chemotherapy. Patients with no peritoneal metastasis and negative cytology received a curative gastrectomy, whereas those with para-aortic LN or bulky LN metastases were subjected to neoadjuvant chemotherapy. After intense chemotherapy, if a follow-up laparoscopy revealed no evident peritoneal disease, a curative gastrectomy was performed.

Statistical Analysis

Statistical analyses were performed using JMP® PRO software (JMP version 12.2.0, SAS Institute, Cary, NC, USA). Overall survival (OS) was assessed using the Kaplan–Meier method, and comparisons were made using the log-rank test. All parameters that were found to be significant in the univariate analysis using the Cox proportional hazards model were included in the multivariate survival analysis. A p-value <0.05 was considered to be significant.

Results

Patient Characteristics

A total of 113 GC patients with an average age of 63.5 years were consecutively enrolled in this study. Approximately two-thirds of patients were male (Table 1), and the majority of patients were diagnosed with type 3 or 4 tumors. Two-thirds of primary tumors were diagnosed as having diffuse-type histology. In addition, preoperative examinations showed that almost all patients had stage T3 and T4 tumors and that 63.7% presented with LN metastasis. Furthermore, preoperative CT scans detected pelvic ascites in approximately 24.8% of patients.
Table 1

Characteristics of study population

Characteristic

No. of patients (%)

Age, yearsa

63.5 (±11.5)a

Sex

 Male

77 (68.1)

 Female

36 (31.9)

Microscopic type

 1

2 (1.8)

 2

28 (24.8)

 3

43 (38.1)

 4

40 (35.4)

Main location of tumor

 U

41 (36.3)

 M

55 (48.7)

 L

17 (15.0)

Pathology

 Intestinal type

39 (34.5)

 Diffuse type

73 (65.5)

Clinical T stage (UICC 7th edition)

 T2

3 (2.7)

 T3

46 (40.7)

 T4a

58 (51.3)

 T4b

6 (5.3)

Clinical N stage (UICC 7th edition)

 N0

41 (36.3)

 N1

31 (27.4)

 N2

32 (28.3)

 N3

9 (8.0)

 Bulky N

4 (3.5)

 Para-aortic lymph node swelling

3 (2.7)

Pelvic ascites with preoperative CT

 Presence of ascites

28 (24.8)

 Absence of ascites

85 (75.2)

UICC Union for International Cancer Control, CT computed tomography, SD standard deviation

aAverage (SD) values in parentheses are percentages unless indicated otherwise

Clinical Outcomes of Gastric Cancer Patients who Underwent a Staging Laparoscopy

Figure 1 illustrates the distribution of enrolled patients treated on the basis of the results of ALA-SL. According to the results of ALA-SL, 113 patients were divided into two groups, including those classified as P0 (45.1%) and those with peritoneal metastasis (54.9%). Patients with peritoneal metastasis were further divided into three groups, including ALA-P (11.5%), P1 plus P2 (23.0%), and P3 (20.4%). Because only one patient was classified as P1, this patient was added to the P2 group as P1-2. Eleven patients in the P0 group were subjected to chemotherapy because of the presence of bulky and/or para-aortic LN metastases, and the remaining 40 patients received a gastrectomy. Sixty-two patients with peritoneal metastasis, including those classified as ALA-P, P1-2, and P3, were treated with induction chemotherapy. The regimens used for induction chemotherapy were S-1 plus cisplatin in 23 patients,23 S-1 plus intraperitoneal (IP) and intravenous (IV) paclitaxel in 15 patients,24 capecitabine plus cisplatin in 7 patients,25 S-1 plus oxaliplatin plus IP paclitaxel in six patients,26 tratuzumab combined with capecitabine plus cisplatin in 3 patients,25,27 and ‘others’ in 8 patients. A gastrectomy was performed on 7 of 13 (53.8%) patients classified as ALA-P, 15 of 26 (57.7%) patients classified as P1-2, and 5 of 23 (21.7%) patients classified as P3. In addition, an R0 resection was performed on 5 of 13 (38.5%) patients classified as ALA-P, 8 of 26 (30.8%) patients classified as P1-2, and 3 of 23 (13.0%) patients classified as P3.
Fig. 1

Distribution of enrolled patients treated on the basis of the results of ALA-SL. P0 no peritoneal metastasis, P1 implantation of peritoneal metastasis adjacent to the stomach and above the transverse colon, P2 scattered implantation within the abdomen but not of great number, P3 numerous implantations throughout the abdomen and pelvis, ALA-P peritoneal metastasis detected only via ALA observation, ALA-SL staging laparoscopy combined with photodynamic diagnosis using ALA, ALA 5-aminolevulinic acid

Cytological Examination

Peritoneal lavage fluid was obtained from the pelvic cavity during the SL and was subjected to cytological examination. Figure 1 shows the association between peritoneal metastasis status and peritoneal lavage cytology. The frequency of positive cytology increased according to the grade of peritoneal status. Samples from 10, 50.0, and 78.3% of P0, P1-2, and P3 patients, respectively, showed positive cytology (CY1). In ALA-P patients, 23.1% of the samples were classified as CY1.

Predictive Factors for Peritoneal Metastasis

The relationships between the presence of peritoneal metastasis and clinicopathological features are shown in Table 2. In a univariate analysis, significant risk factors for peritoneal metastasis included younger age, female sex, the presence of ascites during preoperative CT scans, diffuse-type histology, and advanced clinical T stage. Female sex, the presence of ascites, diffuse-type histology, and more advanced T stage were significantly associated with the presence of peritoneal metastasis in a multivariate analysis.
Table 2

Predictive factors for peritoneal metastasis

Characteristic

Peritoneal metastasis [N = 62 (%)]

No peritoneal metastasis [N = 51 (%)]

Univariate analysis

Multivariate analysis

OR (95% CI)

p-Value

OR (95% CI)

p-Value

Age (<63 years/>63 years)

28 (45.2)/34 (54.8)

11 (21.6)/40 (78.4)

2.994 (1.328–7.114)

0.008

2.482 (0.888–7.357)

0.083

Sex (female/male)

28 (45.2)/34 (54.8)

8 (15.7)/43 (84.3)

4.426 (1.856–11.551)

<0.001

4.298 (1.398–15.514)

0.010

Location of tumor (U/ML)

21 (33.9)/41 (66.1)

24 (47.6)/27 (52.9)

0.576 (0.269–1.233)

0.154

  

Macroscopic type [III or IV/I or II]

49 (79.0)/13 (21.0)

33 (64.7)/18 (35.3)

2.056 (0.895–4.838)

0.090

  

Ascites of preoperative CT (a little–mild/none)

22 (35.5)/40 (64.5)

6 (11.8)/45 (88.2)

4.125 (1.600–12.127)

0.003

7.386 (2.180–29.676)

<0.001

CEA (>5/<5)

15 (24.2)/47 (75.8)

13 (25.5)/38 (74.5)

0.933 (0.395–2.220)

0.874

  

CA19-9 (>37/<37)

22 (35.5)/40 (64.5)

15 (29.4)/36 (70.6)

1.320 (0.599–2.963)

0.493

  

Pathological classification (diffuse type/intestinal)

50 (80.7)/12 (19.4)

24 (47.1)/27 (52.9)

4.687 (2.073–11.135)

<0.001

5.018 (1.814–15.178)

0.002

Clinical T stage (cT4/under cT3)

57 (91.9)/5 (8.1)

31 (69.7)/20 (39.2)

7.355 (2.684–23.851)

<0.001

13.683 (3.643–68.927)

<0.001

Clinical N stage (over cN1/cN0)

40 (64.5)/22 (35.5)

32 (62.8)/19 (37.3)

1.080 (0.498–2.335)

0.846

  

The P values less than 0.05 are given in italics

OR odds ratio, CI confidence interval, CT computed tomography, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9

Survival Analysis and Prognostic Factors

OS curves stratified on the basis of the results of ALA-SL are shown in Fig. 2. The 1-year survival rates were 85.7, 91.7, 72.5, and 54.0% for P0, ALA-P, P1-2, and P3 patients, respectively, and the respective 3-year survival rates for these groups were 72.9, 72.2, 48.8, and 5.9%. Survival estimates for ALA-P patients were similar to those for P0 patients diagnosed via ALA-SL, and were significantly better than those of P1-2 and P3 patients. We then examined associations among various clinicopathological parameters and OS by using the Cox proportional hazards model. Significant prognostic factors included peritoneal metastasis, positive cytology, and diffuse-type histology in both univariate and multivariate survival analyses (Table 3).
Fig. 2

Overall survival curves stratified on the basis of the results of ALA-SL. OS overall survival, P0 no peritoneal metastasis, P1 implantation of peritoneal metastasis adjacent to the stomach and above the transverse colon, P2 scattered implantation within the abdomen but not of great number, P3 numerous implantations throughout the abdomen and pelvis, ALA-P peritoneal metastasis detected only via ALA observation, ALA-SL staging laparoscopy combined with photodynamic diagnosis using ALA, ALA 5-aminolevulinic acid

Table 3

Associations between various clinicopathological parameters and overall survival

Characteristic

Univariate analysis

Multivariate analysis

OR (95% CI)

p-Value

OR (95% CI)

p-Value

Sex (female/male)

1.299 (0.724–2.293)

0.374

  

Clinical T stage (T4/under T3)

2.062 (0.985–5.035)

0.055

  

Clinical N stage (cN+/cN0)

1.196 (0.457–1.484)

0.545

  

Location (U/ML)

0.935 (0.517–1.652)

0.820

  

Pathological classification (diffuse type/intestinal)

4.762 (2.181–12.509)

<0.001

2.915 (1.296–7.809)

0.008

Peritoneal metastasis (P1/P0)

4.639 (2.388–9.918)

<0.001

2.649 (1.245–6.089)

0.011

Positive cytology (CY1/CY0)

5.169 (2.862–9.542)

<0.001

2.674 (1.407–5.257)

0.003

The P values less than 0.05 are given in italics

OR odds ratio, CI confidence interval

Discussion

The ability to discover small peritoneal metastases by preoperative radiological examinations has been disappointing.28 However, laparoscopy has become a good diagnostic modality because abdominal incisions permit greater visibility and access to the peritoneal cavity. Therefore, this procedure permits the discovery of very small, round peritoneal masses in any location within the subphrenic space, mesenteric space or pelvic floor, areas that are difficult to evaluate even by laparotomy.29 This method exhibits increased detection sensitivity compared with conventional inspection methods and may therefore facilitate better treatment outcomes.

PDD with ALA is a new method of diagnosing peritoneal metastasis that uses fluorescence-based exploration.30 32 In addition, some researchers have reported the usefulness of this technique in the detection of metastatic LNs and GC lesions.33,34 In this study, treatment outcomes based on ALA- SL in a cohort of GC cases were assessed to evaluate the therapeutic significance of using ALA-SL to guide advanced GC treatment strategies. According to the results of ALA-SL, 113 patients were classified into four groups, including P0, ALA-P, P1-2, and P3. Almost all patients classified as P0 were subjected to surgery, whereas patients with bulky and/or para-aortic LN metastases received neoadjuvant chemotherapy. All patients classified as ALA-P, P1-2, or P3 received chemotherapy, and a gastrectomy was performed on patients who responded to chemotherapy. The rate of gastrectomy was similar in the ALA-P (53.8%) and P1-2 (57.7%) groups but was decreased in the P3 group (21.7%). The peritoneal metastasis status of patients, as determined by ALA-SL, was significantly associated with patient prognosis, as shown in Fig. 2. All ALA-P patients were subjected to chemotherapy, and half of the patients were treated with surgery after chemotherapy. The prognosis of ALA-P patients was improved and resembled that of P0 patients. This result indicates that early detection and receipt of chemotherapy may be beneficial for patients with peritoneal metastasis. In this cohort, significant prognostic factors included peritoneal metastasis, positive cytology, and diffuse-type histology in a multivariate analysis. These results indicate that ALA-SL was necessary for the selection of GC treatment and that the findings of ALA-SL, in addition to tumor histology, were important prognostic factors for advanced GC patients.

We also assessed predictive factors for peritoneal metastasis in this cohort and examined the indications for ALA-SL in advanced GC. More advanced T stage, diffuse-type histology, the presence of pelvic ascites, and female sex were significant risk factors in a multivariate analysis. Therefore, ALA-SL may be indicated for GC patients with these characteristics. Although several reports on the use of SL in GC exist, the indications for SL remain unclear. According to previous studies, the rate of peritoneal metastasis varies from 13 to 60%. For example, Miki et al. performed an SL on patients with cM0, type 4 or large type 3 gastric tumors, and 36.3% of the enrolled patients were diagnosed with peritoneal metastasis.5 In addition, in a study by Sarela et al., 32.0% of advanced cases with no definitive evidence of M1 and no contraindication for gastrectomy were diagnosed with peritoneal metastasis by using an SL 8. In the present study, 54.9% of enrolled patients were found to have peritoneal metastasis, according to ALA-SL. If ALA-P detection was not available, 11% of patients would have been misdiagnosed as having no peritoneal metastasis. The majority of ALA-P patients in this study had negative cytology results (n = 10/13, 76.9%). Therefore, they might have otherwise undergone non-curative resection, according to the findings of a conventional SL. In this respect, ALA-SL is useful for determining treatment strategies. Forty P0 patients diagnosed via ALA-SL underwent surgery and, with the exception of one patient in which metastasis to the small bowel mesentery was undetected, all received an R0 resection. The false negative rate in this study was very low (1/63, 1.6%) compared with the rates in previous studies (6.2–17.2%), possibly because of the addition of ALA-based detection.

The survival estimates for ALA-P patients were very similar to those of P0 patients diagnosed via ALA-SL, and were significantly better than those of P1-2 and P3 patients. Therefore, early detection of peritoneal dissemination by SL is important for predicting survival and peritoneal recurrence in patients with advanced GC. Significant prognostic factors included peritoneal metastasis, positive cytology, and diffuse-type histology in both univariate and multivariate survival analyses.

The present retrospective study has some limitations. First, because only a subset of patients was examined via SL, we were not able to quantify the exact rates of peritoneal dissemination. Similarly, we were unable to determine the false negative rate of peritoneal dissemination, thus rendering our study susceptible to selection bias. In addition, it was difficult to inspect the entire peritoneal cavity with the rigid laparoscope that we used in this study. In the near future, a new flexible device suitable for observing narrow spaces is expected to be developed.

Conclusions

This is the first report of specific relationships between prognosis and different classes of peritoneal dissemination. ALA-SL may enhance the accuracy of diagnosis and improve therapeutic outcomes for advanced GC patients. ALA-SL should be introduced for patients with advanced GC, particularly individuals with high-stage tumors and/or tumors with diffuse-type histology.

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Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Yuki Ushimaru
    • 1
  • Yoshiyuki Fujiwara
    • 1
  • Kentaro Kishi
    • 1
  • Keijiro Sugimura
    • 1
  • Takeshi Omori
    • 1
  • Jeong-Ho Moon
    • 1
  • Yoshitomo Yanagimoto
    • 1
  • Masayuki Ohue
    • 1
  • Masayoshi Yasui
    • 1
  • Hidenori Takahashi
    • 1
  • Shogo Kobayashi
    • 1
  • Hirofumi Akita
    • 1
  • Norikatsu Miyoshi
    • 1
  • Akira Tomokuni
    • 1
  • Masato Sakon
    • 1
  • Masahiko Yano
    • 1
  1. 1.Department of SurgeryOsaka Medical Center for Cancer and Cardiovascular DiseaseOsakaJapan

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