Abstract
Background: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. Patients and Methods: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. Results: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). Conclusion: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is estimated to be the fourth cause of cancer-related deaths in Japan (1). PDAC remains a lethal disease in that most patients present with distant metastases at the time of diagnosis (2). These patients are usually not indicated for surgery, and their prognosis is dismal.
In 1995, Hellman et al. proposed the idea of oligometastasis (OM) of advanced malignancies, which is defined as a state of limited metastasis (3). The basis of this concept is that a particular group of patients may achieve long-term survival through surgical resection after precise imaging and appropriate multimodal treatment. For instance, hepatic resection of limited colorectal liver metastases led to 5-year overall survival (OS) of 28-58% (4-6). Local therapy was also reported to improve the OS of the patients with OM non-small cell lung cancer (7). Furthermore, Ozawa et al. reported that the 5-year OS rate of the patients treated with curative resection of limited peritoneal metastases was significantly higher than that of patients with diffuse peritoneal metastases (8).
Regarding OM in PDAC, there are no established criteria or consensus on diagnosis and treatment strategy. Damanakis et al. proposed a definition of OM in PDAC as cases with single-organ metastasis, the presence of no more than four metastases in the liver or lung and baseline serum cancer antigen 19-9 (CA19-9) level of <1,000 U/ml. Patients with OM survived significantly longer than those with other types of metastatic unresectable PDAC (9). They excluded cases with isolated peritoneal metastasis in their study since those had the worst survival outcomes rather than liver- or lung-metastatic cases. The current study attempted to create a new definition of OM which also considers peritoneal metastasis among other types of metastasis, using our cohort of patients with metastatic PDAC.
Patients and Methods
Patient cohort. To ensure accurate evaluation of peritoneal metastases, we retrieved 140 consecutive cases of unresectable metastatic PDAC who underwent staging laparotomy or gastrointestinal bypass surgery at Nagoya University Hospital (Nagoya, Japan) from April 2001 to December 2019. Ten cases with multi-organ metastases were excluded, and the remaining 130 patients with single-organ metastasis at diagnosis were enrolled. Preoperative serum CA19-9 values had been recorded for all patients. The clinical background features are summarized in Table I. Lung metastases were excluded from the definition of OM because there were only two cases and they were synchronous metastases. Due to their advanced pancreatic cancer status, two patients died within 30 days after palliative surgery because of pulmonary embolism and cachexia.
Patients’ background characteristics (n=130).
Liver metastases. Information on liver metastases was collected from preoperative computed tomography, magnetic resonance imaging and surgical records. We have attempted to fit the criteria of the Japanese Society of Cancer of the Colon and Rectum (JSCCR) (10) to classify liver metastasis of PDAC. Following the criteria of the JSCCR, liver metastases were classified into four categories. H0: No liver metastasis; H1: 1-4 metastatic tumors, all of which ≤5 cm in maximum diameter; H2: not H1 or H3; H3: five or more metastatic tumors, at least one of which <5 cm in maximum diameter. We also investigated the association between the number of liver metastasis and survival outcomes. We then tried to determine which liver metastasis category (H0-H3) determined by tumor number and size was associated with relatively favorable survival outcomes.
Peritoneal metastases. Information on peritoneal metastases was also collected from preoperative computed tomographic images and surgical records. Peritoneal metastases were also classified into four categories following the criteria of JSCCR. P0: No peritoneal metastasis, P1: metastasis localized to adjacent peritoneum, P2: limited metastasis to distant peritoneum, P3: diffuse metastases to distant peritoneum. We again determined which category was most appropriate as a threshold to identify patients with relatively favorable survival outcomes.
Tumor markers. CA19-9 data were also collected from each patient’s blood test on the day before surgery. To determine the optimal cut-off of preoperative serum CA19-9, receiver operating characteristics curve analyses were performed between CA19-9 values and survival at 5, 10 and 20 months after non-curative operations.
Statistical analysis. Continuous variables were analyzed by the Mann–Whitney U-test as a non-parametric test and Student’s t-test (two-tailed) as a parametric test. Categorical variables were analyzed by Fisher’s exact test. OS was defined as the time from non-curative surgery to the date of death from PDAC. The associations of OM status and clinical factors with OS were evaluated using the log-rank test or Cox proportional hazards model. Values of p<0.05 were considered statistically significant for all statistics. Statistical analyses were carried out using JMP 15 software (SAS Institute, Cary, NC, USA).
Ethics approval and consent to participate. All methods were carried out following relevant guidelines and regulations. The Institutional Review Board of the Nagoya University Graduate School of Medicine approved (registration no. 2020-0344) in Oct 2020. By opt-out, informed consent was obtained from all patients.
Results
Liver metastasis. Among 58 liver-metastatic cases, the survival curves of the three categories (H1, H2, H3) are compared in Figure 1A. Only H1 cases seemed to have a potentially relatively favorable prognosis. Survival curves based on the exact number of liver metastases were also analyzed. Although the cases with solitary liver metastasis did not have significantly longer OS than others, cases with four or fewer liver metastases demonstrated significantly longer OS than others (Figure 1B, p=0.001). Cases of H1 had better OS compared to cases of H2/H3 (Figure 1C, p=0.001).
Survival of patients with pancreatic ductal adenocarcinoma according to liver metastasis. Patients were divided into groups as follows, H1: 1-4 metastatic tumors, all of which ≤5 cm in maximum diameter (n=39); H2: not H1 or H3 (n=14); H3: five or more metastatic tumors, at least one of which <5 cm in maximum diameter (n=5). A: Survival curves according to H category: H1 vs. H2: p<0.001; H2 vs. H3: p=0.261; H1 vs. H3: p=0.229. B: The survival curve for cases with four or fewer liver metastases (n=39) compared with those with five or more (n=19). C: The survival curve for H1 cases compared with H2/H3 cases.
Peritoneal metastasis. Among 70 peritoneum-metastatic cases, survival curves of three categories (P1, P2, P3) are compared in Figure 2. No significant difference was found between P1 and P2-3 groups (Figure 2B), whereas P1-2 cases tended to have more favorable OS than P3 [median OS=14.9 months, 95% confidence intervaI (CI)=8.4-23.4 months for P1-2 vs. 9.7 months, 95% CI=8.4-15.8 months for P3, p=0.140].
Survival of patients with pancreatic ductal adenocarcinoma according to peritoneal metastases. Peritoneal metastases were classified into four categories, P0: no peritoneal metastasis, P1: metastasis localized to adjacent peritoneum (n=27), P2: limited metastasis to distant peritoneum (n=16), P3: diffuse metastasis to distant peritoneum (n=29). A: Survival curves according to P category: P1 vs. P2: p=0.844; P2 vs. P3: p=0.188; P1 vs. P3: p=0.251. B: Survival curves for P1 cases compared with P2-3 cases. C: Survival curves for P1-2 and P3 cases were compared.
Tumor markers. For a serum tumor marker, we chose CA19-9 in this study as the most frequently available and reliable tumor marker of PDAC. Hartwig et al. reported that CA19-9 predicts resectability, stage of disease, and survival in patients with PDAC (11). We chose to use the 20-month survival-specific receiver operating characteristics curve because it had the most significant area under the curve (0.661) compared with others (0.576 for 5-month survival, 0.523 for 10-month survival). The optimal cut-off value for predicting survival of ≥20 months was 2,000 U/ml. The sensitivity and specificity of this setting were 100% and 40%, respectively (Figure 3).
A: Receiver operating characteristics curve for 20-month survival after non-curative surgery for pancreatic ductal adenocarcinoma. The optimal cut-off for the serum cancer antigen 19-9 (CA19-9) level was 2,000 U/ml. B: Survival curves of patients divided into two groups with high (≥2,000 U/ml; n=45) and low (<2,000 U/ml; n=85) according to serum CA19-9 level.
Definition of OM cases. As a result, we defined OM cases as those with single-organ metastasis (H1 or P1,2) and low serum CA19-9 (<2,000 U/ml). All cases were classified according to the number of organs with metastasis, sites of metastasis and serum CA19-9 level (Figure 4). Finally, 130 patients with single-organ metastasis were divided into OM (n=54) and non-OM (n=76). The survival of OM cases was significantly longer than non-OM cases (median=13.0 vs. 8.4 months, p=0.003, Figure 5). Clinical characteristics of both groups are compared in Table II. No difference was found in age, gender, operative procedure, serum CEA nor tumor location, while a significantly greater proportion of patients with OM disease underwent chemotherapy (p=0.015). We next tried to find predictors of OS of this cohort by the Cox hazards model. Administration of chemotherapy (hazard ratio=0.22, 95% CI=0.12-0.39, p<0.001) and OM cases (hazard ratio=0.58, 95% CI=0.36-0.95, p=0.030) were independent factors associated with better OS (Table III).
All cases were classified according to the number of organs with metastasis, number of sites of metastasis and CA19-9 level (U/ml). PDAC: Pancreatic ductal adenocarcinoma; M1: distal metastases; H1: 1-4 metastatic tumors, all of which ≤5 cm in maximum diameter; H2: not H1 or H3; H3: five or more metastatic tumors, at least one of which <5 cm in maximum diameter; P1: metastasis localized to adjacent peritoneum; P2: limited metastasis to distant peritoneum; P3: diffuse metastasis to distant peritoneum; CA19-9: cancer antigen 19-9.
Overall survival curves for cases with oligometastasis (OM) and non-OM cases are shown.
The association of oligometastasis (OM) with clinical characteristics.
Univariate and multivariable analyses of predictors of overall survival.
Chemotherapy. We compared OM cases with non-OM cases depending on postoperative chemotherapy treatment (Figure 6). OM cases treated with chemotherapy had significantly better OS outcomes. On the contrary, there was no survival difference between the OM and non-OM groups in cohort without chemotherapy. Among the subgroup treated with chemotherapy, survival outcomes depending on the regimen were compared in Figure 7. Gemcitabine monotherapy or S-1 treatment significantly elongated the survival of OM cases, while treatment with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, or gemcitabine plus nab-paclitaxel regimen (FFX/GnP) did not lead to any survival difference between the two groups.
Overall survival of patients with oligometastasis (OM) and non-OM cases receiving (A) and not receiving (B) chemotherapy.
Overall survival of patients with oligometastasis (OM) and non-OM cases according to the first chemotherapy regimen. FFX/GnP: 5-Fluorouracil, leucovorin, irinotecan and oxaliplatin/gemcitabine plus nab-paclitaxel.
Discussion
A growing body of evidence shows that metastasectomy can improve the survival outcomes of selected patients with some malignancies (4-7, 12-14). For colorectal and kidney cancers, surgical metastasectomy is the treatment of choice in the National Comprehensive Cancer Network guidelines. In non-small-cell lung cancer, Gomez et al. showed local consolidative therapy with radiotherapy or surgery improved both progression-free survival and OS of OM cases (7). In colorectal cancer, Kobayashi et al. proposed that synchronous resection of localized peritoneal metastases improved survival outcomes (13).
In PDAC with distant metastases, Tachezy et al. suggested a survival benefit for undergoing simultaneous pancreas and liver resection (15). Several prior studies have revealed that the resection of lung and liver metastases prolongs prognosis in PDAC (15-17). Kandel et al. considered OM can be defined as the status of two or fewer metastatic tumors (18). Demanakis et al. reported that OM could be defined as four or fewer metastatic tumors (9). They insist that patients with limited metastases may have good prognosis after metastasectomy, even for PDAC.
Another standard requirement of OM is a low level of serum tumor markers. Although we defined the optimal cut-off value of preoperative serum CA19-9 as 2,000 U/ml, this does not work appropriately for Lewis antigen-negative patients. Luo et al. proposed that carcinoembryonic antigen (CEA) and CA125 can be applied as biomarkers in patients with no CA19-9 secretion from PDACs (19). Wei et al. proposed that tumor marker criterion be at least a 50% reduction of serum CA125 or CEA level if the patient had a normal CA19-9 level before conversion chemotherapy (16). Other rules are needed for these patients.
Our analyses revealed that having four or fewer liver metastases confers a good prognosis. This is the same cut-off number as previous retrospective reports (9, 15, 20). For peritoneal metastases, some studies mentioned that only localized peritoneal metastasis can be included in OM and can be treated (21, 22). It implies that peritoneal metastasis basically has a poor prognosis, and incomplete metastasectomy does not affect survival outcomes. In colorectal cancer, synchronous resection of localized peritoneal metastasis improved survival outcomes, while diffuse or larger sized (>20 mm) peritoneal metastases were an independent factor of poor prognosis (13). Staging laparoscopy of PDAC cases sometimes reveals unsuspected peritoneal dissemination, as Karabicak et al. reported (19%) (23). It is still unknown whether removal of peritoneum metastases affects a patient’s survival or not.
Since our study period was so long, standard chemotherapy regimens have gradually changed. In particular, the introduction of FFX/GnP has led to significant progress. Although the survival difference between OM and non-OM cases was more evident in those receiving chemotherapy than in those without, intensive treatment with FFX/GnP regimen seems effective even in non-OM cases.
The treatment strategy for OM cases following intensive chemotherapy is still controversial. The current study suggests that cases with a small number of metastases in a single organ may have survival relatively long enough to receive intensive chemotherapy. After such treatment, some cases may be able to undergo metastasectomy with radical pancreatectomy before chemotherapy-resistant cancer cells develop. However, we still cannot judge whether metastasectomy or continuous chemotherapy prolongs survival outcomes from this study.
Our study has some limitations. Firstly, patient selection bias may exist because of the retrospective nature of the study. Most patients in this cohort had performance status relatively good enough to receive palliative or probe laparotomy without postoperative complications. Secondly, we were unable to evaluate lung metastases because of the small number of cases. We assume that most patients with lung metastasis only do not require palliative surgery nor staging laparotomy. Thirdly, considerations for Lewis antigen-negative patients have not been made. Additional tumor marker complement is necessary for future larger cohorts.
In conclusion, PDAC OM cases can be identified by limited visible metastatic sites with moderately low serum CA19-9 level. These cases may obtain relatively favorable survival outcomes with intensive chemotherapy. However, the importance of subsequent pancreatectomy with metastasectomy is still an issue for future debate.
Footnotes
Authors’ Contributions
M.Y., M.H. and S.Y. designed the project. M.Y. and M.H. collected clinical data and analyzed them. M.H., S.Y., F.S., H.T. and Y.I. performed multimodal treatment and followed-up the patients. S.Y., D.S., N.H., M.K., C.T., G.N, M.K. and Y.K. reviewed the article. M.Y. and M.H. wrote the article.
Conflicts of Interest
The Authors declare that they have no competing interests.
- Received June 8, 2021.
- Revision received June 21, 2021.
- Accepted June 22, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
