Pancreatic cancer remains the most invariably aggressive and lethal cancer with deadly prognosis for overall survival. Improvements in the outcomes of PC have lagged behind progress made in the treatment of many other malignancies in the last decades. Despite tremendous clinical and laboratory research efforts, the 5-year OS remain as low as 8–10%[2]. PC has particularly challenging biological characteristics, such as insidious onset, biologic aggressiveness and early distant metastases, further enhancing its therapeutic resistance[15]. Most patients are diagnosed in the advanced stages of the disease because of its late presentation and rapid progression, resulting in less than 20% of patients undergoing curative surgery in the early stages [16]. Moreover, even with radical surgery, local and regional recurrence or distant metastasis eventually develops in the majority of these patients[17]. Metastasis occurs in more than half of PC patients, with the liver being the most common site [5, 8]. Liver metastasis from pancreatic cancer is a commonly fatal disease, characterized by refractory course and rapid progress. Therefore, those patients are difficult to treat and often lead to a dismal prognosis with a MST of 3–5 months[8]. This phenomenon necessitates increased understanding and advances in therapeutic approaches to significant improvements in overall survival for these entities. This study is the first attempt to establish a prognostic nomogram to predict the CSS of individual PCLM patients based on routine demographic, staging and treatment information of a large number of PCLM patients.
Age at diagnosis, primary site, histologic grade, T stage, tumor size, number of metastatic organs, and surgery, chemotherapy, and radiotherapy at the primary site were identified as independent prognostic factors for CSS. Higher age, body or tail site, larger tumor size, and higher grade were independently associated with poor prognosis in patients with PC, consistent with previous studies[18–20]. Noticeably, metastatic burden, which classified by the number of metastatic sites, shown significantly relevant to survival of PCLM patients. Preferred prognosis was seen in patients with only liver metastasis than those with extrahepatic metastasis, showing metastatic burden is a critical factor for survival. Lower T stage (T1-3), compared with primary tumors with local invasion of important blood vessels (T4), was associated with improved prognostic outcome, which had been identified in previous studies[21, 22].
The primary goal of care in MPC patients, including those with liver metastases, is to provide symptom palliation that minimizes suffering and maintains an acceptable quality of life. So far, PCLM still lacks effective treatment and is primarily administered by systemic chemotherapy. Similarly, local therapeutic approaches, including surgery and radiotherapy, as interventions to relieve biliary or intestinal obstruction and cancer-related pain, have brought good symptom relief and improved quality of life for patients with PCLM[23]. This proposed nomogram also indicates the prognostic implications of using different treatment methods. It is obviously observed from the nomogram results that combination cytotoxic chemotherapy remains the main treatment modality with the greatest effect on survival. Patients receiving chemotherapy have better survival benefits than those not receiving [MST: 6 vs. 23 months (HR, 0.38; 95% CI, 0.36–0.40; P < 0.001)] (Fig. 5C). Due to the aggressive behavior of the tumor, the chance of surgery for PCLM is very limited and therefore the chemotherapy is the preferred treatment option[24]. The two main effective regimens as first-line treatment options for well-performance metastatic patients are FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) and GEM/NP (gemcitabine plus nab-paclitaxel) with MST of 11.0 and 8.5 months, respectively, compared with 6.7-7.0 months for gemcitabine alone [11, 25]. In addition to the above two regimens, GEM combined with S-1 is recommended as a new option for first-line treatment of metastatic pancreatic cancer in the Asian population with an MST of 10.1 months [26]. Improvement in survival is generally limited to patients with adequate performance. Poorly performing patients may benefit from single-agent chemotherapy with GEM or S-1[27, 28]. Approximately 40–50% of MPC patients will receive second- or later-line chemotherapy. In second-line therapy, favorable patients who have a good performance status in practice often receive an alternative first-line regimen that they did not initially receive. For patients with poor performance status, gemcitabine monotherapy is the preferred choice. In particular, for PCLM, transarterial chemoembolization (TACE) is a well-established modality and a promising treatment for palliative care and symptomatic relief with a MST of 19 months [29].
Surgery is significantly associated with the prognosis of PC patients, but whether surgery benefits patients with PCLM remains controversial. Generally, the presence of liver metastases is a clear indicator of non-surgical treatment. Debulking surgery is not recommended for patients with PCLM according to the latest NCCN guidelines. Historically, surgery has been used to alleviate symptoms, such as duodenal or biliary obstruction in the metastatic setting. With improvements in endoscopic techniques, the rate of duodenal and biliary stent placement has increased while the need for palliative surgical bypasses has decreased. In patients with unresectable disease and biliary obstruction, especially when anticipated survival is limited, an endoscopic biliary sent of palliation ideally will offer durable relief that maximizes life quality while minimizing morbidity and future interventions[30]. Patients can initiate or resume chemotherapy within days of endoscopic stenting, while recovery from a palliative bypass may take 3 to 6 weeks and therefore delay chemotherapy [31]. Therefore, instead of surgery, most of these patients can be relieved by a non-surgical stent procedure. However, as preoperative systemic therapy and perioperative outcomes improve, an increasing number of patients are being considered for surgical treatment. In some cases, carefully selected patients may derive a favorable survival benefit from surgical treatment. For example, conversion surgery following a good response to neoadjuvant chemotherapy in synchronous metastatic disease or metastasectomy for metachronous liver oligometastases with a high potential for a R0 resection is possible and feasible. The MST was from 5.9 to 14.5 months and the 5-year survival rates were from 0% and 7% in reported retrospective studies of surgical resection for PCLM[32–35]. Some studies have revealed that patients with PCLM benefit from resection and have longer survival compared to patients receiving chemotherapy or other palliative treatments, while other studies have failed to find significant differences in survival. In our study, these patients who underwent the surgery to primary site had a better prognosis with MST of 10 months vs. 4 months (HR, 0.47; 95% CI, 0.40–0.56; P < 0.001)] (Fig. 5D). However, there is no agreed consensus concerning the role of surgical management for patients with PCLM, and the long-term prognosis of conversion surgery and metastasectomy for PCLM requires to be sufficiently investigated.
In addition to surgery, radiation (RT), as another local treatment, also is of great importance in the management of PCLM for local control and symptom palliation. Patients with metastatic disease are usually not candidates for RT; however, patients with metastatic disease requiring local palliation for symptoms, like obstruction, pain refractory to analgesic therapy, or bleeding, may be treated with palliative RT [36]. In the present study, patients treated with radiation demonstrate a modest survival benefit with MST of 6 months vs. 4 months (HR, 0.83; 95% CI, 0.73–0.94; P < 0.001)] (Fig. 5E). In selected patients with metachronous liver oligometastases, stereotactic body radiotherapy (SBRT) has been reported as an effective treatment option and has been proven to have a positive effect on patients’ quality of life, local control and potentially survival in the cases of other tumors[37–40]. Reported local control rate at 1 year was 71%, corresponding to a MST of 17.6 months in isolated liver metastases from colorectal and breast primaries[38]. Goodman et al[41] reported the experience of 19 patients with metastatic liver cancer (including 3 patients with PCLM) treated with SBRT, with a prescribed radiation dose of 18-30Gy. All patients tolerated well without severe adverse effects, with a MST of 28.6 months and a 2-year overall survival rate of 50.4%. A significant reduction in pain 4 to 6 weeks was reported after 33Gy SBRT (6.6Gy × 5 fractions) in combination with GEM in patients with PLCM[42]. For patients with synchronous metastatic disease on an initial presentation, intensive systemic therapy stays the standard of care. Immunotherapy has shown clinical benefit with a favorable toxicity profile and are approved in multiple tumor types. An increase in peripheral antitumor immunity following radiation has been revealed in several studies[43–45]. Multimodality care of combined radiation with immune checkpoint inhibitors (ICIs) may offer better local tumor regression and systemic control in the metastatic disease. Xie et al[46] conducted a phase I study to evaluate the safety of ICIs with SBRT in patients with MPC. Results indicated the combination of ICI and SBRT demonstrated a modest treatment benefit with an acceptable safety profile in these patients.
To significantly improve the therapeutic efficiency of tumors, combination therapies have been widely used in the standard of care. Combination therapy showed more desirable survival periods than the single therapy (Fig. 6A-B). The longest MST can reach 17.0 months with systemic therapy combined the surgery and chemoradiotherapy. The traditional standard of care merely manage to extend the survival of the patients with PCLM, which demands various alternative treatment modalities being explored. Currently, in the precision oncologic and immune era, immunotherapy and molecularly targeted therapy outcomes promise to improve lifespan for the metastatic disease. Immunotherapy, represented by immune checkpoint inhibitors with PD-1/PD-L1 monoclonal antibody, has demonstrated promising benefits might enable long-term survival in cases of high microsatellite instability (MSI-H) or deficiency mismatch repair (dMMR)[47]. Aspects of the benefit of poly (ADP-ribose) polymerase (PARP) inhibitior as maintenance therapy for patients with germline BRCA-mutated metastatic disease and no disease progression after 4–6 months of first-line platinum-based therapy represent a signal of progress in molecularly targeted therapy[48].
These breakthroughs have encouraged the pursuit of molecularly targeted therapeutic options to investigate the benefits of personalized strategies for the treatment of PC. Kinases have recently emerged as attractive therapeutic candidates because they mediate key cellular pathways by phosphorylating signaling molecules associated with gene expression, membrane trafficking, cell growth, metabolic pathways, differentiation, and cell death. Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is being explored as a first-line option for metastatic treatment. Results suggested that GEM in combination with erlotinib prolonged overall survival with MST of 6. 24 months vs. 5. 91 months (P = 0. 023), respectively[49]. Other kinases, such as masitinib, ruxolitinib, similarly exhibit evidence of efficacy[50, 51]. In the near future, novel agents specifically targeting pathological signaling pathways and genetic alterations specific to PC patients should be combined with traditional standard of care treatments and novel approaches (ie, immunotherapy and targeting the extracellular tumour microenvironment or metabolism) to achieve substantial survival benefits while reducing side effects. SSGJ-705 is a bispecific antibody simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors[52]. A phase I, multicenter, open-label, first-in-human clinical trial to evaluate the safety, tolerability, pharmacokinetics and potential anti-tumor effects of SSGJ-705 in patients with advanced or metastatic HER2-expressing solid tumors has been approved by FDA. In conclusion, advances in systemic therapy and multidisciplinary standards of care promise to improve both lifespan and health span in this dismal disease.
The present study has several limitations. First, this study is a retrospective analysis with the inherent bias of retrospective data collection. Second, the prediction model was based on data from the SEER database, which makes its application in Asian and Chinese populations immature due to ethnic differences. Third, due to the limitations of the SEER database, details of chemotherapy regimens and radiotherapy doses are not available, which will greatly affect the applicability of the study in the real world. Finally, although the nomogram has achieved acceptable predictive and risk stratification efficacy in training and validation cohorts, further study needs to be warranted.