The current study showed that the clinical status at diagnosis strongly influenced OS rather than the chemotherapy regimen, and that patients without metastatic disease at restaging seemed to benefit from CRT.
Patient characteristics and clinical status
LAPA often influences the clinical status of patients with weight loss and poor PS score (9), indicating that nutrition and supportive care might help patients receive an optimal therapeutic strategy (i.e. induction treatment and resection). In the present study, we confirmed the importance of clinical status (PS score and weight loss), as it was an independent factor of poor OS, along with the serum CA 19-9 level. Thus, a high initial CA 19-9 level might indicate metastatic disease, with a reduced OS of 12 months (10).
Induction treatment
CRT as induction treatment for patients with LAPA was changed to chemotherapy, because CRT could not be consistently used as a local treatment in a large proportion of patients with unknown metastatic disease (11,12). Thus, gemcitabine was the preferred induction treatment for patients with LAPA until 2010 (13), which was the landmark treatment in the FOLFIRINOX era (14). As FOLFIRINOX resulted in more patients being able to undergo resection (1), it also provided a survival advantage over the former gemcitabine regimen in the current study. However, patients who received gemcitabine induction chemotherapy were older or had a weaker clinical status compared to patients who received the FOLFIRINOX regimen. Interestingly, after adjusting for these factors, there was no survival advantage among patients who received the FOLFIRINOX regimen, possibly indicating that the clinical status was more important than the treatment regimen.
Continuing with chemotherapy or CRT at restaging
Data on the therapeutic strategies and their impact on survival are scarce in patients with unresectable LAPA. In the current study, patients who received CRT at restaging more often developed metastasis, reinforcing the concept that pancreatic cancer is a micrometastatic disease (5,12). Our findings are consistent with those of the LAP07 randomised trial that failed to demonstrate any benefit of CRT in patients with LAPA (5).
Nevertheless, CRT had a benefit effect considering the following reasons. First, pancreatic adenocarcinoma shows the expression of different genes (15) and some patients probably had a particular tumour biology that confers radiosensitivity. Accordingly, we performed early neoadjuvant CRT for patients with resectable pancreatic cancer, but abandoned this strategy owing to disappointing results on considering all treated patients (16). However, we observed that some resected specimens had a complete histologic response, indicating radiosensitivity (17,18). Second, in the current study, patients who received CRT had a prolonged progression-free survival and a trend of prolonged OS. This indicates that CRT provided true local control (19), consistent with the loco-regional progression rate of 30% reported previously (15,20). This does not result in a significant improvement in OS, as the micrometastatic part of the disease was probably insufficiently treated. Indeed, patients often receive only 4 to 6 cycles of induction chemotherapy before CRT, which therefore needs to be optimised. Third, continuing with chemotherapy results in a rapid increase in the incidence of adverse events, requiring dose reduction or chemotherapy interruption. In the current study, continued chemotherapy was associated with a higher incidence of adverse events, comparable to the results of a previous series (21) probably because among patients who received CRT, treatment was discontinued until relapse was observed. Fourth, CRT should improve with the development of new techniques such as stereotactic body radiation therapy (22,23) that may provide benefit over conventionally fractionated radiation therapy in the neoadjuvant setting (awaiting the results of the Alliance A021501 trial (24)), and was hence included in the last NCCC version for 2020 considering the treatment for locally advanced pancreatic cancer (25).
Perspectives in patients with non-metastatic LAPA at restaging
Physicians must focus on restaging to determine the appropriate treatment for each patient, including CT, liver MRI (26), explorative laparoscopy (with para-aortic lymph node picking if technically feasible), and serum CA 19-9 level measurements. After restaging, patients with no evidence of metastatic disease should have a discussion with multidisciplinary staff considering the following four aspects. First, physicians should consider the tumour evolution after induction treatment, as it makes sense to continue with chemotherapy in patients with an objective response. In this setting, 18F-flurorodeoxyglucose PET (27–29) imaging was helpful, but the utility has to be validated in large prospective cohorts. Second, the tolerance to induction chemotherapy should be kept in mind, considering the presence of germline mutations (30,31). Third, the number of cycles administered: our results showed that patients might benefit from at least 8 cycles of chemotherapy before CRT, similar to the results of other studies (20). Finally, the level of CA 19-9 should be considered before treatment is switched to CRT, as the current study showed that a CA 19-9 level >500 U/L was an independent predictive factor of survival, indicating persistent tumour activity. Thus, alternating between chemotherapy and CRT might help in treating both local and metastatic disease.
Oncologists should also use biomarkers, such as changes in the CA 19-9 level (20), neutrophil-to-lymphocyte ratio (32), and liquid biopsies (33–35) to propose tailored treatment after restaging among patients with no evidence of metastatic disease.
Study limitations
The present study has some limitations. Owing to the retrospective nature of the study, radiologic assessment of the objective response to induction treatment was not precisely noted. In addition, at the time of restaging, non-metastatic disease was affirmed by using mainly CT and eventually explorative laparotomy. Indeed, any patients diagnosed with non-metastatic disease who received CRT probably had an unknown metastatic disease that negatively influenced the OS. Moreover, we did not take into account objective measures of the quality of life. Considering the statistical analyses, we used the Wilcoxon test to compare the survival curves of patients with rapid disease progression and early risk of death. However, when the classic log-rank test was used, no differences were observed. Nevertheless, the recent period of patient inclusion, the large sample size, and the homogeneity of the studied population are strengths that compensate for these limitations.