The current study showed that the clinical status at diagnosis strongly influenced OS rather than the chemotherapy regimen itself, and that at restaging, patients without metastatic disease benefit from receiving CRT.
Patient characteristics and clinical status
Pancreatic adenocarcinoma often influences the patient’s clinical status with weight loss and poor PS score. Our previous study recently showed the importance of these factors in patients with LAPA(8), and our results indicated that nutrition and supportive care might help patients receive an optimal therapeutic strategy (i.e. induction treatment and resection). However, this finding needs to be further evaluated, as the patients’ recovery course was not as desired considering that a poor clinical status might indicate aggressive tumour biology that cannot be treated with medical support.
At diagnosis, the CA 19-9 serum level and clinical status (PS score and weight loss) were independent factors of poor OS. A high initial CA 19-9 may indicate metastatic disease, with a reduced OS of 12 months(9). Instead of using the CA 19-9 level at diagnosis, the changes in the CA 19-9 level owing to induction chemotherapy might be a useful tool to decide between continuing with chemotherapy (indicated by an increased or still high CA 19-9 serum level) or CRT (indicated by a decrease in the CA 19-9 serum level)(10). Similarly, the neutrophil-to-lymphocyte ratio(11) and liquid biopsies(12–14), by evaluating circulating tumour cells or circulating tumour DNA, might be helpful to decide between local or systemic treatment at restaging in patients with no evidence of metastatic disease.
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(15,16). Thus, gemcitabine was the preferred induction treatment for patients with LAPA until 2010(17), which was the landmark treatment in the FOLFIRINOX era(18). Therefore, the current study focused on patients included in this later period, as we wanted to obtain a clear picture of the patient outcomes in the modern era. As FOLFIRINOX resulted in more patients being able to undergo resection(1), it also provided a survival advantage over the former gemcitabine regimen in our study. However, patients who received gemcitabine induction chemotherapy were older or had a weaker clinical status compared to patients who received the FOLFIRINOX regimen. Moreover, after adjusting for these factors, there was no survival advantage in 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(5,16). Our findings are consistent with those of the LAP07 randomized trial that failed to demonstrate any benefit of CRT in patients with LAPA(5). Considering these points and the related adverse events, it remains unclear if CRT should not be performed for patients with LAPA who did not undergo resection.
Nevertheless, we should not be hasty to conclude that CRT is not beneficial, owing to many reasons. First, all cases of pancreatic adenocarcinoma show the expression of different genes(19). Thus, some patients had a particular tumour biology that confers radiosensitivity. Accordingly, we adopted early neoadjuvant CRT for patients with resectable pancreatic cancer, but we abandoned this strategy owing to disappointing results on considering all treated patients.(20) However, we observed that some resected specimens had a complete histologic response, indicating radiosensitivity.(21,22) Second, in the current study, patients who received CRT had a prolonged recurrence-free survival time and a trend of prolonged OS. This indicates that CRT provided true local control(23), consistent with the loco-regional recurrence rate of 30% reported previously(10,19). This does not result in a significant OS improvement, 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 optimized. Third, continuing with chemotherapy results in a rapid increase in the incidence of adverse events, requiring dose reduction or chemotherapy interruption. Thus, CRT might be a therapeutic sequence that provides a systemic break in an occasionally prolonged therapeutic strategy.
Perspectives in patients with non-metastatic LAPA at restaging
In contrast to the treatment methods available for breast or colorectal cancers, oncologists who treat pancreatic cancer do not have many treatment options at disposal; accordingly, it is not sensible to exclude CRT as an option for patients with unresectable but non-metastatic LAPA at restaging. Therefore, we must focus on restaging to propose the appropriate treatment for each patient, which should include CT, liver MRI(24), explorative laparoscopy (with para-aortic lymph node picking if technically feasible), and CA 19-9 serum 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(25–27) imaging seemed to be helpful, but the utility has to be validated in large prospective cohorts. Second, the tolerance to induction chemotherapy should be kept in mind, as severe adverse events would require chemotherapy switching or interruption. Third, the number of cycles achieved: our results showed that patients might benefit from at least 8 cycles of chemotherapy before CRT, similar to the results of other studies(10). Finally, the level of CA 19-9 should be considered for the switch 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.
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 the toxicity of chemotherapy and objective measures of the quality of life. 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.