This study aimed to evaluate the short-term safety and long-term efficacy of CRT combined with GEM and nab-PTX for UR-LA PDAC. Previous studies that assessed CRT for locally advanced PDAC showed longer survival in patients undergoing CRT than those undergoing chemotherapy or radiation alone21–23. Therefore, the National Comprehensive Cancer Network guidelines recommend CRT for locally advanced PDAC24. In PDAC, the recommended dose for chemotherapy using the GnP regimen consists of one cycle of 1,000 mg/m2 GEM and 125 mg/m2 of nab-PTX and is repeated weekly for 3 weeks, followed by 1 week of rest. In this study, radiotherapy (planned total dose, 50.4 Gy per 28 fractions) was added to the GnP regimen. Thus, we designed the plan with a reduced dose of the GnP regimen (800 mg/m2 or 1000 mg/m2 of GEM and 100 mg/m2 of nab-PTX), which was repeated weekly for 2 weeks, followed by 1 week of rest, and two cycles.
At the starting dose of GEM (1000mg/m2), two patients (2/3, 66.7%) failed to complete the planned dose of CRT due to grade 3 neutropenia or hepatic impairment. Based on these results, we decided to reduce the GEM dose. Four (4/5, 80.0%) patients completed the planned CRT dose. Therefore, the doses for CRT using the GnP regimen in patients with UR-LA PDAC were determined to be 800 mg/m2 of GEM and 100 mg/m2 of nab-PTX with a total dose of 50.4 Gy radiation, and the treatment cycle was repeated weekly for 2 weeks, followed by 1 week of rest. This regimen reduced the dose of GEM, and the treatment cycle was well tolerated, with no unexpected increase in the frequency or severity of toxicities.
Recently, neoadjuvant therapy has been performed using various treatment protocols, including chemotherapy or CRT with conversion surgery. Hackert et al.25 reported that conversion surgery was performed in approximately 50% of patients, and the resection rate with the FOLFIRINOX regimen was 61%. We chose the GnP regimen because the major adverse events, such as anorexia and hematologic toxicity, were more severe with the FOLFIRINOX regimen26. Moreover, most patients receiving FOLFIRINOX require dose reduction because of severe toxicities13.
In this study, conversion surgery was performed in 25.0% (2/8) of the patients with initial UR-LA PDAC. In addition, curative resection (R0) was performed in both patients (100%). Although there were only two cases, the R0 rate was higher than that in previous studies25,27–29.
In addition, it was difficult to determine when conversion surgery was performed. When patients with UR-LA PDAC experience significant tumor shrinkage to the resectable status, determining the use of conversion surgery is easy. However, it is difficult to perform resection for patients with stable disease after these therapies. Satoi et al.30 reported that CA19-9 level < 100U/mL can be a safety marker for performing resection in these situations. Yokose et al.31 reported the usefulness of positron emission tomography-CT for treatment response to neoadjuvant therapy for PDAC. Nakano et al.32 reported perioperative changes in KRAS mutations, indicating that cell-free DNA may be a useful predictive biomarker for survival and treatment response. Moreover, circulating tumor cells and microemboli have been reported to be appropriate for assessing therapeutic effects in patients with UR-LA PDAC33. Therefore, these biomarkers may be candidates for determining the time of conversion surgery and the judgment of therapeutic effects.
In our resected cases, the pathological response was either grade Ib or II. In cases of grade Ib, conversion surgery was performed after this treatment protocol. In contrast, in the case of grade II, surgery was performed after an additional three cycles of GnP treatment. In this study, conversion surgery was considered in patients with stable disease or better, according to RESIST, technically resectable tumors and an Eastern Cooperative Oncology Group performance status of 0 or 1 after this treatment protocol. Yamada et al.34 reported an extremely good pathological response (Grade 3 or 4). In these cases, conversion surgery was performed after the CRT using GnP and an additional six cycles of the GnP regimen. According to these results, the treatment response observed in several additional cycles of the GnP regimen after CRT with the GnP regimen seemed superior to those observed in only CRT with GnP. Therefore, it is difficult for patients with UR-LA PDAC to undergo conversion surgery after CRT alone, and a limit of CRT for UR-LA PDAC was suggested.
In two of the five patients who did not plan to undergo resection, distant metastasis occurred after CRT. Systemic chemotherapy may be necessary to control tumor progression, such as distant metastasis. In addition, induction chemotherapy could be a tool that provides extra time to assess whether distant metastasis appears during this treatment. Thus, we plan to evaluate the efficacy of CRT after induction chemotherapy in patients with borderline resectable PDAC.
This study had several limitations. First, it was a retrospective study with a single-center design. Second, the number of enrolled patients was small. Therefore, multicenter studies with larger sample sizes are warranted to achieve robust conclusions.
In conclusion, the CRT regimen using 800 mg/m2 GEM and 100 mg/m2 nab-PAX per two 3-week cycles with a concurrent total dose of 50.4 Gy (1.8 Gy/28 fractions) radiation is well-tolerated and safe. However, many patients with UR-LA PDAC require additional treatment. Therefore, the limits of CRT for UR-LA PDAC have been suggested.