Neoadjuvant FOLFIRINOX followed by gemcitabine based chemoradiation as a treatment paradigm for Borderline resectable pancreatic adenocarcinoma

Tab.2. Tumour response of the 23 patients with borderline resectable pancreatic cancer

Pancreatic resection

Fourteen (60.9%) of the 23 patients who received this treatment protocol were thought to be candidates for pancreatic resection (either pancreaticoduodenectomy or distal pancreatectomy) based on CT images obtained four weeks after chemoradiation completion. The pre/post-treatment CT scans were reviewed to evaluate the lesion size and its relationship with the vessels before considering surgery. The resection rate in all treated patients was (60.9%), with R0 resections in 10 patients (43.5%). The median number of dissected regional lymph nodes was 10 (range, 5-15), and 9 patients (39.1%) had a positive metastatic nodal disease. No surgery-related mortality was reported.

Survival

All our patients had a regular follow up, with no one having lost follow-up in the current study. The median follow-up period was 24.5 months ± SE 1.01.

Median (OS) for all our patients was 23 months ± SE 8.451, (95% CI, 6.437-39.563) (Figure 1). The 1-year and 2-year OS rates for all our patients were 74.7% and 49.6% respectively (Figure 1). It was 13 months ± SE 2.336, (95% CI, 8.421- 17.579) for unresected patients and 30 months (95% CI, not reached) for resected patients (Figure 2).

Figure 1: Kaplan-Meier curve for overall survival time in all patients with borderline resectable pancreatic cancer

Figure 2: Kaplan-Meier curves for overall survival time in resectable and unresectable pancreatic cancer patients

Median Progression-Free Survival (PFS) for all our patients was 16.000 months ± SE ± 4.440), (95% CI, 7.297-24.703) (Figure 3). The 1-year and 2-year PFS rate was 54.9% and 35.3% respectively, (Figure 3). It was 10.000 months, SE ± 2.942 (95% CI, 4.233-15.767) for unresected patients, and 20 months, ± 2.828 (95% CI, 14.456- 25.544) for resected patients (Figure 4).

Figure 3: Kaplan-Meier curve for progression-free survival time in all patients with borderline resectable pancreatic cancer

Figure 4: Kaplan-Meier curve for progression-free survival time in resectable and unresectable pancreatic cancer patients

Toxicity

To assess non-hematologic/hematologic toxicities (Table 3), all enrolled patients were evaluated for toxicity and adverse events by the common terminology criteria for adverse event (version 3.0; NCI-CTC) [18]. The most common grades (3- 4) haematological toxicities were neutropenia in 10 patients (43.5%), with two patients (8.7%) suffering from febrile neutropenia, and another two patients (8.7%) developed grade (3-4) thrombocytopenia. Grade (3-4) diarrhoea in 4 patients (17.4%), nausea in 9 patients (39.1%) and mucositis in 2 patients (8.7%) were the most common Grade (3-4) non-haematological toxicity. Eight patients (34.8%) were started on prophylactic G-CSF concomitant with the first FOLFIRINOX cycle while additional nine patients (39.1%) had G-CSF support, which was added in later FOLFIRINOX cycles.

Tab.3. Hematologic and non-hematologic grade 3 and 4 toxicity of this regimen in the management of the 23 patients with borderline resectable pancreatic cancer

Four patients (17.4%) had >3 dose delay of gemcitabine during concurrent gemcitabine-IMRT external beam radiation therapy, and 2 (8.7%) patients presented with gastrointestinal bleeding with evidence of duodenal or gastric ulceration. Two (8.7%) patients had radiotherapy interruptions due to toxicity.

Due to treatment-related toxicity, ten (43.5%) of the 23 patients treated with this regimen were admitted to the hospital for supportive care. The median stay was 4 days. Five of these 10 patients were admitted twice and 5 were admitted three times.

Late toxicity

Two episodes (8.7%) of severe late effects that might have been treatment-related occurred. The 2 patients had episodes of duodenal ulceration with bleeding. An endoscopic biopsy was negative for the tumour but showed severe reactive changes consistent with the impact of treatment.

Discussion

Pancreatic cancer management remains a daunting challenge, often requiring a multidisciplinary approach to provide an efficient approach and, preferably, to optimise survival. The combination of local-regional approaches, such as surgery and radiotherapy, and systemic micrometastasis eradication therapies should also be considered for (BRPC) patients and those with locally advanced, unresectable disease [1,2,6].

BRPC has a poor prognosis with upfront surgery due to the high likelihood of microscopic and/or macroscopic residual tumours [20, 21]. However, neoadjuvant therapy may lead to improvement in R0 resection rates and long-term survival [7].

The integration of gemcitabine with radiation in a combined modality regimen may represent one strategy to improve outcomes in patients with pancreatic cancer, considering its activity as a single agent and laboratory studies that have demonstrated potent radiosensitization in human pancreatic cancer cell lines [12,13,15,16, 22].

FOLFIRINOX is clinically beneficial in both metastatic and nonmetastatic pancreatic cancer patients, considering substantial rates of adverse effects and the use of dose modifications. The toxicity of the regimen did not distort overall response and survival [23-26]. In our institution, it is the standard systemic treatment for metastatic, BRPC and locally advanced disease in patients with good performance status.

These observations have led us to document the use of neoadjuvant FOLFIRINOX and gemcitabine-based chemoradiation and its efficacy and tolerance in BRPC patients.

Our treatment schedule was based on data from Tran, et al. study that concluded that the optimal therapeutic index, in BRPC patients, can be achieved with FOLFIRINOX administration followed by gemcitabine-based chemoradiation [13].

In our study, responses were observed in 43.5% (10/23) of patients which were similar to the results of the Tran, et al. study [13], in patients with BRPC published in 2020 (RR was 44%) [13]. However, our results were better than the results of a study carried out between May 2016 and March 2018, in which investigators at Asan Medical Center, Seoul, Korea treated 44 patients with BRPC with neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine [7] who developed response rates of 34.1%.

In the current study, the disease control rate (PR+CR+SD) of 82.1% (19 patients) was comparable to the results of the Tran, et al. trial on FOLFIRINOX followed by gemcitabine-based chemoradiation in (BRPC) (disease control rate of 88%) [13].

In retrospect, it is now obvious from clinical data that when gemcitabine is used simultaneously with radiotherapy, the size of irradiated normal tissue is a crucial variable. The recommended dose of 1000 mg/m2 infused over 100 minutes on days 1, 8, 22, and 29 that we used with 50 Gy in 25 fractions to regional radiotherapy fields to most of the patients in our study is comparable to the dose given in prior study that used IMRT irradiation concurrently with gemcitabine[13]. While Sakamoto, et al. [27], suggest that because of its decreased toxicity, the low-dose gemcitabine infusion regimen can be consistently administered to patients with both locally advanced and systemically spreading pancreatic cancer, resulting in better life quality and an improved safety profile compared with the current care regimen for infusion.

The infusion rate of gemcitabine is a significant variable which has become evident from clinical data. Most studies assessing concomitant radiotherapy and gemcitabine were given at the manufacturer's recommended 30-minute as infusion rate for gemcitabine [28], which may not be ideal based on other clinical studies suggesting that a 10 mg/m²/min infusion rate is more efficient [13,16,29, 30]. The rate of infusion we used could have been serendipitously optimal; however, the smaller radiation volume with the use of IMRT is probably more important and could, in part, explain why we can be able to use higher doses of gemcitabine with good tolerability with the ability to finish gemcitabine-based chemoradiation for all our patients.

It is now obvious that the fractionation/ volume of irradiated normal tissue affects the patients' tolerance with concomitant gemcitabine [1-3]. Omitting elective nodal irradiation is an obvious means of expanding the therapeutic ratio in the studies of concomitant gemcitabine and radiotherapy. This idea has been advocated by researchers at the University of Michigan in patients with irresectable diseases 30 and owing to the enhanced toxicity associated with elective nodal irradiation if gemcitabine is to be used in radiotherapy; it tends to be the most desirable technique. The objective progression rate of the primary tumour was so high, in patients receiving concurrent radiotherapy and gemcitabine, in their study of BRPC patients. Indeed, it is hard to believe that elective nodal irradiation may have been of any benefit. In our study, higher doses of the weekly administered gemcitabine have been tolerated as radiotherapy is delivered to gross disease and involved regional lymph nodes only by the use of IMRT.

Our patients who received neoadjuvant FOLFIRINOX followed by gemcitabine-based chemoradiation were selected carefully (the ECOG PS was ≤ 1, with 39.1% of patients having ECOG PS of 0), yet the rate of hospitalization was elevated due to frequently reported severe acute toxicity. Ten (43.5%) of the 23 patients treated with the current regimen were admitted to the hospital for supportive care due to treatment-associated toxicity, with a median stay period of 4 days. Five of these 10 patients were admitted twice, while 5 patients were admitted three times. Our rate of hospitalization for treatment-related toxicity was higher than the rate of hospitalizations due to adverse events in Peddi, et al. trial (34.4%) [26] and comparable with Faris, et al. trial (41%) [31], most commonly for neutropenic fever, most of the patients in these two trials [26, 31], who displayed neutropenia (grades 3 or 4) had not received prophylactic growth factors with the start of treatment with FOLFIRINOX. Furthermore, the hospitalization rate in our study was higher than that reported in another retrospective single-institution series (14%) [32]. Differences in the rates of hospitalization for treatmentrelated toxicity between our trial and other trials may be due to the variations in the number of patients between these studies, the varying stages of pancreatic cancer included in these trials as well as the differences in the regimens of FOLFIRINOX- based treatment.

In our study 8 (34.8%) patients were started on prophylactical G-CSF concomitantly with the first treatment cycle while an additional 9 (39.1%) patients had G-CSF as supportive added in the later treatment cycles. Thus the 73.9% (17 patients) of our patients who received GCSF were comparable to the proportion of patients who received GCSF in Peddi, et al. [26] trial (73.9% vs. 77%, respectively). In the current study, neutropenia was reported as the most frequent grade (3-4) haematological toxicity in 10 patients (43.5%), compared to 40% in Tran, et al. study. In the ACCORD trial only 42% of patients in the FOLFIRINOX arm, received support with (G-CSF) resulting in a similar proportion of patients suffering from grade 3-4 neutropenia as in our study (45.7% versus 43.5% respectively). Consequently, 1 patient died from febrile neutropenia in the FOLFIRINOX group in the ACCORD trial [33], while, there was no treatment-related death in our study. Washington University physicians used a database to track the FOLFIRINOX efficacy and tolerance [32]. 48% of patients starting with the first cycle were given prophylactic growth factor support; 10% of patients started (G-CSF) in the subsequent cycles. Neutropenia (grades 3 and 4) has been reported in a lower proportion of patients (14%) [32]. Differences in rates of grades 3 and 4 neutropenia between our trial and other trials may be due to the variations in the number of patients in all these studies, the varying stages of included pancreatic cancers as well as the differences in the regimens of FOLFIRINOXbased treatment.

The severe non-haematologic toxicity rate in the present study was similar in patients treated with neoadjuvant FOLFIRINOX followed by gemcitabine-based chemoradiation and in those treated with the same regimen in Tran, et al. [13] study. Grade 3-4 nausea in 9 patients (39.1%) and diarrhoea in 4 patients (17.4%), were the most common Grade 3-4 non-haematological toxicity in our study. Similarly, the most frequently reported non-hematologic treatment-related adverse events in Tran, et al. trial [13] were nausea and vomiting in 40% and diarrhoea in 16%.

In our study, the dose was modified in 48.2% (55/114) of all cycles in response to adverse events. Researchers at Yale University have noted that oncologists were hesitant to use FOLFIRINOX, in a full dose, due to its toxicity profile [34]. A retrospective study has been conducted on pancreatic cancer patients, who were treated with FOLFIRINOX, at their institution between June (2010) and June (2011), to evaluate the possible effect of dose reduction on efficacy/toxicity. In the first cycle, only 17% of patients received a complete dose of FOLFIRINOX. The median relative doses of oxaliplatin, irinotecan, 5-FU bolus, and 5-FU infusion were 90%, 68%, 68%, and 100%, respectively. To track the tolerance and efficacy of FOLFIRINOX, Peddi, et al. used a registry [32]. In the majority of patients, the protocol was empirically altered because of concern about possible toxicities. In 48%, the 5-FU bolus was deleted. In 46%, the dosage of Irinotecan was reduced.

In our study, the median (OS) for all our patients was 23 months similar to that published in many other trials, in which the median OS of their population was in the range of 21.7- 37.7 months [13, 24, 25]. In the current study, the 1-year and 2-year OS rates for all our patients were 74.7% and 49.6% respectively, compared with the 75.4% and 54.2%, respectively reported in the Tran, et al. trial [13].

The median OS survival reported in patients with the unresectable disorder, who were treated with this combination was similar to OS rate in patients treated with the same regimen in Tran, et al. [13] study, (13 months vs. 12.6 months respectively). These observations concluded a very narrow therapeutic index for the utility of neoadjuvant FOLFIRINOX followed by concurrent gemcitabine and radiotherapy administered in this way without tumour resection. In spite of the reported increased toxicity no clear significant increase in efficacy in patients not amenable for curative surgery. However, the OS of the resected cohort was more favourable. In our study, the median OS of the R0 resected patients is 30 months, approximately comparable to that mentioned in R0 resected patients of other studies treated with preoperative FOLFIRINOX followed by chemoradiation for BRPC [13,24,25].

Because curative therapeutic approaches in pancreatic cancer patients must include surgery, all therapies that increase resectability are of interest. A possible benefit of FOLFIRINOX followed by concurrent gemcitabine and radiotherapy in this study was the ability to perform surgery in 14 patients (60.9%) of (BRPC) patients. Ten patients (43.5%) receiving FOLFIRINOX followed by concurrent gemcitabine and IMRT external beam radiotherapy underwent margin negative pancreaticoduodenectomies.

The R0 resection rate in this study was observed to be 43.5% which is lower than the 52% mentioned in Tran, et al. [13] study using the same regimen of our study (FOLFIRINOX followed by concurrent gemcitabine and radiotherapy) and the 64% published in Katz, et al. phase 2, a multi-institutional trial using FOLFIRINOX followed by capecitabine concurrently with radiation in patients with BRPC [24] as well as the 65% R0 resection rate in Murphy, et al. using FOLFIRINOX followed by capecitabine concurrent with radiation in patients with (BRPC) [25]. However, this 43.5% R0 resection rate in our study was observed to be better than the R0 resection rate of 30% in Small, et al. [35] and Katz, et al. [36] studies. Differences in resection rates between our trial and other trials may be due to the small number of patients in all these studies, the varying definitions of (BRPC) as well as the variations in the experience of the surgeons.

According to the results achieved with FOLFIRINOX followed by gemcitabine and 50 Gy IMRT, both local and distant failure rates were significant problems in our patients, regardless of the used chemotherapy. Although the FOLFIRINOX followed by a combination of radiation and gemcitabine, is a potent cytotoxic intervention modality [22], we reported one-year and two-year PFS rates of 53% and 30% respectively. Median (PFS) for all our patients was 16 months, slightly more than the 13.1 months reported in the Tran et al [13] study using the same regimen of our study (FOLFIRINOX followed by concurrent gemcitabine and IMRT radiotherapy). We have used a radiotherapy dose of 50 Gy in 25 fractions. However, some may argue that higher radiation doses may be more appropriate for unresectable diseases with enhanced survival, but there is no compelling proof up till now [37]. In our experience, distant metastasis is the predominant cause of death. Thus, distant metastases are still the main limitation. This clarifies the need for ongoing research into novel systemic agents for this disease [38-40]. Thus far, major improvement in outcome for patients with BRPC has not been demonstrated with this therapy. The study of the impact of higher radiation doses does not seem to be a priority until more reliable systemic therapy is developed. 40.

Conclusion

In conclusion, the FOLFIRINOX followed by concurrent gemcitabine and IMRT external beam radiotherapy regimen has gained increased acceptance due to its better efficacy as first-line therapy in patients with BRPC, improved response rate and median OS over that achieved with gemcitabinebased combination regimens in previous studies. The doses and schedules of concurrent gemcitabine and radiotherapy used in this study had a high toxicity rate than did treatment with other multiagent combinations including, gemcitabine and nab-paclitaxel and radiotherapy [41]. Thus, in spite of, the overall survival rate was significantly better for patients who received neoadjuvant FOLFIRINOX followed by concurrent gemcitabine and radiotherapy, this treatment program still has significant limitations. Considering the toxicity and efficacy, this regimen could be a viable therapeutic option in selected patients with a good PS only.

Further prospective trials should evaluate how to adjust doses to ameliorate the toxicity of this regimen. In addition, patients with BRPC should continue to be enrolled in prospective trials to explore potential formulations of concomitant radiotherapy with cytotoxic agents and/or biologic agents. Future prospective research should also be supported based on further knowledge of tumour biology, targeting different growth factor signalling pathways, and developing new technologies, including the discovery of biomarkers that predict the response to treatment.

Disclosure Statement

No potential conflict of interest was documented by the author(s).

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