Research Article - Onkologia i Radioterapia ( 2022) Volume 16, Issue 1

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

Rasha Abd El-Ghany Khedr1*, Mohamed Ghazaly2, Amira Khedr3 and Mohamed Fathy Sheta1
 
1Department of Clinical Oncology, Faculty of Medicine, Tanta University Hospital, Tanta University, Egypt
2Department of Surgery, Faculty of Medicine, Tanta University Hospital, Egypt
3Department of Radio-Diagnosis and Medical Imaging, Faculty of Medicine, Tanta University Hospital, Tanta University, Egypt
 
*Corresponding Author:
Rasha Abd El-Ghany Khedr, Department of Clinical Oncology, Faculty of Medicine, Tanta University Hospital, Tanta University, Egypt, Email: [email protected]

Received: 06-Dec-2021, Manuscript No. M-49165; Accepted: 12-Jan-2022, Pre QC No. P-49165; Editor assigned: 08-Dec-2021, Pre QC No. P-49165; Reviewed: 31-Dec-2021, QC No. Q-49165; Revised: 12-Jan-2022, Manuscript No. R-49165; Published: 17-Jan-2022

Abstract

Background: The patient’s outcome for Borderline Resectable Pancreatic Adenocarcinoma (BRPC) is dismal. We aimed to evaluate FOLFIRINOX efficacy/toxicity as a neoadjuvant chemotherapy followed by gemcitabinebased chemoradiation in (BRPC).

Methods: 23 chemotherapy/radiotherapy-naïve (BRPC) patients received six months of biweekly FOLFIRINOX chemotherapy. After FOLFIRINOX (12 times), protocol-based concurrent gemcitabine/IMRT external beam radiation therapy was delivered. Gemcitabine was administered on days (1/8/22 and 29). One month later, patients without progressive disease or unacceptable toxicity continued treatment for additional 2 cycles of gemcitabine infusions. The primary endpoint was R0 resection rates. Secondary endpoints were the Overall Response Rate (ORR), progression-free survival, overall survival, and toxicity.

Results: The ORR was 43.5% and the disease control rate was 82.1%. Nine patients had stable disease and 4 patients had disease progression. The resection rate was 60.9%, with R0 resections at 43.5%. Median PFS and OS were 16 and 23 months, respectively.1-year and 2-year OS rates were 74.7% and 49.6% respectively. 1-year and 2-year PFS rate was 54.9% and 35.3% respectively. Neutropenia (43.5%), was and Diarrhoea (17.4%), nausea (39.1%) were the most common grade (3-4) haematological and nonhaematological toxicity, respectively.

Conclusion: FOLFIRINOX followed by gemcitabine-based chemoradiation, was a more efficient regimen with a manageable toxicity profile in (BRPC).

Keywords

borderline resectable pancreatic cancer, FOLFIRINOX, gemcitabine based chemo radiation

Introduction

Carcinoma of the pancreas is a lethal malignancy [1-3]. Over the last few decades, it has a markedly increased incidence and ranked as the 7th leading cause of cancer-related deaths [4]. In the United States, the estimated newly reported cases and deaths from pancreatic cancer were about 55,440 and 44,330 respectively, in 2018 [5]. Cancer of the exocrine pancreas has been traditionally associated with low resectability [6-9]. Poor prognosis [2, 3,10,11], rarely curable and has a 5-year overall survival rate of 8% and a 10-year Overall Survival (OS) of 3% for all the stages [2,12]. Improvements in imaging technology, including positron emission tomographic scans, endoscopic ultrasound examination, magnetic resonance imaging scans, spiral computed tomographic scans, and laparoscopic staging can help to diagnose and identify patients with diseases that are not prone to resection [2, 7, 10, 13].

Patients with pancreatic cancer, at any stage, would be considered as appropriate candidates for the clinical trials, due to the well documented inadequate response to the conventionally used therapeutic modalities including radiation therapy, surgery, and chemotherapy [1, 3, 6, 7, 12, 14].

Patients with Borderline Resectable Pancreatic Cancer (BRPC) and locally advanced unresectable pancreatic cancers are anatomically characterized by the involvement extent of major vessels, which is likely associated with positive resection margin [15]. Several clinical trials have proposed that preoperative chemoradiotherapy for potentially resectable tumours helps to improve local recurrence and survival in resected patients [1, 7, 12, 13]. The 5-year OS was (20%) for patients undergoing resection, which may be improved up to (32%) in patients achieving complete resection and (40%) in those with nodenegative disease [12]. Thus, if the tumour is actually localized to the pancreas, the highest cure rate is recorded; however, unfortunately, only less than (20%) of patients are at this stage of the disease [14].

Several studies have recommended preoperative chemoradiotherapy for the locally advanced tumours, that were subsequently could be resected [1, 10, 12,13,16].

Previously, in a multi-institutional phase 2 study that was conducted on patients with pancreatic cancer to evaluate the neoadjuvant oxaliplatin and gemcitabine together with radiation therapy in patients with pancreatic cancer. They reported a resection rate of 63% for all treated patients, with 53% for R0 resections. Kim and his colleagues reported median survival of (18.2) months for all patients and (27.1) months, for resected patients [15].

Recently, In 2020, in the phase 2 trial on patients with (BRPC), neoadjuvant FOLFIRINOX and Intensity-Modulated Radiation Therapy (IMRT) concurrent with fixed-dose/rate gemcitabine, significantly improved the median OS for resected patients, with a median value of (37.1) months [13].

There was an amazing improvement in the magnitude of median OS, but it came with a price. Notably, there was an increased exposure and duration to local therapy intensification and systemic treatment [13]. However, the clinical evidence of significant activity in (BRPC) stimulated us to conduct this exploratory study. In this study, we investigate the efficacy of neoadjuvant FOLFIRINOX followed by gemcitabine when used concurrently with IMRT external beam radiotherapy as first-line therapy in (BRPC) patients.

Patients and Methods

Patient Eligibility Criteria

This phase II trial was carried out from January (2017) to January (2020). Twenty-three chemotherapy and radiotherapy-naïve patients with, confirmed measurable (BRPC) (BRPC stage has been defined by, the National Comprehensive Cancer Network [9], by quantification of the degree of tumour involvement with its surrounding arteries/ veins on imaging tumour involvement of or portal vein and the superior mesenteric more than (180°) without deformity, venous involvement less than (180°) with deformity, or short segment venous occlusion; celiac/superior mesenteric arteries contact of less than (180°), any common hepatic artery involvement, that is amenable to reconstruction; or direct abutment of the hepatic artery in absence of celiac axis extension) were enrolled.

Inclusion criteria

Includes Chemotherapy/radiotherapy-naïve, (18-70) years old patients; Eastern Cooperative Oncology Group (ECOG) performance status of (0-1); measurable borderline resectable disease; adequate bone marrow reserve (WBC count ≥3.5 × 109/L, ANC count ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, and haemoglobin ≥ 10 g/dL), preserved renal functions (creatinine clearance ≥ 60 mL/min) and preserved liver functions (transaminases<(2) × upper normal limit, and serum bilirubin level< (1.5) mg/dL).

Exclusion criteria

Includes symptomatic heart failure, severe arrhythmia, peripheral neuropathy, prior chemotherapy or radiotherapy, pregnant or lactating mothers, active infection, previous history of hypersensitivity reactions, any other uncontrolled medical problems or other malignancy.

Design of the study

This is a single-arm prospective (phase II) study of a single institution. Protocol approval was given by the Ethics Committee. Prior to initiation of any treatment; an informed consent was signed by all patients.

Pre-treatment evaluation

Pre/on-treatment close monitoring consisted of detailed medical history, physical examination, routine laboratory studies, pelvic and abdominal ultrasound, CT-scan of the pelvis, abdomen, and chest and (CA19.9 and CEA) measurement. Prior treatment, histologic, or cytological evidence of the pancreatic adenocarcinoma was documented in all patients.

Treatment plan and dose modification

Eligible patients received biweekly FOLFIRINOX (oxaliplatin (85) mg/m2 given as a 2-hour intravenous IV infusion, followed immediately by leucovorin 400 mg per square meter, given as a 2-hour IV infusion, with the addition, after 30 minutes, of irinotecan 180 mg per square meter, administered as a 90-minute IV infusion was followed immediately by fluorouracil 400 mg per square meter, administered by IV bolus, followed by a continuous IV infusion of 2400 mg per square meter over 46 hours, repeated every 2 weeks for 6 months of chemotherapy). Patients without Progressive Disease (PD) or unacceptable toxicity continued treatment up to 12 times over 6 months. Adequate hydration, anti-emetic therapy as well as steroids were secured for all patients. Antibiotics and growth factors, as a granulocyte-colony stimulating factor (G-CSF), were given to patients, guided by their continuous clinical evaluation.

Dose adjustment of FOLFIRINOX

Decisions were taken biweekly to modify the doses of chemotherapy, withhold treatment or progress with the schedule. Full biweekly doses of FOLFIRINOX regimen were given only if the absolute granulocyte count (AGC) was >1,000 cells/μl, platelets were > 100,000 cells/μl, and non-hematologic toxicities were ≤ grade 2. If the AGC ranged between (500-1,000) cells/ μl or the platelet count ranged between (50,000-100,000) cells/ μl, the FOLFIRINOX regimen dose was reduced by 25%. FOLFIRINOX regimen dose was reduced by 50% for grade 3 non-hematologic toxic effects. If the AGC was <500 cells/μl, the platelet count was <50,000 cells/μl and/or the non-hematologic toxic effects was grade 4, the FOLFIRINOX regimen dose was withheld, and the patient was reevaluated the following week.

Radiotherapy and gemcitabine administration

After 6 months of FOLFIRINOX, protocol-based concurrent gemcitabine IMRT external beam radiation therapy was delivered at 2.0 Gy per fraction, to a total dose of the mean planning target volume of 50.0 Gy if possible, in 25 fractions. Gemcitabine was administered on days 1, 8, 22, and 29 (1000 mg/m2 infused over 100 minutes).

Patients were treated with IMRT external beam radiation therapy. The radiotherapy field for IMRT encompassed the Gross Tumour Volume (GTV) included primary tumour and regional involved lymphatics identified on the pretreatment CT scan, including the porta hepatis, celiac axis, and superior mesenteric vessels (if involved). The Clinical Target Volume (CTV) included the GTV plus a 0.5 cm. The planning target volume (PTV) included the CTV plus 0.5 cm.

Evaluation during concurrent gemcitabine-IMRT external beam radiation therapy

During therapy, patients were assessed weekly via a directed history as well as physical examination. The occurrence and detailed nature of any adverse events, during treatment, were documented. Before each dose of gemcitabine, a full blood count was conducted. Other levels of blood chemistry were closely monitored as clinically indicated (alkaline phosphatase, bilirubin, aspartate transaminase, alanine transaminase, creatinine, blood urea nitrogen, calcium, phosphorus, glucose, albumin, total protein and electrolyte). One month after completion of protocol-based concurrent gemcitabine-IMRT external beam radiation therapy treatment monitoring consisted of a CT-scan and/or MRI of the abdomen and pelvis. Patients without PD or unacceptable toxicity continued treatment for another additional 2 cycles of gemcitabine infusions to complete neoadjuvant protocol.

Restaging

After treatment completion, all patients were re-evaluated by CTscan and/or MRI of the abdomen and pelvis to radiographically document tumour response. Based on the assessment of CT images taken at the time of restaging, surgery was considered in patients whose disorder was assumed to be technically resectable after therapy completion.

Patient Assessment

Assessment of clinical benefit, and follow-up

Tumour response was assessed based on the Response Evaluation Criteria in Solid Tumors [17], with the overall response rate, including partial/complete response, while, the disease control rate, including partial response, complete response, and stable disease. Patients were evaluated, after treatment completion, by physical examination, abdominopelvic CT, and chest radiography, every 3-4 months. Biopsy from new recurrent disease sites was rarely carried out and was reported at the time of initial occurrence.

Assessment of toxicity

During therapy, all patients were carefully examined bimonthly via a directed history as well as physical examination. The occurrence/nature of any adverse events was reported. The toxicity grading was based upon standard terminology standards for adverse events (NCI-CTC, version 3.0) [18].

Primary and Secondary Endpoints

The primary endpoint of this study was R0 resection rates, (as defined by the absence of both microscopic/gross involvements of tumour resection margins) in (BRPC) population. Secondary endpoints were the overall response rate, OS, progression-free survival and toxicity. Disease progression was assessed from the first chemotherapy dose, and it was defined as increase in the size of a previously present disorder as documented by serial axial CT, the appearance of new local/distant metastatic disorder.

Statistical analysis

Twenty-three patients were enrolled in the current study between January 2017 and January 2020. The date of this analysis was June 2021.

OS rates were calculated, by the Kaplan-Meier method [19], from the start of biweekly FOLFIRINOX to the time of the last follow-up visit or death, using SPSS (Statistical package, version 21.0). Progression-free survival was the time elapsed from the initiation date of biweekly FOLFIRINOX to the date of the first evidence of disorder progression or death in the absence of disease progression. OS and progression-free survival were compared by the Kaplan-Meier method [19] with statistical significance evaluated by the log-rank test. Mean and Standard Deviation (SD) were calculated from quantitative data. All P values were two-tailed; a value of ≤ 0.05 was considered significant.

Results

Patient characteristics

Patient characteristics were listed in Table 1. The median age was 53 years (range, 36-68). Fourteen patients (60.8%) had performance status 1. Twelve patients (52.2%) had involved body and tail pancreatic sites. Three (13.1%) patients had a biliary stent. The median level of CA19.9 was 600 U/ml. The median maximum cross-sectional Tumour Area (TA) was 8.7 cm2.

Patient Characteristics No. %
Sex
Male 15 65.2
Female 8 34.8
Age, years
Median 53
Range 36-68
ECOG performance status
0 9 39.1
1 14 60.9
Tumor location
Head 9 39.1
Body & tail 12 52.2
Overlapped lesion 2 8.7
Biliary stent
Yes 3 13.1
No 20 86.9
Presenting symptoms
Jaundice 16 70
Fatigue 11 48
Abdominal pain 17 74
Change in bowel pattern 10 43.5
Back pain 9 39
Anorexia 7 30
Largest axial area on CT
Median 8.7 cm2
Range 2.5 – 37 cm2
Level of CA19.9, U/ml
Median 600
Range 0 – 101 0,66

ECOG:- Eastern Cooperative Oncology Group

CA19.9:- Carbohydrate antigen

Tab.1. Baseline patient and tumour characteristics of the 23 patients with borderline resectable pancreatic cancer

Treatment administration

A total of 114 FOLFIRINOX chemotherapy cycles were administered. Patients were treated with a median number of 4 cycles of FOLFIRINOX (range 3-6 cycles), with dose modifications (according to criteria of dose adjustment mentioned previously in patients and methods) in 48.2% (55/114) of all FOLFIRINOX cycles.

Four patients (17.4%) had >3 dose delay of gemcitabine during concurrent gemcitabine-IMRT external beam radiation therapy. Two (9%) patients had radiotherapy interruptions due to toxicity. Fifteen patients (65.2%) complete 2 cycles of gemcitabine post radiation therapy.

Patients’ response to this regimen

The overall response rate (CR+PR) was 43.5% (10/23) of all patients and the disease control rate (CR+PR+SD) was 82.1% (19 patients). Nine patients (39.1%) had stable disease and 4 patients (17.4%) had disease progression (Table 2).

Evaluable patients N=23

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).

oncologyradiotherapy-Kaplan-Meier

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

oncologyradiotherapy-patients

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).

oncologyradiotherapy-pancreatic

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

oncologyradiotherapy-unresectable

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.

Enrolled patients No. %
Hematologic Toxicity
Neutropenia 10 43.5
Febrile Neutropenia 2 8.7
Thrombocytopenia 2 8.7
Non-hematologic Toxicity
Diarrhea 4 17.4
Nausea/vomiting 9 39.1
Mucositis 2 8.7
Gastrointestinal bleeding 2 8.7

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).

References

Editors List

  • S.SREEDHAR

    Submitted PhD thesis in Biotechnology at GITAM University, Vizag.

  • Yousef Alomi

    Yousef Alomi
    The Past Head, General Administration of Pharmaceutical Care at Ministry of Health,
    Saudi Arabia Critical Care/TPN
    Clinical Pharmacist Ministry of Health,
    Riyadh, Saudi Arabia.

  • Osamu Tanaka

    Osamu Tanaka
    Assistant Professor,
    Department of Radiation Oncology
    Asahi University Hospital
    Gifu city, Gifu, Japan

  • Maher Abdel Fattah Al-Shayeb

    Department of Surgical Sciences, Ajman University, UAE

  • Andrzej Zdziennicki

    Institute of Gynecology and Obstetrics, Medical University of Lodz, I Clinic of Gynecology and Gynecological Oncology (Lodz, Poland)

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