www.nature.com/scientificreports
OPEN
received: 09 December 2016 accepted: 03 March 2017 Published: 05 April 2017
Phase II study of induction chemotherapy followed by chemoradiotherapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer Michele Fiore1, Sara Ramella1, Sergio Valeri2, Damiano Caputo2, Barnaba Floreno1, Pasquale Trecca1, Luca Eolo Trodella1, Lucio Trodella1, Rolando Maria D’Angelillo1 & Roberto Coppola2 There is not a clear consensus regarding the optimal treatment of locally advanced pancreatic disease. There is a potential role for neoadjuvant therapy to treat micrometastatic disease with chemotherapy, as well as for the treatment of local disease with radiotherapy. We evaluated the safety and efficacy of induction chemotherapy with oxaliplatin and gemcitabine followed by a high weekly dose of gemcitabine concurrent to radiation therapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer. In our study, 41 patients with pancreatic cancer were evaluated. In all cases an accurate pre-treatment staging was performed. Patients with evidence of metastatic disease were excluded, and thus a total of 34 patients were consequently enrolled. Of these, twentyseven patients (80%) had locally advanced unresectable tumours, seven patients (20%) had borderline resectable disease. This protocol treatment represents a well-tolerated promising approach. Fifteen patients (55.5%) underwent surgical radical resection. With a median follow-up of 20 months, the median PFS and OS were 20 months and 19.2 months, respectively. The median OS for borderline resectable patients was 21.5 months compared with 14 months for unresectable patients (p = 0.3). Continued optimization in multimodality therapy and an accurate patient selection remain crucial points for the appropriate treatment of these patients. Pancreatic cancer is the fourth leading cause of cancer death in the U.S. An estimated 53,070 new cases were diagnosed and 41,780 deaths were expected in the U.S. in 20161. Surgery is the only potentially curative treatment, but it is confined to 20% of patients with clinically localized disease. Unfortunately, the majority of patients present with borderline resectable or unresectable pancreatic cancer2. Despite advances in radiation therapy techniques and improved chemotherapeutic regimes, the poor prognosis of patients with pancreatic cancer has not significantly improved. There is no a clear consensus regarding the optimal treatment of locally advanced pancreatic disease. The two most commonly selected therapeutic options are gemcitabine-based chemotherapy and radiochemotherapy (RCT)3. During the last decade, several studies have tested the combination of both approaches as a sequential schedule of induction chemotherapy followed by RCT for patients without evidence of progression4–7. This multidisciplinary treatment strategy allows not only the treatment of systemic disease upfront, but also provides the opportunity for early detection of a rapidly aggressive disease that would not benefit from RCT. In order to better select patients for treatment and to improve clinical outcomes, we designed a prospective phase II study to evaluate the tolerability and efficacy of induction chemotherapy with oxaliplatin and gemcitabine 1 Radiotherapy Unit, Campus Bio-Medico University, Rome, Italy. 2Department of General Surgery, Campus BioMedico University, Rome, Italy. Correspondence and requests for materials should be addressed to M.F. (email: [email protected])
Scientific Reports | 7:45845 | DOI: 10.1038/srep45845
1
www.nature.com/scientificreports/ followed by a high weekly dose of gemcitabine concurrent to radiation therapy in borderline resectable (BRCP) and unresectable locally advanced pancreatic cancer (LAPC).
Materials and Methods
This trial was performed as a single-center one-armed phase II study. Forty-one treatment-naïve patients affected by histologically proven pancreatic cancer, with borderline resectable or locally advanced disease, were included in the study. Definitions of borderline and unresectable disease were as per NCCN guidelines. Borderline resectable tumors were defined by venous involvement of the superior mesenteric vein (SMV) or portal vein (PV), gastroduodenal artery encasement, or abutment of the superior mesenteric artery (SMA) up to 180°. Unresectable disease was defined by greater than 180° of SMA involvement, SMV/PV occlusion that is not amenable to reconstruction, or aortic or inferior vena cava (IVC) invasion or encasement. The selected patients did not have a history of metastatic cancer, prior history of radiotherapy to the abdomen, or younger than 18 years of age. Only patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and hematologic parameters that indicated adequate bone marrow, renal and hepatic function were considered eligible. In all cases a thorough pre-treatment staging was performed, including: physical examination, complete blood tests and tumor markers, endoscopic ultrasonography (EUS) with fine needle aspiration biopsy, multilayer CT scan, PET-CT with 18F-2-fluoro-2-deoxy-D-glucose (FDG) and laparoscopy with peritoneal washing. Jaundiced patients before or during treatment underwent endoscopic biliary stenting. All patients signed a study specific consent form. The induction phase of the treatment plan was designed to administer gemcitabine 1000 mg/mq and oxaliplatin 100 mg/mq every 14 days for four doses. For patients without disease progression as detected through restaging exams (CT scan, 18-FDG PET-CT scan), chemotherapy was followed by RCT which consisted of conformal radiation therapy and concurrent gemcitabine at the dose of 600 mg/mq weekly. In the combined phase of the treatment all patients underwent simulation by using a Siemens 16-CT simulator (Siemens Medical System). Radiotherapy target volumes were established by CT scan and PET-CT scan. For patients with BRPC, the Clinical Target Volume (CTV) included the tumour and involved lymph nodes (>1 cm on CT scan and PET positive); the external beam radiation was delivered with a total dose of 54 Gy with fractionation of 1.8 Gy daily for 5 days a week. For patients with LAPC, the CTV included tumour and involved lymph nodes for a total dose of 59.4 Gy, targeting also frequently involved peripancreatic lymph nodes at risk for the dose of 45 Gy, with fractionation of 1.8 Gy daily for five days a week. In both cases, the Planning Target Volume (PTV) was defined by CTV with a safety margin of 1 cm in all directions to include organ motion and set-up errors. Patients were fixed during therapy by individual immobilization devices. Patients were treated using 3D-conformal radiotherapy. Organs at risk for radiation-induced side effects were contoured on the dose planning CT and dose volume histograms (DVH) were calculated. Doses to the liver, kidneys, stomach and spine did not exceed the tolerance of these normal tissues. All treatments were delivered with a 15-MV linear accelerator (Varian Medical System) with a multifield isocentric technique using a multileaf collimator. All fields were treated daily. A quality-control protocol was applied for all patients with periodical digital portal images to evaluate the precision of the set-up. During treatment, patients were evaluated through a directed history and weekly physical examination. The occurrence and nature of any adverse events were recorded in accordance with the National Cancer Institute Common Toxicity Criteria (version 4.0) scale. When multiple treatment-related adverse events of the same type occurred in the same patient, only the most severe ones were reported. Subsequently, the dose of chemotherapy was adjusted according to the number of occurrences of grade 2 or greater events: after a first occurrence, 75% of starting dose was used, while after a second occurrence, 50% of the starting dose was used. Four weeks after the completion of RCT, restaging, consisting of clinical examination, laboratory test, tumor markers, CT scan and PET-CT scan, was performed. Tumor response was defined in accordance with the World Health Organization (WHO) definition through CT scan and PET-CT scan. Surgery was considered in patients whose tumors were technically resectable. After resection, patients were evaluated every three months by means of a standard surveillance protocol that included history and physical examination, cross-sectional imaging and measurement of serum markers, and the intervals were extended to six months after two years. We followed unresected patients in accordance with their clinical course. All study sample characteristics were summarized with descriptive statistics. The primary endpoint of the study was to analyse the rate of resection. Secondary endpoints were the analysis of toxicity, overall survival (OS), progression-free survival (PFS), local control (LC) and metastases free-survival (MFS). The resection rate achieved in our previous prospective study of neoadjuvant chemoradiation was 33%10. Simon’s minimax two stage phase II design was planned to test the null hypothesis that the resection rate was ≤30% versus the alternative hypothesis that the resection rate was ≥50% with type I and II errors of 5% and 20% respectively. The study was designed to accrue a sample size of 39 patients with an interim analysis of 19 patients. Overall Survival was determined from the day of the histological diagnosis. Progression-free survival was obtained from the beginning of treatment to the observation of progression/recurrence, or to the last follow-up if no event was observed. OS and PFS curves were calculated with the Kaplan-Meier method. This study was reviewed, approved and monitored by the independent Ethics Committee of our University. The methods were carried out in accordance with the approved guidelines. Signed informed consents were obtained from all study participants. This trial was registered at ClinicalTrials.gov with Identifier NCT02984501 on 2 December 2016.
Scientific Reports | 7:45845 | DOI: 10.1038/srep45845
2
www.nature.com/scientificreports/
Characteristic
No of patients (N = 34)
%
Age (years) Median
63.5
Range
40–75
Sex Male
17
50
Female
17
50
0
34
100
1
0
0
ECOG performance status
CA 19-9 at diagnosis, U/mL Median
998
Range
OPEN
received: 09 December 2016 accepted: 03 March 2017 Published: 05 April 2017
Phase II study of induction chemotherapy followed by chemoradiotherapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer Michele Fiore1, Sara Ramella1, Sergio Valeri2, Damiano Caputo2, Barnaba Floreno1, Pasquale Trecca1, Luca Eolo Trodella1, Lucio Trodella1, Rolando Maria D’Angelillo1 & Roberto Coppola2 There is not a clear consensus regarding the optimal treatment of locally advanced pancreatic disease. There is a potential role for neoadjuvant therapy to treat micrometastatic disease with chemotherapy, as well as for the treatment of local disease with radiotherapy. We evaluated the safety and efficacy of induction chemotherapy with oxaliplatin and gemcitabine followed by a high weekly dose of gemcitabine concurrent to radiation therapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer. In our study, 41 patients with pancreatic cancer were evaluated. In all cases an accurate pre-treatment staging was performed. Patients with evidence of metastatic disease were excluded, and thus a total of 34 patients were consequently enrolled. Of these, twentyseven patients (80%) had locally advanced unresectable tumours, seven patients (20%) had borderline resectable disease. This protocol treatment represents a well-tolerated promising approach. Fifteen patients (55.5%) underwent surgical radical resection. With a median follow-up of 20 months, the median PFS and OS were 20 months and 19.2 months, respectively. The median OS for borderline resectable patients was 21.5 months compared with 14 months for unresectable patients (p = 0.3). Continued optimization in multimodality therapy and an accurate patient selection remain crucial points for the appropriate treatment of these patients. Pancreatic cancer is the fourth leading cause of cancer death in the U.S. An estimated 53,070 new cases were diagnosed and 41,780 deaths were expected in the U.S. in 20161. Surgery is the only potentially curative treatment, but it is confined to 20% of patients with clinically localized disease. Unfortunately, the majority of patients present with borderline resectable or unresectable pancreatic cancer2. Despite advances in radiation therapy techniques and improved chemotherapeutic regimes, the poor prognosis of patients with pancreatic cancer has not significantly improved. There is no a clear consensus regarding the optimal treatment of locally advanced pancreatic disease. The two most commonly selected therapeutic options are gemcitabine-based chemotherapy and radiochemotherapy (RCT)3. During the last decade, several studies have tested the combination of both approaches as a sequential schedule of induction chemotherapy followed by RCT for patients without evidence of progression4–7. This multidisciplinary treatment strategy allows not only the treatment of systemic disease upfront, but also provides the opportunity for early detection of a rapidly aggressive disease that would not benefit from RCT. In order to better select patients for treatment and to improve clinical outcomes, we designed a prospective phase II study to evaluate the tolerability and efficacy of induction chemotherapy with oxaliplatin and gemcitabine 1 Radiotherapy Unit, Campus Bio-Medico University, Rome, Italy. 2Department of General Surgery, Campus BioMedico University, Rome, Italy. Correspondence and requests for materials should be addressed to M.F. (email: [email protected])
Scientific Reports | 7:45845 | DOI: 10.1038/srep45845
1
www.nature.com/scientificreports/ followed by a high weekly dose of gemcitabine concurrent to radiation therapy in borderline resectable (BRCP) and unresectable locally advanced pancreatic cancer (LAPC).
Materials and Methods
This trial was performed as a single-center one-armed phase II study. Forty-one treatment-naïve patients affected by histologically proven pancreatic cancer, with borderline resectable or locally advanced disease, were included in the study. Definitions of borderline and unresectable disease were as per NCCN guidelines. Borderline resectable tumors were defined by venous involvement of the superior mesenteric vein (SMV) or portal vein (PV), gastroduodenal artery encasement, or abutment of the superior mesenteric artery (SMA) up to 180°. Unresectable disease was defined by greater than 180° of SMA involvement, SMV/PV occlusion that is not amenable to reconstruction, or aortic or inferior vena cava (IVC) invasion or encasement. The selected patients did not have a history of metastatic cancer, prior history of radiotherapy to the abdomen, or younger than 18 years of age. Only patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and hematologic parameters that indicated adequate bone marrow, renal and hepatic function were considered eligible. In all cases a thorough pre-treatment staging was performed, including: physical examination, complete blood tests and tumor markers, endoscopic ultrasonography (EUS) with fine needle aspiration biopsy, multilayer CT scan, PET-CT with 18F-2-fluoro-2-deoxy-D-glucose (FDG) and laparoscopy with peritoneal washing. Jaundiced patients before or during treatment underwent endoscopic biliary stenting. All patients signed a study specific consent form. The induction phase of the treatment plan was designed to administer gemcitabine 1000 mg/mq and oxaliplatin 100 mg/mq every 14 days for four doses. For patients without disease progression as detected through restaging exams (CT scan, 18-FDG PET-CT scan), chemotherapy was followed by RCT which consisted of conformal radiation therapy and concurrent gemcitabine at the dose of 600 mg/mq weekly. In the combined phase of the treatment all patients underwent simulation by using a Siemens 16-CT simulator (Siemens Medical System). Radiotherapy target volumes were established by CT scan and PET-CT scan. For patients with BRPC, the Clinical Target Volume (CTV) included the tumour and involved lymph nodes (>1 cm on CT scan and PET positive); the external beam radiation was delivered with a total dose of 54 Gy with fractionation of 1.8 Gy daily for 5 days a week. For patients with LAPC, the CTV included tumour and involved lymph nodes for a total dose of 59.4 Gy, targeting also frequently involved peripancreatic lymph nodes at risk for the dose of 45 Gy, with fractionation of 1.8 Gy daily for five days a week. In both cases, the Planning Target Volume (PTV) was defined by CTV with a safety margin of 1 cm in all directions to include organ motion and set-up errors. Patients were fixed during therapy by individual immobilization devices. Patients were treated using 3D-conformal radiotherapy. Organs at risk for radiation-induced side effects were contoured on the dose planning CT and dose volume histograms (DVH) were calculated. Doses to the liver, kidneys, stomach and spine did not exceed the tolerance of these normal tissues. All treatments were delivered with a 15-MV linear accelerator (Varian Medical System) with a multifield isocentric technique using a multileaf collimator. All fields were treated daily. A quality-control protocol was applied for all patients with periodical digital portal images to evaluate the precision of the set-up. During treatment, patients were evaluated through a directed history and weekly physical examination. The occurrence and nature of any adverse events were recorded in accordance with the National Cancer Institute Common Toxicity Criteria (version 4.0) scale. When multiple treatment-related adverse events of the same type occurred in the same patient, only the most severe ones were reported. Subsequently, the dose of chemotherapy was adjusted according to the number of occurrences of grade 2 or greater events: after a first occurrence, 75% of starting dose was used, while after a second occurrence, 50% of the starting dose was used. Four weeks after the completion of RCT, restaging, consisting of clinical examination, laboratory test, tumor markers, CT scan and PET-CT scan, was performed. Tumor response was defined in accordance with the World Health Organization (WHO) definition through CT scan and PET-CT scan. Surgery was considered in patients whose tumors were technically resectable. After resection, patients were evaluated every three months by means of a standard surveillance protocol that included history and physical examination, cross-sectional imaging and measurement of serum markers, and the intervals were extended to six months after two years. We followed unresected patients in accordance with their clinical course. All study sample characteristics were summarized with descriptive statistics. The primary endpoint of the study was to analyse the rate of resection. Secondary endpoints were the analysis of toxicity, overall survival (OS), progression-free survival (PFS), local control (LC) and metastases free-survival (MFS). The resection rate achieved in our previous prospective study of neoadjuvant chemoradiation was 33%10. Simon’s minimax two stage phase II design was planned to test the null hypothesis that the resection rate was ≤30% versus the alternative hypothesis that the resection rate was ≥50% with type I and II errors of 5% and 20% respectively. The study was designed to accrue a sample size of 39 patients with an interim analysis of 19 patients. Overall Survival was determined from the day of the histological diagnosis. Progression-free survival was obtained from the beginning of treatment to the observation of progression/recurrence, or to the last follow-up if no event was observed. OS and PFS curves were calculated with the Kaplan-Meier method. This study was reviewed, approved and monitored by the independent Ethics Committee of our University. The methods were carried out in accordance with the approved guidelines. Signed informed consents were obtained from all study participants. This trial was registered at ClinicalTrials.gov with Identifier NCT02984501 on 2 December 2016.
Scientific Reports | 7:45845 | DOI: 10.1038/srep45845
2
www.nature.com/scientificreports/
Characteristic
No of patients (N = 34)
%
Age (years) Median
63.5
Range
40–75
Sex Male
17
50
Female
17
50
0
34
100
1
0
0
ECOG performance status
CA 19-9 at diagnosis, U/mL Median
998
Range
