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Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer
A single institutional experience
Version of Record online: 6 JUL 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 2, pages 277–284, 15 January 2013
How to Cite
Leone, F., Gatti, M., Massucco, P., Colombi, F., Sperti, E., Campanella, D., Regge, D., Gabriele, P., Capussotti, L. and Aglietta, M. (2013), Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer. Cancer, 119: 277–284. doi: 10.1002/cncr.27736
- Issue online: 4 JAN 2013
- Version of Record online: 6 JUL 2012
- Manuscript Accepted: 7 JUN 2012
- Manuscript Revised: 5 JUN 2012
- Manuscript Received: 3 MAR 2012
- pancreatic neoplasm;
- locally advanced;
- combined modality therapy;
- neoadjuvant treatment
Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol.
Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2). Patients without disease progression then received gemcitabine twice weekly (50 mg/m2 daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability.
Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001).
The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation. Cancer 2013. © 2012 American Cancer Society.
Optimal therapy for patients with locally advanced pancreatic carcinoma (LAPC) is still controversial. Combined-modality therapies have been proposed to achieve better local tumor control or tumor down-staging with a subsequent, potentially curative resection.1 Since the early 1980s, concomitant chemoradiotherapy (CRT) has been adopted as a standard treatment for patients with LAPC on the basis of the study by Moertel et al, who demonstrated that radiation therapy combined with 5-fluorouracil (5FU) treatment prolongs the median survival of patients with unresectable disease compared with radiotherapy alone.2 Because gemcitabine is superior to 5FU in treating patients with symptomatic, advanced pancreatic cancer, the substitution of 5FU with gemcitabine plus concurrent radiotherapy has been evaluated in several phase 1 and 2 trials. In a previous publication, we reported that primary radiotherapy in combination with gemcitabine is feasible and provides a clinical benefit in 55% of patients.3 We demonstrated that such an approach has a high disease control rate (96%) and produces an overall survival (OS) of 14 months. Moreover, combined CRT may render curative resection feasible in a subgroup of patients with LAPC, and we recently demonstrated that patients who underwent resection after CRT for locally advanced tumors had at least the same survival rate as those who underwent primary resection for localized tumors.4
An important concern about administering CRT as first-line treatment in LAPC is that patients who have early, progressive, metastatic disease are unlikely to benefit from locoregional treatment. Recently, 2 randomized trials evaluated treatment with chemotherapy alone compared with induction CRT followed by maintenance chemotherapy. The results from those trials were controversial. Chauffert et al5 demonstrated a significant improvement in median OS for patients who received chemotherapy alone compared with those who received intensive induction 5FU and cisplatin-based CRT (13 months vs 8.6 months). By contrast, the Eastern Cooperative Oncology Group study E42016 randomized patients between induction gemcitabine-based CRT followed by maintenance gemcitabine versus gemcitabine alone. Those authors reported a significant improvement in OS in favor of patients who received CRT (11 months vs 9.2 months).
The receipt of chemotherapy as first-line treatment for LAPC theoretically provides a systemic means of disease control by selecting a subgroup of patients who potentially may benefit from CRT. Several clinical trials have recently addressed this point.7-12 Here, we report a single-center experience with a prospective series of consecutive patients with LAPC who received induction chemotherapy with combined gemcitabine and oxaliplatin (GEMOX) followed by gemcitabine-based CRT.
MATERIALS AND METHODS
Patients with LAPC had histologically or cytologically proven pancreatic adenocarcinoma with tumor infiltration of the celiac axis, the superior mesenteric artery, or the superior mesenteric-portal vein. In a multidisciplinary evaluation by the pancreatic team, patients also were subdivided into a “borderline resectable” group and an “unresectable” group. A tumor was classified as “borderline resectable” when there was an abutment ≤50% in the circumference of the superior mesenteric artery or the celiac axis; a short segment encasement of the common hepatic artery; segmental portal vein/superior mesenteric vein stenosis; or an occlusion amenable to vascular resection. Patients who presented with encasement of the superior mesenteric artery or the celiac axis or with an occlusion of the portal vein or superior mesenteric vein that precluded vascular resection were classified as “unresectable.”13
Pretreatment evaluation included the patient's medical history, a physical examination, and multiphasic multidetector computed tomography (CT) scans of the chest and abdomen. All patients were aged >18 years and were required to have measurable disease defined by CT imaging, an Eastern Cooperative Oncology Group performance score from 0 to 2, a neutrophil count >1500 cells/μL, and a platelet count >100,000/μL. Adequate hepatic and renal functions also were required for inclusion in the study. No prior chemotherapy or radiation to the upper abdomen was permitted for inclusion. Written informed consent was required before the patient's enrollment into the study.
The design of this study was approved by the Institutional Review Board. Patients received induction chemotherapy with 4 cycles of GEMOX (gemcitabine 1000 mg/m2 as a 60-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2), and each cycle lasted for 2 weeks. Before each cycle of chemotherapy, patients were evaluated for toxicity, and weight and performance status were recorded. All toxicity values were graded using the National Cancer Institute Common Terminology Criteria, version 3.0. Patients without disease progression (according to results from a thoracoabdominal multiphasic multidetector CT) received 50.4 grays (Gy) of upper abdominal radiation (1.8 Gy per fraction) over 5.5 weeks using a 3-dimensional CRT technique.
Each patient underwent CT-based planning before treatment was started. Each planning CT scan was obtained using a Toshiba BigBore Aquilion 16-CT simulator (Toshiba Medical Systems Corporation, Otawara-shi, Japan). Volumes were drawn on each individual planning CT slice, and the recommendations of International Commission on Radiation Units and Measurements Report No. 50/6214 were followed. The gross tumor volume was defined as all areas of evident gross disease. The clinical target volume included all gross tumor volume areas as well as potential microscopic disease (pancreatic area) and regional lymph nodes. The planning target volume included the clinical target volume plus a safety margin of 1 cm in all directions to include organ motion and set-up errors. Adjacent organs at risk, such as the kidneys, spinal cord, liver, and bowel, were contoured; then, dose constraints were evaluated with a dose volume histogram analysis.
Treatment was performed with an 18-MV linear accelerator with a multifield isocentric technique using a multileaf collimator. A quality-control protocol was applied for all patients with the periodical acquisition of digital portal images to evaluate the precision of the set-up.
During the 5 weeks of radiation, on a twice-weekly basis, patients received 50 mg/m2 daily of gemcitabine administered intravenously as a 60-minute infusion within 2 hours before radiation treatment. In the event of grade 3 nonhematologic toxicity, both chemotherapy and radiation therapy were stopped until recovery and then resumed. In the even of a neutrophil count <1000/μL, and/or platelets <100,000/μL, and/or grade 2 nonhematologic toxicity, chemotherapy was delayed until recovery, but radiation therapy was continued.
Five weeks after completing radiotherapy, patients were evaluated for clinical benefit response according to Andersen and Rothenberg's definition,15 and a thoracoabdominal CT scan was obtained to evaluate treatment response according to the Response Evaluation Criteria in Solid Tumors group classification.16 All patients were re-evaluated for surgery in a multidisciplinary meeting after each step of the treatment protocol. Those patients who were fit for surgery and who had either a stable or responding “borderline resectable” tumor or a responding “unresectable” tumor were considered for surgical exploration irrespective of vascular involvement, except for patients who had a venous occlusion that was not amenable to vascular resection.
The primary endpoint of this trial was the proportion of patients who were progression free at 6 months. All eligible patients who began treatment were considered assessable for this primary endpoint. A Simon 2-stage optimal design17 was used to test whether we had sufficient statistical power to distinguish between a 6-month progression-free rate ≥70% (ie, clinically promising therapy) and ≤50% (ie, clinically inactive therapy). Patients were enrolled with no interruption between the stages, but an interim analysis was performed when enrollment onto the first stage was completed. The treatment protocol was considered inactive if ≤8 of the initial 15 patients were progression free at 6 months. At least 23 of 32 assessable patients who were progression free at 6 months were required to demonstrate promising activity. By using this design, the study, with α and β error probabilities of .05 and .20, respectively, had 80% power to detect a 6-month progression-free rate ≥70%. The time to disease progression and survival were calculated from the date of patient registration in the study, and were analyzed using Kaplan-Meier methods on an intention-to-treat basis. Secondary objectives that we assessed included the objective radiologic response rates and the disease control rate (complete and partial responses plus stable disease), along with the resectability rate, the clinical benefit response, PFS, OS, and toxicity.
The statistical significance of differences between survival curves was established using the Cox-Mantel test. Chi-square tests and Fisher tests were used to compare proportions, as appropriate.
Between June 2003 and December 2009, 39 patients were enrolled. Characteristics of the patients and their primary tumors are outlined in Table 1.
|Variable||No. of Patients (%)|
|Age: Median [range], y||63 [43-75]|
|CA 19.9 presentation|
|Biliary stent||21 (53.8)|
|Surgical bypass||4 (10.2)|
Treatment and Toxicity
Treatments according to the protocol are summarized in Figure 1. Two patients only received 2 cycles of the induction chemotherapy, which then was stopped because of jaundice. After biliary drainage, these patients continued their CRT. The median number of cycles of GEMOX was 4 (range, 2-5 cycles).
Thirty-seven patients were evaluated for CRT. One patient who had with a borderline resectable tumor had a contraindication to CRT (pancreatic pseudocystis) and underwent surgery directly; 1 patient with stable disease had to stop treatment because of a deterioration in performance status, and 2 patients started second-line chemotherapy for tumor progression. Thirty patients received CRT, and 5 patients received radiotherapy alone for performance status deterioration in the absence of a sufficient recovery during the whole period of radiotherapy. The median number of doses of gemcitabine during radiotherapy was 6 (range, 2-10 doses). The main reasons for gemcitabine omission were grade 1 or 2 thrombocytopenia and grade 2 gastrointestinal toxicity. The median radiation dose was 50.4 Gy (range, 25-57 Gy). Thirty-one of 35 patients (88.6%) received full-dose radiotherapy. The toxicity data are summarized in Table 2.
|Grade 1||Grade 2||Grade 3||Grade 4||All Grades|
|Toxicity||No. of Events||%||No. of Events||%||No. of Events||%||No. of Events||%||No. of Events||%|
|Increased transaminase levels||1||2.5||3||7.6||2||5.1||0||6||15.3|
|Increased transaminase levels||0||1||2.8||2||5.7||0||3||8.5|
The most frequent all-grade GEMOX-related toxicities were neurotoxicity (43.5%), vomiting (35.8%), and fatigue (28.2%), but only 5% to 7% of patients had grade 3 or 4 toxicities (for details, see Table 2). In particular, a considerable proportion of patients had grade 1 neurotoxicity (25.6%) and grade 1 fatigue (15.3%). Gastrointestinal toxicities were mainly grade 2, especially vomiting and diarrhea. Among hematologic toxicities, there were 2 episodes of grade 3 and grade 4 neutropenia (5.1%), and most other toxicities were grade 2 anemia (5.1%) and thrombocytopenia (7.6%).
During CRT, the most frequent all-grade toxicities were vomiting (51.4%), thrombocytopenia (57.1%), and fatigue (60%). Similarly to the induction period, gastrointestinal toxicities were mainly grade 2, especially vomiting, and there was a lower overall incidence of diarrhea (8.5% vs 17.9%), although there were 2 episodes of grade 3 diarrhea. One of these patients had grade 2 diarrhea during induction chemotherapy. Patients had higher (grade 2) fatigue compared with the fatigue from GEMOX treatment (28.5%) that was not always attributable to the worsening of pre-existing fatigue.
In the second part of the treatment protocol, patients had higher hematologic toxicities, especially thrombocytopenia (57.1%), and 11.4% of patients had grade 3 and grade 4 hematologic toxicities. For the other patients, we mostly observed grade 2 thrombocytopenia, which was one of the motivations for omitting gemcitabine. There was minimal life-threatening toxicity (grade 4 thrombocytopenia and neutropenia), and no treatment-related deaths occurred.
The objective response rate and the clinical benefit response rate are summarized in Table 3. Response data indicated that 4 patients had improved performance status, 26 had unchanged performance status, and 9 patients had impaired performance status. Five patients had increased weight during treatment, 14 patients obtained stable weight, and 20 patients had a weight decrease.
|All Patients||Borderline Resectable||Unresectable|
|Objective Response After GEMOX (RECIST)||No. of Patients||%||No. of Patients||%||No. of Patients||%|
|Overall response assessment|
|Clinical benefit rate|
At the end of the treatment, 15 patients were considered for surgery. One patient did not consent to undergoing resection surgery. Fourteen patients underwent surgical exploration, including; 9 who underwent complete (R0) resection, 2 patients who underwent nonradical (R1) resection, and 3 patients who did not undergo resection because their disease was deemed unresectable at laparotomy. Nine of the 11 patients who underwent R0/R1 resection had borderline resectable disease at diagnosis (9 of 15 patients), and 2 patients had unresectable disease at presentation (2 of 24 patients; P = .0009).
The median follow-up for all patients was 12.9 months (range, 3.4-72.0 months), 7 patients remained alive at a median follow-up of 11.7 months, and 5 of 39 patients were progression free. Two of 11 resected patients were disease free after surgery. One patient who underwent R1 pancreatoduodenectomy was relapse-free after 72 months of follow-up. This patient also underwent surgery for a single lung metastasectomy 57 months after primary surgery.
For the whole group, the median PFS was 10.2 months (Fig. 2, top). The proportion of patients who were progression free at 6 months was 82%. Forty percent of patients were disease free at 1 year, and 12% were disease free 2 years after diagnosis.
The median PFS for borderline resectable patients was 16.6 months compared with 9.1 months for unresectable patients (P = .056). (Fig. 2, middle). Resected patients had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively; P = .000001). (Fig. 2, bottom). When considering the first site of progression, the pattern of failure was local in 7 patients and systemic in 32 patients.
For the whole group, the median OS was 16.7 months (Fig. 3, top). The estimated OS rates at the end of 1 year and 2 years were 65% and 33% after diagnosis, respectively. The median OS for borderline resectable patients was 27.8 months compared with 13.3 months for unresectable patients (P = .045). (Fig. 3, middle). The median OS among resected patients was 32 months (Fig. 3, bottom).
In recent years, LAPC increasingly has been considered a separate disease entity. It represents an intermediate stage between metastatic disease, which is treated with systemic chemotherapy, and localized disease that is amenable to surgical resection. This group of patients, accounting for approximately 30% to 40% of patients at the time of diagnosis, has been studied intensively in recent years, and neoadjuvant therapies have been proposed to achieve better local tumor control or tumor down-staging with a subsequent, potentially curative resection. A review of 111 studies revealed that 33% of patients who were at a nonresectable stage before neoadjuvant treatment become resectable after chemotherapy or CRT.18 To date, there is no consensus about standard LAPC care. The only phase 3 randomized study6 that tested the superiority of concurrent gemcitabine and radiation therapy versus gemcitabine alone was terminated prematurely because of poor patient accrual. In the aforementioned systematic review,18 combination chemotherapy resulted in higher estimated responses and resection probabilities for patients with initially nonresectable tumors compared with monotherapy. Retrospective studies have reported encouraging results from systemic induction chemotherapy followed by CRT in patients who achieved disease control.7, 8 In particular, a retrospective study by the French Multidisciplinary Cooperative Oncology Group (GERCOR)7 demonstrated that patients who received CRT after 3 months of chemotherapy with GEMOX had significantly better survival rates than those who continued with chemotherapy alone. This observation suggests that a strategy based on induction chemotherapy can identify those patients (up to 70%) without early progression who may benefit from CRT. However, prospective data from phase 3 trials confirming a survival advantage for such an approach still are lacking. In the current study, we evaluated the efficacy of a combined-modality regimen and report a progression-free rate >80% at 6 months and an OS of 16 months.
Despite an induction treatment period of just 2 months, our data compare favorably with similar studies in which induction chemotherapy ranged from 2 to 6 months. However, considering the observed pattern of disease recurrence (82% distant vs 18% local), we conclude that, although local treatment is fairly effective, systemic disease control should be improved. In our study, disease progression was documented in only 2 patients (5%) after 2 months of induction GEMOX. Therefore, not only does induction systemic chemotherapy play a fundamental role in selecting patients with rapid progressive disease to be excluded from local treatments, it also seems to play a role in the control of systemic disease and prolonging survival.
Surgical exploration was indicated for 38% of patients after neoadjuvant treatment. Seventy-3 percent of these patients were successfully resected, reaching a resectability rate of 28% (with 23% R0 resection rates). These data appear to be encouraging but are not easily comparable to other similar studies. A critical issue in conducting trials on LAPC is the lack of a general consensus of its exact definition. LAPC patients were divided into borderline resectable, in the case of arterial abutment and/or venous stenosis or limited occlusion; or unresectable, in the case of arterial encasement and/or venous extensive occlusion. Inclusion of patients with a stenotic but patent vein in neoadjuvant protocols is justified by our previous data showing that patients requiring a vein resection were less likely to receive a curative operation because of a higher incidence of positive retroperitoneal margin.19 This distinction is of paramount importance to produce comparable and reproducible data, and should always be reported in any protocol design. Both groups, in fact, possess different resectability and expected survival rates, as also evidenced in this report. In our study population, patients with borderline resectable tumors at presentation had a significantly better prognosis than unresectable ones. Median PFS and OS rates were 17 and 28 months, respectively, compared with 9 and 13 months, respectively for unresectable tumors. Surgery indication and resection were more frequent in borderline resectable patients than in unresectable ones. Nonetheless, patients with “unresectable” tumors at presentation could also occasionally undergo resection. This also raises the question concerning which restaging techniques can, at present, reliably distinguish between tumor or residual fibrotic tissue, and which patients should be offered surgical exploration on the basis of imaging findings.
Toxicities were acceptable with minimal life-threatening side effects and no treatment-related deaths. Grade 3 or 4 hematologic toxicity developed in <20% of patients who received both induction chemotherapy and CRT. The most frequent grade 3 nonhematologic toxicities during induction chemotherapy were observed in <10% of patients. During CRT, 51.4% of patients experienced grade 3 or 4 nonhematologic toxicity, and all patients experienced a complete recovery from toxicity after medical treatment. We observed lower gastrointestinal toxicity during CRT (17.1% nausea/vomiting and 37.1% overall gastrointestinal toxicity) compared with our previous work3 (34% nausea/vomiting and 52% overall gastrointestinal toxicity). For the patients enrolled in this study, 5-hydroxytryptamine (5-HT3) inhibitors or steroids were recommended as prophylactic antiemetics during induction chemotherapy. Patients also continued the same protocol during CRT; whereas, in the previous study, the standard antiemetic treatment was metoclopramide. In addition, the induction therapy period provided an opportunity to evaluate each patient's susceptibility to gastrointestinal toxicity and helped investigators to more effectively support symptoms during CRT.
We underline that, during CRT, we had significantly lower toxicities compared with a recent study in which >70% of patients with LAPC who received either weekly gemcitabine (1000 mg/m2) alone or gemcitabine (600 mg/m2) concurrently with radiotherapy6 experienced grade 3 or 4 toxicities. For patients who received CRT, the higher dose of gemcitabine concurrent with radiotherapy was responsible, at least in part, for the higher toxicity. However, the study by Loehrer et al included patients with a median age of 68 years, and nearly 80% had an Eastern Cooperative Oncology Group performance status of 1; whereas, in the current study, patients were younger (median age, 63 years), and only 33% had an Eastern Cooperative Oncology Group performance status of 1 or 2. Finally, in the current study, there were no adverse events after surgery for patients who underwent surgical resection; in particular, we can emphasize an operative mortality rate of 0%.
In conclusion, a regimen of induction chemotherapy with GEMOX followed by gemcitabine-based CRT for LAPC is feasible and well tolerated. A high disease control rate and clinical benefit are achievable in most patients. Patients with strictly defined, borderline resectable LAPC can be resected in up to 60% of cases. The survival of resected patients is at least as long as that of patients who undergo primary resection for localized cancer. Because distant recurrence remains the principal reason for treatment failure, future trials should focus on systemic disease control.
This work was supported by grants from “Progetti di Ricerca Rete Oncologia Piemonte-Valle d'Aosta” and “Associazione Italiana Ricerca sul Cancro (AIRC) 5X1000.”
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 2Therapy of locally unresectable pancreatic carcinoma: a randomisation of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the Gastrointestinal Tumor Study Group. Cancer. 1981; 48: 1705-1710., , , et al.
- 5Phase II trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008; 19: 1592-1599., , , et al.
- 9Concomitant administration of weekly oxaliplatin, fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and oxaliplatin induction in patients with locally advanced pancreatic cancer: a Groupe Coordinateur Multidisciplinaire en Oncologie phase II study. J Clin Oncol. 2008; 26: 1080-1085., , , et al.
- 10Induction chemotherapy with gemcitabine, oxaliplatin, and 5-fluorouracil/leucovorin followed by concomitant chemoradiotherapy in patients with locally advanced pancreatic cancer: a Taiwan Cooperative Oncology Group phase II study. Int J Radiat Oncol Biol Phys. 2011; 81: e749-e757., , , et al.
- 14International Commission on Radiation Units and Measurements. Prescribing, Recording and Reporting Photon Beam Therapy. Bethesda, MD: International Commission on Radiation Units and Measurements; 1993.