Modified GTX as Second-Line Chemotherapy in Advanced Pancreatic Cancer

CASE REPORT

Dr. Dbouk: A 68-year-old woman presented with painless jaundice, dark urine, fatigue, and weight loss of 10 kg (22 pounds) within 2 months. She had a surgical history of cholecystectomy, but no relevant medical comorbidities. She was a never-smoker and reported no alcohol intake. There was no family history of malignancy. Physical examination revealed a jaundiced woman with no other abnormal findings. Laboratory studies showed elevated levels of bilirubin, 33.5 mg/dL (normal range, 0–1.2 mg/dL); aspartate transaminase (AST), 190 IU/L (normal range, 6–18 IU/L); alanine transaminase (ALT), 188 IU/L (normal range, 8–32 IU/L); and carbohydrate antigen (CA) 19-9, 2397 U/mL (normal range, 0–36 U/mL). A computed tomographic (CT) scan of the abdomen and pelvis was obtained.

Dr. Haydar: The CT scan showed a mass in the head of the pancreas without involvement of major vessels, and there was no evidence of distant metastatic disease.

Dr. Abou-Alfa: Dr. Haydar, is there a preferable radiologic modality in this setting?

Dr. Haydar: No significant differences have been observed between CT and magnetic resonance (MR) images in the diagnosis of pancreatic carcinoma, depending on the available technology and radiologic expertise. However, MR imaging has greater sensitivity for depicting liver metastasis than does CT.¹ The sensitivity of CT for pancreatic cancer depends on the technique and is highest (89–97%) with triple-phase multidetector-row helical CT.²

Dr. Abou-Alfa: Dr. Eloubeidi, is there any role for biliary stenting before proceeding with surgery?

Dr. Eloubeidi: In patients with jaundice who have no involvement or minimal involvement of the major vessels according to CT or endoscopic ultrasound (EUS) and no evidence of distant metastases on CT, surgeons may generally proceed directly to surgical resection.

Dr. Dbouk: The patient underwent a pancreaticoduodenectomy (Whipple procedure). The resected specimen revealed grade 2 infiltrating ductal adenocarcinoma of the head of the pancreas (3 × 5 cm), extending into the ampullary region, with lymphovascular and perineural invasion. None of 3 perigastric lymph nodes, but 3 of 16 peripancreatic lymph nodes, showed evidence of tumor. The surgical margins were negative (pT2N1M0, stage IIB).

Dr. Abou-Alfa: Dr. O'Reilly, please tell us about the role of adjuvant therapy in pancreatic cancer.

Dr. O'Reilly: There is no consensus regarding the optimal management of patients after resection of pancreatic cancer. There is level 1 evidence for the use of gemcitabine or modulated fluoropyrimidine chemotherapy. The Charité Onkologie Clinical Studies in GI Cancer (CONKO)-001 trial³ found a significantly improved median disease-free survival in favor of adjuvant gemcitabine (13.4 months; range, 11.4–15.3) compared with observation (6.9 months; range, 6.1–7.8; P < .001). The overall median survival was 22.1 months (range, 18.4–25.8) for the gemcitabine group and 20.2 months (range, 17–23.4) for the surgery-alone group (hazard ratio [HR], 0.79; 95% CI, 0.62–1.01; P = .06). The primary end point was disease-free survival. A confounding factor for overall survival was that a large proportion of the control group received gemcitabine on relapse. The CONKO-001 investigators concluded that chemotherapy with gemcitabine offers the best benefit/risk ratio of all currently available adjuvant treatment options. The individual patient data meta-analysis in the European Study Group for Pancreatic Cancer (ESPAC)-1, ESPAC-1 plus, and ESPAC-3 trials showed significantly better overall survival for patients randomized to 5-fluorouracil/folinic acid (5-FU/FA) with an HR of 0.70 (95% CI, 0.55–0.88; P = .003), indicating a significant reduction in the risk of death (30%) with 5-FU/FA, compared with surgery alone.⁴

Dr. Abou-Alfa: Dr. Geara, what about the role of radiation?

Dr. Geara: The impact of adjuvant chemoradiotherapy on survival has been debated. The Radiation Therapy Oncology Group (RTOG)-9704 trial compared pre- and postchemoradiation gemcitabine (1000 mg/m² per day) to pre- and postchemoradiation 5-FU (250 mg/m² per day, given as a continuous infusion) in patients who had undergone pancreatic resection.⁵ Patients in both arms of the study received 5-FU-based chemoradiotherapy (50.4 Gy), with the chemotherapy given for 3 weeks before and 12 weeks after chemoradiotherapy. Analysis was restricted to 442 “eligible” patients of 538 patients originally recruited. There was no difference in the overall survival between the two arms, but a prospectively powered subgroup analysis of the 380 patients with pancreatic head cancer revealed a reduction in the risk of death for patients in the gemcitabine-based chemoradiation arm (HR, 0.79; 95% CI, 0.63–0.99; P = .047).⁵ Patients who have undergone resection of an exocrine pancreatic cancer should be encouraged to enroll in clinical trials evaluating the potential benefits of chemotherapy and/or chemoradiotherapy, as well as new therapeutic approaches.⁶

Dr. Dbouk: Unfortunately, in less than 8 weeks after surgical resection, the patient presented to the hospital with persistent epigastric pain. A CT scan of the abdomen was obtained.

Dr. Haydar: The CT scan showed nodular soft tissue thickening with an enlarged lymph node at the porta hepatis and a few prominent mesenteric and retroperitoneal lymph nodes. CA 19-9 had increased from 56 to 75 U/mL (normal range, 0–36 U/mL). These findings were considered to represent metastatic pancreatic adenocarcinoma.

Dr. Dbouk: The patient was started on chemotherapy. In view of the high bilirubin level of 2.7 mg/dL (normal range, 0–1.2 mg/dL), the patient received 5-FU and cisplatin instead of gemcitabine. Once the bilirubin improved, therapy was switched to gemcitabine plus cisplatin.

Dr. Abou-Alfa: Dr Slatz, is it a contraindication to use gemcitabine in the presence of a high bilirubin level?

Dr. Saltz: The United States Food and Drug Administration (FDA)-approved labeling does not contain dose-adjustment guidelines for gemcitabine. It simply says to use with caution and to discontinue if severe hepatotoxicity occurs during treatment. The following guidelines have been used by some clinicians: If serum bilirubin is >1.6 mg/dL use an initial dose of 800 mg/m²; the dose may be escalated if tolerated.⁷

Dr. Dbouk: Over the course of chemotherapy, CA 19-9 increased from 107 to 344 U/mL. After 4 cycles, a CT scan showed the interval appearance of several lung nodules in both lung fields, most likely progressive metastatic disease, with no change in the soft tissue thickening at the porta hepatis. The patient received second-line chemotherapy with gemcitabine, docetaxel, and capecitabine (GTX),⁸ in a modified GTX regimen with capecitabine 625 mg/m² orally twice daily on days 6 to 10 and days 20 to 24, intravenous (IV) gemcitabine 1000 mg/m² on days 8 and 22, and docetaxel 40 mg/m² on days 1 and 15, with cycles repeated every 28 days.

Dr. O'Reilly: Dr. Shamseddine, what is the difference between modified GTX and a GTX regimen?

Dr. Shamseddine: The combination of gemcitabine, docetaxel, and capecitabine has been used widely for the treatment of advanced pancreatic cancer in both chemotherapy-naïve and second-line settings. This regimen had response rates of 21.9% and a median overall survival (mOS) of 14.5 months in a phase II study (n = 43).^8,9 It involves the administration of oral capecitabine 750 mg/m² per day, divided into two doses, days 1 to 14; intravenous (IV) gemcitabine 750 mg/m² on days 4 and 11, and IV docetaxel 30 mg/m² on days 4 and 11. We have used a modified schedule of this regimen in the second-line setting, as described by Dr. Dbouk. This modified regimen is aimed at biomodulating the activity of capecitabine by both docetaxel and gemcitabine. Thymidine phosphorylase (TP), the main activating enzyme of capecitabine, is induced by docetaxel, with maximum activity at days 4 to 6, persisting for at least 10 days.¹⁰ Gemcitabine inhibits ribonuclear reductase, resulting in enhanced binding of 5-FU to thymidylate synthase and higher incorporation into DNA.¹¹ Dr. Ajouz, please comment about the American University of Beirut Medical Center's (AUBMC) experience in using modified GTX as a second-line therapy for metastatic pancreatic adenocarcinoma.

Dr. Ajouz: We have retrospectively evaluated the use of modified GTX as a second-line chemotherapy in 9 patients with advanced pancreatic adenocarcinoma at our institution. The median age was 59.5 years (range, 48–66). Most of the patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 2 (range, 1–3). The median number of modified GTX cycles completed was 3 (range, 2–8). The regimen was well-tolerated; commonly observed GTX-related toxicities included leukopenia, anemia, nausea, vomiting, and diarrhea. A complete response by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, was seen in 1 of the patients, a partial response in 2, and stable disease in the remaining 6. Median overall survival from the start of modified GTX therapy was 8 months (range, 5.2–10.8 months). There are no prospective studies of GTX in the second-line setting for pancreatic adenocarcinoma. De Jesus-Acosta et al¹² retrospectively reviewed 154 patients with advanced pancreatic adenocarcinoma who received GTX. Of the 75 patients who received it as a second- or greater line of chemotherapy, 2 had a radiological partial response according to RECIST, and overall survival was 5.7 months, with a 1-year survival of 32%. Dakik et al¹³ retrospectively evaluated 59 patients who received GTX after a median of 2 prior lines of treatment. In this cohort, no patients had a radiological response, and overall survival was 22 weeks. These retrospective studies are summarized in Table 1.

Table 1.

Retrospective studies of GTX chemotherapy in the second-line or later setting for pancreatic adenocarcinoma

Study	Number of patients	Response rate	Median survival (months)	Reference
Dakik et al GTX second-line and later	59	0%	5.1	13
De Jesus-Acosta et al. GTX second-line and later	75	3% (2)	5.7	12
AUMBC experience GTX second-line	9	33% (3)	8

Dr. Abou-Alfa: Dr. Mukherji, any other thoughts on a second-line chemotherapy in metastatic pancreatic cancer?

Dr. Mukherji: To date, no standard of care has been established for a second-line therapy in advanced pancreatic cancer. The CONKO-003 study established the superiority of second-line chemotherapy with oxaliplatin, FA, and 5-FU (OFF) over best supportive care (BSC) for patients progressing while on first-line gemcitabine chemotherapy, despite the fact that the study closed early due to poor accrual.¹⁴ Median survival for patients treated with second-line chemotherapy was 4.82 months vs. 2.3 months with BSC alone (HR, 0.45; 95% CI, 0.24–0.83; P = 0.008). Small phase II and retrospective studies have evaluated various second-line therapies including nab-paclitaxel,¹⁵ gemcitabine, and cisplatin combined with regional hyperthermia,¹⁶ cisplatin plus S-1 (an oral fluoropyrimidine),¹⁷ 5-FU/FA plus irinotecan (FOLFIRI),¹⁸ and GTX.^12,13 Patients who progress on first-line chemotherapy with good performance status should be encouraged to enter clinical trials. If these are not available, we have randomized evidence to support the use of second-line chemotherapy.¹⁴ There appear to be several drugs with activity in the second-line setting, and the choice of agent depends on the first-line treatment and response. Many patients with good performance status are now being treated with the combination of 5-FU, FA, irinotecan, and oxaliplatin (FOLFIRINOX) in the first-line metastatic setting¹⁹ and may benefit from gemcitabine-based second-line combinations. A randomized phase III study has recently demonstrated the superiority of nab-paclitaxel over gemcitabine in the first-line setting. It is likely that this taxane-based regimen will be further developed in pancreatic adenocarcinoma.²⁰

Dr. Dbouk: After 7 cycles of modified GTX chemotherapy, a CT showed a resolution of lung nodules and no new metastatic disease. The CA 19-9 decreased from 344 to 11.5 U/mL. Chemotherapy was stopped for 7 months and then was resumed when a CT scan showed significant progression of the metastatic lung disease and CA 19-9 increased from 11.5 to 73.5 U/mL. The disease in the lungs responded initially to the recommencement of GTX chemotherapy; however, after 8 cycles, a CT scan showed further progression of lung disease with the appearance of multiple new nodules. The patient maintained a performance status of 1, and third-line chemotherapy with FOLFIRINOX was started.

Dr. Shamseddine: In summary, this is a case of a patient who presented with metastatic pancreatic adenocarcinoma shortly after surgical resection who did not respond to the combination of gemcitabine-cisplatin chemotherapy, but had a prolonged response to the combination of GTX. There is currently no standard second-line therapy for advanced pancreatic cancer, and participation in clinical trials is to be encouraged. The modified GTX regimen appears to be effective and well-tolerated, and further prospective trials of this regimen in the second-line setting for advanced pancreatic cancer are warranted.