Case-Based Review

Pancreatic Adenocarcinoma: Management of Advanced Unresectable and Metastatic Disease

2018 May/June;13(3):24-33

References

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Following publication of the trial conducted by Burris and colleagues,⁹ a plethora of clinical trials have tried to outperform gemcitabine monotherapy, with all trials studying gemcitabine monotherapy compared with gemcitabine plus another agent (fluorouracil, cisplatin, oxaliplatin, irinotecan, pemetrexed, novel biologics including cetuximab, bevacizumab, axitinib, sorafenib, aflibercept). These combinations have failed to significantly extend OS compared to single-agent gemcitabine, although some showed a marginal clinical benefit:

Capecitabine¹⁰ (hazard ratio [HR] 0.86 [95% confidence interval {CI} 0.75 to 0.98])
Erlotinib¹¹ (HR 0.81 [95% CI 0.69 to 0.99])
Cisplatin, epirubicin, fluorouracil, gemcitabine¹² (HR 0.65 [95% CI 0.43 to 0.99])

The best outcomes were obtained with gemcitabine plus nab-paclitaxel compared to gemcitabine monotherapy. The gemcitabine/nab-paclitaxel combination has not been compared to FOLFIRINOX in the front-line setting, as the ACCORD 11 and MPACT trials were ongoing simultaneously. However, a large retrospective trial that compared use of the regimens in the US Oncology Network in the United States demonstrated similar efficacy, although more patients treated with FOLFIRINOX needed white blood cell growth factor administration.¹³

Gemcitabine/nab-paclitaxel was studied in a phase 1/2 clinical trial with 67 untreated metastatic pancreatic cancer patients.¹⁴ Patients received nab-paclitaxel at doses of 100, 125, or 150 mg/m² followed by gemcitabine 1000 mg/m² on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) was 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel once a week for 3 weeks every 28 days. Dose-limiting toxicities were sepsis and neutropenia. Patients who received the MTD had a response rate of 48%, median OS of 12.2 months, and a 1-year survival rate of 48%.

The landmark phase 3 MPACT trial confirmed that adding nab-paclitaxel to gemcitabine prolongs survival compared with gemcitabine monotherapy.⁵ This multinational randomized study included 861 treatment-naive patients with a Karnofsky performance score of 70 or higher. The median OS in the nab-paclitaxel/gemcitabine group was 8.5 months, as compared to 6.7 months in the gemcitabine monotherapy group (HR for death 0.72 [95% CI 0.62 to 0.83], P < 0.001). The survival rate was 35% in the nab-paclitaxel/gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. Median progression-free survival (PFS) was 5.5 months in the nab-paclitaxel/gemcitabine group, compared to 3.7 months in the gemcitabine group (HR for disease progression or death 0.69 [95% CI 0.58 to 0.82], P < 0.001). The overall response rate according to independent review was 23% compared with 7% in the 2 groups, respectively (P < 0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel/gemcitabine group versus 27% in the gemcitabine group), fatigue (17% versus 7%), and neuropathy (17% versus 1%). Febrile neutropenia occurred in 3% of the combination group versus 1% of the montherapy group. In the nab-paclitaxel/gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower a median of 29 days after discontinuation of nab-paclitaxel. In 2013, nab-paclitaxel in combination with gemcitabine received U.S. Food and Drug Administration (FDA) approval as first-line therapy for metastatic pancreatic cancer.

A pilot phase 1b/2 trial that added cisplatin to nab-paclitaxel and gemcitabine in treating 24 treatment-naive metastatic pancreatic adenocarcinoma patients showed impressive tumor response (complete response 8.3%, partial response 62.5%, stable disease 16.7%, progressive disease 12.5%) and extended median OS to 16.5 months.¹⁵ A phase 1b trial conducted in Europe added capecitabine to the cisplatin, nab-paclitaxel, and gemcitabine regimen, albeit with a different schedule and doses, in 24 patients with locally advanced and metastatic disease.¹⁶This trial demonstrated an impressive overall response rate of 67%, with 43% of patients achieving a complete metabolic response on positron emission tomography scan and the CA 19-9 level decreasing by ≥ 49% in all 19 patients who had an elevated basal value. Moreover, PFS at 6 months was 96%. After chemotherapy 17 patients remained unresectable and 7 patients were taken to surgery; of the latter group, only 1 was determined to be unresectable at the time of surgery. This regimen is being explored in a larger study in patients with stage III and IV disease.

FOLFIRINOX

A randomized phase 2 clinical trial comparing FOLFIRINOX to gemcitabine monotherapy in 88 patients with treatment-naive metastatic pancreatic cancer revealed a high response rate for FOLFIRINOX (39% versus 11%, respectively) with a tolerable toxicity profile.¹⁷ FOLFIRINOX became the front-line standard of care therapy in pancreatic adenocarcinoma after the results of the subsequent phase 3 ACCORD 11 study preplanned interim analysis showed an unprecedented significantly improved OS benefit.⁶ The ACCORD 11 trial randomly assigned 342 patients with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and a serum bilirubin level less than 1.5 times the upper limit of normal to receive FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² given as a bolus followed by 2400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The median OS in the FOLFIRINOX group was 11.1 months as compared with 6.8 months in the gemcitabine group (HR 0.57 [95% CI 0.45 to 0.73], P < 0.001). The FOLFIRINOX group also had a longer median PFS (6.4 months versus 3.3 months, HR 0.47 [95% CI 0.37 to 0.59], P < 0.001) and higher objective response rate (31.6% versus 9.4%, P < 0.001). More adverse events were noted in the FOLFIRINOX group, including grade 3 or 4 neutropenia (46% versus 21%), febrile neutropenia (5.4% versus 1.2%), thrombocytopenia (9.1% versus 3.6%), sensory neuropathy (9% versus 0%), vomiting (15% versus 8%), fatigue (23% versus 18%), and diarrhea (13% versus 2%). Despite the greater toxicity, only 31% of the FOLFIRINOX group had a definitive degradation of quality of life, as compared to 66% in the gemcitabine group (HR 0.47 [95% CI 0.30 to 0.70], P < 0.001), thus indicating an improvement in quality of life.

Of note, combinations containing irinotecan require adequate biliary function for excretion of its active glucuronide metabolite, SN-38. Approximately 10% of patients in the United States are homozygous for the UGT1A1*28 allele polymorphism, which causes increased SN-38 bioavailability and hence a potential for severe toxicities (eg, life threatening-refractory diarrhea).¹⁸ Therefore, it is recommended that physicians start with a lower dose of irinotecan or choose a different regimen altogether in such patients.

Current Approach and Future Directions

Based on results of the ACCORD 11 and MPACT trials, both front-line regimens (nab-paclitaxel/gemcitabine and FOLFIRINOX) can be considered appropriate treatment options for treatment-naive patients with good performance status who have locally advanced unresectable or metastatic pancreatic adenocarcinoma. FOLFIRINOX has a higher objective response rate than nab-paclitaxel-gemcitabine (32% versus 23%, respectively), but the adverse effect profile favors the nab-paclitaxel/gemcitabine combination, acknowledging this conclusion is limited due to lack of a comparative trial. Modifications to both regimens have been presented at American Society of Clinical Oncology symposiums, with preliminary data showing an extended median OS and a more tolerable toxicity profile.^19,20 In a recent retrospective observational cohort comparative analysis of nab-paclitaxel/gemcitabine versus FOLFIRINOX, results showed no statistical difference in median OS. The real-world data showed that gemcitabine-based therapy is being offered commonly to elderly patients and patients with poor performance status.¹³ There is no current research proposal for conducting a direct head-to-head comparison between these 2 regimens. Based on extrapolated data from the prior mentioned trials and retrospective analysis reviews, current guidelines recommend offering younger (< 65 years old), healthier (no comorbidity contraindication) patients with excellent performance status (ECOG 0) first-line FOLFIRINOX or gemcitabine/nab-paclitaxel. Elderly patients with stable comorbidities and good performance status (ECOG 1 or 2, Karnofsky performance status ≥ 70) could be preferably considered for treatment with nab-paclitaxel/gemcitabine as first-line or modified FOLFIRINOX if performance status is excellent. Patients with poor performance status (ECOG ≥ 2), advanced age, and significant comorbidities could still be considered candidates for gemcitabine monotherapy. However, there are promising indications that the combination of gemcitabine, nab-paclitaxel, and cisplatin could be a frontline therapy in advanced pancreaticobilliary malignancies in the future.