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short review memo (2017) 10:136–140 DOI 10.1007/s12254-017-0352-2 Cross-over comparison and new chemotherapy regimens in metastatic pancreatic cancer Markus Kieler · Matthias Unseld · Daniela Bianconi · Gerald W. Prager Received: 8 May 2017 / Accepted: 10 August 2017 / Published online: 7 September 2017 © The Author(s) 2017. This article is an open access publication. Summary Despite decades of research, pancreatic Introduction ductal adenocarcinoma (PDAC) is still one of the most lethal malignant diseases with a devastating 5-year Despite decades of research, pancreatic ductal ade- overall survival of only 4–5%. Indeed, long-term sur- nocarcinoma (PDAC) is still one of the most lethal vival was not affected by the introduction of new malignant diseases with a devastating 5-year overall systemic cytotoxic chemotherapies which remain the survival of only 4–5%. Indeed, long-term survival was key cornerstone in the treatment of metastatic PDAC. not affected by the introduction of new chemothera- In the first-line setting, FOLFIRINOX based upon the pies. PDAC is projected to become the second lead- results of the PRODIGE/ACCORD trial and gemc- ing cause of cancer-related deaths before 2030 [1]. itabine with albumin-bound paclitaxel (GNP) based In comparison to other malignant diseases such as upon the MPACT trial have both been approved as melanoma or non-small cell lung cancer that have therapeutic options for patients with no significant witnessed the implementation of targeted therapies comorbidities and good performance status. As there or immune-related drugs in daily clinical practice [2, is no direct comparison between these regimens, the 3], systemic cytotoxic chemotherapy remains the key choice in first-line treatment depends on the toxi- cornerstone in the treatment of metastatic pancreatic city profile, patient’s preferences and reimbursabil- cancer (mPDAC). ity. In the second-line setting, the results of the In 1997, gemcitabine became the standard treat- NAPOLI-1 trial have led to the approval of nano- ment option when Burris and colleagues demon- liposomal irinotecan (nal-iri) in combination with strated a modest survival improvement and an in- 5-fluorouracil (5-FU) for the treatment of patients crease in disease control rate from 4.2 to 23.8% com- with mPDAC progressing under gemcitabine-based pared with 5-fluorouracil therapy [4]. After ten years chemotherapy and therefore this regimen is the first of no significant survival benefit shown in any of the to be approved for use in second-line therapy. many clinical trials, Sultana and colleagues published two meta-analysis in 2007 and 2008, demonstrat- ing a survival benefit for gemcitabine combinational Keywords Pancreatic ductal adenocarcinoma · Che- therapies versus gemcitabine alone [5, 6]. Then with motherapy · FOLFIRINOX · Gemcitabine and nab- the increase in the understanding of PDAC genome, paclitaxel · Nanoliposomal irinotecan distinct alterations in certain signaling pathways were revealed [7]. The hope for broadly applicable molec- ular targeted therapies was not fulfilled because most of the genomic alterations like TP53, SMAD-4 and the most common KRAS-mutation is currently not M. Kieler, M.D. · M. Unseld, M.D., Ph.D. · D. Bianconi, M.Sc., targetable. With just one targeted agent, namely er- Ph.D.· G. W.Prager,M.D. () lotinib that has demonstrated a small, but significant Department of Medicine I, Division of Oncology, survival benefit in combination with gemcitabine Comprehensive Cancer Center, Medical University Vienna – compared to gemcitabine monotherapy, the golden General Hospital, Waehringer Guertel 18–20, 1090 Vienna, age has not yet come for precision medicine in this Austria gerald.prager@meduniwien.ac.at disease [8]. 136 Cross-over comparison and new chemotherapy regimens in metastatic pancreatic cancer K short review nearly 42% of the patients presented with a Karnofsky First-line chemotherapy in metastatic pancreatic performance status of under 90. cancer Quality of life (QoL) was measured in the PRODIGE/ In 2011, the results of the PRODIGE/ACCORD trial ACCORD trial and this regimen significantly reduces revealed that FOLFIRINOX (oxaliplatin, irinotecan, QoL impairment compared with gemcitabine [14], fluorouracil, and leucovorin) significantly increases whereas QoL was not measured in the MPACT trial. the survival and quality of life at the cost of higher However a Quality-adjusted Time Without Symptoms toxicity compared to monotherapy with gemcitabine of disease progression or Toxicity methodology (Q- in first-line treatment [9]. Two years later another TWiST) analyses showed a significant gain in quality- multicenter randomized phase III trial (MPACT trial) adjusted survival by treatment with GNP compared was published and showed superior survival rates for with gemcitabine [15]. the combinational treatment with gemcitabine and The safety profile of a chemotherapy is important NAB(albumin bound)-paclitaxel (GNP) compared to when it comes to implementing it in the daily clinical monotherapy with gemcitabine [10]. These two new practice. Concerning the hematological toxicity, the therapeutic options have been integrated in clini- rates of grade 3 and 4 neutropenia and febrile neu- cal practice guidelines such as from the European tropenia were higher in patients treated with FOLFIRI- Society of Medical Oncology (ESMO), the American NOX (45.7% and 5.4%) than in patients treated in the Society of Clinical Oncology (ASCO) and the Na- GNP arm (38% and 3%). This resulted in a much tional Comprehensive Cancer Network (NCCN) and higher rate of G-CSF(granulocyte-colony stimulating are recommended both as regimens in the first-line factor)-usage in the FOLFIRINOX arm (42.5%) com- treatment [11–13]. While in patients with significant pared to the rate in the GNP arm (26%). Grade 3/4 comorbidities and an Eastern Cooperative Oncology diarrhea was observed in 12.7% versus 6% of patients Group (ECOG) performance status of 2 the optimal treated with FOLFIRINOX and GNP. For other side ef- first-line treatment still remains monotherapy with fects we refer to Table 1. Significant toxicity was ob- gemcitabine, the best choice for first-line treatment served in both trials, leading to the development of in fit patients with an ECOG performance status of more tolerable regimens. Phase II trials with a modi- 0–1 has not yet been fully elucidated. fied FOLFIRINOX regimen for example leaving out the 5-FU bolus and or a 25% of reduction of the 5-FU bo- lus and irinotecan doses have demonstrated compara- FOLFIRINOX and gemcitabine with albumin- ble efficacy like the regimen used in the phase III trial bound paclitaxel as first-line regimens in the while at the same time reducing toxicity [16–18]. In treatment of mPDAC an analysis of the GNP trial it was shown that patients Table 1 shows a listing of the core data of the two with dose reductions and delays had better outcomes pivotal trials. In the PRODIGE/ACCORD trial, median because these dose reductions were effective when overall survival (OS) with the experimental arm was necessary to ameliorate toxicity allowing greater treat- 11.1 months compared with 6.8 months with gemc- ment exposure without compromising efficacy [19]. itabine (hazard ratio [HR], 0.57; 95% confidence inter- Overall, both regimens have demonstrated a sur- val (CI), 0.45 to 0.73; p = 0.001). In the MPACT, median vival benefit and better quality of life compared with OS with the experimental arm was 8.5 months com- gemcitabine. As there is no direct comparison be- pared with 6.7 months with gemcitabine (HR, 0.72; tween these regimens, the choice in first-line treat- 95% CI, 0.62 to 0.83; p = 0.001). ment depends on the toxicity profile, age, patient’s These trials are not comparable as they differ in preferences and reimbursability. certain points. The PRODIGE/ACCORD trial was designed as a clinical phase II trial which was con- New chemotherapies in second-line treatment of secutively extended to a clinical phase III trial con- mPDAC ducted in 48 centers in France including 342 patients with mPDAC, whereas the GNP trial was designed Before the implementation of more efficacious first- as a multinational trial in 151 centers and enrolled line treatment, there was little use for a second-line in 861 patients. Another point of criticism is that in mPDAC. For this reason the current level of evidence the French trial no central radiological assessment to support a particular regimen sequencing first-line has been performed. Two other facts that add to treatment with GNP or FOLFRINOX is very low. There the controversy concerning the preferred treatment have been three phase III trials investigating 5-FU in in the first-line setting is the age limit and better combination with oxaliplatin after failure of first-line performance status of the patients in the PRODIGE/ treatment with gemcitabine. While the results of two ACCORD trial. Patients older than 75 years and an trials (CONKO-01 and CONKO-003) suggested a sur- ECOG performance status over 1 were excluded from vival benefit for treatment with 5-FU and oxaliplatin the FOLFIRINOX trial. In contrast, the age of the pa- [20, 21], in the PANCREOX trial survival of patients tients in the GNP trial ranged from 27 to 86 years and treated with either FOLFOX or 5-FU alone did not show any differences [22]. Thedifferences in theout- K Cross-over comparison and new chemotherapy regimens in metastatic pancreatic cancer 137 short review Table 1 Tabular comparison of the FOLFIRINOX and NAB-paclitaxel trial FOLFRIRINOX vs. gemcitabine[9] Gemcitabine/NAB-paclitaxel vs. gem- (PRODIGE/ACCORD trial) citabine[10] (MPACT trial) Study characteristics Study phase II/III III No. of patients 342 861 Location France (48 centers) Multinational (151 centers) Patient characteristics Median age 61 62 Female/male 38%/62% 43%/57% Performance status ECOG 0 (37.4%) KPS 100 (16%) ECOG 1 (61.9%) KPS 80–90 (77%) ECOG 2 (0.6%) KPS 60–70 (7%) Site of metastasis Liver (87.6%) Liver (85%) Lung (19.4%) Lung (35%) Peritoneum (19.4%) Peritoneum (4%) Response and survival OS 11.1 months 8.5 months PFS 6.4 months 5.5 months ORR 31.6% 23% DCR 70.2% 48% PR 31% 23% SD 38.6% 27% Toxicity (Grade 3–4) Treatment-related deaths 1% 4% Neutropenia 45.7% 38% Febrile neutropenia 5.4% 3% Thrombocytopenia 9.1% 13% Anemia 7.8% 13% Fatigue 23.6% 17% Peripheral neuropathy 9% 17% Diarrhea 12.7% 6% Alopecia 11.2% 50% Receipt of growth factors 42.5% 26% OS overall survival, PFS progression free survival, ORR overall response rate, DCR disease control rate, PR partial response, SD stable disease Table 2 Summary of basic clinical data and results from the comes have to be interpreted in the context of the NAPOLI-1 trial different chemotherapy regimens used, as patients in Nal-iri plus Nal-iri 5-FU the CONKO trials were treated with OFF and in the 5-FU monother- monother- PANCREOX trial with FOLFOX6. It is currently not apy apy clear if oxaliplatin has its role in second-line therapy No. of patients – 117 151 149 and if it may still provide a valid option. Median age, – 63 65 63 Favorable preclinical data on nanoliposomal irinote- years can (nal-iri) and early phase trials led to the recently Female/male – 41%/59% 42%/58% 46%/54% published phase III trial (NAPOLI-1) investigating Previous lines of 0 13% 11% 13% liposomal irinotecan in patients with mPDAC pro- chemotherapy >1 53% 57% 58% gressing to at least to first-line treatment [23]. In all, ≥2 34% 32% 30% 417 patients, who were previously treated with gem- Karnofsky 100 15% 15% 15% citabine-based chemotherapy, were randomly as- performance signed to receive either liposomal irinotecan mono- 80–90 76% 75% 77% status therapy (120 mg/m ) every 3 weeks or 5-FU 50–70 9% 10% 7% (2000 mg/m over 24 h every week for the first 4 weeks Response and OS 6.1 months 4.9 months 4.2 months survival of every 6-week cycle). Median OS was 6.1 months PFS 3.1 months 2.7 months 1.5 months in the combination arm and 4.2 months in patients ORR 16% 6% 1% assigned to the 5-FU control arm (HR 0.67, 95% CI OS overall survival, PFS progression free survival, ORR overall response 0.49–0.92; p = 0.012). In patients who were allocated rate to liposomal irinotecan monotherapy, median OS was 4.9 months, which was not significantly different to the control arm (HR 0.99, 95% CI 0.77–1.28; p = 0.94). 138 Cross-over comparison and new chemotherapy regimens in metastatic pancreatic cancer K short review Based upon these results the United States Food and References Drug Administration (FDA) and European Medicines 1. Rahib L,Smith BD,Aizenberg R, Rosenzweig AB, Flesh- Agency (EMA) approved nal-iri in combination with man JM, Matrisian LM. 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Gemcitabine based combination In the case of GNP as first-line treatment, patients chemotherapy in advanced pancreatic cancer-indirect could be offered an approved second-line treatment comparison. BMCCancer. 2008;8:192. with nal-iri plus 5-FU according to the NAPOLI-1 trial 7. Bailey P, Chang DK, Nones K, Johns AL, Patch A, Gingras or with less evidence treatment with oxaliplatin plus M, Miller DK, Christ AN, Bruxner TJC, Quinn MC, Nourse 5-FU (OFF regimen) according to the CONKO trials. C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood Summary and perspective S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez The therapeutic management of patients with mPDAC LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin has been changed by the results of the main trials dis- EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, cussed in this review. Systemic cytotoxic chemother- Humphris J, Giry-laterriere M, Rooman I, Chou A, Pajic apy remains the cornerstone in the management of M, Scarlett CJ, Andreia V, Kench JG, Lovell JA, Merrett patients with mPDAC and clinicians now have two ND, Christopher W, Musgrove EA, Bailey UH, Hofmann O, SutherlandRL,WheelerDA,WaddellN,AndrewV.Genomic potential treatment sequences available for the first analyses identify molecular subtypes of pancreatic cancer. time in the management of this disease. Nature. 2016;531(7592):47–52. Acknowledgements Open access funding provided by Medi- 8. MooreMJ,GoldsteinD,HammJ,FigerA,HechtJR,Gallinger cal University of Vienna. S, Au HJ,Murawa P,Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Conflict of interest G.W. Prager received speaker’s fee from Parulekar W. 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memo - Magazine of European Medical Oncology – Springer Journals
Published: Sep 1, 2017
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