Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes From the CONKO-003 Trial

Oettle, Helmut; Riess, Hanno; Stieler, Jens; Heil, Gerhard; Schwaner, Ingo; Seraphin, Jörg; Görner, Martin; Mölle, Matthias; Greten, Tim F.; Lakner, Volker; Bischoff, Sven; Sinn, Marianne; Dörken, Bernd; Pelzer, Uwe

doi:10.1200/jco.2013.53.6995

Cited by 425 publications

(335 citation statements)

References 24 publications

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“…In the OFF arm, the median OS and TTP were significantly extended in comparison to the 5-FU arm. The toxicities were similar between the two groups except for neurotoxicity, in 38.2% of OFF group patients [72] . However, oxaliplatinbased regimens for second-line chemotherapy have not given only positive outcomes.…”

Section: Current Knowledgementioning

confidence: 73%

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Spadi¹

2016

WJCO

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Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease.

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Section: Current Knowledgementioning

confidence: 73%

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Spadi¹

2016

WJCO

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“…This approach was informed in large part by results from one of the largest randomized studies (a German trial called CONKO-003) in this disease setting demonstrating a survival advantage of OFF (oxaliplatin, folinic acid, and fluorouracil) compared to FF alone (median OS: 5.9 vs 3.3 months, HR =0.66; log-rank P=0.010). 18 Conversely, a later trial conducted in Canada called PANCREOX showed almost the precise opposite results in a similar patient population, with patients treated with FOLFOX (chemotherapy regimen of folinic acid, 5-FU, and oxaliplatin) faring no better -and possibly worse -than those receiving 5-FU/LV alone. 19 In addition to nal-IRI, several other novel agents have shown promising results in the second-line (and beyond) setting for metastatic pancreatic cancer and are moving ahead in clinical development.…”

Section: Nanoliposomal Irinotecan In Pancreatic Cancermentioning

confidence: 99%

Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan

Ko¹

2016

IJN

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Nanoliposomal irinotecan (nal-IRI) was originally developed using an efficient and high-loading capacity system to encapsulate irinotecan within a liposomal carrier, producing a therapeutic agent with improved biodistribution and pharmacokinetic characteristics compared to free drug. Specifically, administration of nal-IRI results in prolonged exposure of SN-38, the active metabolite of irinotecan, within tumors, while at the same time offering the advantage of less systemic toxicity than traditional irinotecan. These favorable properties of nal-IRI, confirmed in a variety of tumor xenograft models, led to its clinical evaluation in a number of disease indications for which camptothecins have proven activity, including in colorectal, gastric, and pancreatic cancers. The culmination of these clinical trials was the NAPOLI-1 (Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy) trial, an international Phase III study evaluating nal-IRI both alone and in combination with 5-fluorouracil and leucovorin in patients with metastatic pancreatic adenocarcinoma following progression on gemcitabine-based chemotherapy. Positive results from NAPOLI-1 led to approval of nal-IRI (with 5-fluorouracil/leucovorin) in October 2015 by the US Food and Drug Administration specifically for the treatment of metastatic pancreatic cancer in the second-line setting and beyond, a clinical context in which there had previously been no accepted standard of care. As such, nal-IRI represents an important landmark in cancer drug development, and potentially ushers in a new era where a greater number of patients with advanced pancreatic cancer can be sequenced through multiple lines of therapy translating into meaningful improvements in survival.

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“…Second line OFF chemotherapy regimen was significantly improved OS and PFS in patients with metastatic pancreas cancer who were progressed during first-line gemcitabine monotherapy. 35 After the positive results of these trials, the NCCN Guidelines recommends fluropyrimidine plus oxaliplatin as a second-line treatment option. Although these trials used the OFF regimen most of the clinicians used the FOLFOX (oxaliplatin 85 mg/m 2 on day 1, 5-FU 400 mg/m 2 IV on day 1 followed by 2400 mg/m 2 continuous infusion over 46 hours, and leucovorin 400 mg/m 2 IV on day 1 repeated every 14 days) regimen as a second line therapy.…”

Section: Off or Folfoxmentioning

confidence: 99%

Current Treatment Options for Metastatic Pancreatic Adenocarcinoma.

Şendur¹

2015

UHOD

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Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death and have extremely poor prognosis. Although, declining trends for some major cancers, death rates are rising in both sexes for pancreatic cancer. Surgical resection is the only curative treatment of pancreatic cancer, but only 10 to 20 percent of patients are candidates for curative surgery. Fifty to sixty percent of patients with pancreatic cancer diagnosed in metastatic stage and 5-year overall survival (OS) rate is less than 5% for metastatic pancreatic cancer. Gemcitabine was the first chemotherapeutic agent that superior to 5-Fluorouracil. In most of the phase II trials combination gemcitabine with cytotoxic chemotherapy or targeted therapy showed promising results, but phase III trials with gemcitabine in combination with cisplatin, oxaliplatin, capacitabine, pemetrexed, irinotecan, bevacizumab, aflibercept, axitinib and cetuximab failed to improve primary endpoint OS. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in OS and S-1 approved for pancreatic cancer in Japan. In a randomized phase II/III ACCORD trial median progression free survival (PFS), response rate (RR), median OS and quality of life were significantly prolonged in FOLFIRINOX arm compared to gemcitabine alone arm. In phase III (MPACT) trial, like FOLFIRINOX regimen, median PFS, RR and OS significantly prolonged with the combination nab-paclitaxel and gemcitabine compared to gemcitabine arm alone. As a targeted agent erlotinib is the first and only agent that demostrate signifiacnt activity with gemcitabine combination in patients with metastatic pancreatic cancer. Gemcitabine plus erlotinib combination significantly prolonged PFS and OS compared to gemcitabine alone arm. Although some combination regimens showed significant OS benefit compared to single-agent gemcitabine, the median OS was less than 1 year. On these grounds, future directions are needed to integrate new targeted agents and combination protocols for metastatic pancreatic cancer. Keywords: Pancreatic cancer, Adenocarcinoma, Metastatic disease, Chemotherapy ÖZET Metastatik Pankreatik Adenokanserinde Güncel Tedavi SeçenekleriPankreas kanseri, kansere bağlı ölümlerin en sık 4. sebebi olup, son derece kötü prognoza sahiptir. Çoğu önemli kanserinde son yıllarda mortalitede belirgin azalma olmasına rağmen, pankreas kanseri mortalitesinde her 2 cinsiyette de artış devam etmektedir. Cerrahi rezeksiyon tek küratif tedavi yaklaşımı olmasına rağmen, sadece hastaların %10 ile %20'si küratif cerrahiye adaydırlar. Pankreas kanseri tanısı konulan hastaların %50-60'ı metastatik evrede tanı almaktadır ve 5 yıllık genel sağkalım (GS) %5'in altındadır. Gemsitabin 5-Fluorourasil'e kıyasla GS ve progresyonsuz sağkalım (PFS) avantajı sağlayan ilk ajandır. Birçok faz II çalışmada gemsitabin ile diğer sitotoksik veya hedefe yönelik tedavi kombinasyonları ümit verse de faz III çalışmalarda gemsitabin ile sisplatin, oxaliplatin, kapasitabin, pemetrexed, irinotekan, bevasizumab, aflibercept, axitinib v...

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Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes From the CONKO-003 Trial

Abstract: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.

Cited by 425 publications

References 24 publications

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan

Current Treatment Options for Metastatic Pancreatic Adenocarcinoma.

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