Updates on the Management of Advanced Hepato-pancreato-biliary Malignancies

Updates on the Management of Advanced Hepato-pancreato-biliary Malignancies

Updates on the Management of Advanced Hepato-pancreato-biliary Malignancies: A Report from the 14th European Cancer Conference (ECCO)

Introduction

The 14th European Cancer Conference of the European Cancer Organisation (ECCO) was held in Barcelona, Spain, September 23-27, 2007. The small size and very limited selection of abstracts for oral presentation allowed for detailed discussion of the proofread papers. In the Gastrointestinal Tract (Non-colorectal) session, new data in the fields of hepatocellular carcinoma and pancreatic cancers were discussed.

Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma is the fifth leading cause of cancer worldwide and most patients die within one year of diagnosis.[1] Historically, there have been no effective systemic treatment strategies for this difficult disease. Results from a Phase III randomized trial of sorafenib versus placebo (the SHARP trial) were presented at the 2007 annual meeting plenary session of the American Society of Clinical Oncology (ASCO).[2] The study indicated that sorafenib, an orally available multikinase inhibitor,[3] significantly improved survival and doubled the time to progression among patients with advanced HCC. This is the first agent to ever demonstrate a significant improvement in survival in the treatment of HCC and data presented at ECCO continues to support the activity of sorafenib.

Based on promising results of a Phase I study which evaluated sorafenib in combination with doxorubicin,[4]a randomized phase II, double blind trial of sorafenib plus doxorubicin and placebo plus doxorubicin in chemotherapy-naïve HCC patients was initiated. The final data was presented at this ECCO meeting.[5]

The study, with a primary endpoint of time to progression (TTP), has been interrupted prematurely earlier in 2007, based on an unplanned interim analysis held by an Independent Data Monitoring Committee (DMC) in view of the positive interim analysis results of the SHARP trial. The DMC of this preliminary analysis found that the TTP and OS in the sorafenib/doxorubicin arm appear(ed) to be encouraging. The results for the Phase II trial, although immature, indicate that the patients randomized to receive doxorubicin may be at a considerable disadvantage. Thus, the DMC advised the sponsor to consider discontinuation of the study.

The data presented at the meeting is based on the March 2007 cutoff, right before patients on the placebo/doxorubicin arm were allowed to cross-over to the sorafenib/doxorubicin arm. The analysis is based on 38 TTP and 70 progression-free-survival (PFS) events, and 50 deaths. TTP of the sorafenib/doxorubicin and placebo/doxorubicin arms were 8.6 and 4.8 months, respectively. Overall survival (OS) was 13.7 months for the experimental arm and 6.5 months for the doxorubicin/placebo arm, and PFS was 6.9 and 2.8 months, respectively. The toxicity profiles of both arms were similar to the toxicities of the single agents, including fatigue, diarrhea, and neutropenia. Sorafenib-induced hand foot syndrome was obviously more noted in the sorafenib/doxorubicin arm. Grade 3/4 left ventricular dysfunction was limited to one event in the sorafenib/doxorubicin arm. The author concluded that this randomized Phase II study of doxorubicin plus sorafenib and doxorubicin plus placebo, showed encouraging TTP and OS outcome for the doxorubicin plus sorafenib arm. This trial supports the growing body of evidence of the activity of sorafenib in HCC. Yet, any synergistic role between sorafenib plus doxorubicin in HCC needs to be further defined. Dr. Cunningham, co-chair of the session, commented on the rigorous data and positive outcome of this study and was in support of further evaluating the combination of sorafenib plus doxorubicin in advanced HCC.

Dr. Llovet presented updated results of the SHARP trial at ECCO, evaluating sorafenib versus placebo in a double-blind, randomized Phase III trial in Childs Pugh A patients with advanced HCC.[6] This trial, powered for overall survival and time to symptomatic progression (TTSP), has demonstrated a statistically significant (p=0.00058) improvement in median overall survival (OS) in favor of sorafenib (10.7 months) versus placebo (7.9 months). The study did not show any difference in TTSP (p= 0.77). Grade 3/4 diarrhea and hand foot syndrome were reported in 8% of the patients in the sorafenib arm. Bleeding events were reported at less than 1% in both arms.

Phase II data on the oral multitargeted tyrosine kinase inhibitor, sunitinib malate, was also presented in a poster discussion at this years ECCO meeting.[7] The Phase II, open-label, single-agent study evaluated the efficacy and safety of sunitinib in European and Asian patients with unresectable HCC. The investigators reported that major tumor necrosis was observed in almost half of the patients and further studies were warranted. This finding is commensurate with the tumor necrosis phenomenon noted in the Phase II study evaluating sorafenib in patients with advanced HCC. Validation of tumor necrosis as a indicator for response is still needed. A correlative study evaluating DCE-MRI was conducted as part of the randomized Phase II, double blind trial of sorafenib plus doxorubicin and placebo plus doxorubicin in chemotherapy-naïve HCC. The results are due later in 2008.

Pancreatic Cancer

Pancreatic cancer remains a deadly cancer with almost equal incidence and mortality.[8] To improve on outcome, multiple studies have evaluated different adjuvant therapy modalities. A chemotherapeutic approach based on the ESPAC-1[9] and the CONKO-001[10] studies has been adapted in Europe. Commensurate with the approach, Dr. Kosuge shared with the audience at ECCO the experience of 10 Japanese centers of 3 cycles of gemcitabine given in the adjuvant setting, part of a randomized Phase III study comparing gemcitabine to observation.[11] The primary endpoint of the study was OS. Patients were stratified by pathologic stage, completion of resection, and centers. All of the 118 patients that were accrued were eligible. Both arms were balanced in terms of baseline characteristics. Known and reversible toxicities of gemcitabine were noted in the treatment arm. The OS primary endpoint of the study was not met: 22.3 months for the gemcitabine arm, and 18.4 months for the observation arm (p=0.79). Disease free survival (DFS), a secondary endpoint of the study, was 11.4 months for the experimental arm and five months for the observation arm (p=0.01). The presenter attempted a comparison of the data to the CONKO -001 study. This comparison is, however, limited in its scope and may be deemed inappropriate for the following reasons: the current study offered only 3 cycles of chemotherapy versus 6 on the CONKO-001 study; and this study included patients with vascular involvement who were operated on with R0 or R1 outcome, which would require an independent evaluation given the rarity of such scenario.

On the metastatic front, the randomized trial reported in 1997 by Dr. Burris, et al. defined the superiority of gemcitabine over bolus 5-FU in the treatment of advanced pancreatic cancer.[12] Since then, single-agent gemcitabine has been a standard of care for this disease. Multiple strategies have been evaluated in clinical trials including gemcitabine and cytotoxics and gemcitabine plus novel agent combinations. Most combinations have shown disappointing results, when compared to gemcitabine alone. Gemcitabine plus erlotinib[13] and gemcitabine plus capecitabine[14] have shown a survival improvement when compared to gemcitabine alone, the latter based on an interim analysis.

Two oral presentations evaluating new agents for the management of advanced pancreatic cancer were presented at ECCO. A randomized Phase III study evaluating glufosfamide plus best supportive care (BSC) versus BSC in the second-line setting in patients previously treated with gemcitabine was presented by Dr. Ciuleanu.[15] This novel chemotherapeutic agent consists of the active metabolite of ifosfamide linked to glucose, with possible preferential uptake by malignant cells. The trial included only patients with distant metastases and accrued a total of 303 patients. The primary endpoint, aimed at detecting 50% improvement in OS with 90% power, was negative. Median OS was 3.5 months for the glufosfamide plus BSC arm, and 3.1 months for the BSC arm (p=0.19). Median PFS was close to 1.5 months in both arms. A subgroup analysis showed patients with diabetes that is controlled by oral agents to have an improvement in OS, and those controlled with insulin to have worse outcome. The most common side effects of glufosfamide were nausea (29%) and vomiting (22%). The study was concluded as negative and would not recommend glufosfamide therapy in the setting of second-line treatment for stage IV pancreatic cancer.

On behalf of his colleagues, Dr. Spano presented the final results of a randomized Phase I/II study of the novel anti-VEGF agent axitinib plus gemcitabine and single agent gemcitabine in patients with advanced pancreatic cancer.[16] The primary objective of the study was to evaluate OS. A 2:1 randomization was applied in favor of the combination arm, on which patients received 5 mg of axitinib twice daily plus standard gemcitabine 1000mg/m2 every three weeks. The single agent arm utilized the same gemcitabine schedule. The OS was 6.9 months for the combination arm and 5.6 months for the gemcitabine alone arm, both comparable with historical control gemcitabine median OS. A subset analysis of patients with locally advanced disease showed a difference in OS in favor of the combination arm (12.5 months versus 6.5 months). Grade 3/4 fatigue and asthenia were more noticeable on the combination arm. Despite the limitations of this unblinded Phase II study and the fact that the study did not seem to capture any sign of improvement in OS in favor of axitinib plus gemcitabine, the presenter reported that a randomized Phase III study aiming at evaluating an improvement in OS by about 20%, which requires close to 600 patients, is underway. Expectations seem to be modest.

Conclusion

Mature study results evaluating sorafenib for the management of advanced HCC presented and published in 2007 are encouraging and may result in a new treatment paradigm for this difficult to treat disease. Despite the positive outcome of the two studies of sorafenib discussed above, more work is still needed to further improve on the outcome of HCC.

Many targeted and novel agents are under investigation in the management of resected and advanced pancreatic cancer. The results of the three studies presented at ECCO are sobering and should be used as reminders of the need for new strategies to improve on the outcome of pancreatic cancer.

References:

[1] McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF Jr. International trends and patterns of primary liver cancer.Int J Cancer. 2001 Oct 15;94(2):290-6.

[2] Llovet J, et al. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). Proceedings from the American Society of Clinical Oncology Conference. Chicago,IL. 2007. Late-Breaking Abstract (LBA) #1.

[3] Wilhelm S, Carter C, Tang L, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis. Cancer Research 64, 7099-7109, October 1, 2004.

[4] Richly H, Henning BF, Kupsch P, Passarge K,, et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Annals of Oncology. 2006 May;17(5):866-73. Epub 2006 Feb 24.

[5] Abou-Alfa G, Johnson P, Knox J, et al. Preliminary results from a Phase II, randomized, double-blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. Proceedings of the 2007 meeting of the European Cancer Organization. European Journal of Cancer Supplements. 2007; 5:259. Abstract #3500.

[6] Llovet J, Mazzaferro V, Ricci S, et al. Sorafenib improves survival in a large multi-center, randomized, placebo-controlled Phase III trial in patients with hepatocellular carcinoma. European Journal of Cancer Supplements. 2007; 5:261. Abstract #3507.

[7] Faivre SJ, Raymond E, Douillard J, et al. Phase II trial investigating the efficacy and safety of sunitinib in patients with unresectable hepatocellular carcinoma (HCC). European Journal of Cancer Supplements, Vol 5 No 4, Page 270. Abstract #3535.

[8] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66.

[9] Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer.A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;18;350(12):1200-10.

[10] Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;17;297(3):267-77.

[11] Kosuge T, Ueno H, Matsuyama Y, et al. A randomized Phase III study comparing gemcitabine monotherapy with observation in patients with resected pancreatic cancer. European Journal of Cancer Supplements. Vol 5 No 4, Page 260. Abstract #3504.

[12] Burris HA III, Moore MJ, Andersen J, et.al. Improvements in survival and clinical benefit with Gemzar as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413 1997.

[13] Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23.

[14] Cunningham D et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. ECCO 13, Abstract PS11, presented Nov. 2, 2005.

[15] Langmuir V, Ciuleanu T, Pavlovsky A, et al. Glufosfamide (GLU) in metastatic pancreatic adenocarcinoma previously treated with gemcitabine: Results of a Phase III trial. Proceedings from the 14th The European Cancer Conference (ECCO). Barcelona, Spain. European Journal of Cancer Supplements, Vol 5 No 4, Page 260. Abstract #3505.

[16] Spano J, Chodkiewicz C, Maurel J, et al. Axitinib (AG-013736) and gemcitabine vs gemcitabine in advanced pancreatic cancer: a randomised phase II study. Proceedings from the 14th European Cancer Conference (ECCO). Barcelona, Spain. Abstract # 3506.

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