There had been no trials or publications of Xeloda and Abraxane for pancreatic cancer, as far as I could determine. The GAX combination is in a clinical trial: Nab-paclitaxel (Abraxane), Gemcitabine, and Capecitabine (Xeloda) for Pancreatic Adenocarcinoma, NCT01161186. The purpose of this study is to evaluate optimal dose and safety of the combination of Abraxane, gemcitabine, and Xeloda (capecitabine) (AGX) as first-line therapy in patients with metastatic pancreatic cancer. The trial was completed and awaits publication.

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This mechanism of action provoked an interest is using this drug for other solid cancers, especially for pancreatic cancer, where new agents are sorely needed. A single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafeni combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1–3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a Ki value of 2.7 μmol/l. The investigators concluded: “Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m2 or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.”

Although a phase I study was promising, a phase II study of gemcitabine/sorafenib combination showed that these combination was inactive for pancreatic cancer(Wallace et al). Data from the BAYPAN study presented at the American College of Clinical Oncology’s 2011 Annual Meeting did not support the addition of sorafenib to gemcitabine therapy in the treatment of advanced pancreatic cancer (APC). Anthony Goncalves, MD, of the Institut Paoli-Calmettes, Marseilles, France, and colleagues noted that this is in contrast to an earlier Phase I study(Siu et al) that demonstrated that the gemcitabine (G) + sorafenib (S) combination was well tolerated and had activity in APC patients.  Unfortunately, similar results were obtained in studies of sorafenib with other combinations of drugs, such as erlotinib , cisplatin and capecitabine.

Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res. 2006 Jan 1;12(1):144-51.

ttp://www.ejcancer.info/article/S0959-8049(06)00803-3/abstract

Wallace JA, Locker G, Nattam S, Kasza K, Wade-Oliver K, Vokes EE, Kindler HL. Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium. 2007 Gastrointestinal Cancers, Symposium; Abstract No: 137.

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http://www.annalsofhepatology.com/PDF/vol9n1/HP101-13-Hepatoblastoma.pdf

Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010.

NeoPlas Innovation’s Stephen Cantrell, M.D., has opened a clinic where he uses lovastatin with interferon for a variety of cancer diagnosis. We await peer-reviewed publications on the results of this approach.

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Another disadvantage of proton beam therapy (PBT)is that the equipment that can produce it is very expensive, ensuring that it is only available in a limited number of academic centers.

Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system (CNS) and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.

A report by the American Society of Therapeutic Radiology (ASTRO) Emerging Technologies Committee states that there is reason to be optimistic about the potential developments in proton beam therapy (PBT) and the prospective research that is ongoing at centers worldwide. Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, gastro-intestinal malignancies (with the exception of hepatocellular(liver) cancer) and pediatric non-Central Nervous System malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dose measuring benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical research is needed and should be encouraged (ASTRO, 2011).

American College of Radiology (ACR) appropriateness criteria state that the physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. Results from larger, prospective, controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer (ACR, 2010).

A Blue Cross Blue Shield technology assessment evaluated health outcomes following proton beam therapy compared to stereotactic body radiotherapy (SBRT) for the management of Proton Beam Radiation Therapy: Medical Policy 12 non-small-cell lung cancer. The report concluded that, overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer. All PBT studies are case series, and there are no studies directly comparing proton beam therapy (PBT) and stereotactic body radiotherapy (SBRT). In the absence of randomized, controlled trials, the comparative effectiveness of PBT and SBRT is uncertain (BCBS, 2011).

The only guideline that I found that offers a qualified support is NCCN. The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints (NCCN, 2012).

It is quite clear from limited studies that proton beam is not inferior to other radiotherapy techniques. What has not been proven is that it is superior and that its ability to spare the tissues translates to a better outcome. It makes sense that it should, but in science that would be called a hypothesis that needs to be proven. Because PBT is only available in limited centers and is much more complex and expensive than other tissue sparing radiation therapy techniques, it should still be considered investigational.

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At this time gemcitabine is not well supported, alone or in combination for adjuvant therapy of breast cancer.

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