In two placebo-controlled clinical studies in patients with bone metastases from prostate cancer (n=643), meaning that 643 patien were enrollled on one arm, or from other solid tumors (n=773), meaning that 773 patietns were enrolled on the other arm, a large and meaningful study, both the percentage of patients with skeletal events (e.g., pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression) and the time to first skeletal event were decreased relative to placebo. This data was published and its size and prestige was accepted by FDA as a basis for approval and, therefore, general use. In these randomized controlled studies submitted to FDA for approval, there were 11 percent fewer skeletal events in zoledronic acid-treated patients with metastatic prostate cancer and 7 percent fewer skeletal events in treated patients with other metastatic solid tumors compared to placebo-treated patients.  This was a statistically significant difference.

I underscore that all patients in these studies were prostate cancer patients.

The United States Pharmacopeial Convention has concluded that zoledronic acid has an established role in prophylaxis of drug-induced osteopenia secondary to androgen-deprivation therapy in prostate cancer patients (USPDI, 2005). The USPDI explains that long-term androgen deprivation therapy can lead to significant decreases in bone mineral density. Results of a multicenter, double-blind, placebo-controlled study demonstrated increased bone mineral density of the hip and spine of men with non-metastatic prostate cancer beginning androgen deprivation therapy plus zoledronic acid (4 mg IV every three months) for 1 year (Smith, et al., 2005). The USPDI notes that a smaller, open-label controlled trial, published in abstract form, demonstrated similar preliminary results.

Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy, which is the case here.

Ryan CW, Huo D, Demers LM, et al. Zoledronic Acid Initiated During the First Year of Androgen Deprivation Therapy Increases Bone Mineral Density in Patients with Prostate Cancer. Journal of Urology . 2006;178:972-978.

Eaton CL, Coleman RE. Pathophysiology of bone metastases from prostate  cancer and the role of bisphosphonates in treatment. Cancer Treat Rev. 2003;29(3):189-198.

Smith MR. Bisphosphonates to prevent skeletal complications in men with metastatic prostate cancer. J Urol. 2003;170(6 Pt 2):S55-S57; discussion S57-S58.

Saad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-882.

Saad F, Eastham J. Zoledronic Acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology. 2010;76(5):1175-1181.

Van Poznak CH, Temin S, Yee GC, et al; American Society of Clinical Oncology. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-1227.

nccn, prostate cancer 2012

TheraSphere — a therapy that consists of millions of microscopic, radioactive glass microspheres (20-30 microns diameter) — is infused into the arteries that feed inoperable liver tumors, bathing the malignancy in high levels of extremely localized radiation. In some studies of highly selected pateints the response rates and stabilization rates ranged between 20-40 percent. No survival benefit has been demonstrated and the technique is still in phase II studies. This therapy is currently considered to be investigational. A recent guideline states: “radio-labeled Yttrium glass beads, radio-labeled lipiodol or immunotherapy cannot be recommended as standard therapy for advanced HCC outside clinical trials”.

A recent study(Salem 2010) may be changing the standard of care. It enrolled 291 patients (77% male, 25% were more than 75 years old, and 73% had multifocal disease). This is the largest series ever presented of the treatment of primary unresectable liver cancer using radiation microspheres. Results showed that overall time to progression was 7.9 months (95% confidence interval [CI], 6.0 – 10.3). Using World Health Organization guidelines, the overall response rate was 42%. Using the European Association for the Study of the Liver guidelines, the overall response rate was 57%. Survival times differed significantly by cancer staging system (26.9 months for BCLC A vs 17.2 months for BCLC B) and by liver function score (17.2 months for Child-Pugh A vs 7.7 months for Child-Pugh B). The promise here is that the disease can be converted to something that can become surgically resectable or that the patients may be able to be liver transplanted.

Although the phase III trials of radioembolization are ongoing as a first-line treatment of patients with metastatic colorectal cancer, there are sufficient phase II and retrospective clinical data supporting its use in salvage therapy for most patients. Patients with hepatocellular cancer, neuroendocrine tumors, and other primary sites, including breast and lung, although they also have also shown promising response and survival increases in multi-institutional experiences.

L. A. Dawson Hepatic Arterial Yttrium 90 Microspheres: Another Treatment Option for Hepatocellular Carcinoma J. Vasc. Interv. Radiol., February 1, 2005; 16(2): 161 – 164.

Andrew Kennedy, Subir Nag, Riad Salem, Ravi Murthy, Alexander J. McEwan, Charles Nutting, Al Benson, Joseph Espat, Jose Ignacio Bilbao, Ricky A. Sharma Recommendations for Radioembolization of Hepatic Malignancies Using Yttrium-90 Microsphere Brachytherapy: A Consensus Panel Report from the Radioembolization Brachytherapy Oncology Consortium International Journal of Radiation Oncology*Biology*Physics, Volume 68, Issue 1, Pages 13-23
R. Salem, R. J. Lewandowski, B. Atassi, S. C. Gordon, V. L. Gates, O. Barakat, Z. Sergie, C.-Y. O. Wong, and K. G. Thurston Treatment of Unresectable Hepatocellular Carcinoma with Use of 90Y Microspheres (TheraSphere): Safety, Tumor Response, and Survival J. Vasc. Interv. Radiol., December 1, 2005; 16(12): 1627 – 1639

Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005 Nov;42(5):1208-36. [322 references]

R. Salem, Society of Interventional Radiology (SIR) 35th Annual Scientific Meeting: Abstract 34. Presented March 14, 2010.

In order to provide a framework for erythropoietin therapy, several evidence-based guidelines have been developed, differing in scope and methodological rigor. Evaluation of iron stores is essential to proper application of these guidelines. In iron deficiency, erythropoietic factors are presumed not to be effective and the guidelines aim to avoid adminsitration of Aranesp or Procrit without prior or concommitant iron therapy in such cases. The most authoritative guideline to date was developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), as well as NCCN. Guidance on the use of darbepoetin alfa was given in the more-recently published guidelines of the European Organization for Research and Treatment of Cancer (EORTC), the National Comprehensive Cancer Network and Cancer Care Ontario. To summarize, erythropoietin or darbepoietin may be used routinely outside of clinical trials to increase Hb levels and to reduce the need for transfusion in patients with Hb levels of less than 10 g/dl and in patients with falling Hb levels approaching 10 g/dl and kept between 1o and 112, but not above 11.

There are required parameters to exclude coexisting iron deficiency which center on iron saturation above 20%. Ferritin alone can be misleading in cancer patients since it is an acute phase reactant. Iron saturation tends to rise rather than a decrease in cancer patients.

Procrit, Prescribing Information 2018

Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR.
American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.
Blood. 2010 Oct 25.

J. Seidenfeld, M. Piper, C. Flamm, V. Hasselblad, J. O. Armitage, C. L. Bennett, M. S. Gordon, A. E. Lichtin, J. L. Wade III, S. Woolf, and N. Aronson Epoetin Treatment of Anemia Associated With Cancer Therapy: a Systematic Review and Meta-analysis of Controlled Clinical Trials J Natl Cancer Inst, August 15, 2001; 93(16): 1204 – 1214

Rizzo JD et al. (2002) Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20: 4083-4107

Bokemeyer C et al. (2004) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40: 2201-2216

http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf, 2012

Steinbrook R. Medicare and erythropoietin. N Engl J Med. 2007; 356:4-6.

Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis. J Intern Med. 2012 Jan;271(1):51-63.

Jones D, Kamel-Reid S, Bahler D, Dong H, Elenitoba-Johnson K, Press R, Quigley N, Rothberg P, Sabath D, Viswanatha D, Weck K, Zehnder J.
J Mol Diagn. 2009 Jan;11(1):4-11. doi: 10.2353/jmoldx.2009.080095. Epub 2008 Dec 18.

Gluckman, J. Reiffers, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood, January 1, 2007; 109(1): 58 – 60.

J. V. Melo, T. P. Hughes, and J. F. Apperley. Chronic Myeloid Leukemia. Hematology, January 1, 2003; 2003(1): 132 – 152.

Hematology Disease Site Group. Walker I, Makarski J, Stevens A, Meyer RM. Treatment of chronic myeloid leukemia with imatinib. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jul 16. 27 p. (Practice guideline report; no. 6-15). [39 references]

http://www.cdhb.govt.nz/chlabs/miscdocuments/CML_Monitoring_Guidelines_Jul%202007.pdf

Despite optimal treatment, the prognosis of patients with malignant gliomas remains poor. Patients with glioblastoma multiforme have a median survival of 9 to 14 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. There is a need for more effective therapies.
Tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in an increasing number of cancers. There is growing evidence that specific inhibitors of these tyrosine kinases have potential therapeutic applications in oncology and Gleevec is being actively investigated in this disease. in one phase II component, the 6M-PFS for glioblastoma multiforme patients was 3%, whereas that for anaplastic glioma was 10%. In comparison, a retrospective review of negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS of 15% for glioblastoma multiforme and 31% for anaplastic glioma. The results are especially disappointing for anaplastic gliomas where the relative importance of PDGF raised the possibility of potential benefit from imatinib.

The European Organization for Research and Treatment of Cancer and the North Central Cancer Treatment Group are also conducting phase II studies of imatinib in recurrent gliomas. In the European Organization for Research and Treatment of Cancer study, glioblastoma multiforme and anaplastic glioma patients were initially treated with imatinib at a dose of 300 mg twice daily, increasing after 8 weeks to 400 mg twice daily if no grade II toxicity was observed. Subsequently, the protocol was amended to treat patients initially with 400 mg imatinib twice daily, increasing to 500 mg twice daily if no toxicity was observed after 8 weeks. The majority of these patients were on EIAED, and there was no attempt to adjust the dose according to the type of AED. Preliminary results of the European Organization for Research and Treatment of Cancer phase II study in glioblastoma multiforme patients showed 3 partial response and 5 stable disease over 6 months in 51 patients, with a 6M-PFS of 15.7%. In anaplastic glioma patients, there was only 1 partial response in 36 anaplastic oligodendroglioma/anaplastic oligoastrocytoma patients and 1 partial response in 25 anaplastic astrocytoma patients. These results are consistent and suggest that imatinib has minimal single-agent activity in malignant gliomas.

The next step was studying Gleevec in combiantion with other drugs. As an example of the trend, I will focus on Gleevec and Hydrea data. Researchers from Germany have reported clinical benefit in 57% of patients with refractory glioblastoma multiforme treated with Gleevec (imatinib) and hydroxyurea. The details of this phase II study appeared in the September 2005 issue of Annals of Oncology. The current trial included 30 patients with progressive glioblastoma multniorme refractory to chemotherapy and radiation therapy. The combination of Gleevec and hydroxyurea led to a 20% response rate and a disease stabilization rate of 37%. The median time to disease progression was 10 weeks and the overall survival was 19 weeks. Three patients continue on therapy for 106 or more weeks. The two-year progression-free survival was 16% with 32% of patients surviving at least six months. These authors suggest that this combination shows promise. Clearly much more investigation needs to be done before this combination can be routinely prescribed.

Reardon D, Egorin M, Quinn J, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme. Journal of Clinical Oncology. 2005; 23: 9359

Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Annals of Oncology. 2005;16:1702-1708.
McLaughlin ME, Robson CD, Kieran MW, et al. Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (ST0571), Gleevec: a case report and laboratory investigation. Journal of Pediatric Hematology and Oncology . 25:644-648.
Patrick Y. Wen et al, Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08 Clinical Cancer Research Vol. 12, 4899-4907, August 15, 2006
M.P. Omuro, S. Faivre, and E. Raymond
Lessons learned in the development of targeted therapy for malignant gliomas
Mol. Cancer Ther., July 1, 2007; 6(7): 1909 – 1919.

Following the observation that the combination of cisplatin plus cetuximab was safe, different clinical trials were performed to test this approach. In a phase III study in metastatic or recurrent SCCHN, 117 patients were randomised to receive cisplatin plus cetuximab, or cisplatin plus placebo. Median PFS was 2.7 months for the control arm and 4.2 months for the experimental arm. Median overall survival was 8.0 months and 9.2 months, respectively. Objective response rates were 10% and 26%. The toxicity was similar in both groups, except for the cutaneous rash associated with cetuximab. Recently, a retrospective evaluation of these clinical trials has been reported. In the study, a total of 330 platinum-refractory patients with recurrent or metastasic SCCHN treated with cetuximab alone or in combination with platinum-based chemotherapy were considered and compared with a historical series of 151 patients. The observed toxicity was mainly cutaneous (69% with the monotherapy treatment and 72% with the combination). The median survival time of around 6 months achieved with cetuximab in platinum-refractory SCCHN is similar to that seen with first-line therapy and represents an increase in survival of 2.5 months compared with platinum-refractory historical controls.

One interpetation of these results is that Erbitux restores platinum sensitivity.

Taking all these data into consideration, the administration of cetuximab in combination with a platinum compound in recurrent or metastatic platinum-resistant SCCHN could be an appropriate therapeutic approach that increases response rate and possibly time to treatment progression, without increased toxicity

In regard to Taxol/platin + cetuximab: A phase II trial evaluating this induction chemotherapy plus cetuximab (Erbitux) resulted in a 100% overall response rate among patients with head and neck cancer. These results were presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO).The trial known as Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME), involved 442 patients. About a third had cancer in the oral cavity or hypopharynx, nearly half had metastases, and most patients had already received treatment with radiotherapy (77% – 80%) and chemotherapy (36% – 41%). In this trial, all patients were treated with a chemotherapy regimen containing either carboplatin (in about a third of patients) or cisplatin plus 5-fluorouracil, and 1 group of patients also received cetuximab (400 mg/m² as an initial dose, followed by 250 mg/m² weekly).

I did not find any currently ongoing trials of this combination with either Taxol or Taxotere (except with radiation in stage III) but the consensus of experts is that these results must be confirmed before accepted as standard of care. Per most plan definitions, this renders this combination experimental.  NCCN(CHEM-A) does not list this three drug combination for metastatic disease.  It does list cisplatin and docetaxel and cisplatin/cetuximab.

 L. Licitra, P. Bossi, L. D. Locati, and C. Bergamini
Is Restoring Platinum Sensitivity the Best Goal for Cetuximab in Recurrent/Metastatic Nasopharyngeal Cancer?
J. Clin. Oncol., October 20, 2005; 23(30): 7757 – 7758.

JJ Cruz, A Ocaña, E Del Barco and A Pandiella Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer
Annals of Oncology 2007 18(3):421-430;

nccn.org, head and neck

Vermorken J, Bourhis J, Trigo M, et al. (2005) Cetuximab (Erbitux®) in recurrent/metastatic (R&M) squamous cell carcinoma of the head and neck (SCCHN) refractory to first-line platinum-based therapies. Proc Am Assoc Clin Oncol 501s: (Abstr 5505).

Kies M, Garden A, Holsinger C, et al. Induction Chemotherapy (CT) with Weekly Paclitaxel, Carboplatin, and Cetuximab for Squamous Cell Carcinoma of the Head and Neck (HN). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 5520.

NY State Gudielines for Hep. C. - http://www.health.state.ny.us/diseases/communicable/hepatitis/guidelines/appena.htm

Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004 Apr;39(4):1147-71. [213 references]

^{Several studies indicate that Avastin alone is also effective for renal cell carcinoma. A randomized, double-blind, Phase II trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks in 166 patients with renal cancer. Subjects were randomized to three groups: 40 to placebo, 37 to low-dose bevacizumab, and 39 to high-dose bevacizumab. The investigators reported that there was a significant prolongation of the time to progression of disease in the high-dose–antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). Although there were no significant differences in survival, this study cannot rule out such a benefit due to the fact that the study was too underpowered to detect differences in survival between treatment groups that may be clinically significant. According to updated results from a phase II clinical trial presented at the 23rd annual Chemotherapy Foundation Symposium, treatment with the combination of Tarceva® (erlotinib) and Avastin® (bevacizumab) resulted in good survival among patients with metastatic renal cell carcinoma.}

^{Current NCCN guidelines recommend Avastin as an option for crossover therapy of renal cell carcinoma after first line therapy with IL2, sorafenib or sunitinib and for first line with interferon.}

Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Systematic Rev. 2004;3:CD001425.

Hainsworth J, Spigel D, Greco A. Combination Therapy with Bevacizumab and Erlotinib for Patients with Metastatic Clear Cell Renal Carcinoma. Proceedings from the 23rd annual Chemotherapy Foundation Symposium. New York. 2005; Abstract #22.

Aimery de Gramonta, Eric Van Cutsemb, Investigating the Potential of Bevacizumab in Other Indications: Metastatic Renal Cell, Non-Small Cell Lung, Pancreatic and Breast Cancer, Oncology Suppl. 3, 2005

Escudier B, Koralewski P, Piuzanska A, et al. A randomized, controlled, double-blind Phase III study (AVOREN) of bevacizumab/interferon/a2a vs placebo/interferon-a2a as first-line therapy in metastatic renal cell carcinoma. Proceedings from the American Society of Clinical Onclology. Chicago, IL. 2007 Abstract # 3.

NCCN KID-7, 2011

EU Guidelines on Renal Cancer 2010

Ana M. Molina and Robert J. Motzer Clinical Practice Guidelines for the Treatment of Metastatic Renal Cell Carcinoma: Today and Tomorrow The Oncologist February 2011 vol. 16 Supplement 2 45-50

Locally advanced and metastatic pancreatic adenocarcinomas carry a very poor prognosis. In patients treated with the standard palliative treatment gemcitabine (GEM), median survival still remains only 6 months. Over the last several years, many trials have been designed combining GEM with various other drugs to treat chemo-naive patients, with the aim to improve overall survival. Unfortunately, none of the GEM-based combinations studied so far have reached that objective, with the exception of GEM plus Erlotinib, which showed a slight increase in OS to 6.4 months. However, some trials – mainly those using platinum based combinations – have shown an increase in response rate and time to progression. Some supportive evidence is available also for Taxotere/gemcitabine, the regimen used in this case.

The EORTC-GI Group compared a regimen of Taxotere® and Gemzar® to a regimen of Taxetore® and Platinol® for the treatment of advanced or metastatic (80%) pancreatic cancer.  This was a randomized trial, with 49 patients receiving Taxotere® and Gemzar® and 47 receiving Taxotere® and Platinol®. Six cycles of treatment were administered to 44% of patients, with 29% receiving more than 6 cycles. The Gemzar®/Taxotere® arm was associated with low platelets and edema, while the Taxotere®/Platinol® arm had more neutropenia. The response rate was 15.8% for the Gemzar®/Taxotere® arm and 16.1% for the Taxotere®/Platinol® arm. The median survival was 7.4 months for Gemzar®/Taxotere® and 6.3 months for the Taxotere®/Platinol®. There were 11 patients alive in the Gemzar®/Taxotere® arm and 9 in the Taxotere®/Platinol® arm. They concluded that the Gemzar®/Taxotere® arm had more manageable toxicity and possibly better activity. They will be performing a randomized phase III trial to confirm these results.

The Hoosier Oncology Group evaluated a regimen of Gemzar® and Taxotere®.  The response rate was 24%, with a median duration of response of 16 weeks. Thirty-five percent of patients had stable disease. The one-year survival was 27.3% and toxicity appeared to be acceptable.

German researchers also evaluated the combination of Gemzar® and Taxotere® for the treatment of patients with advanced pancreatic cancer. They observed a 24% response rate, with 3% (one patient) achieving a CR. The median survival was 9 months and toxicity was mild to moderate.

These results are not impressive and NCCN does not list this regimen.

Researchers from Austria evaluated the effects of Gemzar® with or without Xeloda® in 83 patients with metastatic pancreatic cancer. 3 Forty-two patients received bi-weekly Gemzar® (2200 mg per square meter as a 30 min. infusion) and 41 patients received the same GemzarÒ dose and schedule plus oral Xeloda® at a dose of 2500 mg per square meter from days 1 to 7. The PR rate was 14 % for the Gemzar® alone group and 17% for the Gemzar® plus Xeloda® group. Stable disease was observed in 43% of Gemzar® alone patients and 56% of the combined group. Median survival was 4 months for the Gemzar® group and 5.1 months for the Xeloda® group, with overall survivals of 8.2 and 9.5 months, respectively. Using a clinical benefit scale, there was clinical benefit for 33% of patients receiving Gemzar® alone and 48.3% for those receiving Gemzar® and Xeloda®. The toxicities of the two regimens appeared to be equivalent and these investigators were enthusiastic about this drug combination. However, there was no improvement in objective or subjective response. It was speculated that the number of patients studied was too small, possibly the dosage was suboptimal and possibly these agents are not really additive or synergistic.NCCN lists gemcitabien and fluoropyrimidine.

It is natural to put all three drugs together and this triple drug combination is being investigated in a phase II trial.

Practice guideline - http://www.cancercare.on.ca/pdf/pebc2-7s.pdf

Lutz MP, Ducreux M, Wagener T, et al, Docetaxel/gemcitabine or docetaxel/cisplatin in advanced pancreatic carcinoma: a randomized phase II study of the EORTC-GI group. Proceedings of the American Society of Clinical Oncology 2002;21:125a, abstract 498

Scheithauer W, Schüll B, Ulrich-Pur H, et al, Gemcitabine alone or in combination with capecitabine in patients with advanced pancreatic adenocarcinoma. Proceedings of the American Society of Clinical Oncology;21:126a, abstract number 500

nccn.org, pancreatic

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
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
J Clin Oncol. 2007 May 20;25(15):1960-6.

Schneider BP, Ganjoo KN, Seitz DE, et al, Phase II study of gemcitabine and docetaxel in combination for advanced pancreatic cancer – a Hoosier Oncology Group study. Proceedings of the American Society of Clinical Oncology 2002; 21:137a, abstract number 546

Schmidt C, Fahlke J, Kettner E, et al, Phase II multicenter study of gemcitabine and docetaxel in patients with inoperable or metastatic pancreatic cancer. Proceedings of the American Society of Clinical Oncology 2002;21:145a, abstract number 577.

V. Heinemann, R. Labianca, A. Hinke, and C. Louvet
Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study
Ann. Onc., October 1, 2007; 18(10): 1652 – 1659.

D. H. Palmer, D. D. Stocken, H. Hewitt, C. E. Markham, A. B. Hassan, P. J. Johnson, J. A. C. Buckels, and S. R. Bramhall
A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin
Ann. Surg. Oncol., July 1, 2007; 14(7): 2088 – 2096.

NCCN, Pancreatic PNAC-G, 1 2016

T. Seufferlein, J.B. Bachet, E. Van Cutsem, P. Rougier and on behalf of the ESMO Guidelines W, Pancreatic adenocarcinoma: ESMOESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2012) 23 (suppl 7): vii33-vii40

Nexavar has not been proven to be effective for melanoma. A Phase III trial administering Nexavar® (sorafenib) or placebo tablets in combination with the chemotherapeutic agents carboplatin and paclitaxel in patients with advanced melanoma did not meet its primary endpoint of improving progression-free survival (PFS). The treatment effect was comparable in each arm. The international Phase III, double-blind, randomized, placebo-controlled trial evaluated Nexavar when administered in combination with a standard dosing schedule (21-day cycles) of carboplatin and paclitaxel. Two hundred seventy patients progressing after one previous systemic chemotherapeutic treatment (with either dacarbazine (DTIC) or temozolomide) were enrolled into the study. The study was designed to measure the safety and efficacy of Nexavar when co-administered with chemotherapy, and had PFS as its primary endpoint. PFS is defined as the time that a patient lives without meaningful tumor growth. The safety profile of these agents in combination (Nexavar with carboplatin/paclitaxel) was comparable to those previously reported for these agents in combination. Preliminary results from a randomized Phase II study of a Temodar and Nexavar combination shows promise. An abstract showing effectiveness of Nexavar and dacarbaxine was presented in the 2007 ASCO meeting. randomized, 17-center, phase II study of 101 chemotherapy-naive patients showed a 50% improvement in progression-free survival and a 62% improvement in time to progression when sorafenib (Nexavar) was added to dacarbazine (DTIC-Dome) compared with dacarbazine plus placebo. Improved progression-free survival did not translate into a survival benefit, however. Thus, for now, Nexavar with Temodar or IV dacarbazine there are two phase 2 studies that show effectveness for melanoma. A recent review said this: “However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. Recently reported was a study in which, 101 patients with advanced stages of melanoma were randomly assigned to receive either chemotherapy alone with the drug dacarbazine or dacarbazine plus Nexavar. Patients who received both dacarbazine and Nexavar experienced an average time until disease progression that was nearly double the time experienced by those treated with dacarbazine alone (12 weeks versus 21 weeks). Overall survival among patients who received both dacarbazine and Nexavar was also improved compared with those treated with dacarbazine only (51 weeks versus 46 weeks). The place of nexavar is not yet estabished in the treatment of melanoma and it is still investigational.

McDermott, DF., Sosman, JA., Gonzalez, R, et al. Double blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: A report from the 11715 Study group. Journal of Clinical Oncology. 2008;26:2178-2185.

Egberts F, Kahler KC, Livingstone E, Hauschild A..Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results.Onkologie. 2008 Jul;31(7):398-403 http://www.oncologyreport.com/melanoma/70994b.html