Cancer Treatment

Nexavar for bladder cancer

Sorafenib(Nexavar) is an oral agent that is currently approved by the U.S. Food and Drug Administration for the treatment of kidney cancer. Several trials were began based on pre-clinical findings. A recent trial suggests that it is ineffective: "Sorafenib does not show sufficient activity as a single agent in first-line metastatic urothelial cancer to warrant further investigation." It is in active trials, for example: Sorafenib in Urothelium Cancer of Bladder, NCT01215266 as well as with radiation.

Srikala S. Sridhar, Eric Winquist, Andrea Eisen, Sebastien J. Hotte, Elaine McWhirter, Ian F. Tannock, Som D. Mukherjee, Lisa Wang, Chantale Blattler and John J. Wright, et al.
A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium Investigational New Drugs DOI: 10.1007/s10637-010-9408-4, 2010

Zolinza and Valcade for myeloma

Zolinza is approved in the USA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. However, it mayb e effective in myeloma as well.Results from two Phase 1 studies of ZOLINZA® (vorinostat), Merck's oral histone deacetylase (HDAC) inhibitor, administered in combination with bortezomib, showed early anti-tumor activity in patients with relapsed and/or refractory multiple myeloma, including those previously treated with and no longer responding to bortezomib. Results of these studies, which were designed primarily to determine the maximum tolerated dose of the combination regimen, were presented at the 50th Annual Meeting of the American Society of Hematology (Abstract #871). 

Based on this information, Merck initiated phase II studies, VANTAGE 088 and VANTAGE 095, as well as a Phase III, global, randomized, double-blind, placebo-controlled, 742-patient multicenter trial investigating Zolinza plus Velcade in relapsed MM after one to three prior anti-myeloma. However, the therapy remains investigational so far.

Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.

nccn.org, myeloma

Cisplatin etoposide for head and neck cancer

Cisplatin and etoposide has been reported for the treatment of recurrent head and neck cancer but it is not a well-supported regimen or one that has been popular over teh past two decades. I have not been able to find recent literature to support this combinaiton. There is more evidence for etoposide alone, but it is not a very active drug as a single agent. A 1987 comparative phase III study of cisplatin etoposide versus etoposide alone revealed  no difference in toxicity or efficacy between the two treatments with regard to leukopenia, thrombopenia, vomiting and nephrotoxicity. This regimen seems to have been abandoned in the mainstream oncologic practice.

D. Osoba, P. R. Band, J. H. Goldine, J. M. Connors, K. Gelmon, M. A. Knowling Efficacy of weekly cisplatin-based chemotherapy in recurrent and metastatic head and neck cancer
Ann Oncol (1992) 3 (suppl 3): S57-S62.

W. Rauschning, M. Schröder, R. Bätge, H. G. Luhr, J. -H. Beyer and G. A. Nagel
Cisplatin (DDP) and etoposide (VP-16) as primary chemotherapy in patients with squamous cell carcinoma of the head and neck region (SCC-HN) Deutsche Krebsgesellschaft Proceedings 18th National Cancer Congress of the German Cancer Society March 4–8, 1986 Munich, Federal Republic of Germany

Marechal F, Nasca S, Morel M, Jezekova D, Coninx P, Legros M, Nguyen TD, Cattan A.
A phase III of cisplatinum versus cisplatinum-etoposide for previously untreated squamous cell carcinoma of the head and neck.Anticancer Res. 1987 May-Jun;7(3 Pt B):455-8.

nccn.org, head and neck cancer

Revlimid for Hodgkin's

Revlimid is an orally administered derivative of thalidomide, which is a very active agent for the treatment of multiple myeloma but has serious side effects, especially thromboembolism. Revlimid is reported to have less toxicity than thalidomide but retains antimyeloma effects. Revlimid has recently been approved by the FDA for review of treatment of myelodysplastic syndromes (MDS) wih a 5q- mutation and for first line treatment of multiple myeloma in conjunction with dexamethasone. The only publisehd reprot that I could find was of 12 patients, only two of whom had lymphocyte predominant disease, who had a response rate of 50%.

Revlimid is currently in a study: Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin's Lymphoma, NCT00478959.

Boris Böll; Peter Borchmann; Max S Topp; Mathias Hänel; Katrin S Reiners; Andreas Engert; Ralph Naumann British journal of haematology     Volume:  148     ISSN:  1365-2141     Br. J. Haematol, 2010 Feb 

nccn.org, hodgkin's

Folfirinox for pancreatic cancer

Currently gemcitabine or gemcitabine with erlotinib are FDA approved for pancreatic cancer . First-line treatment with the FOLFIRINOX regimen for metastatic pancreatic adenocarcinoma in patients with a good performance status significantly improved OS, PFS. Combination chemotherapy is the new frontier for metastatic pancratic cancer. A major recent advance has been the combination of irinotecan, florouracyl and oxaliplatinsponse rate and time to degradation of quality of life compared with gemcitabine, according to the phase 3 results of the PRODIGE 4/ACCORD 11 trial.

Prolongation of survival is particularly notable for pancreatic cancer, a recalcitrant cancer to therapy. This has generated widespread enthusiasm. The trial is being widely adopted for clinical care, even before being fully published  or reflected in the guidelines.

 

Here is a quote from a recent review in HemOnc today:

 "

These data may be practice-changing in terms of establishing a new chemotherapy regimen as front-line treatment of metastatic pancreatic cancer, using a non-gemcitabine-based regimen. It is the most positive phase 3 study we have ever seen in advanced pancreatic cancer, with an absolute improvement in median survival of 4.3 months compared to single-agent gemcitabine. Compared with prior phase 3 studies, the overwhelming majority of which have been negative, these data are too striking to ignore.

Of concern, however, is the tolerability and toxicity of this elaborate multidrug regimen. However, NCCN has now included Fofirinox in its recommendations (2011, PANC-E) as a level 1 recommendation.
 ASCO 2010, [Presentation title: Randomized Phase III Trial Comparing FOLFIRINOX (5FU/ Leucovorin, Irinotecan and Oxaliplatin) vs Gemcitabine as First-Line Treatment for Metastatic Pancreatic Adenocarcinoma. Prodige 4 - ACCORD 11/0402 Trial: Final Results. Late-Breaking Presentation]

Thierry Conroy, M.D., Françoise Desseigne, M.D., Marc Ychou, M.D., Ph.D., Olivier Bouché, M.D., Ph.D., Rosine Guimbaud, M.D., Ph.D., Yves Bécouarn, M.D., Antoine Adenis, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Sophie Gourgou-Bourgade, M.Sc., Christelle de la Fouchardière, M.D., Jaafar Bennouna, M.D., Ph.D., Jean-Baptiste Bachet, M.D., Faiza Khemissa-Akouz, M.D., Denis Péré-Vergé, M.D., Catherine Delbaldo, M.D., Eric Assenat, M.D., Ph.D., Bruno Chauffert, M.D., Ph.D., Pierre Michel, M.D., Ph.D., Christine Montoto-Grillot, M.Chem., and Michel Ducreux, M.D., Ph.D. for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup, FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer,” May 12, i2011 New England Journal of Medicine. 

Humira for sarcoidosis

Humira is a drug similar to Remicaid. It is potentially effective in sarcoidosis but there is not much supporting evidence. There are several case reprots but I could not find prospective studies. A study was planned but suspended prior to enrollment: Efficacy Study of Humira in the Treatment of Cutaneous Sarcoidosis, NCT00731757
Trial of Adalimumab in Progressive Sarcoidosis NCT00311246
was terminated due to difficulty in recruiting. Two other trials for cutaneous sarcoidosis are listed on the clinicaltrials.gov site. Humira for sarcoidosis is a potentially efective but not literature supported treatment at this time.

A.-M. Thielen, C. Barde, J.-H. Saurat, E. Laffitte
Refractory Chronic Cutaneous Sarcoidosis Responsive to Dose Escalation of TNF-Alpha Antagonists Dermatology Vol. 219, No. 1, 2009 

Michael P. Heffernan, MD; David I. Smith, MD
Adalimumab for Treatment of Cutaneous Sarcoidosis Arch Dermatol. 2006;142:17-19.

Gupta et al. Treatment of sarcoid granulomatous interstitial nephritis with adalimumab
NDT Plus 2009;2:139-142.

Rivkina AM, Stump LS. Infliximab in graft-versus-host disease. Am J Health-Syst Pharm 2002;59(13):1271-1275.

Ball LM, Egeler RM. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. Jun 2008;41 Suppl 2:S58-64. [
 

Followup in osteosarcoma

It is not entirely clear how to followup definitively treated osteosaroma. ESMO recommends clinical followup every 6 weeks to 3 months in years 1 and 2 after diagnosis, every 2–4 months in years 3 and 4, every 6 months in years 5–10 and every 6–12 months thereafter. Each visit should include a history and physical examination and a chest X-ray [IV, C]. X-rays of the primary tumor site are recommended every 4 months until the end of year 4 [IV, C]. Late metastases may occur >10 years after diagnosis and there is no universally accepted stopping point for tumor surveillance. NCCN in its osteosarcoma guideline, p. 8 recommends "chest imaging" without specification. It does recommend PET for initial staging and thereafter (also bone scan, p. 11). It says that CT scan should be done if chest Xray becomes abnormal9p.29).

S. Bielack et al, Osteosarcoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up Ann Oncol (2009) 20 (suppl 4): iv137-iv13 

nccn.org, Bone Cancer, Osteosarcoma

Octreotide for chemotherapy induced diarrhea

Chemotherapy induced diarrhea is a common complication of chemotherapy. First steps are stopping the chemo, hydration and anti-diarrheal agents. Several small trials have reported good results using subcutaneously administered, short-acting octreotide acetate in patients who have failed initial therapy with loperamide. Although several recent studies appear to show that octreotide is nto effective in prophylaxis, it continues to be recommended in review articles and guidelines. While the optimal dose of octreotide has not been determined, a panel of experts has recommended that complicated cases of diarrhea should be managed with IV fluids, octreotide at a starting dose of 100 to 150 μg subcutaneously (SC) 3 times a day or 25 to 50 μg/hour IV with a dose escalation to 500 μg 3 times a day, and administration of antibiotics. This regimen should be continued until the patient has been diarrhea free for 24 hours.
Based on these, admittedly older guidelines, octreotide is still "supported".

Zidan J, Haim N, Beny A, et al: Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 12:227-229, 2001.

Barbounis V, Koumakis G, Vassilomanolakis M, et al: Control of irinotecan-induced diarrhea by octreotide after loperamide failure. Support Care Cancer 9:258-260, 2001.

James A. Martenson, Michele Y. Halyard, Jeff A. Sloan, Gary M. Proulx, Robert C. Miller, Richard L. Deming, Stephen J. Dick, Harold A. Johnson, T.H. Patricia Tai, Angela W. Zhu, Joan Keit, Kathy J. Stien, Pamela J. Atherton Phase III, Double-Blind Study of Depot Octreotide Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy: Results of North Central Cancer Treatment Group N00CA JCO November 10, 2008 vol. 26 no. 32 5248-5253

A. Stein, Review: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management
Therapeutic Advances in Medical Oncology Jan 1, 2010:51-63

B. Zachariah et al, Octreotide Acetate in Prevention of Chemoradiation-Induced Diarrhea in Anorectal Cancer: Randomized RTOG Trial 0315
JNCI J Natl Cancer Inst Apr 21, 2010:547-556

Benson AB 3rd, Ajani JA, Catalano RB, et al.: Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22 (14): 2918-26, 2004.

Rapamune for Graft Versus Host Disease

Graft-versus-host disease (GVHD) represents a serious complication of allogeneic BMT and remains one of the most difficult challenges for clinicians. Renal Transplantation
Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. It is off-label for grft versus host disease that may occurr after an allogeneic stem cell transplant.

A retrospective study of 190 patients suggested that Rapamune is beneficial in reduced intesnity allogeneic transplantation. The publicatio of thsi study was follwoed by a dissenting voice that pointed out that it was a retrospective study that hinged on outcome of only 23 patients.

A prosective phase II study is ongoing: "A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone, Sirolimus/Extracorporeal Photopheresis Plus Prednisone, and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN #0801)”

 

Susan J. Allison Off-label prescribing: a matter of trust Nature Reviews Nephrology 6, 441 (August 2010)

Perez-Simon JA, Sanchez-Abarca I, Diez-Campelo M, et al. Chronic graft-versus-host disease: Pathogenesis and clinical management. Drugs. 2006;66(8):1041-1057.

Bolanos-Meade J. Update on the management of acute graft-versus-host disease. Curr Opin Oncol. 2006;18(2):120-125.

Philippe Armand, Supriya Gannamaneni, Haesook T. Kim, Corey S. Cutler, Vincent T. Ho, John Koreth, Edwin P. Alyea, Ann S. LaCasce, Eric D. Jacobsen, David C. Fisher, Jennifer R. Brown, George P. Canellos, Arnold S. Freedman, Robert J. Soiffer, Joseph H. Ant, Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation With Reduced-Intensity Conditioning in JCO December 10, 2008 vol. 26 no. 35 5767-5774

Jayesh Mehta Sirolimus-Containing Graft-Versus-Host Disease Prophylaxis in Patients With Lymphoma JCO October 1, 2009 vol. 27 no. 28 e138

PEM: Positron Emission Mammography

Positron-emission mammography (PEM), uses isolated molecular imaging to examine the breast, producing a precise and comprehensive image tissue within. LIke for PET, F-18 tracer binding to fluorodeoxyglucose (FDG) within the breast’s cells indicates abnormailities. PEM reveals the size, shape, location and malignancy of the mass in a high-resolution 3D tomographic image.

At the 2008 Radiological Society of North America (RSNA) meeting, the single-site study of 208 women with confirmed breast cancer revealed that PEM was significantly more sensitive (93 percent) than whole-body PET (68 percent) in detecting index malignant lesions, and equivalent to breast MRI (93 percent). Of the 182 lesions detected, PEM successfully identified 90 percent of the 30 ductal carcinoma in situ (DCIS) cases, more than the 83 percent detected by MRI. PEM specificity was 74 percent versus 48 percent for MRI in the ipsilateral breast. PEM specificity was 82 percent versus 67 percent with MRI in the contralateral breast. Both PEM and MRI were 89 percent accurate in detecting index lesions in fatty breasts. Accuracy reached 77 percent with PEM in extremely dense breasts, compared with 69 percent using MRI.

Commetn for a reader J.:

Several prospective comparative studies have been published.

Positron emission mammography in breast cancer presurgical planning: comparisons with magnetic resonance imaging.

Schilling K, Narayanan D, Kalinyak JE, The J, Velasquez MV, Kahn S, Saady M, Mahal R, Chrystal L.

Eur J Nucl Med Mol Imaging. 2010 Sep 25. [Epub ahead of print]

PMID: 20871992 [PubMed - as supplied by publisher]

and

High-resolution fluorodeoxyglucose positron emission tomography with compression ("positron emission mammography") is highly accurate in depicting primary breast cancer.

Berg WA, Weinberg IN, Narayanan D, Lobrano ME, Ross E, Amodei L, Tafra L, Adler LP, Uddo J, Stein W 3rd, Levine EA; Positron Emission Mammography Working Group.

Breast J. 2006 Jul-Aug;12(4):309-23.

PMID: 16848840 [PubMed - indexed for MEDLINE]

Also a 388 subject prospective trial comparing PEM and MRI will be published in Radiology in the coming months. 

David Mankoff Imaging in breast cancer – breast cancer imaging revisited, Breast Cancer Research 2005, 7:276-278

Benard F, Turcotte E: Imaging breast cancer with single photon computed tomography and positron emission tomography. Breast Cancer Res 2005, 7:153-162.

RSNA 2008: 94th Scientific Assembly and Annual Meeting of the Radiological Society of North America: Scientific Session VB31-04: Presented December 3, 2008.

Laino, Charlene RSNA Annual Meeting Newer Breast Imaging Techniques Offer Advantages over Mammography, MRI  Oncology Times:
10 February 2009 - Volume 31 - Issue 3 - pp 6-8