Cancer Treatment

Rituximab for rheumatoid artritis

 

Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor alpha (TNF-alpha) inhibitor therapy. This combination treatment is FDA indicated.

However, in a situation in which ,methotrexate is contraindicated, literature supports Rituxan alone. In the phase II trial, the ACR responses of patients treated with rituximab in combination with MTX (ACR20, ACR50 and ACR70: 73%, 43% and 23%, respectively) were numerically superior to those receiving rituximab monotherapy (65%, 33% and 15%, respectively). As the difference between responses to rituximab monotherapy and the placebo control arm (ACR20, ACR50 and ACR70: 38%, 13% and 5%, respectively) did not reach statistical significance for ACR50 and ACR70 responses14 (category Ib), rituximab is licensed only in combination with MTX.  Nevertheless, rituximab monotherapy was also shown to be more effective (ACR20 response) than placebo (category Ib).

National Institute for Health and Clinical Excellence (NICE). Rituximab for the treatment of rheumatoid arthritis. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Aug. 26 p. (Technology appraisal guidance; no. 126).

J S Smolen, E C Keystone, P Emery, F C Breedveld, N Betteridge, G R Burmester, M Dougados, G Ferraccioli, U Jaeger, L Klareskog, T K Kvien, E Martin‐Mola, and K Pavelka, The Working Group on the Rituximab Consensus StatementConsensus statement on the use of rituximab in patients with rheumatoid arthritis, Ann Rheum Dis. 2007 February; 66(2): 143–150.

Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T.
Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.N Engl J Med. 2004 Jun 17;350(25):2572-81.

Danazol for myelodysplastic syndrome

Danazol stimulates erythropoiesis (there is a smaller effect on thrombopoiesis as well)  through, it is thought, erythropoietin stimulation and it has been raditionally used to support blood counts. There amay be an anti-immune component in how it works and there are reports of its use for hemolytic anemia. However, the use of danazol for anemia has declined since the availability of synthetic erythropoeitin, a hormone produced by the kidney that promotes the formation of red blood cells in bone marrow. Procrit and Aranesp have largely supplanted Danazol. In the past, it has often been used in myelodysplasia for anemia. However, most supporting evidence is old and not rigorous. I searched for recent articles supporting Danazol and did not find more recent refernces than 2000 and these consist of retrospective reviews and case reports. The most recent review, in 1997, says: "Clinical activity for danazol, a semisynthetic attenuated androgen, appears to be limited to a small subset of patients with an associated immune-mediated cytopenia".

http://onlinelibrary.wiley.com/doi/10.1002/ajh.21118/pdf

F, Hernández-Boluda JC, Alvarez A, Nadal E, Montserrat E.
Danazol treatment of idiopathic myelofibrosis with severe anemia.Haematologica. 2000 Jun;85(6):595-9.

Nora Viniou, Eleni Plata, Evangelos Terpos, Eleni Variami, John Meletis, George Vaiopoulos, Dimitris Loukopoulos, Georgia Chatzidimitriou, Xenophon Yataganas
Danazol Therapy for Thrombocytopenia in Patients with Myelodysplastic Syndromes
Acta Haematol 2002;107:234-236

Cheson, Bruce D.
The Myelodysplastic Syndromes
Oncologist 1997 2: 28-39

Sutent for neuroendocrine and carcinoid cancer

Evidence supporting Sutent of neuroendocrine cancer cancer is was limited but a recent phase III trial was encouraging. 

 A Phase III study in 2008   concluded that Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. An editorial by Bajetta et al inm teh Journal of CLinical Oncology questioend whether results for neuroendocrine cancer can be generalized to the more benign carcinoid subtypes. The Phase III clinical trial was among 171 patients who had experienced cancer progression. Half the patients were treated with Sutent, and half were treated with a placebo.

• Progression-free survival was 11.4 months among patients treated with Sutent and 5.5 months among patients treated with placebo.
• Patients treated with Sutent also experienced better overall survival than patients treated with placebo.
• The most common serious side effect of Sutent was neutropenia (a low white blood cell count), which affected 12% of patients.

These results suggest that Sutent may improve outcomes among patients with advanced pancreatic neuroendocrine tumors. This study was publisehd in the NEJM of February 10, 2011 but NCCN has not incorporated the recommendation for Sutent as of March 2nd, 2011. In December 2010,  he European Commission has approved SUTENT® (sunitinib malate) for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (NET) with disease progression in adults. In May 2011, U.S. Food and Drug Administration (FDA) has approved SUTENT® (sunitinib malate) as the first anti-VEGF therapy to treat progressive, well-differentiated pancreatic neuroendocrine tumors (NET) in patients with unresectable locally advanced or metastatic disease.

References:

Raymond E, Niccoli-Sire P, Bang Y et al. Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium. January 22-24, 2010, Orlando, FL. Abstract 127.

Emilio Bajetta, Valentina Guadalupi, Giuseppe Procopio, Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors
JCO Jan 10, 2009:319-320

Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors JCO July 10, 2008 vol. 26 no. 20 3403-3410
 Kulke MH, Lenz H-J, Meropol NJ, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403-3410, 2008

Acyclovir prophylaxis for Velcade based therapies

The bortezomib and dexamethasone treatment is myelosupressive. The APEX trial demonstrated an incidence of H. Zoster of 13% in the bortezomib-treated arm compared with 5% in the dexamethasone-treated arm (p<0.001)in patients treated for myeloma. Some subsequent studies showed lower H. Zoster infection rates and others showed similar rates. For this reason, many experts recommend routine acyclovir prophylaxis for high-risk patients treated with bortezomib. National Comprehensive Cancer Network guidelines recommend that herpes zoster prophylaxis be considered for patients receiving bortezomib or bortezomib-based therapies.

Routine acyclovir prophylaxis is not guideline recommended in transplant patients. MMWR says: "Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy". Supressive therapy because of previous shingles is noto prospectively studied in this setting, to my knowedge.

Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Eng J Med. 2005a;352:2487–98.

Dasanu CA, Alexandrescu DTDoes bortezomib induce de facto varicella zoster virus reactivation in patients with multiple myeloma? J Clin Oncol, doi: 10.1200/JCO.2008.21.0138.

Chanan-Khan A, Sonneveld P, Schuster MW, et al.(2008) Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 26:4784–4790.

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm

Prostate Px

This approach represents a cutting edge of diagnostic science, sometimes termed, "Personalized Medciine". The concept that one can individualize cancer therpay based on specific tumor characteristics is attractive but needs to be proven before being widely adapted. As of now, there is little evidence to support it and no guidelines or professional bodies recommending it.

The approach relies on published information but the way it is put together and validated is not confirmed in studies or accepted in the medical community. From the manufacturer: Prostate Px provides several endpoints which assess disease severity and disease recurrence, including:

Px SCORE™
Disease Progression (metastasis, progression through ADT)
Favorable Pathology
Relative Risk of Disease (outcome compared to test’s validation cohort)
The power of Prostate Px results from its comprehensive analysis of the cancer tissue obtained from each patient. Clinical data is integrated with an exhaustive analysis of each patient’s cancer using spatial analysis of tissue histology and examining molecular biomarkers, such as androgen receptor, associated with disease progression.

An advanced mathematical approach is applied to a large patient cohort to generate a personalized report that is sent to the physician for discussion with the patient.

This processand  information remains proprietary and not peer-reviewed.

P 16 mutation in melanoma and pancreatic cancer

Approximately 6-12% of melanoma cases are hereditary, and may have a strong link to the development of pancreatic cancer. The gene responsibel for this type of melanoma is autosomal dominant and located on chromosome 9p21. This gene, called p16 (also known as CDKN2A, INK4A, or MTS1), accounts for up to 40% of hereditary melanoma cases. It is a tumor suppressor gene involved in regulating cell growth.

Currently, identification of teh P16 gene is not clinically significant. All individuals considered at high risk for melanoma should be managed similarly regardless of p16 mutation status. Individuals at increased risk for melanoma should be identified. Family history information should be obtained from all individuals with melanoma or dysplastic nevi, and first-degree relatives should be screened because of the increased risk of CMM in melanoma-prone families in any case. These individuals should be educated about sun protection, avoidance of intense sun exposure, and other preventive measures, such as learning how to detect dysplastic nevi characteristics and melanoma warning signs.

Management recommendations also include examination of the entire skin surface by a skilled healthcare provider every 6 months from 10 years, or earlier for suspicious nevi, until nevi are stable and annually thereafter.

Similarly there are no guidelines that recommend pancreatic cancer screening based on identification of the p 16 mutation.

http://www.moffitt.org/moffittapps/ccj/v4n1/department2.html (Guidelines)

Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351:998-1012.

Parker JF, Florell SR, Alexander A, DiSario JA, Shami PJ, Leachman SA.
Pancreatic carcinoma surveillance in patients with familial melanoma. Arch Dermatol. 2003 Aug;139(8):1019-25.

Intra-arterial chemotherapy of brain cancers

The brain-blood barrier is considered  to be a major obstacle for delivering chemotherapy to brin tumors and obtaining durable disease control in patients with high-grade gliomas. Intra-arterial drug injection after selective catheterization of cerebral arteries has been performed in some small clinical trials in order to achieve higher drug concentration in the tumor while minimizing systemic exposure. This approach has potentail which has not yet been demonstrated.

A recent review of studies with intra-arterial administration of nitrosoureas and platinum derivatives, as well as the principal aspects and perspectives of the new strategy of blood–brain barrier disruption with osmotic agents or bradykinin analogs demonstrated no superiority of intra-arterial chemotherapy over its intravenous counterpart . It concluded that although the incidence of serious neurotoxicity is reduced with teh intra-arterial route, the risk of  acute complication still contraindicates internal carotid or vertebral artery catheterization for chemotherapy administration outside the setting of well-controlled clinical trials.

IUmberto Basso, Sara Lonardi, Alba A Brandes, Is intra-arterial chemotherapy useful in high-grade gliomas? Expert Review of Anticancer Therapy
October 2002, Vol. 2, No. 5, Pages 507-519

Herbert B. Newton. (2005) Intra-arterial chemotherapy of primary brain tumors. Current Treatment Options in Oncology 6:6, 519-530

CrossRef Maciej M Mrugala, Santosh Kesari, Naren Ramakrishna, Patrick Y Wen. (2004) Therapy for recurrent malignant glioma in adults. Expert Review of Anticancer Therapy 4:5, 759-782