Cancer Treatment

Donor lymphocyte infusion to treat chimerism

The donor cell reinfusion in this case is not being used to provide new graft versus leukemia effect but to destroy remaining normal patient cells and to provide engraftment. It ahs been observed that chimerism is risk factor for relapse of the leukemia. The status of DLI to treat disase is still unsettled and the use of DLI to decrease chimerism is even less established. There would have been no objection to a reinfusion of stem cells to re-engraft which I would see as a continuation of the previously approved stem cell transplant. However, using DLI in this fashion is experimental since the contention that it does os is supported by case reports and series only

Because of the large number of acute leukemia patients who relapse after alloBMT, there has been a substantial experience in the treatment of these patients with DLI. Using median doses of >/=108 T cells/kg, DLI alone induces complete remissions in 8% of patients with ALL and 22% of patients with acute myeloid leukemia (AML). When patients who receive chemotherapy prior to DLI are included, complete response rates are significantly higher, ranging from 33% to 37%. However, follow- up of ALL patients reveals few, if any, long-term survivors, although 1 has been reported. Relapse occurs in approximately one quarter to one half of patients with AML in remission after DLI, leaving a long-term survival rate of approximately 10% to 15%.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Fewer patients with relapsed myelodysplasia have been treated with DLI. However, because myelodysplasia progresses more slowly than AML, the rate of complete remissions may be higher. The natural history of myelodysplasia patients who enter into a remission following DLI has not been described.

It is not clear whether administration of induction chemotherapy at the time of relapse improves long-term survival following DLI. It is usually thought that it does but without a strong conifrmation in the literature. A randomized trial with analysis performed on an intent-to-treat basis is needed to answer this question.

Litzow, Mark R Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Current Opinion in Hematology. 14(2):130-137, March 2007.

Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.Cancer Control. 2002 Mar-Apr;9(2):123-37.

Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplantation. 2003; 31:1057-1059.

Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.

E . Orsini , E . Alyea , A . Chillemi , R . Schlossman , S . McLaughlin , C . Canning , R . Soiffer , K . Anderson , J . Ritz Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma . 
Biology of Blood and Marrow Transplantation , Volume 6 , Issue 4 , Pages 375 - 386, 2000

Suradej Hongeng et al, Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome Acta Hematologica Vol. 114, No. 3, 2005

Adjuvant chemotherapy for stage I ovarian cancer

The stage of ovarian cancer is an important prognostic factor that influences survival and the choice of therapy. The quality of the surgical staging is a key determinant of treatment recommendations. Women who have undergone optimal surgical staging, including pelvic and para-aortic lymph node sampling, and have stage I disease may or may not benefit from adjuvant platinum-based chemotherapy. The results of the largest trial comparing adjuvant chemotherapy to no chemotherapy in women with early stage ovarian cancer (International Collaborative Ovarian Neoplasm Study/Adjuvant ChemoTherapy In Ovarian Neoplasm [ICON/ACTION] Trial) are controversial because:
A subgroup analysis of the ACTION Trial showed no benefit from adjuvant chemotherapy in women who underwent optimal surgical staging, but that analysis was underpowered.
The entry criteria for the ICON Trial were vague and did not reflect the standard of surgical care generally offered. The meta-analysis demonstrates that stage I patients have an improved outcome with adjuvant chemotherapy. However, an estimated 90% of women undergoing surgical resection for ovarian cancer do not undergo optimal surgical staging. If the restaging of a suboptimally staged patient reveals a more advanced disease, chemotherapy is the preferred treatment option. If reoperation confirms stage I disease, there is insufficient evidence for or against adjuvant chemotherapy. However,
NCCN lists adjuvant chemotherapy or observation alone as an option for stage Ia ovarian cancer. The most established regimen is Taxol and carboplatin.

http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf, p.7

Gynecology Cancer Disease Site Group. Elit L, Fyles A, Chambers A, Fung Kee Fung M, Covens A, Carey M. Adjuvant care for stage I ovarian cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 May 3. 33 p. (Practice guideline report; no. 4-13). [62 references]

Revlimid and thalidomide for prostate cancer

Not much is known about the effects of thalidomide and Rvlimid on prostate cancer. At the International Conference on Molecular Targets and Cancer Therapeutics in November of 2005, held in

Philadelphia

,

Pennsylvania

, an abstract was presented by Dr. Robert J. Amato.  This conference was organized jointly by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer.  In Dr. Amato’s paper, eighteen prostate cancer patients were treated with Leukine and thalidomide.  All had rising PSAs following local therapy, and had not previously been treated with hormone blockade.  All of the men in his study had at least a 26% reduction in their level of PSA, with a median reduction of 59%.  His response rate was 100%.

Not much more own about Revlimid, a thalidomide analogue, an oral antiangiogensis inhibitor (it blocks blood vessel growth) that the FDA has approved to treat another cancer called multiple myeloma. Revlimid is closely related to Thalidomide, which has known activity in prostate cancer. In many cases, however, the intolerable side effects of Thalidomide (constipation, fatigue and nerve damage) have precluded its widespread use. Revlimid appears to be much better tolerated, and in a small study by the Cleveland Clinic, it appears to be active when used in combination with Leukine. Sixteen patients were treated with a large dose: 25 mg a day. Nine of the men had some degree of PSA decline. Side effects included low blood counts, diarrhea and fatigue. More studies are awaited.

NCT00348595 is Study of 2 Different Doses of Revlimid in Biochemically Relapse Prostate Cancer

The primary objectives of the study are:

• To evaluate feasibility, safety and tolerance of 6 months administration of Revlimid at 5mg/day and 25mg/day, given orally in subjects with prostate cancer with evidence of biochemical relapse (M0) following local treatment (i.e., surgery or radiation).
• To assess the rate of PSA progression at 6 months after treatment with 5mg/day and 25mg/day of Revlimid (CC-5013) in patients with evidence of biochemical relapse after local therapy

Revlimid is investigational for prostate cancer at this time.

J. A. Garcia, P. Triozzi, S. Smith, B. I. Rini, T. Gilligan, D. Peereboom, P. Elson, E. Klein, R. Dreicer Abstract Phase I/II study of lenalidomide and GM-CSF in hormone refractory prostate cancer (HRPC). No: 229 2007 Prostate Cancer Symposium 

The phase 2 study can be seen here- http://www.druglib.com/trial/95/NCT00348595.html

Folfox and Folfiri for metastatic colorectal cancer

Currently, there are seven active and approved chemotherapy drugs for patients with metastatic colorectal cancer: 5-FU, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab. Among the best studied ways of putting some of these drugs together are the regimen Folfox and Folfiri. Three randomized studies demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin. Intergroup study N9741 then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced an improved PFS (median, 6.9 months vs. 8.7 months; P = .014; HR = 0.74; 95% CI, 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR = 0.66; 95% CI, 0.54–0.82) compared with patients randomized to IFL. Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively. PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer. Avastin is also approved with 5FU containing regimens for first line.

Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.
Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.
Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200.  J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005.
Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.
nccn.org, colorectal

Autoimmune hemolytic anemia basics

Lay Summary: I discuss some very basic facts about AIHA.

Autoimmune hemolytic anemia (AIHA) due to the presence of warm agglutinins is almost always due to IgG antibodies that react with protein antigens on the red blood cell (RBC) surface at body temperature. For this reason, they are called "warm agglutinins" even though they seldom directly agglutinate the RBCs. IV Gammaglobulin blocks this process.

I some cases, AIHA can be characterised by a chronic course and an unsatisfactory control of haemolysis, thus requiring prolonged immunosuppressive therapy. Sometimes when medical measures fail, it may be necessary to surgically remove the spleen (splenectomy). The clinical course of the disease may show either resistance to steroids or dependence on high-dose steroids with subsequent development of severe side effects on growth, bone mineralisation, and the endocrine system. Splenectomy is effective in about 50 to 60 percent of the time in IgG antibody diseases but is not usually effective in IgM antibody haemolysis. Splenectomy is of benefit in these people because the spleen behaves like a sieve and if it is removed, even though the RBCs are coated by antibodies, they are no longer caught and destroyed in the spleen.

IVIG is an accepted treatment for autoimmune hemolytic anemia. Unlike steroids, it does not induce remissions but is a temporizing measure until a definitve treatment can be planned and delivered.  IVIG is not as effective in AIHA as it is in ITP. Other treatments can sometimes be used.

Ucar K. Clinical presentation and management of hemolytic anemias. Oncology [Huntingt] 2002;16(9 suppl 10):163-70.

Schwartz RS, Berkman EM, Silberstein LE. Autoimmune hemolytic anemias. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, et al., eds. Hematology: basic principles and practice. 3d ed. Philadelphia: Churchill Livingstone, 2000:624.

Is Waldenstrom's a "cancer"?

Waldenstrom's (WM) should be considered cancer since it is apresentation of a lymphoma. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion.  Waldenström macroglobulinemia is a clonal disorder of B lymphocytes. This condition is considered to be lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies.

Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA.
Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.Semin Oncol. 2003 Apr;30(2):110-5.

Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al: Waldenstrom's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000 Jan; 18(1): 214-26

Dimopoulos MA, Galani E, Matsouka C: Waldenstrom's macroglobulinemia. Hematol Oncol Clin North Am 1999 Dec; 13(6): 1351-66

Procrit and Aranesp for aplastic anemia

Is aranesp considered medically necessary for aplastic anemia?

Erythropoietin levels are elevated in apalstic anemia patients. This raises the probability that additional exogenous erythropoietin may not be effective. However, despite the same concern, erythropoietin is effective in  in myelodysplastic syndrome. I reference a Japanese editorial that advocated the use of erythropoietin ( and this would include darbepoetin) for aplastic anemia.

However, there is very little supporting literature and no recommendations that are based on credible studies. Some experts do not support erytropoietin therapy in apalstic anemia. A noted authority, Dr. Jerry L. Spivak said this: "Myelofibrosis, leukemia, and aplastic anemia are other situations where erythropoietin therapy is usually ineffective, and when infection or inflammation is sufficiently severe, the response to erythropoietin will be blunted.", at http://www.anemia.org/professionals/asktheexpert/treatment.jsp

My conclusion is that darbepoietin is investigational and not medically necessary in aplastic anemia.



http://www.journalarchive.jst.go.jp/english/jnlabstract_en.php?cdjournal=internalmedicine1992&cdvol=37&noissue=3&startpage=235

V. Pavlovic-Kentera

Erythropoietin in aplastic anemia Annals Hematology

Volume 39, Number 5 / November, 1979

M Bessho, I Jinnai, A Matsuda, M Saito and K Hirashima

Improvement of anemia by recombinant erythropoietin in patients with myelodysplastic syndromes and aplastic anemia International Journal of Cell Cloning, Vol 8, 445-458, Copyright © 1990 by AlphaMed Press

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned emchanism of action, there is interest in studying it in colorectal and oterh solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2'-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Vectbix after Erbitux for colon cancer

Panitumumab (Vectibix, Amgen) was approved by the FDA for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, or irinotecan-containing regimens. The NCCN Colon Cancer panel added panitumumab as alternate option to cetuximab after first or second progression on previous therapy. This addition came with a recommendation that patients should not be excluded from therapy on the basis of EGFR results. NCCN does not recommend using either of theese two EGFR blockers after the other. This recommendation is based on a lack of studies showing otherwise and the similar mechanism of action of the two drugs.

NCCN.ORG, colon cancer, p.24

Neoadjuvant chemotherapy for resectable gastric cancer.

Lay Summary: Questions remain about pre-surgery chemo and radiation in stomach cancer that can be resected without these treatments.

The practice of administering chemotherapy before surgery is referred to as neoadjuvant therapy. In theory, neoadjuvant chemotherapy can decrease the size of the cancer, thereby making it easier to remove with surgery. The major problems with this approach are the higher mortality rates that occur when radiation therapy and/or chemotherapy are administered before surgery and the delay of surgery for some patients who do not respond to therapy. In most but not all studies chemotherapy, radiation therapy or both given before surgery have not improved survival following surgery in patients with stage III gastric cancer. This may be related to the ineffectiveness of the drug combinations tested, which include various combination of 5-FU, doxorubicin and methotrexate. Many current clinical trials are directed at improving outcomes of patients with stage III gastric cancer by administering newer neoadjuvant treatment regimens containing taxane chemotherapy and/or radiation therapy.

There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiation therapy or immunotherapy, either alone or in combination, outside of a clinical trial

Gastrointestinal Cancer Disease Site Group. Earle CC, Maroun J, Zuraw L. Neoadjuvant or adjuvant therapy for resectable gastric cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 May 21 [online update]. 21 p. (Practice guideline; no. 2-14). [79 references]
nccn.org, stomach cancer.