Cancer Treatment

Thalidomide for Myelodysplasia (MDS)

Thalidomide exerts in vitro heterogeneous biological effects on hematopoiesis which have supported its possible use in treating myelodysplastic syndromes (MDS). Some recent clinical trials have confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-risk MDS (11–56%, on intention-to-treat analysis). Of interest, erythroid responses may be achieved also in transfusion-dependent subjects with high serum levels of endogenous erythropoietin, a subset of MDS patients with little chance of responding to recombinant erythropoietin, alone or in combination with G-CSF.

Although the FDA currenlty apporvies thalidomide only for the 5q- deletion, there are many trials confirming effectiveness , albeit lesser effectiveness, in patients with MDS who do not have this deletion.NCCN mentions thlidomide and notes that it has greater effectiveness in the cases with 5q- deletion.Thus, it is recognized as a reasonably effective treatment for MDS, even without the 5q- diletion.

P . Musto Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives .  Leukemia Research , Volume 28 , Issue 4 , Pages 325 - 332, 2004

http://www.moffittcancercenter.com/CCJRoot/v11s6/pdf/07.pdf

nccn.org, myelodysplastic

Erytropoietin therapy for myelofibrosis

 Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is limited.There are a number of reprots of small numbers of patiens demonstrating responsiveness but also a recent report  which presents a picture of non-responsiveness of transfusion dependent myelofibrosis to erythropoietin therapy.
Initial studies failed to show significant improvements in hemoglobin levels upon administration of recombinant erythropoietin (rEpo). However, more recent investigations have demonstrated significant responses and decreased transfusion dependence in anemic patients with CIMF. The rEpo doses employed in those studies were in the range of 300–1,500 U/kg weekly. This finding underscores the current uncertainty about the optimal dose and schedule of rEpo in this disease. It is important to note that many patients with CIMF have normal serum erythropoietin levels, suggesting a potential lack of efficacy of rEpo in this setting [54]. Rodriguez et al. [ showed that a serum erythropoietin level <123 mU/ml was highly predictive of response to rEpo. This was recently corroborated by Cervantes et al. [53] in a study in which rEpo was given at an initial dose of 10,000 U three times per week to 20 patients with CIMF. Nine patients (45%) responded, including four who achieved normal hemoglobin levels. A serum erythropoietin level <125 mU/ml was associated with a favorable response to rEpo in the multivariate analysis. The combination of rEpo and thalidomide may represent a valid approach for patients with advanced CIMF
Future investigation will focus on stratification. Favorable cytogenetic findings was associated with response to erythropoietin therapy in one study.

In summary, there is sufficient evidence that Procrit raises Hblevels in many myelofibrosis patients. How to select patients is not entirely clear yet and at this time, a trial for effectivenesss is standard practice.It is not known whetehr it is a better long - term approach than periodic transfusions

Tsiara S, Kapsali H, Dimos GA, Chaidos A, Stoura M, Bourantas LK, Tzouvara E, Bourantas KL:
Treatment of anemia with recombinant human erythropoietin administration in patients with myelofibrosis, Archives of Hellenic Medicine 20 (3) : 281-285 (May 2003)

S.N. Tsiara, A. Chaidos, L.K. Bourantas, H.D. Kapsali, K.L. BourantasRecombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis Heamatoloica Vol. 117, No. 3, 2007  

EAuthor  Huang, J. Lasho, T.L. Li, C.Y. Pardanani, A.D. Mesa, R.A. Tefferi, A. 
rythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level &gt;or= 10 g/dL
 BLOOD 2007, VOL 110;  pages 3555 

Tefferi A, Lasho TL, Schwager SM et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131:320–328

Thalidomide for melanoma

Thalidomide appears to possess cytostatic activity in patients with metastatic melanoma.Thalidomide has antiangiogenic and biologic modulatory properties21 and has been used successfully in the treatment of Kaposi’s sarcoma, myeloma, and renal cell cancer. Thalidomide has been used in metastatic melanoma as a single agent with mixed results. There are a number of phase II studies that show effectiveness, singly and in combination.One randomized phase II study and six phase II studies have shown encouraging response rates when thalidomide is combined with temozolomide.It is listed in teh Drug Index for melanoma but is considered "off-label, insufficient evidence" by Caremark.However, given the number of studies, I consider thalidomide as a singel agent for melanoma to be supported by credible medical evidence.

Pawlak WZ, Legha SS.Phase II study of thalidomide in patients with metastatic melanoma.Melanoma Res. 2004 Feb;14(1):57-62.

Danson, S., Lorigan, P., Arance, A., Clamp, A., Ranson, M., Hodgetts, J., Lomax, L., Ashcroft, L., Thatcher, N., Middleton, M.R. (2003). Randomized Phase II Study of Temozolomide Given Every 8 Hours or Daily With Either Interferon Alfa-2b or Thalidomide in Metastatic Malignant Melanoma. JCO 21: 2551-2557

Eisen T, Boshoff C, Mak I, et al: Continuous low dose thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 14:17–20, 2000 (suppl 13)

Kudva G, Collins BT, Dunphy FR: Thalidomide for malignant melanoma. N Engl J Med 345:1214–1215, 2

Quirt I, Verma S, Petrella T, Bak K, Charette M, Melanoma Disease Site Group. Temozolomide for the treatment of metastatic melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Mar 20. 25 p. (Evidence-based series; no. 8-4). [38 references]

Thalidomide for cancer cachexia

The cancer cachexia syndrome is common. Significant weight loss occurs in approximately 50% of oncology patients, with even higher values in those with gastrointestinal tumours.1 In pancreatic cancer, approximately 80% of patients will become severely malnourished. The development of cachexia is not only distressing for patients and their families, it is also associated with a much worse clinical outcome. Malnourished patients undergoing surgery for cancer have morbidity and mortality rates of three to four times those of their better nourished counterparts,2 and wasted weakened patients also tolerate chemoradiation poorly. Ultimately, malnutrition itself can be considered to be the final cause of death in approximately 30% of cancer patients. It occurs once patients have lost about one third of their premorbid body weight.

Pancreatic cancer patients with cachexia may benefit from thalidomide, according to the results of a randomized study published in the April, 2008 issue of Gut.

In this single-center, double-blind trial, 50 patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomized to receive thalidomide, 200 mg daily, or placebo for 24 weeks. The main outcome measure was change in weight and nutritional status.

Of 33 patients (17 receiving thalidomide and 16 control subjects) evaluated at four weeks, 20 patients (12 thalidomide, eight control) were also evaluated at eight weeks. At four weeks, patients who received thalidomide had average gains of 0.37 kg in weight and 1.0 cm3 in arm muscle mass (AMA), whereas the placebo group had an average loss of 2.21 kg (absolute difference, 22.59 kg; 95% confidence interval [CI], 24.3 - 20.8; P = .005) and 4.46 cm3 (absolute difference, 25.6 cm3 (95% CI, 28.9 - 22.2; P = .002).

At eight weeks, losses were 0.06 kg in weight and 0.5 cm3 in AMA in the thalidomide group compared with a loss of 3.62 kg (absolute difference, 23.57 kg; 95% CI, 26.8 - 20.3; P = .034) and 8.4 cm3 (absolute difference, 27.9 cm3; 95% CI, 214.0 - 21.8; P = .014) in the placebo group. Improvement in physical functioning was positively correlated with weight gain (r = 0.56; P = .001).

In an accompanying editorial, M. Stroud, from Southampton General Hospital, U.K., discusses the mechanisms underlying cancer cachexia and its amelioration by thalidomide.

Stroud, M Thalidomide and cancer cachexia: old problem, new hope?
Gut 2005 54: 447-448
Gut. 2005;54:447-448, 540-545

Velcade for low grade lymphoma

Bortezomib is a drug that belongs to the class of drugs called proteasome inhibitors. The proteasome is a protein complex that breaks down rusty and modified proteins that cells are meant to dispose off. Its housekeeping job is very important for the cells to keep functioning. Research studies have shown that if the proteasome is inhibited (or stopped from functioning) some cancer cells, including some lymphoma cells may find it difficult to carry out normal functions and even die. Bortezomib (Velcade) is a type of drug that inhibits proteasomes. Theoretically it can be efective in a wide spectrum of malignancies.

It has shown great results in the treatment of relapsed multiple myeloma, another type of cancer that affects the bone marrow. Trials that have tried Velcade in relapsed lymphomas over the past few years have resulted in good responses in certain types of lymphoma, especially Mantle Cell Lymphomas. Bortezomib (Velcade) has been granted approval for the treatment of relapsed or refractory Mantle Cell Lymphoma by the FDA in December 2006. It represents an important step in the approach to second-line treatments in Mantle Cell Lymphoma, a potentially difficult to treat lymphoma.

A number of trials in low grade lymhomas are ongoing. For example, Millennium Pharmaceuticals and development partner Johnson & Johnson have initiated a phase III clinical trial of Velcade in non-Hodgkin's lymphoma. The trial will evaluate the drug in combination with rituximab in patients with relapsed or refractory follicular lymphoma, a subtype of non-Hodgkin's lymphoma (NHL). Anoterh study that Millenium is sponsoring is to determine if the combination of VELCADE and rituximab improves progression free survival relative to rituximab alone in patients with relapsed or refractory B-cell non-Hodgkin"s lymphoma (B-NHL) who never received rituximab or who have previously responded to rituximab. This is an international study being conducted in the United States and in many countries around the world.
An Italian study,NCT00509379,  A Phase II Multicenter Non-Randomized Study to Assess Safety, Toxicity and Clinical Activity of the Association of Bortezomib(VELCADE)With Rituximab in Relapsed/Refractory Indolent Non Follicular and Mantle-Cell Non-Hodgkin Lymphoma, is looking at activity in several low grade lymphoma types, including SLL.

Schenkein D. Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma. 2002;3(1):49-55.

Cheson BD. Hematologic malignancies: New developments and future treatments. Semin Oncol. 2002;29(4 Suppl 13):33-45.

nccn.org, chronic lymphocytic leukemia

IN-111 octreotide to treat carcinoid

GThe most important treatment modality for the carcinoid syndrome (flushing, diarrhea etc) due  to carcinoid secreted hormones)  is octreotide, a synthetic hormone similar in structure to the naturally-occurring hormone, somatostatin. Octreotide, like somatostatin, binds to receptors on the cells of carcinoid tumors and inhibits the manufacture and release of tumor hormones. Octreotide is very effective in controlling the symptoms of flushing and diarrhea that are part of the carcinoid syndrome. Octreotide has been found to reduce the excretion of 5-HIAA in some patients. Octreotide also has been found to slow the growth of carcinoid tumors, and, in a few patients, even reduce the size of the tumors and their metastases. Treatment with octreotide prior to surgery is important in order to prevent life-threatening carcinoid crisis in patients with carcinoid syndrome undergoing surgery.

Octreotide generally is well tolerated. Side effects include nausea, headache, dizziness, abdominal pain, diarrhea, elevated blood sugar levels, and gallstones. The major drawback of octreotide is the need to inject it under the skin three times daily. Other longer-acting synthetic hormones resembling somatostatin (for example, lanreotide) can be given intramuscularly every two weeks, but they are not yet available in the U. 

This patient received this therapy but what is being proposed is high-dose IN-111 octreotide as therapy.
There are a number of cse reports of this modlaity that suggest effectiveness and tumor regression; however, there have been no randomized studies and it remains an unproven treatment. In addition, this patient appears to be enrolled into a clincail study of this treatment.

S.. A. Kaltsas, G. M. Besser, and A. B. Grossman
The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors
Endocr. Rev., June 1, 2004; 25(3): 458 - 511.

P. L. Filosso, E. Ruffini, A. Oliaro, E. Papalia, G. Donati, and O. Rena
Long-term survival of atypical bronchial carcinoids with liver metastases, treated with octreotide
Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 913 - 917.

nccn.org, carcinoid

Buscombe, J. R.; Caplin, M. E.; Hilson, A. J.W Treating disseminated NETs with high activity In-111 Octreotide.  Nuclear Medicine Communications. 21(6):567, June 2000.

http://www.liebertonline.com/doi/pdf/10.1089/cbr.2005.20.215?cookieSet=1

Donor lymphocyte infusion

DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. 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. Whetehr a second DLI adds something to GVHD is not known.

While DLI-induced remissions are achieved in only a small number of AML patients, many of these remissions may be durable. Of 10 patients in the North American registry who had achieved a complete remission (CR) from DLI, only two subsequently relapsed at 1–3 years. At a median follow-up of 1 year, five patients were alive and in CR. The two that relapsed died of disease and three other patients had died of treatment-related causes.

The effects of DLI appear to be similar in patients receiving unrelated donor transplants, although only small numbers of recipients of unrelated DLI (UDLI) have been reported. In collaboration with the National Marrow Donor Program, we retrospectively identified 23 AML patients who received UDLI for relapsed AML.5 The median follow-up was 10 weeks (range 4–102 weeks). Of the patients evaluable for response to DLI alone, 42% achieved a CR. However, only 4/23 of all patients (17%) had a durable CR. From this study and others, it is clear that the most significant predictor of survival and disease-free survival (DFS) was the time from transplant to relapse. Of interest, there was no dose–response effect identified in the unrelated donor setting though the majority of patients received more than 1  107 mononuclear cells/kg. This might argue agains a second DLI.

Unfortunately, not only response to DLI in AML is disappointing, but also the toxicity is significant. Up to 30% of patients will develop grade III–IV acute GVHD, and treatment-related mortality rates are estimated to be up to 20%.

Porter D, Collins R, Hardy C, Kernan N, Drobyski W, Giralt S et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214–1221.

Leis J, Porter D. Unrelated donor leukocyte infusions to treat relapse after unrelated donor bone marrow transplantation. Leukemia Lymphoma 2002; 43: 9–17.

Levine J, Braun T, Penza S, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol 2001; 20: 405–412.

Christoph Schmid, Myriam Labopin, Arnon Nagler, Martin Bornhäuser, Jürgen Finke, Athanasios Fassas, Liisa Volin, Günham Gürman, Johan Maertens, Pierre Bordigoni, Ernst Holler, Gerhard Ehninger, Emmanuelle Polge, Norbert-Claude Gorin, Hans-Jochem Kolb, Vanderson Rocha Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4938-4945

Donor Lymphocyte Infusion after Allogeneic Stem Cell Transplantation
ASCO Educational Book, January 1, 2008; 2008(1): 334 - 337.

Single agent Rituxan for CLL

Rituximab has been shown to prolong survival when used with chemotherapy in CLL.
The findings come from a comparative analysis of two completed national phase II and phase III clinical trials. The two multicenter clinical trials compare the antibody rituximab plus fludarabine, a chemotherapeutic drug, to fludarabine alone. Rituximab is an antibody-based drug approved for lymphoma. The findings of the two studies show that after an average of 43 months, rituximab plus the drug fludarabine increases progression-free survival by 22 percent and overall survival by 12 percent compared to fludarabine alone.

There is insufficient evidence at this time to support or refute the use of single-agent rituximab or a rituximab-containing chemotherapy regimen in patients with chronic lymphocytic leukemia (CLL). Rituximab, the mAb targeting CD20, was approved by the US FDA for patients with relapsed low-grade non-Hodgkin lymphoma. Relatively low levels of CD20 are expressed on CLL B cells, compared to normal B or neoplastic B cells of other lymphomas. In addition, soluble CD20 has been demonstrated in plasma of patients with CLL; this may inhibit the capacity of rituximab to bind to CLL B cells, thereby resulting in rapid clearance and negatively affecting pharmacokinetics.31 Standard-dose rituximab (375 mg/m2 weekly for 4 weeks) has very limited activity for patients with CLL. Dose-intense33 and dose-dense34 single-agent rituximab has been shown to increase efficacy. Rituxan is not listed by NCCN as a single agent.

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

W. G. Wierda Current and Investigational Therapies for Patients with CLL
Hematology, January 1, 2006; 2006(1): 285 - 294.

Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326–1331.

R-MCOP for lymphoma

The aging of the population and the increased incidence of non-Hodgkin's lymphoma will result in a large number of elderly patients with this disorder. Newer therapies will be required for this group of patients. One common modification is substituting Novantroen for Doxorubicin in the standard CHOP or R-CHOP regimen. This produces less cariotoxicity which is a particular problem for the elderly.

Mitoxantrone was evaluated in combination with other agents for the treatment of NHL. A total of 28 patients were treated with different regimens. A first-line comparative trial of the combination of intermediate dose methotrexate with leucovorin rescue + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone (m-BACOD) versus the same combination with 10 mg/mmitoxantrone replacing doxorubicin (m-BNCOD) has shown activity: 4 PR's in 6 evaluable patients with m-BNCOD and 3 PR's in 6 with m-BACOD. The combination of mitoxantrone at 10 mg/m daily for 3 days, + vincristine + dexamethasone (NOD) produced 3 PR's in 5 evaluable patients. A first-line comparative trial of the combination of cyclophosphamide + vincristine + prednisone + doxorubicin (CHOP) versus the same combinations with 10 mg/mmitoxantrone replacing doxorubicin (CNOP) showed equivalence.

R-CHOP is now standard of care for diffuse large cell lymphomaas and follcular lymphomas. The substituion is supported by a randomized study referenced below. These dose-reduced regimens can be given with nearly 100% dose intensity with 65% of patients completing all the treatment. Survival is comparable to that observed with the more intensive regimens given in this age group.Although Rituxan ahs not been sepcifically proven with MCOP regimen, since ti is aprt of the standrd R-CHOP and the CHOP part is equivalent to MCOP ro CNOP, addition of Rituxan should not deem R-MCOP to be experimental

Bessell EM, Burton A, Haynes AP, Glaholm J, Child JA, Cullen MH, Davies JM, Smith GM, Ellis IO, Jack A, Jones EL; Central Lymphoma Group UK.A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma.Ann Oncol. 2003 Feb;14(2):258-67.

nccn.org, lymphoma

Gleevec and Sprycel for sarcoma

Sprycel is currently in trials for variosu types of srcoma. The letter by Dr. George mentions her phase I trial, although the aptient is not on that trial. I found several other trials in different types of sarcome, none specifically in chodrosarcoma.

An ongoing multi-institutional study by the Sarcoma
Alliance for Research Through Collaboration (SARC)
consortium is evaluating the activity of imatinib in non-
GIST sarcoma subtypes based on the postulated mechanism
of action involving inhibition of polymorphisms of
PDGFR and/or downstream effectors. Early results
demonstrate a progression-free survival benefit in
liposarcoma, leiomyosarcoma, and fibrosarcoma; however,
the final results have not been published.8 The Children’s
Oncology Group has recently published results of
a phase II study of imatinib in refractory solid tumors
that demonstrated no benefit in pediatric sarcoma.

Dasatinib, a small-molecule inhibitor of Src kinase
activity, is a promising cancer therapeutic agent with oral
bioavailability. Currently, dasatinib is approved for use in
imatinib-refractory chronic myelogenous leukemia. The
therapeutic potential of dasatinib was evaluated in 12
soft tissue and bone sarcoma cell lines. Dasatinib inhibited
Src kinase activity at nanomolar concentrations (3 to
68 nM) all 11 of the cell lines that exhibited activated Src
kinase activity. Inhibition of Src signaling was accompanied
by blockade of cell migration and invasion, consistent
with Src inhibition. Moreover, apoptosis was induced
in the osteosarcoma and Ewing’s subset of bone
sarcomas at nanomolar concentrations of dasatinib, indicating
that these bone sarcoma cell lines are dependent
on Src activity for survival. These results demonstrate
that dasatinib inhibits migration and invasion of diverse
sarcoma cell types and selectively blocks the survival of
bone sarcoma cells. Therefore, dasatinib might provide
therapeutic benefit by preventing the growth and metastasis
of sarcomas in patients.

Sprycel is promising but there are no published trials of Sprycel that I could find.