Cancer Treatment

Revlimid for myeloma maintenance

Lenalidomide is an immunomodulatory drug and a structural analogue of thalidomide which has been developed by Celgene. REVLIMID (lenalidomide) in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.

 Off-label, however, Revlimid with dexamethasone is considered an appropriate induction regimen for potential transplant candidates since it does not possess bone marrow toxicity. It is listed as such, for example, by the NCCN.

It can also be used as maintenance, which has been studied in the post-transplant setting. Italian researchers presented the results of a study where Revlimid was administered as consolidation/maintenance therapy after a reduced-intensity autologous stem cell transplants in elderly patients with newly diagnosed myeloma. This study included over 100 patients aged 65-75 years with newly diagnosed myeloma. All received induction therapy with Velcade, dexamethasone, and doxorubicin followed by tandem autologous stem cell transplants with 100 mg/m2 of melphalan. Peripheral blood stem cells were harvested after Cytoxan and Neupogen® (figrastim). Revlimid was given after recovery from tandem autologous transplants. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and was de- escalated by 5 mg or maintained at 5, 10 or 15 mg/day as tolerated. After consolidation/maintenance Revlimid, 88% of patients achieved at least a very good partial remission, and 53% a complete remission. One-year survival was 92%.

Results of the fifth interim analysis of this CALGB ECOG BMT-CTN 100104 trial showing data out to a median of 18 months were presented in Paris, France, at the 13th International Myeloma Workshop by principal investigator Philip McCarthy Jr, MD, director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute in Buffalo, New York in 2011. In this latest analysis, there continued to be a significantly longer time to progression in the patients who received lenalidomide therapy when compared with placebo. As of April 17, 2011, 69 of the original 231 lenalidomide patients experienced an event — disease progression or death — compared with 116 of the original 229 patients randomized to placebo (P < .0001), for a 56% reduction in the risk for disease progression in the lenalidomide arm (hazard ratio, 0.44; 95% confidence interval, 0.32 – 0.60).With regard to overall survival, patients receiving continuous lenalidomide therapy demonstrated an overall survival rate of 90% at more than 2 years after transplantation, compared with 83% for patients receiving placebo (P = .018).

However, this trial raised concerns because there appears to be a higher incidence of cancers in the Revlimid group.

I consider Revlimid maintenance to still be investigational because that study is continuing and the results will continue to be update, because the increased cancer incidence in the experimental arm needs to be understood and explained.

P. L. McCarthy, K. Owzar, K. C. Anderson, C. C. Hofmeister, H. Hassoun, D. D. Hurd, E. A. Stadtmauer, S. Giralt, V. Hars, C. A. Linker, for CALGB, ECOG and BMT-CTN; Roswell Park Cancer Institute, Buffalo, NY; Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University, Columbus, OH; Memorial Sloan-Kettering Cancer Center, New York, NY; Wake Forest University, Winston Salem, NC; University of Pennsylvania Cancer Center, Philadelphia, PA; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of California, San Francisco, San Francisco, CA Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol 28:15s, 2010 (suppl; abstr 8017)

Matthew Strobeck From the analyst's couch: Multiple myeloma therapies Nature Reviews Drug Discovery 6, 181-182 (March 2007)

 Weber D, Chen C, Niesvizky R, et al. Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of a North American Phase III Study (MM-009). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 7521.

How long to treat metastatic breast cancer.

It is common practice to continue treating metastatic breast cancer patients as long as responses are expected. NCCN recommends singel agents mostly but also a few combinations for second line.  However, there is little evidence to support this practice after the first few lines. In any case, Herceptin is now being continued in a third consecutive regimen, which is not supported by guidelines or literature and is considered experimental. NCCN on p. MS-43 recommends continuing Herceptin into consecutive line of therapy but says that the duration of that is unknown. It also says on MS-2that continuation of chemotherapy past third line is not recommended and only supportive care should be given.

Refractory Acute Lymphocytic Leukemia: Role of Stem Cell Transplantation

Although acute lymphoblastic leukemia is curable in one third of adult patients, results vary greatly on account of different clinical, immunologic, and cytogenetic/genetic characteristics. These data, along with the kinetics of response to early treatment, help establish the individual risk class with considerable accuracy, and support risk-specific treatments that should warrant optimal results with as little as possible nonrelapse mortality. Modern first-line therapy consists of standard- and high-dose chemotherapy (increasingly inspired to pediatric principles), hematopoietic stem-cell transplantation, and new targeted therapy, all integrated with the analysis of prognostic factors and the study of subclinical residual disease for key therapeutic decisions. These changes are improving long-term outcome, which in ongoing studies is expected close to 50% or greater.

When ALL does not respond, the prognosis is grim. What to do is not known. Clofarabine has been approved for this situation in pediatric ALL and various combination treatmetns are being explored. Clolar® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. CBMT(Canadian BMT Group) suggests taht such pateints whould be enrolled into clincial trials. It is generallya ccepted, however, that at the very least, a remission be obtained before an allogeneic transplant is attempted.

Relatively few studies have compared transplantation with chemotherapy in adults with acute lymphoblastic leukemia (ALL). The Italian ALL R-87 study suggested that a small number of patients who experience relapse will survive long-term after allogeneic bone marrow transplantation (BMT).

Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532-43.

Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol. 2010;151:430-434.

Giona F, Annino L, Rondelli R, Arcese W, Meloni G, Testi AM, et al. Treatment of adults with acute lymphoblastic leukaemia in first bone marrow relapse: results of the ALL R-87 protocol. Br J Haematol. Jun 1997;97(4):896-903. [Medline].

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. Oct 1 2003;102(7):2379-86.

CBMT - http://www.cbmtg.org/~ASSETS/DOCUMENT/Guide/Stem%20Cell%20Transplantation%20for%20Acute%20Lymphoblastic%20Leukemia1.pdf

Prolonged Neupogen administration after a stem cell transplant

 

There is some concern that administration of Neupogen will delay engraftment of non-myeloid cells after a stem cell transplant but a recent review found this not to be the case. It also found that G-CSF is beneficial  in allogeneic as well as autologous transplantation. It did recommend that it be delayed for 5 days after transplantation because there was no difference in outcome between delaying it for up to 5 days or starting immediately after transplant. The administration of Neupogen in most studies was for variable periods, including for more than 14 days.

REFERENCES:

M Trivedi et al, Optimal use of G-CSF administration after hematopoietic SCT Bone Marrow Transplantation (2009) 43, 895–908

Smith TJ, Khatcheressian J, Lyman GH: 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based, clinical practice guideline. J Clin Oncol 24:3187-3205, 2006

Lyman GH: Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: A review of the evidence. J Natl Compr Canc Netw 3:557-571, 2005

Thalidomide and Leukine for prostate cancer

Both Leukine and thalidomide are investigational for prostate cancer, singly or together.

 Much research had gone on about the effects of thalidomide and the related drug Revlimid on prostate cancer. A new randomized phase 2 study has recently been published. Thalidomide may have use in the treatment of men who have biochemical recurrence of prostate cancer or a rise in their prostate-specific antigen (PSA) count after definitive therapy, according to this study from the National Cancer Institute. In this population, the use of thalidomide was associated with an increase in PSA progression-free survival after intermittent androgen-deprivation therapy (ADT). Thalidomide is listed by AHFS and in Micromedex. However, in this case PSA does not appear to be rising.

Granulocyte macrophage colony-stimulating factor is a pleiotropic cytokine capable of inducing systemic immune responses against experimental and human tumors. GM-CSF stimulates the differentiation of hematopoietic progenitors to monocytes and neutrophils, and reduces the risk for febrile neutropenia in cancer patients. GM-CSF also has been shown to induce the differentiation of myeloid dendritic cells (DCs) that promote the development of T-helper type 1 (cellular) immune responses in cognate T cells. GM-CSF has been used to augment the activity of rituximab in patients with follicular lymphoma and to induce autologous antitumor immunity in patients with hormone-refractory prostate cancer. A number of studies and reports focus on its activity, alone or in combination, for prostate cancer. It has been used with thalidomide, revlimid, provenge and a variety of other drugs and vaccines as an immunolodulator.

For that two together, a study had been competed but not yet published and another study is ongoing: Lenalidomide and GM-CSF in Treating Patients With Prostate Cancer NCT00939510

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 

Prostate Cancer Immunology: Biology, Therapeutics, and Challenges
W. S. Webster, E. J. Small, B. I. Rini, and E. D. Kwon
JCO November 10, 2005 23:8262-8269

Immunotherapeutics in Development for Prostate Cancer
A. L. Harzstark andE. J. Small
The Oncologist April 1, 2009 14:391-398

Figg WD, Dahut W, Duray P, Hamilton M, Tompkins A, Steinberg SM, Jones E, Premkumar A, Linehan WM, Floeter MK, Chen CC, Dixon S, Kohler DR, Kruger EA, Gubish E, Pluda JM, Reed E (2001) A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res 7: 1888–1893

 

CAD for MRI

CAD assists radiologist in interpreting MRIs by color coding areas with differing accumulation of contrast. Its value has nto been proven. Computer-aided detection has been used to aid radiologists’ interpretation of contrast-enhanced MRI of the breast, which is sometimes used as an alternative to mammography or other screening and diagnostic tests because of its high sensitivity in detecting breast lesions, even among those in whom mammography is less accurate (e.g., younger women and those with denser breasts).  The BlueCross and BlueShield Association’s Technology Evaluation Center (TEC) Medical Advisory Panel (2006) assessed the evidence on the use of CAD with MRI of the breast by comparing the sensitivity, specificity, and recall rate (percentage of patients asked to come back for further evaluation) of MRI with and without the use of commercially available CAD systems in detecting malignant lesions, evaluating the extent of disease in women with cancer, or gauging the impact of treatment.  According to this assessment, many of the studies on the use of CAD with MRI of the breast mainly reported on the development of CAD systems, or testing new CAD approaches.  The assessment noted that few of them evaluated commercially available CAD systems.  The TEC assessment stated that the literature is unclear on how CAD systems are to be used.  In the case of CAD with mammography, the radiologist reads the original films first, makes a diagnosis, and then reviews the CAD results. Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel concluded that there is insufficient evidence to evaluate if the use of CAD systems would maintain or increase the sensitivity, specificity, and recall rates of MRI of the breast.  The TEC assessment concluded that, given the inability to evaluate these intermediate outcomes, it is impossible to evaluate the impact of CAD on health outcomes such as treatment success and survival of patients with breast cancer. As such, the CAD method required farther testing and is investigtional per policy.

Bruening W, Launders J, Pinkney N, et al. Effectiveness of noninvasive diagnostic tests for breast abnormalities. Comparative Effectiveness Review No. 2. Prepared by the ECRI Evidence-Based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). AHRQ Publication No. 06-EHC005-EF. Rockville, MD: AHRQ; February 2006.

Muralidhar GS, Bovik AC, Sampat MP et al. Computer-aided diagnosis in breast magnetic resonance imaging. Mt Sinai J Med. 2011 Mar-Apr; 78(2):280-90. doi: 10.1002.msj.20248.

Dorrius MD, der Weide MC, van Ooijen PM et al. Computer-aided detection in breast MRI: a systematic review and meta-analysis. Eur Radiol. 2011 Aug;21(8):1600-8. Epub 2011 Mar 15

 

Erbitux for pancreatic cancer

Erbitux is an attractive drug to investigate for panceatic cancer. Unfortunately it has generally come up short in trials. The addition of the targeted agent Erbitux® (cetuximab) to the chemotherapy combination Gemzar® (gemcitabine) and Platinol® (cisplatin) does not improve outcomes compared with chemotherapy only in advanced pancreatic cancer (Cascinu et al). It is not ecommended by NCCN or ESMO in 2011but several trials in various combiations are still ongoing.

 

Cascinu S, Berardi R, Labianca R, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, Phase II trial. Lancet Oncology. 2008;9:39-44.S. Cascinu et al, This article appears in: ESMO Clinical Practice Guidelines

Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol (2010) 21 (suppl 5): v55-v58.    

Treatment of intravascular lymphoma

Inravascular lymphoma is a fairly new entity that is only recently described. It is is a rare form of diffuse LBCL characterized by preferential intravascular growth of malignant lymphocytes, aggressive behavior, and an often fatal course. IVLBCL usually affects elderly patients with poor performance status, elevated lactic dehydrogenase serum levels, anemia, and B symptoms. There is no standard therapy and most information about therapy comes from case reports. CHOP, adriamycin and other regimens have been tried. There is a report of excessive toxicity from rituxan. There is no credible medical evidence supporting an autologous transplant after a compete response.

Maurilio Ponzoni, Andrés J.M. Ferreri, Elías Campo, Fabio Facchetti, Luca Mazzucchelli, Tadashi Yoshino, Takuhei Murase, Stefano A. Pileri, Claudio Doglioni, Emanuele Zucca, Franco Cavalli, Shigeo Nakamura  Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3168-3173

Joachim M. Baehring, Janina Longtine and Fred H. Hochberg

A New Approach to the Diagnosis and Treatment of Intravascular Lymphoma Journal of Neuro-Oncology Volume 61, Number 3, 237-248,

 

WU Shang-Ju ; CHOU Wen-Chien  ; KO Bo-Sheng ; TEN Hwei-Fang  ; Severe pulmonary complications after initial treatment with rituximab for the Asian-variant of intravascular lymphoma Haematologica    2007, vol. 92, n^o1, pp. 141-142