Tuesday, February 3, 2009

Trends in Melanoma -----Sanjiv. S. Aqarwala, MD January 29, 2009 Jim Breitfeller

Trends in Melanoma

Sanjiv. S. Aqarwala, MD
January 29, 2009

Sunbelt Melanoma Trial: Final Results
The Sunbelt Melanoma Trial, a multicenter prospective randomized trial, assessed high-dose interferon alfa-2b (IFN) or completion lymph node dissection (CLND) in the treatment of melanoma staged by sentinel lymph node (SLN) biopsy.

Eligible patients 18 to 70 years of age who had primary melanoma with Breslow thickness Ž1.0 mm underwent SLN biopsy and were assigned to one of two protocols. In protocol A, patients with a single positive lymph node after SLN biopsy and CLND were randomized to observation vs high-dose IFN (20 MU/m2/day IV 2 4 weeks followed by 10 MU/m2 /three times per week SC 2 48 weeks). Protocol B included patients with negative SLN determined by standard histopathology and immunohistochemistry. To detect melanoma-specific mRNA, these patients underwent molecular staging of the SLN by RT-PCR. Patients with RT-PCR–positive SLN were randomized to observation vs CLND vs CLND plus IFN (20 MU/m2/day IV 2 4 weeks only).

Randomization was stratified for Breslow thickness and ulceration. The primary end points were disease-free survival (DFS) and overall survival (OS). Intent-to-treat (ITT) and efficacy analyses were performed by Kaplan-Meier and Cox proportional hazards models, and the Data Safety and Monitoring Committee (DSMC) approved the final analysis.

Patients were enrolled between June 24, 1997, and October 31, 2003; median follow-up was 64 months. In the protocol A ITT analysis, there were no significant differences in DFS (HR 0.82; 95% CI, 0.47-1.40; P=0.46) or OS (HR 1.07; CI 0.65-1.78; P=0.79) for patients randomized to IFN (n=112) vs observation (n=106). In protocol B, there were no significant differences in DFS or OS among patients randomized to CLND (n=192; DFS: HR 0.72; CI 0.42-1.23; P=0.23; OS: HR 0.94; CI 0.55-1.59; P=0.81) or CLND plus IFN (n=184; DFS: HR 0.90; CI 0.54-1.50; P=0.69; OS: HR 0.96; CI 0.56-1.63; P=0.88) vs observation (n=180). The efficacy analysis did not demonstrate significant differences in DFS or OS.

This study failed to demonstrate a benefit for adjuvant high-dose IFN for patients with a single positive SLN. In addition, there was no significant benefit to CLND or CLND plus IFN among patients with melanoma cells detected in the SLN by RT-PCR analysis.

Combination Thalidomide Plus Temozolomide in a Phase II Trial in Metastatic Malignant Melanoma (MMM): SWOG S0508
After response rates up to 32% were achieved in single-institution phase II studies of thalidomide plus temozolomide as combination therapy in MMM, some clinicians have used thalidomide plus temozolomide as a standard therapy. This large multicenter phase II trial evaluated the clinical efficacy of this
therapy and the immune modulatory effects of thalidomide when combined with temozolomide in patients with MMM.

Eligible patients had cutaneous MMM proven by biopsy, no active brain metastases, Zubrod PS 0-1, no more than 1 prior systemic therapy for melanoma (excluding thalidomide, temozolomide, or dacarbazine), and adequate organ function. Six-month progression-free survival (PFS) was the primary end point; per study design, if the 6-month PFS rate was 10%, the regimen would not be of interest; if PFS was Ž25%, further study would be warranted. Response rate, OS, toxicities, and assessment of the relationship between immunologic biomarkers and clinical outcomes were secondary end points.

Patients received thalidomide (200 mg/day escalated to 400 mg/day for patients younger than 70 years, or 100 mg/day escalated to 250 mg/day for patients 70 years of age or older) plus concomitant temozolomide (75 mg/m2/day 2 6 weeks with a 2-week rest between cycles). Anticoagulation agents were not required. Treatment was continued until toxicity became unacceptable or disease progressed.

Of the 64 patients enrolled, 2 were ineligible, and 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%-24%), and 1-year OS was 36% (95% CI, 24%-49%). Fifty-one patients had measurable disease by RECIST and were evaluable for response. All responses were partial, at a rate of 14% (95% CI, 6%-26%). One treatment-related death occurred due to MI. Three grade 4 events occurred: one case each of PE, neutropenia, and CNS ischemia; fatigue was the most common of 21 grade 3 events. Immunologic biomarkers were obtained at baseline and at 5, 9, and 13 weeks, including PBMC as a percentage and as an absolute count of CD4+/CD25+/CD69+ and CD16+/CD56+ cells, and ELISPOT reactivity to a recall pool of antigens.

Thalidomide plus temozolomide has little additional clinically meaningful activity compared with temozolomide alone in MMM. In a meta-analysis of systemic therapy for MMM, thalidomide plus temozolomide compared poorly. This regimen should not be considered a standard treatment for MMM.
Clark J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 9007

Unresectable Metastatic Melanoma: A Phase II Clinical Trial With a Second-Generation GM-CSF–
Encoding Oncolytic Herpesvirus
OncoVEX (GM-CSF) is a second-generation oncolytic herpes simplex virus that encodes granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase I trial, it was well tolerated in patients with several types of tumors, and antitumor effects were seen in both injected and uninjected tumors.
Patients eligible for this phase II trial had unresectable stage IIIc/IV melanoma with Ž1 injectable tumor (ultrasound allowed) and had failed prior therapy. Patients with clinically active brain, liver, or bone metastases were excluded. Fewer than 10 lesions were to be injected, and more than 1 lesion was to be left uninjected. The dosing schedule consisted of one injection of 4 mL of 106 plaque forming units (pfu)/mL split between target tumors, followed 3 weeks later by 24 injections of 108 pfu/mL every 2 weeks. The study was designed to assess single-arm monotherapy in up to 50 evaluable patients, and more than one RECIST response among the first 24 patients was required to continue the trial. Response rate was the primary end point; safety, response kinetics, and survival were secondary end points.

At the time of this report, the study had enrolled 40 patients, 31 of whom were evaluable. Patients had up to 18 injection cycles. By 2 months on therapy, injected tumors routinely responded, often with local complete response (CR); often, palliative benefit was also achieved. Systemic responses included: 3 patients with CR, 3 with partial response (PR), 4 with durable stable disease (SD), and 2 with mixed response (ŽPR of existing disease and ŽPR of lesions, which later became measurable); 2 patients had posttreatment objective responses. Patients with both stage IIIc and IV disease achieved systemic responses, including resolution of visceral disease. Systemic responses are delayed since injected tumor responses take up to 10 months to fully develop. All objective responses have been maintained to date at 4 to 23 months after the first dose, with those patients not achieving CR still on therapy. Side effects have been grade 1 flu-like symptoms.

Data show that 32% of patients achieved CR, PR, or durable SD. Other patients also experienced clinical benefit: 2 patients had response in tumors that were first noted during therapy; 2 patients responded after leaving the study due to progressive disease; additional patients experienced local palliative benefit in otherwise difficult-to-treat tumors. The rate and durability of response is considered impressive compared with other treatments for advanced melanoma, particularly in the second-line/salvage therapy setting, and further evaluation is therefore warranted.

Tremelimumab and Temozolomide or Dacarbazine: A Phase III, Open-Label, Randomized, Comparative Study in Patients With Advanced Melanoma
This phase III study compared OS achieved with tremelimumab, a fully human anticytotoxic T lymphocyte–associated antigen 4 monoclonal antibody, with OS achieved with standard, single-agent chemotherapy.
Eligible patients had unresectable stage IIIc/IV melanoma without brain metastasis, LDH below 2 2 ULN, and no prior systemic treatment for advanced melanoma. Patients were randomized 1:1 to either tremelimumab 15 mg/kg IV every 90 days, or physician's choice of temozolomide 200 mg/m2 po on days 1-5 every 28 days or dacarbazine 1000 mg/m2 IV every 21 days (chemotherapy arm). Primary end point was OS, and secondary end points included response, durable tumor response, 6-month PFS, and safety. Two equally spaced interim analyses were planned based on the group sequential design using the Lan-DeMets alpha and beta spending approach to an O'Brien-Fleming boundary.

Between March 2006 and July 2007, 655 patients enrolled, with 328 patients randomized to tremelimumab (324 treated) and 327 to chemotherapy (319 treated). Significant imbalances were not noted in age, sex, LDH, or disease stage (5% stage IIIc, 15% M1a, 22% M1b, 58% M1c). The most common treatment-related adverse events in the tremelimumab arm were diarrhea (43% overall, 14% grade 3/4), pruritus (25%), and rash (23%). Pituitary or adrenal gland toxicities occurred in 3% of patients, and thyroid toxicities in 4%. There were three treatment-related deaths in the tremelimumab arm but none in the chemotherapy arm.

The independent DSMC advised researchers to end the study on March 28, 2008, because the log-rank test-statistic (P=0.729) had crossed the O'Brien-Fleming futility boundary based on a protocol-specified second interim analysis that reported 340 deaths. The ITT median OS was 11.8 months (95% CI, 10.4-13.9) in the tremelimumab arm and 10.7 months (95% CI, 9.3-12.0) in the chemotherapy arm, with a HR (chemotherapy over tremelimumab) of 1.04 (95% CI, 0.84-1.28).

Tremelimumab as a single agent failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy. Analysis of the secondary end points may yield additional information.

Ribas A, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA9011.

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..


Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.


Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by "About.com : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.