Cancer Treatment

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]

Temodar alone and in combination for melanoma

Lay Summary: Temozolamide is guidelines recommended alone or with DTIC containing comibnations for melanoma.

The referenced guidelines says: "It is reasonable to use temozolomide at a dose of 200 mg/m2 orally for five days every four weeks as initial systemic treatment for patients with unresectable metastatic malignant melanoma.
The addition of moderate-dose interferon-alpha 2b has produced a significantly higher response rate than single-agent temozolomide in a large randomized phase III study. However, overall survival was not altered and grade 3 and 4 hematologic toxicities were higher with the combined treatment. At the present time, the addition of interferon-alpha to temozolomide is not recommended.
One randomized phase II study and six phase II studies have shown encouraging response rates when thalidomide is combined with temozolomide. However, dosing schedules of temozolomide in those studies differed from conventional prescribed doses and schedules. It is not clear whether the improved response rates were due to the small number of patients in the studies, the different dose schedules of temozolomide, or the addition of thalidomide. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and thalidomide. Therefore, it is not recommended that thalidomide be combined with temozolomide at this time." This is also what NCCN recommends but it also notes dacarbazine combinations.

Danson S, Lorigan P, Arance A, et al. Randomized Phase II Study of Temozolomide Given Every 8 Hours or Daily with Either Interferon Alfa-2b or Thalidomide in Metastatic Malignant Melanoma. Journal of Clinical Oncology 2003;21:2551-2557.

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]

nccn.org, melanoma

Interleukin 2 for melanoma

Cytokines are proteins that activate the immune system in a general way. Two cytokines, interferon alpha and interleukin 2, can help boost immunity in patients with melanoma. Both drugs can help shrink metastatic (stage III and IV) melanoma in about 10% to 20% of patients. There are no studies that compare interleukin-2 (IL-2) to the current standard of care, dacarbazine (DTIC), or to placebo in the treatment of metastatic melanoma. IL2 can be given as low dose, intermediate dose of high dose. HIgh dose is probably the most effective but ti is also toxic.
After weighing and reviewing the evidence that does exist, the opinion of the Melanoma Disease Site Group is that high-dose IL-2 is a reasonable treatment option for a select group of patients with metastatic melanoma:
Patients should have a good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1), and a normal lactate dehydrogenase (LDH) level.
Patients should have less than three organs involved or have cutaneous and/or subcutaneous metastases only and no evidence of central nervous system metastases. In this select group of patients IL-2 treatment can produce durable complete remissions.
The recommended dose and schedule of high-dose IL-2 is 600,000 IU/kg/dose intravenously over 15 minutes, every eight hours, for a maximum of 14 doses.
If high-dose IL-2 is delivered, the recommendation is that it be done in a tertiary care facility with staff trained in the provision of this treatment with appropriate monitoring. Low or intermediate dose IL2 is nto recommended by the referenced guideline or by NCCN.

Petrella T, Quirt I, Verma S, Haynes A, Charette M, Bak K, Melanoma Disease Site Group. Single-agent interleukin-2 in the treatment of metastatic melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Mar 20. 32 p. (Evidence-based series; no. 8-5). [32 references]

NCCN.ORG, melanoma

Taxotere and single agents for melanoma

Lay Summary: Chemo for melanoma is discussed.

Single-agent chemotherapy or immunotherapy remain the treatments of choice when systemic therapy is offered. Dacarbazine (DTIC) is the chemotherapy of choice with a response rate of 16%. Other chemotherapies, including cisplatinum, paclitaxel, docetaxel and the DTIC analogue temozolomide, have shown activity in this disease. Based on their single-agent activity, several combination chemotherapies have been investigated with preliminary results that appeared promising. However, in randomized phase III trials the two most active chemotherapy combination regimens, cisplatin, vinblastine, and DTIC (CVD) and the Dartmouth regimen (DTIC, cisplatin, bischloroethylnitrosourea [BCNU], and tamoxifen), did not prove to be superior to single-agent DTIC for overall survival. Immunotherapy with either interleukin (IL)-2 or interferon (IFN) has demonstrated response rates of 10% to 15% in appropriately selected patients. In patients who achieve a complete response, responses can be of greater durability than those with chemotherapy. However, IL-2 and IFN administration are associated with multiple side effects, and only physicians experienced in the management of such therapies should administer them. The potential benefit of combining chemotherapy with immunotherapy has led to multiple phase II trials of biochemotherapy that appeared to be associated with higher response rates and longer median survivals. However, several phase III trials have been completed that have not consistently demonstrated an improvement in either response rates or overall survival, and these approaches to therapy cannot be routinely recommended outside the context of a clinical trial. The surgical resection of isolated metastatic disease has demonstrated an important palliative benefit in those patients who present with solitary single-organ disease with the exception of the liver. Radiation has an important role in the palliative management of brain metastasis and symptomatic bony metastasis. Both stereotactic radiosurgery and whole brain radiotherapy have been used alone and in combination to benefit patients in this troubling clinical circumstance. Isolated limb perfusion and a newer technique, isolated limb infusion have demonstrated high response rates for those uncommon patients who develop recurrent disease isolated to a limb. In our opinion, if complete metastasectomy is not feasible and in the absence of brain metastases, single-agent IL-2 is a good initial treatment choice in appropriately selected patients. Single-agent chemotherapy with DTIC is the treatment of choice for patients who are not candidates for IL-2. Adoptive immunotherapy combining nonmyeloablative chemotherapy with high-dose IL-2 is a potentially promising therapeutic strategy under investigation. Targeted therapy is also an area of promising development as single agents, in combination, and combined with chemotherapy. The latter will be the focus of at least one upcoming cooperative group phase III trial.

Docetaxel was first reported  to be active in melanoma in 1994 and this was followed by several other phase II trials in the subsequent years demonstrating activity. Over  the past decasde there have been a number of trials in combination with other agents. As a sinlge agent is in the same league with toher single chemotehrapy agnets in terms of response rates in the 10-25% range.There are many trials of paclitaxel,a  closely related drug to Taxotere, and it should also be consdiered an appropriate single agent for melanoma.

Textbook of Melanoma By Donald L. Morton, Bin B. R. Kroon, Dr John F Thompson, p. 627, 2003

nccn.org, melanoma

Nexavar for melanoma

Lay Summary:Nexavar has not been proven to be effecive for melanoma.

A Phase III trial administering Nexavar®
(sorafenib) or placebo tablets in combination with the chemotherapeutic agents
carboplatin and paclitaxel in patients with advanced melanoma did not meet its
primary endpoint of improving progression-free survival (PFS). The treatment
effect was comparable in each arm. The international Phase III, double-blind, randomized, placebo-controlled  trial evaluated Nexavar when administered in combination with a standard
dosing schedule (21-day cycles) of carboplatin and paclitaxel. Two hundred
seventy patients progressing after one previous systemic chemotherapeutic
treatment (with either dacarbazine (DTIC) or temozolomide) were enrolled into
the study. The study was designed to measure the safety and efficacy of
Nexavar when co-administered with chemotherapy, and had PFS as its primary
endpoint. PFS is defined as the time that a patient lives without meaningful
tumor growth. The safety profile of these agents in combination (Nexavar with
carboplatin/paclitaxel) was comparable to those previously reported for these
agents in combination. Thus, for now, Nexvar remains an experiemental modality for melanoma.

B. Kasper, V. D’Hondt, P. Vereecken, A. Awada Novel treatment strategies for malignant melanoma: A new beginning?.  Critical Reviews in Oncology/Hematology, Volume 62, Issue 1, Pages 16-22 2006

T Eisen et al, Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis British Journal of Cancer (2006) 95, 581-586.

Adjuvant treatment for melanoma

Adjuvant treatment of melanoma with interferon is controversial. This is because phase III trials have provided conflicting evidence of effectiveness and the treatment is prolonged and toxic. There are no adjuvant therapies of proven benefit for melanoma as yet, but several clinical trials are actively recruiting patients. Past trials gave conflicting results. Patients and practitioners should be aware that there have been four randomized trials of high-dose interferon alpha in patients at high risk for recurrent melanoma. The evidence from the randomized trials is conflicting. The Eastern Cooperative Oncology Group (ECOG) 1684 trial detected a significant improvement in overall survival, but a subsequent large randomized trial (ECOG 1690) failed to find any survival benefit for interferon compared with observation. Results from a third trial (ECOG 1694) that compared high dose interferon with a melanoma vaccine demonstrated a significant survival benefit for interferon. A fourth trial of high-dose interferon over a shorter treatment time failed to detect any benefit.  NCCN has taken the psition that this teatmetn can be offered to apteints with sufficeint counslling so that they can understand the issues involved.

Roberts DL, Anstey AV, Barlow RJ, Cox NH, Newton Bishop JA, Corrie PG, Evans J, Gore ME, Hall PN, Kirkham N. U.K. guidelines for the management of cutaneous melanoma. Br J Dermatol 2002 Jan;146(1):7-17. [60 references]

Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N, Melanoma Disease Site Group. Systemic adjuvant therapy for patients at high risk for recurrent melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Aug 30. 39 p. (Evidence-based series; no. 8-1). [61 references]

nccn.org melanoma

Oxaliplatin for melanoma

Oxaliplatin is a platinum derivative without nephrotoxicity with in vitro activity against human melanoma cell lines. A Phase I and II trials suggested activity in melanoma, although a combination of oxaliplatin, docetaxel, and GM-CSF had limited clinical activity in previously treated patients with advanced melanoma. A non-nephrotoxic platinum compound active in melanoma is of interest in the development of combination chemo-or chemoimmunotherapy. This trial is an attempt to begin doing this in a pahse I trial setting, that is, with dose escalation of oxaliplatin.

The proposed study is: A Phase I Study of Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic Fluorouracil, Leucovorin and Avastin for Patients with Advanced Solid Tumors Metastatic to the Liver. The goal of this clinical research study is to find the highest tolerable dose of oxaliplatin used in combination with 5-fluorouracil, leucovorin, and Avastin® (bevacizumab) for patients with advanced cancer that has spread to the liver. The safety and effectiveness of this study drug combination will also be studied. This si celarly experiemntal by any definition.

Oxaliplatin is a platinum derivative without nephrotoxicity with in vitro activity against human melanoma cell lines. A Phase I and II trials suggested activity in melanoma, although a combination of oxaliplatin, docetaxel, and GM-CSF had limited clinical activity in previously treated patients with advanced melanoma. A non-nephrotoxic platinum compound active in melanoma is of interest in the development of combination chemo-or chemoimmunotherapy. This trial is an attempt to begin doing this in a pahse I trial setting, that is, with dose escalation of oxaliplatin.

The proposed study is: A Phase I Study of Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic Fluorouracil, Leucovorin and Avastin for Patients with Advanced Solid Tumors Metastatic to the Liver. The goal of this clinical research study is to find the highest tolerable dose of oxaliplatin used in combination with 5-fluorouracil, leucovorin, and Avastin® (bevacizumab) for patients with advanced cancer that has spread to the liver. The safety and effectiveness of this study drug combination will also be studied. This is clearly experimental by any definition.

Leukine for melanoma

Lay Summary: Leukine is being explored for treating melanoma.

Leukine (granulocyte macrophage colony stimulating factor, GM-CSF, Sargramostim), which is approved for marketing for hematopoietic reconstitution and reversal of iatrogenic neutropenia, also has activity as a macrophage activator. It has been reported that Leukine stimulates peripheral blood monocytes in vitro to become cytotoxic for human melanoma cells. It has further been shown in clinical trials that in vivo administration of Leukine at low doses also results in monocyte activation as shown by enhanced cytotoxicity. Finally, Leukine causes release of an angiogenesis inhibitor by the macrophages. Becasue of these effects, interest was aroused in its use for melanoma.

A trial of therapy in the adjuvant setting was favourable. The median survival was prolonged over three-fold in patients who received Leukine to 34.3 months compared to matched historical controls (median survival 10.2 months). The observed 2-year survival was 64% in the study patients vs. 15% in the controls, (p < 0.001). Toxicity was minimal, the major side effect being mild fatigue; there were no reports of Grade 4 toxicity or serious adverse events.

An interim analysis of another trial was presented at the 6th International Conference on Admuvant Therapy of Melanoma in Stockholm in 2006 and 5th International Conference on Adjuvant Therapy of Melanoma in Athens in March, 2004. It supports the results of the earlier trial and suggests that Leukine improves survival in this patient population. In addition, one of the cooperative study groups, the Eastern Cooperative Oncology Group, has initiated a Phase III prospective randomized trial to further evaluate this therapy (E4697). Accrual of 800 patients has ben completed, but many patients are still undergoing treatment and results of this study will not be known for several years. Finally, there is a trial to gather additional information about efficacy of this treatment and to determine the immunologic effects of GM-CSF in patients with melanoma.

The therapy is being currently investigated and is clearly experimental/investigational. The only adjuvant therapy approved at this time is interferon.

For metastatic setting, it is even more experimental, since immune mechanisma may not work for metastatic disease. A trial in this setting as well is referenced.

Spitler, LE, Grossbard, ML, Ernstoff MS, et al:  Adjuvant therapy of Stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 18:1614-1621, 2000

http://clinicaltrials.mayo.edu/clinicaltrialdetails.cfm?trial_id=100307

nccn.org, melanoma

Oncotech chemosensitivity and chemoresistance assays

Lay Summary: Chemosensitivity assays are controversial but most experts believe that they do not reliably assist in selecting chemotherapy. There is more evidence for chemoresistance assays but this also remains disputed.

Oncotech ER is a form of chemosensitivity testing, or rather, a modification that tests resistance to chemo rather than sensitivity. The recent article by Schrag et al1 criticized the field of chemosensitivity and drug resistance, concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a casue celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The Amreican Society of Clnical Oncology vigorously objected and recommended: "
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority."  I believe that the So. California branch of ASCO disssented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient's tumor cells. This lab test is claimed to determine the probability of a tumor's resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either "assay-directed therapy" or the treatment of the "physician's choice". The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician's choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician's choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician's choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most expersts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is as described above.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 - 5259.

M. Markman Chemosensitivity and Chemoresistance Testing
J. Clin. Oncol., October 10, 2005; 23(29): 7363 - 7364.

R. Nagourney Chemosensitivity and Resistance Assays: A Systematic Review?
J. Clin. Oncol., May 20, 2005; 23(15): 3640 - 3641.

J. P. Fruehauf and D. S. Alberts
In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins
J. Clin. Oncol., May 20, 2005; 23(15): 3641 - 3643.
 
H. S. Wieand
Chemotherapy Sensitivity and Response Assays: Are the ASCO Guidelines for Clinical Trial Design Too Restrictive?
J. Clin. Oncol., May 20, 2005; 23(15): 3643 - 3644.
 
M. Castro Resisting a Fundamentalist Policy
J. Clin. Oncol., May 20, 2005; 23(15): 3645 - 3646.