Sprycel (dasatinib) is an attractive drug for use in melanoma because it affects mutations that re sometimes expressed in melanoma cells, A recent phase II study (Kluger et al) found that it had minimal activity in melanoma, except in patients with the C-KIT mutations. Thirty-nine patients were enrolled, 36 of whom were evaluable for activity and toxicity. Five, 4, and 3 patients had acral-lentiginous, ocular, or mucosal primaries, respectively. Two patients had confirmed partial responses lasting 64 and 24 weeks (RR 5%). One patient with an exon-13 c-kit mutation had a partial response, whereas disease in another patient with an exon-11 c-kit mutation progressed. The study suggests that identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials. There si an ongoing trial: Dasatinib in Treating Patients With Locally Advanced or Metastatic Mucosal Melanoma, Acral Melanoma, or Vulvovaginal Melanoma That Cannot Be Removed By Surgery, NCT00700882

Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer. 2011 May 15;117(10):2202-8.

BC. Bastian, Targeting Activated KIT Signaling for Melanoma Therapy

JCO September 10, 2013 vol. 31 no. 26 3288-3290

In general, a variety of similar tests has recently been licensed and marketed in various tumor types and at this time, none of them are generally accepted or recommended by guidelines.

Of all Decision Dx, the uveal melanoma test has the most support.  It has been validated in retrospective analysis, especially in showing that prognoses varied between different stages of melanoma and shown to be independent of and more accurate than current histologic factors used to predict an individual patient’s metastatic risk, including AJCC stage, Breslow’s thickness and mitotic rate. It had not been prospectively tested. The DecisionDx for uveal melanoma, however, has support for AJCC(American Joint committee on Cancer, version 7, 2010).

Harbour, J.W. (2011). Molecular Research in Uveal Melanoma: Ushering in a New Standard of Care. Retina Times, 29, 36-7

Aaberg, (2012). Practical Approaches to Needle Biopsy and Genetic Diagnosis for Ocular Melanoma. Retina 2012: The Winds of Change. Lecture conducted from The American Academy of Ophthalmology, Chicago, IL.

Chappell, et al. (2012). Uveal Melanoma: Molecular Pattern, Clinical Features, and Radiation Response. American Journal of Ophthalmology, 227-232.

Petrausch U,Martus P,Tönnies H,et al.Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases.Eye.2008;22:997-1007.

Damato B, Coupland SE.Translating uveal melanoma cytogenetics into clinical care. Arch Ophthalmol. 2009;127:423-429.

Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol 2010;28:2452-9.

Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 2011; 65(5): 1032-1047.

Plasseraud KM, Cook RW, Tsai T, et al. Clinical Performance and Management Outcomes with the DecisionDx-UM Gene Expression Profile Test in a Prospective Multicenter Study. J Oncol. 2016;2016:5325762.

For Lay version see

For DecisonDx for glioblastoma see here

In 2009, Hersh and colleagues initiated the phase 3 CA033 trial.

The international, multicenter, randomized study compared nab-paclitaxel with dacarbazine (DTIC) in chemotherapy-naive patients with metastatic malignant melanoma.

The investigation included 529 patients with stage IV disease, a performance status of 0 to 1, and no brain metastasis.

The researchers assigned 264 patients to receive nab-paclitaxel 150 mg/m2 IV on days 1, 8 and 15 every 4 weeks. The other 265 patients received dacarbazine 1,000 mg/m2 once every 3 weeks.

Patient characteristics — including age (media, 63 years; range, 21 to 87 years), sex, region of the world, ECOG performance status and metastatic stage — were similar between the two arms.

PFS served as the primary endpoint and OS served as the secondary endpoint. Other endpoints included overall response rate, disease control rate and safety/tolerability.

The results, presented in November at the Society for Melanoma Research Congress, showed that patients assigned to nab-paclitaxel demonstrated superior median PFS (4.8 months vs. 2.5 months; HR=0.792; 95.1% CI, 0.631-0.992).

At the time of planned interim analysis, nab-paclitaxel also was associated with longer OS (12.8 months vs. 10.7 months; HR=0.831; 99.9% CI, 0.578-0.1.196).

As a single agent, Avastin has been found to produce responses and disease stabilization in patients with metastatic melanoma. A study from Spain has also found the combination of Taxol and Avastin to have clinical benefit in over half of the patients with metastatic melanoma(Gonzalez Cao et al).  NCCN lists it as an alternative, but not specifically for second line.

Abraxane and Avastin is under study in a phase II trial at Northern California Melanoma Center, an open-label, single arm multicenter Phase II study to evaluate the safety and efficacy of the combination of Abraxane and Avastin as first-line therapy for patients with unresectable metastatic malignant melanoma. Early experience suggests that nab-paclitaxel and bevacizumab is an effective and well-tolerated regimen as first-line therapy in patients with metastatic melanoma(Boasberg et al).

P. Boasberg, S. Cruickshank, O. Hamid, S. O’Day, R. Weber, L. Spitler;  Nab-paclitaxel and bevacizumab as first-line therapy in patients with unresectable stage III and IV melanoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 9061^)

Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009;115:119-127.

Jaissle GB, Ulmer A, Henke-Fahle S, et al. Suppression of melanoma-associated neoangiogenesis by bevacizumb. Archives of Dermatology. 2008;144:525-527.

Varker KA, Biber JE, Kefauver C, et al. A randomized phase 2 trial of bevacizumab with J Clin Oncol 29: 2011 (suppl; abstr 8532)

L. A. Kottschade, V. Suman, D. G. Perez, R. R. McWilliams, J. S. Kaur, T. Amatruda, F. J. Geoffroy, H. M. Gross, P. A. Cohen, A. J. Jaslowski, M. L. Kosel, S. Markovic; Mayo Clinic, Rochester, MN; Minnesota Hematology/Oncology, PA, St. Louis Park, MN; Hubert H. Humphrey Cancer Center, Robbinsdale, MN; Illinois Cancer Care, Peoria, IL; NSABP; Dayton CCOP, Dayton, OH; Mayo Clinic, Scottsdale, AZ; Green Bay Oncology, Green Bay, WI, A randomized phase II trial of temozolomide (TMZ) and bevacizumab (BEV) or nab-paclitaxel (nab-P)/carboplatin (CBDCA) and bevacizumab (BEV) in patients with unresectable stage IV metastatic melanoma: A North Central Cancer Treatment Group Study (N0775). J Clin Oncol 29: 2011 (suppl; abstr 8532)

Gonzalez-Cao M, Viteri S, Diaz-Lagares A, et al. Preliminary results of the combination of bevacizumab and weekly paclitaxel in advanced melanoma. Oncology. 2008;74:12-16.

Hersh E, O’Day S, Gonzalez R, et al.Multicenter phase II study of ABI-007 (Abraxane) in previously treated and chemotherapy nave patients with metastatic malignant melanoma (MMM). Proceedings from the 23rd annual Chemotherapy Foundation Symposium. 2005. New York, NY. Abstract #27.

Walker L, Schalch H, King DM, et al. Phase II trial of weekly paclitaxel in patients with advanced melanoma. Melanoma Research . 2005;15:453-459.

Bedikian AY, Plager C, Papadopoulos N, et al. Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma. Melanoma Research . 2004;63-66.Hersh EM. Taxanes in melanoma: Are they the new chemotherapy standard? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies meeting; March 22-23, 2013; New York.

For Lay version see here

More on melanoma treatment

More than 30 mutations of the BRAF gene associated with human cancers have been identified. The most common one is BRAFE, a substitution of  valine (V)  glutamate (E) at codon 600, and it is referred to as  BRAF600E. Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, Preclinical evidence is that most of these mutations  stimulate enhanced B-Raf kinase activity toward MEK. A few mutants have reduced activity toward MEK but adopt a conformation that activates wild-type C-RAF, which then signals to ERK.

With this in mind, other BRAF mutations than E should also respond to Zelboraf. There is some evidence for that in individual cases, for example for the BRAFK mutation as well as for BRAFR. In the Chapman study, on which the FDA approval was based, there were ten patients with BRAFK and they showed some response. Ten patients in the vemurafenib group were later found to have BRAF V600K mutations; of these patients, 4 had a partial response (40%). Being that there are so many different BRAF mutations, it is not reasonable to require large studies performed for each mutation subtype.

Zelboraf, Prescribing Information, 2012
Flaherty K. “Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer”. 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000).

Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). “Inhibition of mutated, activated BRAF in metastatic melanoma”. N. Engl. J. Med. 363 (9): 809–19.

Paul B. Chapman, M.D., Axel Hauschild, M.D., Caroline Robert, M.D., Ph.D., John B. Haanen, M.D., Paolo Ascierto, M.D., James Larkin, M.D., Reinhard Dummer, M.D., Claus Garbe, M.D., Alessandro Testori, M.D., Michele Maio, M.D., David Hogg, M.D., Paul Lorigan, M.D., Celeste Lebbe, M.D., Thomas Jouary, M.D., Dirk Schadendorf, M.D., Antoni Ribas, M.D., Steven J. O’Day, M.D., Jeffrey A. Sosman, M.D., John M. Kirkwood, M.D., Alexander M.M. Eggermont, M.D., Ph.D., Brigitte Dreno, M.D., Ph.D., Keith Nolop, M.D., Jiang Li, Ph.D., Betty Nelson, M.A., Jeannie Hou, M.D., Richard J. Lee, M.D., Keith T. Flaherty, M.D., and Grant A. McArthur, M.B., B.S., Ph.D. for the BRIM-3 Study Group, Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation, N Engl J Med 2011; 364:2507-2516

For Lay version see here

About Zelboraf

Ipilimumab(Yervoy) is directed against an antigen on the surface of T cells. It is an FDA approved drug for the treatment of unresectable or metastatic melanoma. Some patients have only a partial response or progress and many physicians would retreat in such a situation. Due to potentially severe or even fatal safety issues, the FDA approved this agent with a Risk Evaluation and Mitigation Strategy (REMS) to ensure the benefits of the agent outweigh the risks, although this requirement was later suspended. It remains a toxic drug and the decision to retreat with it is not without potential risks.  It is , unfortunately, not known whether retreatment with Yervoy is of benefit in those who do not respond or have only a partial response. There is a study looking at this question: Study to Compare the Effect of Ipilimumab Retreatment With Chemotherapy in Advanced Melanoma, NCT01709162. The purpose of the study is to determine whether additional doses of Ipilimumab have a positive effect on survival in the treatment of advanced melanoma that has progressed after successful initial treatment with Ipilimumab.

Neverthelesss, currently several guidelines recommend retreatment for partial responders, provided Yervoy was well tolerated at first administration. This appears to be based on some trials allowing retreatment under such conditions. For example, NCCN on p. ME-E, 1 says in footnote 2: “Reinduction with ipilimumab may be considered for select patients who experience no significant systemic toxicity during prior ipilimumab therapy and who relapse after initial clinical response  or progress after stable disease more than 3 months”.

O’Day S, Hodi FS, McDermott DF et al. A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 4.

Hwu P. A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 N Engl J Med 2010; 363:779 – 781

Dummer R, Hauschild A, Guggenheim M, Jost L, Pentheroudakis G. Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. May 2010;21 Suppl 5:v194-197.

For Lay version see here

The role of PET in melanoma is not fully defined. Medicare currently covers PET for initial staging of melanoma and restaging, although it states, “CMS guidelines state that PET would rarely be used in the diagnosis of melanoma”.  CMS does not cover PET for evaluation of regional nodes when there is not suspicion for more extensive disease. NCCN does list PET as a staging option. The most recent review (Petrella et al) concluded: “PET scanning facilitates the appropriate management of high-risk melanoma patients being considered for operative intervention. PET imaging in addition to CT scanning should be strongly considered before operation in patients at high risk for occult metastatic disease.”  It also says that a recommendation cannot be made for or against the use of PET for routine surveillance due to insufficient evidence.

2012 NCCN incorporates PET/CT into its followup recommendations. For stages 0-IIA it recommends reimaging with CT or PET/CT only for specific signs or symptoms. For stage IIB-IV it recommends: “consider chest-X-ray, CT or PET/CT every 6-12 months to screen for recurrent or metastatic disease, for up to 5 years. Francken et al (2008)proposed a new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

 Morton RL, Craig JC, Thompson The role of surveillance chest X-rays in the follow-up of high-risk melanoma patients. Ann Surg Oncol. 2009;16(3):571.

Francken AB, Accortt NA, Shaw HM, Colman MH, Wiener M, Soong SJ, Hoekstra HJ, ThompsonFollow-up schedules after treatment for malignant melanoma. Br J Surg. 2008;95(11):1401

Petrella T, Walker-Dilks C. PET imaging in melanoma: recommendations. Toronto (ON): Cancer Care Ontario (CCO); 2009 Jan 19. 24 p. (Recommendation report – PET; no. 3). [19 references]

Brady MS, Akhurst T, Spanknebel K, Hilton S, Gonen M, Patel A, Larson S.
Utility of preoperative [(18)]f fluorodeoxyglucose-positron emission tomography scanning in high-risk melanoma patients.Ann Surg Oncol. 2006 Apr;13(4):525-32

http://tech.snmjournals.org/cgi/content/full/32/1/33/T3

Jeffrey D. Wagner Fluorodeoxyglucose Positron Emission Tomography for Melanoma Staging: Refining the Indications, Annals of Surgical Oncology 13:444-446 (2006)

For Lay version see here

“The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation” (Cavo M. et al., 2017).

“18F-FDG PET/CT plays an important role in MM where it combines functional imaging provided by PET with morphological evaluation assessed by CT. It enables the detection of metabolically active plasma cells both inside and outside the BM, thus predicting patients’ clinical outcomes.” (Sundaram, S., Driscoll, J., Fernandez-Ulloa, M., de Lima, M., & Malek, E., 2018).

“In addition to the skeletal survey or CT, MRI or PET/CT are needed to exclude the presence of additional lesions and the use of at least one of these examinations is mandatory (Grade 1A). Both are recommended based on small prospective studies, while PET/CT has additional prognostic value. Using both PET/CT and MRI may offer complementary information. When both PET/CT and MRI are not available, a WB-CT approach can be used to exclude other lesions. (Grade 2C). To detect additional soft tissue lesions, PET/CT is recommended for patients with EMP (Grade 1B).” (Caers, J., Paiva, B., Zamagni, E., Leleu, X., Bladé, J., Kristinsson, S. Y., Touzeau, C., Abildgaard, N., Terpos, E., Heusschen, R., Ocio, E., Delforge, M., Sezer, O., Beksac, M., Ludwig, H., Merlini, G., Moreau, P., Zweegman, S., Engelhardt, M., & Rosiñol, L., 2018).

LITERATURE:

Agarwal, A. et al. (2013) Evolving Role of FDG PET/CT in Multiple Myeloma Imaging and Management. American Journal of Roentgenology. 2013;200: 884-890

Caers, J., Paiva, B., Zamagni, E., Leleu, X., Bladé, J., Kristinsson, S. Y., Touzeau, C., Abildgaard, N., Terpos, E., Heusschen, R., Ocio, E., Delforge, M., Sezer, O., Beksac, M., Ludwig, H., Merlini, G., Moreau, P., Zweegman, S., Engelhardt, M., & Rosiñol, L. (2018). Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel. Journal of hematology & oncology, 11(1), 10. https://doi.org/10.1186/s13045-017-0549-1

Cavo M. et al. (2017). Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Lancet Oncol. 2017 Apr;18(4):e206-e217. doi: 10.1016/S1470-2045(17)30189-4.

NCCN Myeloma 2020

Sundaram, S., Driscoll, J., Fernandez-Ulloa, M., de Lima, M., & Malek, E. (2018). FDG PET imaging in multiple myeloma: implications for response assessments in clinical trials. American journal of nuclear medicine and molecular imaging, 8(6), 421427.

Usually 10 mm or smaller is the appropriate sze of melanomas for this procedure. However, the American Brachytherapy Society’s guidelines state: “..some patients with large melanomas (>10 mm height or >16 mm basal diameter) may also be candidates.”

Previous publications have found several tumor features to correlate with increased mortality, including larger size, anterior location, transscleral extension, growth through the Bruch membrane, optic nerve extension, lack of pigmentation, and histologic characteristics (eg, mitotic activity and cell type). Although metastases from the primary intraocular melanoma can first be detected years later, their highest incidence is in the first year after diagnosis. There are no studies showing effectiveness of any kind of followup. As yet, no effective treatment exists for metastatic uveal melanoma and it is not certain that eraly diagnosis affects ultimate prognosis. As such, surveillacne cannot be recommended.

Eye plaques are individually designed and constructed for each patient.  The precise distribution of radiation throughout the eye is calculated and used to determine the risks of secondary radiation complications. Because there si potential radiation exposure to others, laws regulate length of stay. Depending on the radiation laws of the state in which treatment is given, a patient may be required to stay in the hospital for the entire length of treatment(around 5 days).  In any case, it is reasonable precaution.

REFERENCES:
Boldt HC, Melia BM, Liu JC, Reynolds SM; Collaborative Ocular Melanoma Study Group.
I-125 brachytherapy for choroidal melanoma photographic and angiographic abnormalities: the Collaborative Ocular Melanoma Study: COMS Report No. 30.Ophthalmology. 2009 Jan;116(1):106-115.e1.

Thomas Riley O.D. et al, Treatment options for choroidal malignant melanoma: a case report featuring transpupillary thermotherapy Optometry – Journal of the American Optometric Association
Volume 75, Issue 2, February 2004, Pages 103-114

http://www.cancer.org.au/File/HealthProfessionals/ManagementofOcularmelanomasupplementarydocument2008.pdf

American Brachytherapy Society recommendations for brachytherapy of uveal melanomas.Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):544-55. .

I-125 brachytherapy for choroidal melanoma photographic and angiographic abnormalities: the Collaborative Ocular Melanoma Study: COMS Report No. 30.Boldt HC, Melia BM, Liu JC, Reynolds SM; Collaborative Ocular Melanoma Study Group.Ophthalmology. 2009 Jan;116(1):106-115.

Thomas Riley O.D. et al, Treatment options for choroidal malignant melanoma: a case report featuring transpupillary thermotherapy Optometry – Journal of the American Optometric Association
Volume 75, Issue 2, February 2004, Pages 103-114

Taxol also has activity. There are a number of phase II studies suggesting that it is active in melanoma. and was recently studied in combination with carboplatin. There are no phase III studies but the evidence is sound and, unless plan language specifically disqualifies phase II evidence, it should not be considered experimental.

Hersh E, O’Day S, Gonzalez R, et al.Multicenter phase II study of ABI-007 (Abraxane) in previously treated and chemotherapy naïve patients with metastatic malignant melanoma (MMM). Proceedings from the 23rd annual Chemotherapy Foundation Symposium. 2005. New York, NY. Abstract #27.

Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001).
The authors concluded that “although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.” However NCCN lists biochemotherapy (p.16) as an option.

A. A. Trinh
Current management of metastatic melanoma
Am. J. Health Syst. Pharm., December 15, 2008; 65(24_Supplement_9): S3 – S8.

Maja A. Hofmann , Wolfram Sterry , and Uwe Trefzer
Complex Combination Biochemotherapy Regimen in Advanced Metastatic Melanoma in a Non-intensive Care Unit: Toxicity or Benefit?
Jpn. J. Clin. Oncol. 37: 224-229.