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Patient

Patient. 64 yo caucasian woman noted to have elevated LFTs on annual P.E. Felt well. US Liver: 9 cm mass in right lobe of liver Biopsy: Melanoma, high mitotic rate PMH: Melanoma in situ removed from scalp 14 years earlier. Patient. PMH: Htn, osteoporosis

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Patient

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  1. Patient • 64 yo caucasian woman noted to have elevated LFTs on annual P.E. Felt well. • US Liver: 9 cm mass in right lobe of liver • Biopsy: Melanoma, high mitotic rate • PMH: Melanoma in situ removed from scalp 14 years earlier

  2. Patient • PMH: Htn, osteoporosis • FamHx: Fa had prostate cancer; died of other causes at age 89; mother died of natural causes at age 84. Two healthy children. No other malignancies in family • SH: Married. Choir director, pianist. Rare EtOH. Remote, brief tobacco use.

  3. Patient • ROS: Mild fatigue, mild dyspnea with exertion, dry cough, 3# wt loss • PE: Normal vital signs. Normal funduscopic exam. No adenopathy. Normal lung exam. Normal abdominal exam. Normal skin exam. • Labs: Alk Phos 160; AST 64; ALT 46

  4. Patient • CT chest: 3 nodules, largest 7 cm in right lung base • CT abdomen: 4 liver mets, largest 9 cm; bilateral adrenal mets, 7 cm • MRI brain: Normal

  5. Melanoma • 54,000 new cases in 2003; 7600 deaths • Incidence rising • Lifetime risk 1 in 82 for women; 1 in 58 for men • Ninth most common cancer; second in terms of loss of years of potential life • At presentation, 84% localized; 12% regional; 4% distant metastatic disease

  6. Risk Factors for Melanoma • Fair complexion with red/blonde hair • Living in Australia (3X US incidence) • >5 nevi >5mm or >50 nevi over 2mm • Dysplastic nevus syndrome • Intense, intermittent sun exposure (ages 10-19) • Family history of melanoma- 1/3 have mutation in p16 (INK4a =CDKN2A cyclin dependent kinase) on chromosome 9p21

  7. UV Light & Melanoma • Intense intermittent exposure does not give time for melanocytes to synthesize melanin to protect them from UV-B irradiation & subsequent DNA mutations • Melanocytes contain antiapoptotic proteins that inhibit cell death after intense UV exposure

  8. Genetic Basis of Hereditary Melanoma • CDKN2A gene on 9p21: p16 protein that prevents phosphorylation of RB protein which regulates transcription factors and cell division • Mutations in this tumor suppressor gene can lead to unregulated cell growth • Associated with increased risk of pancreatic ca • Association of this mutation with atypical moles is unclear • Genetic testing is commercially available

  9. Other proto-oncogene links • Mutation in B-raf protooncogene in 65% of melanomas • This gene product is similar to the tyrosine kinase targeted by Gleevec which has been very successful in treating CML and GIST • Inhibitors of this gene are undergoing testing (BAY 43-9006)

  10. Melanoma Staging • Stage 0: melanoma in situ (95% cure rate) • Stage IA: <1 mm, level II-III, no ulceration (88% • IB: <1mm, level IV-V or 1-2 mm, no ulcer(79%) • IIA: 1-2mm with ulcer; 2-4mm, no ulcer (64%) • IIC: >4mm, with ulcer (45%) • IIIA: Microscopic node met (55%) • IIIB: Micro2 or 3 regional nodes (37%) • IIIC: Macroscopic dz in 2 or 3 nodes (20%) • IV: Distant metastases (<5%)

  11. Melanoma • Breslow: thickness of the melanoma, most useful prognostic factor • Clark’s: level of penetration- (I)confined to epidermis, (II) into papillary dermis, (IV) into reticular dermis, (IV) into subcutaneous fat

  12. Melanoma • Prognostic factors for localized disease: Breslow’s thickness, ulceration, Clark’s level (only for <1mm), primary tumor site, gender • Ulceration: absence of an intact epidermis overlying the melanoma (microscopic) • Likelihood of regional nodal involvement rises with increasing tumor thickness

  13. Treatment of Melanoma • In situ: Excision • < 1mm deep, 1 cm excision margin • 1-2 mm deep, 1 to 2 cm margin • >2 mm deep, 2 cm margin • Consider sentinel node evaluation if >1mm deep with Clark level IV or ulcerated; node dissection only if positive

  14. Adjuvant Therapy in Melanoma • Most pts with in situ or early stage disease are cured by excision alone • For node negative patients with <4mm without ulceration or <1mm with ulceration, no proven benefit • Clinical trial or high dose interferon adjuvant therapy appropriate for >4mm without ulceration & >1mm with ulceration • Improved relapse free survival but no improvement in overall survival in these node negative patients

  15. Adjuvant Therapy in Melanoma • For node positive patients whose disease has been resected: Adjuvant high dose interferon prolongs survival (37% 5yr RFS vs 26% with no Rx) • 20 million U/m2 IV 5 d/wk x 4 wks then 10 million U/m2 SQ 3 d/wk x 48 wks

  16. Follow up after excision • Stage 0: skin exams for life • IA: exam q3 to 12 mos • IB-III: history, physical exam (attn to regional node area), skin exam q3-6 mos x 3 yrs, q4-12 mos x 2 years, then annually. CXR, LDH, CBC “amy be considered”. CTs and PET scans not recommended. • Lifetime risk for developing second melanoma: 5%

  17. Treatment of Metastatic Disease • Solitary site: resect (often wait 8 to 12 wks to be sure there are not many subclinical sites) • Multiple sites: clinical trial vs systemic therapy (Dacarbazine or Temazolamide or IL-2 or combination chemoimmunotherapy [Dacarbazine + Vinblastine+ cisPlatin + IL2 + Interferon)

  18. Treatment of Metastatic Disease • Biochemotherapy • Cisplatinum 20mg/m2 daily x 4d • Vinblastine 1.6 mg/m2 daily x 4d • DTIC 800 mg/m2 day 1 only • Interleukin-2 9 million U/m2/d x 4d CIV • Interferon alpha: 5 million U/m2 SQ qd x 5 • Repeat q3 wks

  19. Treatment of Metastatic Disease • Biochemotherapy • 21% Complete response • 43% partial response • Half of the patients with CR remained in remission >5 years. • This complete response rate is ~3X greater than with single agent chemo

  20. Other drugs • Thalidomide: active in myeloma, gliomas, renal cell cancer • Antiangiogenesis and anti-inflammatory properties; inhibits TNF • When given with temozolomide, 25% respond

  21. Vaccine therapy in melanoma • Rare spontaneous regression of metastatic melanoma suggests host immunity plays important role in control • CancerVax: whole cell vaccine from 3 melanoma cell lines helpful in initial trial • Melacine: immunizes with 3 peptides present in/on melanoma cells; studies ongoing • No vaccine has thus far improved survival in adjuvant or metastatic setting

  22. Patient Follow Up • 3 cycles of chemoimmunotherapy • Lung nodule decreased from 7 to 5 cm • No change in liver masses but LFTs normalized • Adrenal metastases decreased from 7 to 5 cm • Mesenteric adenopathy improved • Thalidomide + Temozolamide planned for 8 weeks

  23. Lessons • Even in situ lesions can spread • Don’t allow kids to get sunburns • Look at your patients skin (everywhere) during annual exam • Understanding the molecular biology may lead to better treatments

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