Download Resectable Stage IV Disease

CLINICAL PRACTICE GUIDELINE CU-009
Version 2
MANAGEMENT OF RESECTABLE STAGE IV
PRIMARY CUTANEOUS MELANOMA
WITHOUT NODAL DISEASE
Effective Date: February 2013
The recommendations contained in this guideline are a consensus of the Alberta Cutaneous Tumour Team and are a
synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature.
Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the
context of individual clinical circumstances to direct care.
CLINICAL PRACTICE GUIDELINE CU-009
Version 2
BACKGROUND
Stage IV metastatic melanoma is associated with a poor prognosis. Approximately four percent of all
patients with melanoma are diagnosed with metastatic (distant stage) disease and have a five-year
relative survival rate of 15.3%. 1 High level evidence regarding the best treatment modalities is still lacking
and there is little consensus on a standard approach for patients. 2 As such, there is a need for clinical
trials. The goal of care for patients with stage IV disease is improvement of survival time and palliation.
GUIDELINE QUESTION
What are the best treatment and management options for improving the survival and management of
symptoms in patients with resectable stage IV primary cutaneous melanoma?
DEVELOPMENT PANEL
This guideline was reviewed and endorsed by the Alberta Cutaneous Tumour Team. Members of the
Alberta Cutaneous Tumour Team include surgical oncologists, radiation oncologists, medical oncologists,
dermatologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working
group comprised of members from the Alberta Cutaneous Tumour Team and a Knowledge Management
Specialist from the Guideline Utilization Resource Unit. A detailed description of the methodology followed
during the guideline development process can be found in the Guideline Utilization Resource Unit
Handbook.
SEARCH STRATEGY
The MEDLINE, Cochrane, ASCO Abstracts and proceedings, and CANCERLIT databases were searched
(1985 through November 2009) for clinical trials. Search terms included: “resectable” or “stage IV” or
“advanced” or “metastatic” and “primary cutaneous melanoma” AND “surgery” or “metastectomy” or
“radiation therapy” or “chemotherapy” or “interleukin” or “interferon” or “taxane” or “supportive care” or
“palliative care.” A total of 82 clinical trials (limits: human and English language) were returned, from which
29 documents were selected. In addition, the National Guidelines Clearinghouse and individual guideline
organizations were searched for practice guidelines relevant to this topic.
For the 2013 update of the guideline, PubMed was searched for evidence on resectable stage IV
melanoma. The search term “melanoma” was used and results were limited to clinical trials, published
between December 2009 and January 2013. Citations were hand-searched for studies pertaining to intransit disease. Following a review of the evidence by the Alberta Cutaneous Tumour Team, no major
changes to the recommendations were made.
TARGET POPULATION
This guideline outlines treatment and management strategies for patients with resectable stage IV primary
cutaneous melanoma without nodal disease. Resectable disease is defined as melanoma metastasis that
is surgically completely removable with acceptable patient morbidity.
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RECOMMENDATIONS
For staging please refer to the Appendix.
Primary Treatment
•
Minimum work up should include CT scan of the head, chest, abdomen and pelvis, or CT PET scan,
or either of the above with brain MRI.
• Enrolment in a clinical trial is preferred.
• Resection
o Complete resection results in a 5% long-term complete remission or cure rate and may contribute
greatly to the quality of life.
o If primary chemotherapy is used, consideration should be given to subsequent resection.
Systemic Therapy
• Options include:
o Enrolment in a clinical trial (preferred)
o Observation
• Following resection, a number of systemic therapies have been investigated (e.g. interferon-alpha,
dacarbazine, temozolomide, high-dose interleukin-2, combination chemotherapy with cisplatin or
vinblastine with or without IL-1 and IFN-alpha, and paclitaxel alone or in combination with platinumbased chemotherapy); however, no convincing disease-free survival or overall survival benefits have
been documented.
• Following systemic therapy, scans should be repeated.
o If scans are negative for other disease, resect as necessary. If there is no further evidence of
disease, consider clinical trial OR interferon-alpha OR observation. If there is residual disease, treat
as disseminated (unresectable) disease (e.g. additional systemic therapy, surgical resection, or
radiation for palliative care and symptom management).
o If scans are positive for other disease, treat as disseminated (unresectable) disease.
DISCUSSION
These recommendations were developed based on evidence from clinical trials as well as existing
guidelines from the following developers: the National Comprehensive Cancer Network,2 the European
Society for Medical Oncology, 3 the German Cancer Society and German Dermatologic Society, 4 and
Cancer Care Ontario. 5,6,7
Chemoimmunotherapy
Overall, treatment with chemoimmunotherapy has not shown particularly promising results, both in terms
of response rate and survival, for patients with metastatic melanoma. Several trials have combined
interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) or both with various chemotherapy regimens (i.e.
cisplatin and dacarbazine, with or without carmustine or vinblastine). As compared to chemotherapy
alone, chemoimmunotherapy with IL-2 alone has achieved significantly higher overall response rates (33
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CLINICAL PRACTICE GUIDELINE CU-009
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to 48% for chemoimmunotherapy versus 21 to 25% for chemotherapy alone) in two phase III randomized
trials; however, this has not resulted in longer survival times (median 11 to 12 months for chemoimmunotherapy versus 9 to 12 months for chemotherapy alone). 8,9 The addition of IFN-alpha to this
regimen, versus chemotherapy alone, has also failed to improve overall response rates (19.5 to 34.3% for
chemoimmunotherapy versus 13.8 to 29.9% for chemotherapy alone) or overall survival times (median 9
to 12 months for chemoimmunotherapy versus 8.7 to 13 months for chemotherapy alone) in three phase
III randomized trials. 10,11,12 Similarly, the addition of IL-2 to a regimen of dacarbazine, cisplatin, and IFNalpha (versus chemotherapy and IFN-alpha alone) in a phase III randomized trial by the EORTC did not
improve overall response rate (22.8% versus 20.8%) or overall survival time (9 months in both arms). 13
Because chemoimmunotherapy is significantly more toxic (grade 3+ events) than chemotherapy,12 it
should be used only in select patients (i.e. those with good performance status (ECOG 0-1) and normal
LDH levels. 14
Complete Surgical Resection of Distant Sites
Most studies to examine the efficacy of complete resection on survival outcomes in patients with distant
metastases have been retrospective in design. These studies have shown that, as compared with
incomplete resection or palliative surgery, complete resection results in significantly longer overall survival
times (median 16 to 18.2 months for complete resection versus 12.5 months for palliative surgery/
incomplete resection and 5 to 5.9 months for non-surgical management) and 5-year survival rates (20 to
24% for complete resection versus 0 to 7% for palliative surgery/incomplete resection and 2% for nonsurgical management). 15,16,17 Predictors of survival include the following: presence of a solitary metastasis
(versus four or more metastases; P<.001) 18 and in the case of pulmonary metastases, the absence of
nodular histology (P=.033), the presence of a solitary metastasis (P<0.0005), a disease-free interval
greater than five years (P<.001), the absence of extra-thoracic/extra-pulmonary metastasis (P=0.01), and
performance of pulmonary metastasectomy (P<.001). 19,20 For patients with melanoma metastatic to the
lung, complete resection has been shown to result in a median survival time of 35 to 40 months (versus
13 months in patients who were not selected for surgery), with a five-year survival rate of 33%.20,21
To date, only one randomized phase III trial has been published. This study 22 randomized patients with
an intermediate-thickness primary cutaneous melanoma either to wide excision with postoperative
observation of regional lymph nodes plus lymphadenectomy if nodal relapse occurred or to wide excision
and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on
biopsy. Mean disease-free survival at five years was 78.3% in the group that received biopsy and 73.1%
in the observation group (P=0.009), while melanoma-specific survival at five years was similar between
the two groups (87.1% and 86.6%, respectively). A retrospective review of data from stage IV patients
(N=161) enrolled in the MSLT-1 trial compared outcomes associated with excision (i.e., metastectomy)
with or without SLNB and systemic therapy versus systemic therapy alone. Median survival was
significantly longer in the surgery group (15.8 months vs. 6.9 months; p<.0001), Subgroup analysis by
stage (i.e., M1a, M1b, and M1c) revealed a significantly greater benefit with surgery for M1a (>60 months
vs. 12.4 months; 4-year OS 69.3% vs. 0%, p=.0106) and M1c (15.0 months vs. 6.3 months; 4-year OS
10.5% vs. 4.6%, p=.0001) patients, but did not reach significance for M1b (17.9 months vs. 9.1 months; 4year OS 24.1% vs. 14.3%, p=.1143) patients. 23 A phase III randomized trial by Morton, et al. 24 is currently
recruiting patients with stage IV melanoma and assigning them to one of three arms: complete surgical
resection plus bacillus calmette-guerin as an immune adjuvant; complete surgical resection plus
observation; or best medical therapy (choice will be left to the individual investigator and may include
clinical trials of new agents or standard non-protocol treatments). Survival (progression-free, overall, and
melanoma-specific) will be assessed when 75, 150, and 225 events have occurred for each outcome.
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GLOSSARY OF ABBREVIATIONS
Acronym
IL-2
IFN
LDH
Description
interleukin-2
interferon
lactate dehydrogenase
DISSEMINATION
•
•
•
Present the guideline at the local and provincial tumour team meetings and weekly rounds.
Post the guideline on the Alberta Health Services website.
Send an electronic notification of the new guideline to all members of CancerControl Alberta.
MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2015. If critical new
evidence is brought forward before that time, however, the guideline working group members will revise
and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Cutaneous Tumour Team in the development of this guideline has
been voluntary and the authors have not been remunerated for their contributions. There was no direct
industry involvement in the development or dissemination of this guideline. CancerControl Alberta
recognizes that although industry support of research, education and other areas is necessary in order to
advance patient care, such support may lead to potential conflicts of interest. Some members of the
Alberta Cutaneous Tumour Team are involved in research funded by industry or have other such potential
conflicts of interest. However the developers of this guideline are satisfied it was developed in an
unbiased manner.
REFERENCES
1
Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto
A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2006,
National Cancer Institute. Bethseda, MD, http://seer.cancer.gov/csr/ 1975_2006/.
2
National Comprehensive Cancer Network. Melanoma Guidelines, 2009. URL: http://www.nccn.org/
professionals/physician_gls/PDF/melanoma.pdf
3
Dummer R, Hauschild A, Pentheroudakis G. Cutaneous malignant melanoma: Clinical Recommendations for
diagnosis, treatment and follow-up Annals of Oncology 20 (Supplement 4): iv129–iv131, 2009.
4
Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann R, Kettelhack C, Frerich B,
Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, and Kaufmann R. Evidence and
interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma. Melanoma
Research 2008, 18:61–67.
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5
Quirt I, Verma S, Petrella T, Bak K, Charette M, the Melanoma Disease Site Group. Temozolomide for the
Treatment of Metastatic Melanoma: A Clinical Practice Guideline. A Quality Initiative of the Program in Evidencebased Care (PEBC), Cancer Care Ontario (CCO); Report Date: March 20, 2006. Evidence-based Series #8-4:
Section 1. URL: http://www.cancercare.on.ca/common/pages/ UserFile.aspx?fileId=14220.
6
Petrella T, Quirt I, Verma S, Haynes A, Charette M, Bak K, the Melanoma Disease Site Group. Single-Agent
Interleukin-2 in the Treatment of Metastatic Melanoma: A Clinical Practice Guideline. A Quality Initiative of the
Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO). Developed by the Melanoma Disease Site
Group; Report Date: March 20, 2006. Evidence-based Series #8-5: Section 1. URL:
http://www.cancercare.on.ca/common/pages/ UserFile.aspx?fileId=14222.
7
Verma S, Petrella T, Hamm C, Bak K, Charette M, Melanoma Disease Site Group. Biochemotherapy for the
Treatment of Metastatic Malignant Melanoma: A Clinical Practice Guideline. A Quality Initiative of the Program in
Evidence-based Care (PEBC), Cancer Care Ontario (CCO); Report Date: April 30, 2007. Evidence-based Series #83: Section 1. URL: http://www.cancercare.on.ca/common/pages/ UserFile.aspx?fileId=14218.
8
Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ,
Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a
phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52.
9
Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha
SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the
same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann
Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9.
10
Atzpodien J, Neuber K, Kamanabrou D, Fluck M, Bröcker EB, Neumann C, Rünger TM, Schuler G, von den
Driesch P, Müller I, Paul E, Patzelt T, Reitz M. Combination chemotherapy with or without s.c. IL-2 and IFN-alpha:
results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy
Group (ACIMM). Br J Cancer. 2002 Jan 21;86(2):179-84.
11
Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P,
Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and
interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized
clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7.
12
Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative
Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine,
interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic
malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008
Dec 10;26(35):5748-54. Epub 2008 Nov 10.
13
Keilholz U, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, Thomas J, Proebstle TM, Schmittel A, Schadendorf D,
Velu T, Negrier S, Kleeberg U, Lehman F, Suciu S, Eggermont AM. Dacarbazine, cisplatin, and interferon-alfa-2b with
or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for
Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2005 Sep 20;23(27):6747-55.
14
Keilholz U, Martus P, Punt CJ, Kruit W, Mooser G, Schadendorf D, Liénard D, Dummer R, Koller J, Voit C,
Eggermont AM. Prognostic factors for survival and factors associated with long-term remission in patients with
advanced melanoma receiving cytokine-based treatments: second analysis of a randomised EORTC Melanoma
Group trial comparing interferon-alpha2a (IFNalpha) and interleukin 2 (IL-2) with or without cisplatin. Eur J Cancer.
2002 Jul;38(11):1501-11.
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15
Ollila DW, Hsueh EC, Stern SL, Morton DL. Metastasectomy for recurrent stage IV melanoma. J Surg Oncol. 1999
Aug;71(4):209-13.
16
Wood TF, DiFronzo LA, Rose DM, Haigh PI, Stern SL, Wanek L, Essner R, Morton DL. Does complete resection of
melanoma metastatic to solid intra-abdominal organs improve survival? Ann Surg Oncol. 2001 Sep;8(8):658-62.
17
Collinson FJ, Lam TK, Bruijn WM, de Wilt JH, Lamont M, Thompson JF, Kefford RF. Long-term survival and
occasional regression of distant melanoma metastases after adrenal metastasectomy. Ann Surg Oncol. 2008
Jun;15(6):1741-9. Epub 2008 Apr 1.
18
Essner R, Lee JH, Wanek LA, Itakura H, Morton DL. Contemporary surgical treatment of advanced-stage
melanoma. Arch Surg. 2004 Sep;139(9):961-6; discussion 966-7.
19
Petersen RP, Hanish SI, Haney JC, Miller CC 3rd, Burfeind WR Jr, Tyler DS, Seigler HF, Wolfe W, D'Amico TA,
Harpole DH Jr. Improved survival with pulmonary metastasectomy: an analysis of 1720 patients with pulmonary
metastatic melanoma. J Thorac Cardiovasc Surg. 2007 Jan;133(1):104-10.
20
Neuman HB, Patel A, Hanlon C, Wolchok JD, Houghton AN, Coit DG. Stage-IV melanoma and pulmonary
metastases: factors predictive of survival. Ann Surg Oncol. 2007 Oct;14(10):2847-53. Epub 2007 Aug 7.
21
Andrews S, Robinson L, Cantor A, DeConti RC. Survival after surgical resection of isolated pulmonary metastases
from malignant melanoma. Cancer Control. 2006 Jul;13(3):218-23.
22
Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ,
Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ; MSLT Group. Sentinel-node biopsy or nodal
observation in melanoma. N Engl J Med. 2006 Sep 28;355(13):1307-17.
23
Howard JH, Thompson JF, Mozzillo N, Nieweg OE, Hoekstra HJ, Roses DF, et al. Metastasectomy for distant
metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Ann
Surg Oncol. 2012 Aug;19(8):2547-55.
24
Morton DL and Faries M. Stage IV Surgery Versus Best Medical Therapy (STG4SURG). ClinicalTrials.gov
identifier: NCT01013623. URL: http://clinicaltrials.gov/ct2/show/
NCT01013623?term=Morton&cond=%22Melanoma%22&rank=4.
24
Balch, C.M. et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27(36):
6199-206.
APPENDIX
AJCC 2009 (7th Edition) Anatomic Stage Groupings for Cutaneous Melanoma
Clinical Staging a
24
Pathologic Staging b
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0
IA
IB
T
N
M
Tis
T1a
T1b
T2a
T2b
T3a
T3b
T4a
T4b
Any T
N0
N0
N0
M0
M0
M0
T
N
M
0
IA
IB
5-year Survival
(%)
100%
95%
90%
Tis
N0
M0
T1a
N0
M0
T1b
N0
M0
T2a
IIA
N0
M0
IIA
T2b
N0
M0
78%
T3a
IIB
N0
M0
IIB
T3b
N0
M0
65%
T4a
IIC
N0
M0
IIC
T4b
N0
M0
45%
III
N > N0
M0
IIIA
T1-4a
N1a
M0
66%
T1-4a
N2a
T1-4b
N1a
50%
IIIB
T1-4b
N2a
T1-4a
N1b
T1-4a
N2b
T1-4a
N2c
T1-4b
N1b
27%
IIIC
T1-4b
N2b
T1-4b
N2c
Any T
N3
IV
Any T
Any N
M1
IV
Any T
Any N
M1
13%
a
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for
metastases. By convention, it should be used after complete excision of the primary melanoma with
clinical assessment for regional and distant metastases.
b
Pathologic staging includes microstaging of the primary melanoma and pathologic information about the
regional lymph nodes after partial (i.e., sentinel node biopsy) or complete lymphadenectomy. Pathologic
stage 0 or IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.
th
AJCC 2009 (7 Edition) TNM Staging Categories for Cutaneous Melanoma
T
Tis
Thickness (mm)
NA
24
Ulceration Status/Mitoses
NA
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T1
≤ 1.00
T2
1.01-2.00
T3
2.01-4.00
T4
> 4.00
N
N0
N1
Number of Metastatic Nodes
0
1
N2
2-3
a: without ulceration and mitosis < 1/mm2
2
b: with ulceration or mitoses ≥ 1/mm
a: without ulceration
b: with ulceration
a: without ulceration
b: with ulceration
a: without ulceration
b: with ulceration
Nodal Metastatic Burden
NA
a: micrometastasisa
b: macrometastaisb
a: micrometastasisa
b: macrometastaisb
c: in transit metastases/satellites without metastatic
nodes
N3
4+ metastatic nodes, or matted
nodes, or in transit metastases/
satellites with metastatic nodes
M
Site
Serum LDH (lactate dehydrogenase)
M0
No distant metastases
not applicable
M1a
Distant skin, subcutaneous or nodal metastases
Normal
M1b
Lung metastases
Normal
M1c
All other visceral metastases
Normal
Any distant metastases
Elevated
a
Micrometastases are diagnosed after sentinel lymph node biopsy.
b
Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.
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