Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV.

0.22 MB·English

by  Cybulska-Stopa, Bozena

Wspolczesna Onkol 2012; 16 (6): 532–545 DOI: 10.5114/wo.2012.32487
Original paper
AAiimm ooff tthhee ssttuuddyy:: The incidence of me la- Results of systemic treatment of
noma is increasing rapidly worldwide.
Metastatic melanoma is still an incurable cutaneous melanoma in inoperable
disease, although an era of new drugs
is approaching. Current methods to pre-
stage III and IV
dict outcomes in patients with advanced,
metastatic melanoma are limited. Aret-
rospective analysis of acontemporary
large group of advanced melanomas was
performed to determine clinical prog-
nostic factors that accurately predict
survival in patients with metastatic Bożena Cybulska-Stopa1, Marta Skoczek2, Marek Ziobro1, Tomasz Świtaj3,
melanoma before the era of new tar- Sławomir Falkowski3, Tadeusz Morysiński3, Marcin Hetnał4, Ida Cedrych1,
geted/immunological therapy. Piotr Rutkowski3
MMaatteerriiaall aanndd mmeetthhooddss:: The retrospective
analysis of 427 patients with metasta-
1Department of Systemic and Generalized Malignancies, Centre of Oncology,
tic melanoma treated between 1995 and
Maria Skłodowska-Curie Memorial Institute Cracow Branch, Poland
2005 at two reference oncological cen-
2Department of Chemiotherapy, Szpital Specjalistyczny JP2, Cracow, Poland
tres.
3Klinika Mięsaków Tkanek Miękkich iKości oraz Czerniaków, Centre of Oncology,
RReessuullttss:: The median overall survival
Maria Skłodowska-Curie Memorial Institute, Warsaw, Poland
time (OS) was 7.1 months (95% CI: 6.7–
4Department of Radiotherapy, Centre of Oncology, Maria Skłodowska-Curie Memorial
7.9) and the 1-year, 2-year and 5-year
Institute Cracow Branch, Poland
survival rates were 32.3%; 12.5%; 3.9%,
respectively. The median progression-
free survival time (PFS) after the first line
of treatment was 3.5 months (95% CI:
3.1–3.8). There were 19.1% objective
Introduction
responses (CR – 6.1%, PR – 13.0%) and
SD – 45.5% after the first line of thera- Skin melanomas are relatively rare neoplasms; the standardised incidence
py. The most common adverse events rate in Poland is about 4/100 000 [1]. However, in recent years there has been
were anaemia, neutropenia, thrombo-
asudden growth in the incidence. It is estimated that in the years 1982–2002
cytopenia, nausea and vomiting.
the morbidity increased three-fold [2].
In multivariate analyses: PS (perfor-
Prognosis in cutaneous melanoma depends strongly on the primary stage
mance status) 0–1, normal serum levels
of lactate dehydrogenase (LDH) and according to TNM; thus 5- and 10-year survival rates in stage IA are 97% and
aspartate transaminase (AspAT), older 93% respectively, while in stage IIIC they are only 53% and 39%. Stage IV –
age in women, palliative surgical treat- metastasis to distant organs – is characterised by the worst prognosis, and
ment and palliative radiotherapy, type
1-year survival is 62% for M1a, 53% for M1b and 33% for M1c [3].
of the first line of therapy (DTIC), and
Despite advances in diagnosis and treatment, the inoperable stage III and
metastatic melanoma of unknown pri-
stage IV melanoma remains an incurable disease, and the median survival time
mary site were independent positive pre-
dictors for survival. in those stages is 6–11 months [4–7]. For this reason numerous patients with
CCoonncclluussiioonnss::The survival rate of patients inoperable skin melanoma are still being included in clinical trials with vari-
with metastatic melanoma has not ous chemotherapy regimens, immunotherapy and targeted therapies, which
changed significantly over the last years.
give hope for changing the results of treatment in the near future. So far the
We identified aset of independent pos-
greatest advance in the treatment of those patients has been connected with
itive predictors for OS treated with sys-
introduction of monoclonal anti-CTLA-4 antibodies, which have been registered
temic therapy. DTIC still may be useful
in treatment of patients in agood gen- in Europe for the treatment of advanced (unresectable or metastatic) me la-
eral condition and with normal serum noma in adults after previous therapy failure, but they lack predictive factors
levels of LDH. Because the results of for response to treatment with simultaneous considerable side effects of this
treatment of metastatic melanoma are
therapy. The second promising treatment is molecular-targeted therapy with
still not satisfactory, the majority of
tyrosine kinase inhibitors acting on BRAF or KIT protein mutations pathways.
patients should be treated within
Currently there is no consensus regarding the role of systemic treatment in
prospective, randomized clinical trials.
this group of patients, and in the era of novel treatment methods and still numer-
KKeeyy wwoorrddss:: melanoma, metastases, ous group of patients treated only symptomatically, it is vital to define the results
therapy, outcomes, prognostic factors. and potential role of chemotherapy in treatment of advanced, unresectable
skin melanoma. Melanomas are cancers with low chemosensitivity, and the
benefit from the chemotherapy is confined to selected subgroups of patients
[8–10]. The most important drug used in monotherapy and as part of multidrug
regimens is dacarbazine (DTIC), the only chemotherapeutic to have been
approved by the FDA for the treatment of melanoma. The objective response
rate to treatment with DTIC, after analysing 23 randomised, controlled clin-
ical trials, was found to be 15.3% [11]. The impact of dacarbazine on overall
survival was not evaluated, because no clinical trials comparing dacarbazine
with placebo have been conducted [12]. The next group of chemotherapeu-
553333
Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV
tics is vinca alkaloids: vindesine, vinblastine, used mostly with ical parameters such as stage of the disease (stage III or IV),
other chemotherapeutics, taxanes (mostly paclitaxel), and affected sites, performance status, menopausal status in
nitrosourea derivatives: carmustine (BCNU), lomustine women and biochemical parameters was performed when
(CCNU) and fotemustine. Their activity in monotherapy is sim- diagnosing inoperable metastasis or disqualifying from
ilar to that of dacarbazine, but unfortunately they are surgical treatment. For each patient not only basic epi-
characterised by greater toxicity, especially myelosuppres- demiological information was recorded, such as age, sex, and
sion. Although fotemustine is not registered by the FDA, it the date of histological diagnosis, but also the date of dis-
is available in Europe and used for treating melanoma, es - semination of the disease (or qualifying changes as inop-
pecially in the case of brain metastases. Immunotherapy with erable) and date of possible death.
interferon α-2b and interleukin 2 plays an important role in The disease stage was assessed on the basis of the med-
the treatment of melanoma. High dose interleukin 2 (HD ical reports of clinical and imaging examinations (chest/bone
IL-2) was approved by the FDA in 1998 for the treatment of X-ray, bone scan, ultrasonographic tests and CT/MR scans).
patients with metastatic melanoma. The basis for registra- No PET examinations were performed. In single cases addi-
tion was achieving durable complete responses correlating tional data were provided by histological and cytological tests
with prolonged overall survival in asmall group of patients. of the material obtained during diagnostic procedures
Because of the high percentage of severe adverse events that (trepano-biopsy, cerebrospinal fluid collection, palliative
can occur during HD IL-2 treatment, such immunotherapy resections). In the case of metastasis from an unknown pri-
is recommended for carefully selected younger patients, in mary melanoma, the date of diagnosis was treated as the
good general condition [14, 15]. date of metastasis.
Because of an opinion that a combination of a few Any form of systemic therapy used by an oncologist which
chemotherapeutics may increase the rate of objective is not standard symptomatic/supportive care was taken as
responses to the treatment and lengthen overall survival, systemic treatment (analgesics, treatment of non-oncological
research on multidrug chemotherapy was carried out. How- comorbidities, typical symptomatic treatments, e.g. admin-
ever, no expected results were found, and the increase in istering dexamethasone in brain oedema, were excluded).
objective responses to the treatment did not result in over- Some forms of treatment with questionable efficacy, e.g. hor-
all survival lengthening [16–19]. Similar results were acquired monal therapy with tamoxifen and medroxyprogesterone,
by adding interleukin 2 and/or interferon α-2b to the mul- were classified as systemic treatment. This is justified by the
tidrug schemes (biochemotherapy). It increased the objec- fact that, for the time being, there are no data from ran-
tive responses to the treatment with asimultaneous con- domized clinical trials confirming the influence of any form
siderable increase in treatment toxicity, without asignificant of systemic treatments including dacarbazine (and exclud-
impact on overall survival [20–22]. ing anti-CTLA4 and BRAF inhibitors) on overall survival in the
Therefore, research regarding factors that predict the clin- entire group of patients with metastatic melanoma. The fol-
ical course of advanced melanomas and their response to lowing active drugs were used in monotherapy or in multi -
systemic treatment is being carried out in order to establish drug regimens: dacarbazine (DTIC), carmustine (BCNU), vin-
optimal criteria for selecting patients for the treatment. It is cristine, vinblastine, cisplatin, carboplatin, cyclophosphamide,
vital to fully determine the set of prognostic and predictive dactinomycin, methotrexate, 5-fluorouracil, bleomycin,
factors within the group of melanoma patients with unre- temozolomide, paclitaxel, tamoxifen, medroxyprogesterone,
sectable metastases to regional lymph nodes/in-transit interleukin-2, interferon α-2b.
metastases or metastases to distant organs treated with clas- The kind of systemic treatment was classified in one of
sical therapeutic methods, taking into consideration the the following categories [15, 17, 18, 41]: DTIC monotherapy,
approaching introduction of drugs with new mechanisms of multidrug chemotherapy with DTIC, multidrug chemother-
action which will change the landscape of advanced apy without DTIC, immunotherapy, hormonal therapy, or oth-
melanoma therapy. er monotherapy (without DTIC). Single cases of chemoim-
munotherapy (chemotherapy + interleukin-2) were classified
Material and methods as multidrug chemotherapy with respect to simultaneous-
We performed aretrospective analysis on 427 patients ly used cytostatics (multidrug chemotherapy with or with-
with inoperable stage III and IV melanoma, aged 51.4 on aver- out DTIC), because it would be necessary to create an addi-
age (19–82 years), comprising 236 (55.27%) men and 191 tional (small) category of treatment.
(44.73%) women who started systemic treatment in the Response to treatment was evaluated according to
Department of Systemic and Generalized Malignancies of RECIST – Response Evaluation Criteria in Solid Tumors v. 1.0.
the Centre of Oncology (Cracow Branch) – 177 (41.45%) The assessment of toxicity in all cases was based on CTCAE
patients and in the Department of Soft Tissue/Bone Sarcoma – Common Terminology Criteria for Adverse Events v. 3.0. In
and Melanoma of the Centre of Oncology (Warsaw) – 250 all cases adverse symptoms from respective organs and sys-
(58.55%) patients in the years 1995–2005. The analysed group tems are scored on afour-point scale (1–4). All forms of exci-
included only patients with histologically confirmed diagno- sion of metastatic lesions in patients with distant metasta-
sis of skin melanoma. Patients with ocular and mucosal sis of melanoma were considered as palliative resection. Those
melanoma were not included in the analysis [8, 23–25]. Com- were most commonly resections within soft tissues, brain,
plete information on tested clinical factors, survival and treat- gastrointestinal tract, and in a few cases resections of
ment method was gathered. Evaluation of time-varying clin- metastatic changes from lungs or liver. Radiotherapy of dis-
553344
współczesna onkologia/contemporary oncology
tant metastases (mainly in central nervous system and skele- with the log-rank test, and in the case of non-parallel curves
tal system) were considered palliative radiotherapy. the p values for Wilcoxon’s test were also given (differences
in the initial parts of acurve). Independent prognostic fac-
Statistical analysis tors having an influence on the survival time were searched
for with multivariate analysis using the Cox proportional haz-
Descriptive analysis was performed; averages and standard
deviations, and medians and values for numerical variables ards regression model including factors with ap-value ≤ 0.1
in univariate analysis. None of the tested factors diverged sub-
as well as category rate distribution for categorical variables
stantially from the assumption of parallel curves. Both sta-
were given. For comparison of distribution of categorical vari-
tistically significant factors and those which changed the oth-
ables between groups the chi-square test was used, and in
er parameters’ values were included within the model using
smaller groups in four-field tables, Fisher’s exact test. The over-
the backward selection method. Also statistically significant
all survival (OS) was counted from the date of diagnosis of unre-
interactions between the variables were included in the mod-
sectable metastases in stage III/IV to the date of death, and
el. Differences were considered statistically significant if
in patients who lived after the end of the test (censored obser-
p-values were < 0.05. The statistical analysis was per-
vations) to the date of the last follow-up. The date of start-
formed with SAS v. 9.1 software.
ing the first cycle of the next treatment was taken as the start-
ing date to calculate the time to progression after every line
Results
of therapy. The date of progression was adopted as the end-
ing date (uncensored observations), or, if not exactly known, In the entire analysed group the median overall survival
the date of introducing the next line of treatment or the date (OS) was 7.1 months (95% CI: 6.7–7.9); 1-, 2-, and 5-year OS
of the patient’s death. In censored observations (patients who rates were 32.3%, 12.5%, and 3.9%, respectively (Fig. 1).
did not die and had no features of progression during the last
visit) the date of the last follow-up is the end date. Univariate analysis for OS
The survival curves, the survival time median with con- The results of the univariate analysis for individual vari-
fidence interval and 6-month, 1-, 2-, and 3-year survivals were ables are shown in Table 1. The variables having asignificant
estimated by Kaplan-Meier’s method. Because of the low rate impact on OS were: sex, age at the time of diagnosis of unre-
of patients who survived and were observed for alonger time, sectable metastases in women, initial activity of lactate dehy-
no rate of patients who survived over 3 years was assessed drogenase (LDH) (Fig. 2), AlAT and AspAT in serum, initial num-
for overall survival estimations, as well as patients who sur- ber of affected sites (organs), metastases in lungs and liver,
vived over 2 years in case of progression after successive lines performance status (Fig. 3), disease stage according to the
of treatment. AJCC/UICC (American Joint Committee on Cancer/Interna-
The univariate analysis of factors having an influence on tional Union Against Cancer) staging system, type of first-
overall survival was performed by comparing survival curves line treatment, response to first-line treatment (Fig. 4), num-
1.0
0.9
0.8
0.7
e 0.6
at
val r 0.5
vi
ur
s 0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72
month from disqualification date
overall survival curve
95% confidence interval
(observations censored)
FFiigg.. 11.. OS curve for the whole group of patients diagnosed with advanced melanoma (n= 427)
553355
Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV
TTaabbllee 11..Results of single-factor analysis with estimated number of surviving patients depending on variable option
TTeesstteedd vvaarriiaabbllee VVaarriiaabbllee ooppttiioonn NN MMeeddiiaann 9955%% CCII 11--yyeeaarr 22--yyeeaarr 55--yyeeaarr PPvvaalluuee
iinn mmoonntthhss ffoorr mmeeddiiaann ssuurrvviivvaall [[%%]] ssuurrvviivvaall [[%%]] ssuurrvviivvaallss [[%%]] ((ssiiggnniiffiiccaannccee
ooff ddiiffffeerreennccee ffoorr
aallll ssuurrvviivvaall ccuurrvveess))
whole group 427 7.1 6.7–7.9 32.3 12.5 3.9
center Cracow 177 7.1 6.7–9.0 30.5 10.7 3.2
0.9702
Warsaw 250 7.1 6.3–8.2 33.6 13.8 4.4
sseexx ffeemmaallee 119911 1100 77..88––1122..77 4444..55 2200..00 66..66
<< 00..00000011
mmaallee 223366 66..55 55..88––77..00 2222..55 66..55 11..77
menopause yes 85 12.7 8.8–15.1 51.8 24.7 8.6
0.0812
no 105 7.8 6.4–10.2 38.1 15.4 4.9
age at removing primary < 30 35 6.1 3.4–9.2 28.6 8.6 ne
0.357
change (in years) 30+ 392 7.1 6.7–8.0 32.7 12.9 4.0
age at disqualification < 30 34 5.4 3.3–9.1 26.5 5.9 ne 0.2049 (log-rank)
from radical treatment or 30+ 393 7.1 6.7–8.0 32.8 13.1 4.0 0.0357
distant metastasis (in years) (Wilcoxon)
aaggee aatt ddiissqquuaalliiffiiccaattiioonn << 3300 1155 55..77 33..33––77..88 2200 nnee nnee
ffrroomm rraaddiiccaall ttrreeaattmmeenntt 3300++ 117766 1100..66 88..22––1122..99 4466..66 2211..77 77..11
00..00002299
oorr ddiissttaanntt mmeettaassttaassiiss ––
aammoonngg ffeemmaalleess ((iinn yyeeaarrss))
age at disqualification from < 30 34 5.4 3.3–9.1 26.5 5.9 ne
radical treatment or distant 30–< 50 159 6.4 5.6–7.2 27.7 10.7 1.3 0.0589
metastasis (in years) 50+ 234 7.8 7.1–9.6 36.3 14.7 5.7
aaggee aatt ddiissqquuaalliiffiiccaattiioonn ffrroomm << 3300 1155 55..77 33..33––77..88 2200..00 nnee nnee
rraaddiiccaall ttrreeaattmmeenntt oorr ddiissttaanntt 3300––<< 5500 7788 77..66 66..00––1100..66 3377..22 1133..77 22..77 00..00000088
mmeettaassttaassiiss –– aammoonngg ffeemmaalleess 5500 ++ 9988 1122..88 1100..44––1155..66 5544..11 2288..11 1100..66
((iinn yyeeaarrss))
time from diagnosis to < 36 339 6.8 6.3–7.8 30.4 10.9 3.9 0.1289
metastasis (in months) ≥36 88 8.4 7.2–11.3 39.8 18.8 3.9 (log-rank)
0.0490 (Wilcoxon)
disease duration before after primary 124 6.8 5.7–9.3 31.5 15.3 3.0
diagnosis of melanoma source excision
metastasis after regional lymph 277 7.1 6.5–7.8 31.0 10.4 3.7 0.114
node metastasis
metastasis during 26 12.4 7.5–19.1 50.0 21.6 ne
diagnosis
metastasis during no 401 7 6.5–7.8 31.2 11.9 3.6
0.0599
diagnosis yes 26 12.4 7.5–19.1 50.0 21.6 ne
metastasis from no 398 7 6.4–7.8 31.4 12.0 3.6
0.0935
unknown primary source yes 29 10.8 7.1–18.8 44.8 19.4 ne
EECCOOGG 00 119944 99 77..88––1100..00 3388..11 1177..22 44..99
11 117777 66..77 55..66––77..88 3311..11 88..66 22..77
<< 00..00000011
22 4499 44..66 22..99––66..99 1166..33 99..77 nnee
33 66 11..88 11..44––44..33 nnee nnee nnee
bbaasseelliinnee LLDDHH aaccttiivviittyy nnoorrmmaall 119911 99..66 77..66––1111..55 4422..99 1177..99 66..44
<< 00..00000011
iinn sseerruumm eelleevvaatteedd 114455 55..22 44..22––66..44 1199..33 55..77 11..44
bbaasseelliinnee AAllAATT aaccttiivviittyy nnoorrmmaall 228899 77..44 66..77––99..11 3344..66 1133..33 55..11
00..000022
iinn sseerruumm eelleevvaatteedd 6644 55..66 44..33––77..22 2211..99 77..88 nnee
bbaasseelliinnee AAssppAATT aaccttiivviittyy nnoorrmmaall 330011 77..55 66..88––99..11 3355..55 1133..88 44..99
<< 00..00000011
iinn sseerruumm eelleevvaatteedd 5533 55..11 33..77––77..00 1133..22 33..88 nnee
baseline HBG level normal 312 7.3 6.7–9.0 36.5 13.9 4.8
0.1557
reduced 68 6.5 5.7–8.5 20.6 5.9 2.9
nnuummbbeerr ooff iinnvvoollvveedd llooccaa-- 11 117722 77..99 77..00––99..66 3344..99 1155..77 66..11
ttiioonnss ((oorrggaannss)) aatt tthhee ttiimmee 22 221133 66..77 55..55––77..33 3300..00 99..55 nnee 00..00333355
ooff ddiissqquuaalliiffiiccaattiioonn ffrroomm 33 oorr >> 33 3388 88..66 55..66––1111..33 3344..22 1155..88 22..66
rraaddiiccaall ttrreeaattmmeenntt
553366
współczesna onkologia/contemporary oncology
TTaabbllee 11..cont.
TTeesstteedd vvaarriiaabbllee VVaarriiaabbllee ooppttiioonn NN MMeeddiiaann 9955%% CCII 11--yyeeaarr 22--yyeeaarr 55--yyeeaarr PPvvaalluuee
iinn mmoonntthhss ffoorr mmeeddiiaann ssuurrvviivvaall [[%%]] ssuurrvviivvaall [[%%]] ssuurrvviivvaallss [[%%]] ((ssiiggnniiffiiccaannccee
ooff ddiiffffeerreennccee ffoorr
aallll ssuurrvviivvaall ccuurrvveess))
llooccaattiioonn ooff mmeettaassttaassiiss soft tissuesno 232 6.9 6.3–7.8 28.0 9.6 3.2 0.0902
aatt tthhee mmoommeenntt ooff ddiissqquu-- yes 190 7.2 6.5–9.1 35.8 15.3 4.8
aalliiffiiccaattiioonn ffrroomm rraaddiiccaall nodes no 273 7.1 6.4–7.9 30.0 12.5 3.9 0.5814
ttrreeaattmmeenntt yes 149 7.1 6.4–9.1 34.2 11.6 4.1
lluunnggss nnoo 224499 77..88 77..00––99..55 3366..55 1155..44 55..11 00..00002299
yyeess 117733 66..33 55..22––77..11 2244..33 77..55 22..55
lliivveerr nnoo 333399 77..11 66..77––88..33 3333..66 1122..88 44..77 00..00224444
yyeess 8833 66..22 44..66––77..99 2222..99 99..66 nnee
bones no 399 7 6.7–7.8 31.6 12.1 4.2 0.4725
yes 23 7.2 2.9–9.8 30.4 ne ne
CNS no 400 7.1 6.6–7.8 31.5 12.2 4.2 0.8925
yes 22 7.8 4.8–13.1 31.8 11.4 ne
other no 341 7.1 6.7–7.9 31.4 12.1 3.8 0.9380
yes 81 6.2 4.9–9.6 32.5 13.5 ne
lliivveerr//lluunnggss nnoo 118888 88..44 77..11––1100..77 3399..44 1166..77 66..22 << 00..00000011
oonnllyy 221122 66..77 55..77––77..88 2266..99 99..00 22..33
iinn oonnee
llooccaattiioonn
iinn bbootthh 2222 44..22 22..55––77..22 99..11 nnee nnee
llooccaattiioonnss
ssttaaggee aaccccoorrddiinngg ttoo 33 2244 1122..66 77..11––2222..66 5544..22 2255 nnee
AAJJCCCC//UUIICCCC 44aa 3366 1133..77 99..22––2222..66 5588..33 3300..66 1111..11
00..00002299
44bb 4411 77..11 55..88––1100..55 2266..88 88..00 nnee
44cc 331111 66..77 55..99––77..44 2288..99 1100..33 33..00
ssttaaggee aaccccoorrddiinngg ttoo 33 2244 1122..66 77..11––2222..66 5544..22 2255..00 nnee
00..00004499
AAJJCCCC//UUIICCCC 44 336644 66..99 66..33––77..55 2299..99 1111..11 33..22
ffiirrsstt--lliinnee ttrreeaattmmeenntt DDTTIICC 8800 99..88 77..44––1133..00 4433..88 2222..55 1111..66
((ddeettaaiilleedd ddiivviissiioonn)) mmuullttiiddrruugg wwiitthh DDTTIICC 330022 66..77 55..99––77..44 2299..11 99..99 22..44
mmuullttiiddrruugg wwiitthhoouutt DDTTIICC 99 66 33..99––99..00 1111..11 nnee nnee
00..00000044
iimmmmuunnootthheerraappyy 44 1199..66 1100..77––2222..55 7755 nnee nnee
hhoorrmmoonnaall tthheerraappyy 2255 99..33 66..22––1155..66 4400 2200..00 nnee
ootthheerr mmoonnootthheerraappyy 77 44..11 11..44––77..11 nnee nnee nnee
first-line treatment chemotherapy 398 7.1 6.6–7.8 31.7 12.2 4.3
(overall division) immunotherapy 4 19.6 10.7–22.5 75 ne ne 0.3832
hormonal therapy 25 9.3 6.2–15.6 40 20.0 ne
ffiirrsstt--lliinnee ttrreeaattmmeenntt rreessppoonnssee PPDD 115500 44..11 33..77––44..66 99..33 22..77 00..66
SSDD 119933 77..99 77..33––99..99 3377..33 1133..99 22..11 << 00..00000011
CCRR ++ PPRR 8822 1177 1122..99––1188..77 6622..22 2277..77 1144..22))
nnuummbbeerr ooff lliinneess ooff ttrreeaattmmeenntt 11 225511 55..77 55..11––66..44 2222..77 1111..55 44..8800
22 112266 88..22 77..11––1100..55 3388..11 88..33 nnee
<< 00..00000011
33 3366 1133..99 1100..55––1188..00 6611..11 2255..00 nnee
44++ 1144 1177..22 1122..99––3311..99 8855..77 nnee nnee
nnuummbbeerr ooff ddrruuggss uusseedd 11 111166 99..44 77..44––1122..55 4422..22 2200..22 77..77
iinn tthhee ffiirrsstt--lliinnee ttrreeaattmmeenntt 22––33 8822 66..33 44..88––77..99 2266..88 22..66 nnee 00..00000022
rreeggiimmeenn 44++ 222299 66..77 55..88––77..88 2299..33 1122..11 nnee
ppaalllliiaattiivvee rraaddiiootthheerraappyy nnoo 228822 66..77 55..99––77..11 2266..66 99..22 nnee
00..00002266
yyeess 113399 99..88 77..55––1122..00 4422..44 1188..33 44..00
ppaalllliiaattiivvee rreesseeccttiioonnss nnoo 334422 66..77 66..00––77..11 2277..88 99..77 22..99
yyeess 7777 1122..55 99..22––1144..88 5500..66 2244..00 77..66 00..00000044
ddaaccaarrbbaazziinnee iinn mmoonnootthheerraappyy 11000000 mmgg ii..vv.. 4499 77..44 66..77––1100..55 3322..77 1144..33 77..77
11 ddaayy eevveerryy 33 ww
225500 mmgg ii..vv.. 3311 1177..33 1100..00––2255..55 6644..55 3355..55 1177..22 00..00330099
11––55 ddaayyss eevveerryy
44 ww
553377
Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV
1.0
0.9
0.8
0.7
e 0.6
at
val r 0.5
vi
ur
s 0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72
month from disqualification date
LLDDHH lleevveell:: normal
elevated
observations censored
observations censored
FFiigg.. 22..OS curves in relation to baseline LDH activity in serum (p< 0.0001)
1.0
0.9
0.8
0.7
e 0.6
at
val r 0.5
vi
ur
s 0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72
month from disqualification date from radical therapy
OOvveerraallll ccoonnddiittiioonn aaccccoorrddiinngg ttoo EECCOOGG:: 0 (observations censored)
1 (observations censored)
2 or more (observations censored)
FFiigg.. 33..OS curves depending on patient’s general condition (ECOG) (p< 0.0001)
553388
współczesna onkologia/contemporary oncology
1.0
0.9
0.8
0.7
e 0.6
at
val r 0.5
vi
ur
s 0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72
month from disqualification date from radical therapy
RReessppoonnssee ttoo ffiirrsstt--lliinnee cchheemmootthheerraappyy::
PD (observations censored)
CP + PR (observations censored)
SD (observations censored)
FFiigg.. 44..OS curve in relation to first-line treatment response (p< 0.0001)
1.0
0.9
0.8
e
al rat 0.7
v
vi 0.6
ur
s
e
e 0.5
n-fr
sio 0.4
s
e
gr
o 0.3
pr
0.2
0.1
0.0
0 12 24 36 48 60 72
time from starting line of treatment (months)
LLiinnee ooff ttrreeaattmmeenntt:: 1 (observations censored)
2 (observations censored)
3(observations censored)
4 (observations censored)
FFiigg.. 55..Curves depicting PFS after successive lines of treatment
553399
Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV
TTaabbllee 22.. Responses to treatment in successive lines
TTyyppee ooff ttrreeaattmmeenntt CCRR PPRR SSDD** PPDD NNoo ddaattaa AAllll
NN((%%)) NN((%%)) NN((%%)) NN((%%)) NN NN
RReessppoonnsseess ttoo ffiirrsstt--lliinnee ttrreeaattmmeenntt ddeeppeennddiinngg oonn tthheerraappyy ttyyppee
all 26 (6.1) 55 (13.0) 193 (45.5) 150 (35.4) 3 427
DTIC chemotherapy 8 (10.0) 8 (10.0) 34 (42.5) 30 (37.5) 0 80
multidrug chemotherapy with DTIC 18 (6.0) 41 (13.6) 143 (47.5) 99 (32.9) 1 302
multidrug chemotherapy without DTIC 0 1 (11.1) 1 (11.1) 7 (77.8) 0 9
immunotherapy 0 0 2 (66.7) 1 (33.3) 1 4
hormonal therapy 0 3 (12.0) 12 (48.0) 10 (40.0) 0 25
other monotherapy 0 2 (33.3) 1 (16.7) 3 (50.0) 1 7
RReessppoonnsseess ttoo sseeccoonndd--lliinnee ttrreeaattmmeenntt ddeeppeennddiinngg oonn tthheerraappyy ttyyppee
all 2 (1.0) 11 (5.6) 42 (21.2) 141 (72.1) 6 202
DTIC chemotherapy 0 1 (11.1) 1 (11.1) 7 (77.8) 0 9
multidrug chemotherapy with DTIC 0 6 (7.3) 16 (19.5) 60 (73.2) 0 82
multidrug chemotherapy without DTIC 1 (6.3) 0 8 (50.0) 6 (43.8) 1 16
immunotherapy 0 0 2 (50.0) 2 (50.0) 1 5
hormonal therapy 1 (1.5) 3 (4.5) 14 (21.2) 47 (72.7) 3 69
other monotherapy 0 1 (5.0) 1 (5.0) 18 (90.0) 1 21
RReessppoonnsseess ttoo tthhiirrdd--lliinnee ttrreeaattmmeenntt ddeeppeennddiinngg oonn tthheerraappyy ttyyppee
all 1 (1.85) 2 (3.7) 16 (29.64) 35 (64.81) 6 60
DTIC chemotherapy 0 0 1 (33.33) 2 (66.67) 0 3
multidrug chemotherapy with DTIC 1 (4.55) 1 (4.55) 8 (71.65) 12 (54.55) 2 24
multidrug chemotherapy without DTIC 0 0 6 (42.86) 8 (57.14) 1 15
immunotherapy 0 0 1 (33.33) 2 (66.67) 1 4
hormonal therapy 0 0 0 5 (100.0) 1 6
other monotherapy 0 1 (14.3) 0 6 (85.71) 1 8
RReessppoonnsseess ttoo ffoouurrtthh--lliinnee ttrreeaattmmeenntt ddeeppeennddiinngg oonn tthheerraappyy ttyyppee
all 0 2 (11.0) 6 (33.3) 10 (55.6) 2 20
DTIC chemotherapy 0 0 0 0 0 0
multidrug chemotherapy with DTIC 0 1 (20.0) 2 (40.0) 2 (40.0) 0 5
multidrug chemotherapy without DTIC 0 0 1 (25.0) 3 (75.0) 0 4
immunotherapy 0 0 2 (100.0) 0 0 2
hormonal therapy 0 1 (50.0) 0 1 (50.0) 2 4
other monotherapy 0 0 1 (20.0) 4 (80.0) 0 5
ber of lines of treatment, number of used drugs in the first- that in the majority of patients the treatment was changed
line treatment regimen, use of palliative radiotherapy and after 2–3 cycles due to progression or complications, which
palliative resections. also influenced the relationship between OS and number of
treatment lines. The multidrug therapies containing dacar-
Analysis of the applied systemic treatment bazine were used the most often, both the first and the sec-
Because of the widely discussed impact of systemic treat- ond line of treatment. The less numerous group of patients
ment on OS, and no definite answer on the effectiveness of was treated with dacarbazine in monotherapy or with hor-
the applied therapy in treating metastatic melanomas, monal therapy. It can be concluded from the analysis that
adetailed analysis of the applied treatment (Table 2) and its the best therapeutic choice in the first line of treatment with-
influence on OS was performed. We assessed the possible in the tested group was dacarbazine in monotherapy.
impact of the number of treatment lines, the number of drugs Also the influence of the responses to the first-line treat-
in the first-line regimen and the kind of therapy used in first- ment on OS was assessed. Astatistically significant influence
line treatment. Longer survival of patients who received more of the responses to the treatment on OS was demonstrated.
lines of treatment may be related to survival bias, which We also found that the rates of objective responses (CR
means that the person had to live until the next lines, and + PR) drop, and they equal 19.1% in the first line, 6.6% in the
so by assumption lived longer. However, it is worth noting second line, and 5.6% in the third line.
554400
współczesna onkologia/contemporary oncology
TTaabbllee 33..Influence of clinical factors on progression-free survival after first line of treatment (in months)
FFaaccttoorr VVaarriiaabbllee NN NN AAvveerraaggee MMeeddiiaann 9955%% CCII ppvvaalluuee
ooppttiioonn pprrooggrreessssiioonn ffoorr mmeeddiiaann
wwhhoollee ggrroouupp 442277 441177 66..99 33..55 33..11––33..88
ttyyppee ooff ffiirrsstt--lliinnee tthheerraappyy DDTTIICC 8800 7755 1100..11 55..55 33..88––66..44
mmuullttiiddrruugg wwiitthh DDTTIICC 330022 229977 66..22 33..22 33..00––33..77
mmuullttiiddrruugg wwiitthhoouutt DDTTIICC 99 99 33 11..77 11..55––22..00
00..00000077
iimmmmuunnootthheerraappyy 44 44 77..88 77..22 33..11––1133..66
hhoorrmmoonnaall tthheerraappyy 2255 2255 99..55 55..88 33..00––99..22
ootthheerr mmoonnootthheerraappyy 77 77 22..66 22..99 11..44––44..00
center Cracow 177 175 6.5 3.5 3.1–4.1
0.73
Warsaw 250 242 7.1 3.5 3.0–3.9
sseexx ffeemmaallee 119911 118833 88 33..88 33..55––55..66
00..00001122
mmaallee 223366 223344 55..77 33..22 33..00––33..88
disqualification age < 30 34 33 4.5 2.5 1.8–3.9
0.1392
(in years) 30+ 393 384 7 3.7 3.2–4.0
state at melanoma no metastasis 401 392 6.8 3.5 3.1–3.8
0.3279
diagnosis metastasis 26 25 7.1 5.3 3.9–7.4
LLDDHH lleevveell aatt nnoorrmmaall 119911 118844 88..22 33..99 33..44––55..22
00..00000055
ddiissqquuaalliiffiiccaattiioonn eelleevvaatteedd 114455 114444 55..11 33..11 22..55––33..88
AAssppAATT lleevveell aatt ddiissqquuaalliiffiiccaa-- nnoorrmmaall 330011 229933 77..22 33..77 33..22––44..11
00..00111166
ttiioonn ffrroomm rraaddiiccaall tthheerraappyy eelleevvaatteedd 5533 5533 44..55 22..99 11..99––33..88
AAllAATT lleevveell aatt ddiissqquuaalliiffiiccaa-- nnoorrmmaall 228899 228811 77..33 33..77 33..22––44..11
00..00227711
ttiioonn ffrroomm rraaddiiccaall tthheerraappyy eelleevvaatteedd 6644 6644 44..77 33 22..11––33..99
haemoglobin level from normal 312 303 7.2 3.7 3.2–4.0
0.2633
radical therapy initial reduced 68 67 5.9 3.1 2.7–4.2
lung metastasis no 249 242 6.9 3.8 3.4–4.8
0.0808
yes 173 170 6.2 3 2.6–3.7
lliivveerr mmeettaassttaassiiss nnoo 333399 332299 77..22 33..55 33..11––33..99
00..00229966
yyeess 8833 8833 44..88 33..22 22..66––44..00
soft tissue metastasis no 232 228 6.2 3.2 3.0–3.8
0.1129
yes 190 184 7.2 3.8 3.2–4.6
lymph nodes metastasis no 273 265 6.9 3.5 3.0–3.8
0.9663
yes 149 147 6.2 3.7 3.1–4.7
CNS metastasis no 400 391 6.6 3.5 3.0–3.8
0.1646
yes 22 21 9.1 4.4 3.2–9.0
bone metastasis no 399 389 6.8 3.7 3.2–3.9
0.2506
yes 23 23 5.6 2.3 1.8–3.0
other metastasis no 382 372 6.8 3.5 3.1–3.9
0.8115
yes 40 40 6 3.6 2.2–5.5
ppaattiieenntt ppeerrffoorrmmaannccee 00 119944 118877 77..99 33..88 33..33––55..44
ssttaattuuss aaccccoorrddiinngg ttoo 11 117777 117755 66..55 33..55 33..11––44..11
00..00000066
EECCOOGG ssccaallee 22 4499 4488 44..11 22..22 11..88––33..22
33 66 66 22..77 11..66 11..44––33..55
ssttaaggee aaccccoorrddiinngg 33 2244 2200 1111..77 66..66 33..55––1111..22
ttoo AAJJCCCC//UUIICCCC ssttaaggiinngg 44aa 1122 1122 99..11 66..66 22..11––1133..00
00..00007766
44bb 4411 4411 77..66 33..77 22..44––55..55
44cc 331111 330077 55..77 33..33 33..00––33..77
Univariate analysis for progression-free survival PFS during the first-line treatment: type of therapy (Fig. 5),
The median progression-free survival (PFS) after the first sex, initial level of LDH, AspAT, AlAT in serum, metastases to
line of treatment was 3.5 months (95% CI: 3.1–3.8) for the the liver, patient’s performance status according to the ECOG
whole group of patients, and the 6-month PFS rate was 31.8%. scale and staging according to AJCC/UICC (Table 3). The PFS
We identified the following factors significantly influencing medians after the 1st, 2nd, and 3rdline of systemic treatment
554411
Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV
TTaabbllee 44.. Multi-factor analysis of results for the whole group
FFaaccttoorr CChhii--SSqquuaarree PPrr >> χ22 HHaazzaarrdd 9955%% HHaazzaarrdd rraattiioo
rraattiioo ccoonnffiiddeennccee lliimmiittss
aaggee ooff ddiissqquuaalliiffiiccaattiioonn ffrroomm 30–50 years vs. < 30 years 0.1916 0.6616 1.60 0.817 1.376
rraaddiiccaall tthheerraappyy aammoonngg ffeemmaalleess ≥≥5500 yyeeaarrss vvss.. << 3300 yyeeaarrss 1177..88775533 << 00..00000011 00..557766 00..444466 00..774444
aaggee ooff ddiissqquuaalliiffiiccaattiioonn ffrroomm 30–50 years vs. < 30 years 2.3173 0.1279 1.220 0.944 1.575
rraaddiiccaall tthheerraappyy aammoonngg mmaalleess ≥ 50 years vs. < 30 years 1.352 0.1755 1.178 0.929 1.494
LLDDHH lleevveell elevated vs. N 1166..88555566 << 00..00000011 11..669977 11..331188 22..118844
AAssppAATT lleevveell elevated vs. N 99..773377 00..00002233 11..770099 11..221100 22..441133
EECCOOGG ≥2 vs. 0–1 1155..66337711 << 00..00000011 22..003344 11..443311 22..889933
ffiirrsstt--lliinnee ttrreeaattmmeenntt mmuullttiiddrruugg wwiitthh DDTTIICC vvss.. 88..77779977 00..00003300 11..334499 11..110077 11..664444
mmoonnoo DDTTIICC
hormonal therapy vs. 1.200 0.1773 0.631 0.323 1.232
mono DTIC
ppaalllliiaattiivvee rreesseeccttiioonnss YY vvss.. NN 33..99334477 00..00447733 00..773333 00..553399 00..999966
ppaalllliiaattiivvee rraaddiiootthheerraappyy YY vvss.. NN 44..11880044 00..00440099 00..777733 00..660044 00..998899
mmeessttaassttaassiiss dduurriinngg ddiiaaggnnoossiiss YY vvss.. NN 55..11663366 00..00223311 00..556699 00..335500 00..992255
mmeettaassttaassiiss ffrroomm uunnkknnoowwnn YY vvss.. NN 77..77559955 00..00005533 00..337777 00..119900 00..774499
pprriimmaarryy ssoouurrccee
were 3.5, 2.0, 1.8, respectively. Atrend for shortening of the practice various kinds of therapy have been used, whose effec-
PFS after successive lines of systemic treatment is visible. tiveness is not always confirmed in clinical trials. The basic
The PFS after successive lines of treatment is shown graph- assessed parameter in the analysed large group of 437
ically in Figure 2. The PFS length after the fourth line may be patients was overall survival. The median OS in the whole
thought-provoking, but because of the small size of the group analysed group was 7.1 months, with 1-, 2-, and 5-year sur-
it does not seem meaningful, or it is agroup of patients with vival rates of 32.3%, 12.5% and 3.9% respectively. Similar
natural long course of disease. results were obtained by different authors who analysed over-
all survival of patients with inoperable, metastatic melanomas,
Multivariate analysis for OS
with median OS ranging from 5.6 to 8.1 months [6, 7, 23, 26–
The variables showing an independent influence on OS 29]. In ameta-analysis of 83 research projects of stage II per-
in the constructed model are shown in Table 5. Due to the formed in the years 1974–1999 (6322 patients) [29] the OS
scarcity of groups receiving respective types of therapy in the median was 8.1 months, and 2- and 5-year survival rates were
first line of treatment, it was decided to include only the 13.6% and 2.3% respectively. It is worth noting the signifi-
largest groups in the multivariate analysis – those treated cant differences between median OS before and after
with dacarbazine in monotherapy or multidrug schemes with 1985: 5.8 and 8.9 months respectively. When taking confi-
dacarbazine and hormonal therapy. dence intervals for OS in the discussed analysis into con-
The variables independently influencing overall survival sideration, the results of our group are fully within their range,
were: initial serum LDH level, initial serum aspartate transam- which confirms the representativeness of the group.
inase (AspAT) level, initial performance status (ECOG), the type Anumber of clinical factors which may affect OS in the
of first-line treatment used, women’s age, metastases at the
patient group were analysed. In univariate analysis male sex
time of diagnosis, metastases from an unknown primary site,
proved to be afactor related to worse prognosis, which was
using palliative radiotherapy and palliative resections.
not, however, confirmed in multivariate analysis. In some pub-
lished studies male sex was afactor related to worse prog-
Treatment toxicity
nosis [6, 10, 26, 27, 32] (especially when assessing patients’
The most common grade 3 and 4 adverse events were survival in stages I-III), while in other works such acorrela-
haematological disturbances (anaemia, thrombocytope- tion was not confirmed [5, 13, 25, 28, 30, 31, 33–35]. We did
nia, neutropenia), nausea and vomiting. Both haematolog- not find an influence on OS by overall patient’s age at the
ical and non-haematological complications were found time of metastasis or by period of time between the
more commonly in multidrug chemotherapy with DTIC. In melanoma diagnosis and metastases. However, we found
9.5% of patients the complications resulted in premature atrend for worsening prognosis for younger patients and
treatment termination. those whose metastasis has happened in ashorter time since
the diagnosis. In the available literature, excluding afew works
Discussion
in which apositive influence of the time period before metas-
Melanomas at the inoperable/metastatic stage are still tasis on OS was found [7, 35], this parameter was not sta-
incurable, and lead to death within afew months. In routine tistically significant [5, 6, 10, 31–33]. Multivariate analysis also