prognostic factors in metastatic melanoma

2995

Prognostic Factors in Metastatic Melanoma Louise Ryan, Ph.D.,* Andrew Kramar, Ph.D.,t and Ernest Borden, M.D.S

Background. Each year, 6000 people die in the United States from metastatic melanoma. Further study of factors affecting the prognosis of patients with this disease is needed.

Methods. The authors analyzed response and survival data from 635 patients who had entered three East- ern Cooperative Oncology Group trials for metastatic melanoma.

Factors associated with poorer survival after study entry included poor performance status and the presence of symptoms, such as reduced appetite, fever, or nausea/vomiting. Male patients had poor survival, as did patients entering the study less than 1 year after a documented recurrence to study entry. As expected, characteristics of the initial primary disease (treatment and symptoms) had little association with survival after entering the advanced disease protocol. Two summary measures of the extent of metastatic involvement had a strong influence on survival. These were the number of nonbone metastases and the clinician’s assessment as to the most significant metastatic site. Patients with the liver as their clinically most significant metastatic site had a poorer prognosis than those otherwise classified, including those with central nervous system metastases. The prognosis also worsened with an increasing number of sites of nonbone metastases, including skin and soft tissue. Tumor response occurred in only 11% of the patients. Patients with poor performance status and those with lung involvement had a significantly lower response rate than did others. Although the frequency of response was low, patients with objective re- sponses survived significantly longer than did the nonresponders (based on an analysis appropriately adjusted

Results.

From the *Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts; the tlnstitut Gustave Roussy, Villejuif, France; and the $University of Wisconsin Clinical Cancer Center, Madison, Wisconsin.

Supported by grants from the National Cancer Institute, Be- thesda, Maryland.

This study was conducted by the Eastern Cooperative Oncology Group (Douglass Tormey, M.D., Chairman, grant CA 21115).

Address for reprints: Louise Ryan, Ph.D., Dana-Farber Cancer Institute, Harvard School of Public Health, 44 Binney Street, Boston, MA.

Accepted for publication January 8, 1993.

for the time of response using a time-dependent proportional-hazards model).

Conclusions. These results provide useful guide- lines for the design and analysis of clinical trials in metastatic melanoma. Cancer 1993: 712995-3005.

Key words: response, survival, cutaneous melanoma.

More than 6000 patients will die of metastatic melanoma this year and more than 60,000, during the next 10 years. In addition to the common regional sites, lung metastases may often be an initial site for systemic relapse.’ At autopsy, pulmonary metastases occur in approximately 75% of patients.2 Although the commonest metastatic sites are skin, lymph nodes, or lungs, visceral involvement of the liver, gastrointestinal tract, and central nervous system (CNS) are common and often lead to patient mortality. CNS involvement has also been a common manifestation found at autopsy in more than 49% of cases3 More than 70% of patients had metastases in other organs detected at autopsy.* The visceral metastatic involvement has been correlated with the prognosis in metastatic d i ~ e a s e . ~

Two multifactorial analyses of prognostic factors in metastatic melanoma have been reported.’t6 Each exam- ined different parameters, differed somewhat in their conclusions, and involved less than 50% of the number of patients analyzed in our study. Thus, as a basis for decisions in patient management and for stratification in future clinical studies, we assessed the outcome in 635 evaluable patients with nonresectable, cutaneous metastatic malignant melanoma entered in three East- ern Cooperative Oncology Group (ECOG) studies. This data set for analysis was derived from all patients entered over a 10-year interval (1975-1985) on ECOG trials aimed at identifying new agents with activity in melanoma; the trial results have been separately re-

In this analysis, we combined the information from these three studies to investigate the natural history of this disease and to identify factors that are associated with the response to therapy and survival using the advanced disease protocol. Our specific ob-

2996 CANCER May 15, 2993, Volume 71, No. 10

jectives were to investigate (1) the time from the primary diagnosis to the development of clinical metastatic disease, (2) the survival time after study entry and the factors that influence it, and (3) the factors that are important in predicting a response in metastatic melanoma. Such data are important in the follow-up of patients who have undergone primary resection for melanoma, for identifying prognosis in individual patients with metastatic disease, and for identifying poor-risk patients who may not benefit from treatment interven- tions. Of course, the results must be cautiously inter- preted because patients who enter clinical trials are not necessarily representative of the general population of patients with a disease,

Materials and Methods

Patient Population

The patients included those entered in three ECOG studies, Protocols EST 1675, EST 2681, and EST 2683. Each was a Phase I1 protocol studying different single agents and combinations, including nitrosourea, dacar- bazine, or Phase 11 single-agent chemotherapeutic regi- mens.

The patient population was similar for each of the studies. The patients were required to have a histologi- cally confirmed, surgically incurable metastatic melanoma with an area of measurable disease. The eligible patients had a performance status 0, 1, or 2 (EST 1675 also allowed patients with a performance status of 3). The patients were required to have adequate renal and hematologic function, should have recovered from the effects of major surgery or radiation therapy, and had to be free of significant infection.

Prior radiation therapy to measurable lesions did not exclude the patient if there was evidence of measurable progressive disease and if the radiation therapy was not given in the 4 weeks before the study. Initially, patients who had received prior chemotherapy were eligible in one study (EST 1675). However, after 4 years, the criteria were changed to exclude patients who had been given prior chemotherapy for recurrent or metastatic disease. This exclusion also applied to the two subsequent studies, EST 2681 and EST 2683.

For each of the three studies, tumor response (based on standard ECOG criteria for solid tumors) was the primary end point, and the survival time from study entry was a secondary end point. Although no single study accrued enough patients to investigate survival and associated prognostic factors thoroughly, the combined data base provided a unique opportunity for such an analysis.

Statistical Analysis

Chi-square or Fisher exact testsI2 were used to compare the patient characteristics in the different studies and patient subgroups. All analyses were stratified by the study and/or treatment arm within the study to protect against biases that could arise through changes in the patient population over time or differences between treatments. Our main analysis was based on survival measured from the time of entry into the study. A stratified log-rank test13 was applied to make univariate com- parisons of survival between various groups and to identify factors for consideration in the multivariate analysis. Multivariate survival analyses were based on the stratified Cox proportional-hazards model. The most parsimonious model was selected using the step- wise-regression procedure from the statistical package BMDP. The predicted median survivals were calculated using methods described by Cox and Oakes.13 These same techniques were applied to assess the goodness of fit of the Cox model.

Despite our interest in this disease's natural history, the survival time from the initial diagnosis of melanoma was not analyzed. Such an analysis is likely to be biased because this time from diagnosis was obtained retro- spectively and patients who never had metastases were not represented in this study population. However, we were interested in studying the time from the initial melanoma diagnosis to recurrence because this information could be useful in predicting the clinical course of patients when they initially present with melanoma. Unfortunately, the time to recurrence was not recorded for all patients in our studies. In an attempt to address this issue, we conducted two analyses: one in the sub- group of patients with a recorded recurrence date and one in which the time of entry into the study was taken as a proxy for the time to recurrence. The latter is reason- able because survival after the onset of metastatic disease is generally short. As discussed later, both analyses yielded comparable results. Because the data base included only patients with metastatic disease, the analysis does not represent a prospective study of the time to recurrence in patients with primary melanoma. How- ever, it provides useful information about the time to recurrence for patients who will eventually have a relapse.

Results

Of the 770 patients who entered the three studies (600 on EST 1675,89 on 2681, and 81 on 2683), 23 patients were canceled, and 31 were ineligible. Two patients were improperly entered, and one was lost to follow-

Metastatic MelanomalRyan et al . 2997

up. Seventy-eight patients were reported as having ocu- lar, subungual, or anogenital melanomas. Because our analysis focused on cutaneous melanoma, these 78 were excluded. Thus, the data base included a total of 635 patients.

Of the 635 patients, 97% were white, 61% were men and 27% were postmenopausal women. The median age was 56 years (range, 19-93 years), and 244 patients (39%) were 60 years of age or older. The three studies did not significantly differ with respect to these basic demographic variables.

Disease History

The primary site of melanoma was unrecorded for 259 patients (36%). Of those patients with known sites, 164 had primaries located on the trunk, 80 on the head and neck, and 132 on the limbs. Most patients (69%) presented with at least one symptom, including pigment change, palpable nodule, itching, ulceration, or bleeding.

Almost all patients (90%) had undergone surgery for their primary disease, with 52% having primary surgery alone and 26%, primary surgery plus lymphad- enectomy. Of the 635 patients analyzed, 14% hadprevi- ously received immunotherapy; 13%, radiation therapy; and 6%, chemotherapy.

The time of diagnosis of the melanoma was recorded for 629 (99%) patients. The median time from the first diagnosis of melanoma to the entry into one of the three studies was 19 months (Fig. 1). Thus, approximately 50% of patients entered treatment protocols for metastatic disease less than 2 years after their initial diagnosis, However, almost 20% of the patients had lived more than 5 years from the initial diagnosis to study entry, and the maximum time to study entry was 35 years.

One hundred nine patients had no information re- garding whether or not their disease recurred after their initial diagnosis but before they entered the study. Whether these patients presented with metastatic disease or whether the time of recurrence was simply unrecorded could not be defined. Of these 109, most (88%) entered the study less than 2 years after their initial diagnosis, suggesting that they may have had initially metastatic disease. Among the 526 patients with a documented recurrence, the median time to recurrence was 20 months, and for 20% of these patients, more than 4 years had elapsed between the initial diagnosis and their recurrence, with the maximum time to recurrence being 34 years. The median time from the recurrence of disease to study entry for these 526 patients was 4 weeks. Most of the 526 patients (94%) en-

Diagnoaie to recurrence

1 . O h

P

0 . 7 B A 0 . 6

I

T y 0.2 "\- 0.1 0 . 0 0 42 84 126 168

MONTES

ALIVE DEAD TOTAL MEDIAN 0 524 524 19.3 -

Figure 1. The time from first diagnosis of melanoma until entry into one of the three studies.

tered the study less than 2 years after their recurrences. The maximum recorded period from recurrence to study entry was 10 years.

The time between the initial diagnosis and entry into one of the studies and the time to recurrence for the subset of patients with a documented recurrence was analyzed by sex, primary symptoms, and number of metastases (Table 1). Patients with metastases to the lung tended to have a longer period from diagnosis to study entry ( P = 0.04), as did female patients (P < 0.02). Furthermore, the presence of ulceration or palpable lymph nodes at first diagnosis were both associated with a short time to recurrence ( P < 0.01 in both cases).

Clinical Data a t Study Entry

Most patients (85%) had a performance status 0 or 1 at the time of study entry. Some patients presented with evidence of primary disease symptoms (such as ulceration or itching). A number of patients had other chronic diseases at the time of study entry, including cardiac disease (12%), respiratory disease @YO), liver disease (2%), and diabetes (5%). As discussed later, the presence of these primary disease symptoms conditions


Table 1. Months From Initial Diagnosis

Diagnosis to on-study Diagnosis to recurrence

Median Median No. (mo) P value No. (mo) P value

Overall 629 19 520 19 Sex

Male 386 15 < 0.001 315 14 < 0.001 Female 242 27 205 26

Primary disease Symptoms

Change in pigment 205 19 0.621 176 16 0.145 Itching 72 12 0.302 57 12 0.140 Ulceration 79 12 0.045 65 12 0.006 Palpable nodule 309 14 < 0.001 244 15 < 0.001 Bleeding 139 1 4 0.041 109 12 0.011 Other 157 16 0.545 123 19 0.955

Lung 321 22 0.015 263 23 0.056 Pleura 36 26 0.329 33 28 0.400 Liver 163 18 0.109 129 21 0.055 Brain 41 34 0.029 35 30 0.467 Bone/rnarrow 108 22 0.752 89 23 0.327 Skin/

subcutaneous 270 15 0.507 222 17 0.152 Gastrointestinal 40 30 0.832 33 29 0.588

Metastatic sites

did not have a significant impact on subsequent survival.

The most common systemic symptoms present at study entry were reduced appetite (24%) and nausea/ vomiting (14%). As discussed later, both these symptoms were associated with the presence of liver metastases. Sixty patients (24%) had lost more than 5% of their body weight in the 6 months before study entry, with 5% of the patients losing more than 10%. The most common metastatic disease symptoms were palpable nodules (56%), respiratory (20%), hepatic (IS%), bone pain or fracture (12%), and gastrointestinal symptoms (10%). The most common medications being taken by the patients at the time of study entry were analgesic (14%) and diuretic agents (10%).

Patterns of Metastases

The sites of distant metastases played an important role in determining a patient’s prognosis. The data base classified patients according to whether or not they had metastases in the lung, pleura, brain, liver, bone or bone marrow, skin or subcutaneous, gastrointestinal tract, lymph nodes, or ”other.” The most frequent sites of distant metastases were lung (51%), lymph nodes (43%), skin or subcutaneous (42%), liver (26%), and

bone or bone marrow (17%). The pattern of metastatic involvement was complicated; 67% of patients had more than one site involved (Table 2). The overall fre- quencies of organ metastases (percentages of all patients with involvement in various sites) were analyzed to identify the organ distributions among the subgroups of patients with a particular site involved. For example, among patients with liver involvement, only 39% had lung involvement compared with 49% overall (P < 0.01). Thus, liver and lung had a significant negative association. A positive association occurred between liver and bone or bone marrow, i.e., 23% of patients with liver involvement also had bone involvement compared with only 17% overall ( P < 0.01). Palpable lymph nodes and skin or subcutaneous metastases were positively associated. Of patients with skin or subcutaneous involvement, 49% had nodes involved compared with 40% overall ( P < 0.001).

A useful summary of the sites of metastatic involvement was the clinician’s judgment as to the “most clinically significant metastatic site.” This assessment was coded on four levels, ranging in order of perceived decreasing severity from CNS (Level 4); through liver (LeveI 3); then lung, bone, or viscera (Level 2); to finally soft tissue or nodes (Level 1). The patients with the soft tissue or nodes as the most clinically significant site (30%) tended to have only one or two metastatic sites,

Metastatic Melanoma/Ryan e t al. 2999

Table 2. Associations Between Metastatic Disease Sites

Metastatic site (%)

Bone/ Skin/ Lung Pleura Liver Brain Marrow Subcutaneous Gastrointestinal Nodes Overall

Lung 26 (72)’ 72 (44)’ 26 (63) 57 (53) 120 (44) 20 (50) 108 (40)’ 321 (51)

Liver 72 (22)* 9 (25) - 11 (27) 43 (40)* 67 (25) 12 (30) 75 (28) 163 (26) Brain 26 (8) 2 (6) 11 (7) - 8 (7) 15 (6) 6 (15)* 10 (4)’ 41 (6) Bone/marrow 57 (18) 9 (25) 43 (26)* 8 (20) - 53 (20) 6 (15) 48 (17) 108 (17) Skin/

subcutaneous 120 (37)* 15 (42) 67 (41) 15 (37) 53 (49) - 21 (52) 136 (50)* 269 (42)

Palpable nodes 108 (34)* 13 (36) 75 (46) 10 (24)* 48 (44) 136 (50)* 18 (45) - 270 (43) Total 321 36 163 41 108 269 40 270 635

Pleura 26 (8)* - 9 (6)* 2 (5) 9 (8) 15 (6) 4 (10) 13 (5) 36 (6)

Gastrointestinal 20 (6) 4 (11) 12 (7) 6 (15)’ 6 (6) 21 (8) 18 (7) 40 (6) -

* Sienificance association ( P < 0.051.

and little involvement of the lung, liver, and other major organs. Those with the liver as the most clinically significant site (19%) had up to eight sites of metastatic involvement, and 40% of these patients had three or more sites involved. The majority of patients (46%) were classified as having lung, bone, or viscera involvement as the most clinically significant site, with 34% of these patients having involvement in three or more sites.

There was some correlation between the clinically most significant metastatic site and the initial disease site. For example, patients with primaries in the lower limbs (42%) tended to be classified as having the soft tissue or nodes as their clinically most significant site.

In general, metastatic disease symptoms were highly predictive of metastatic involvement. The sensitivity and specificity of these disease symptoms were analyzed for their predictive power in identifying metastases (Table 3). The sensitivity of a symptom was defined as the probability that the symptoms were pres-

Table 3. Sensitivity and Specificity of Metastatic Disease Symptoms

SvmDtom*

~~

Sensitivity Specificity W O ) (%I

Central nervous system 70 Bone pain/fracture 58 Hepatic 52 Gastrointestinal 78

Lune 37 Palpable nodule 78

98 97 98 94 59 98

*With indicated symptoms, sensitivity was defined as the probability that an associated symptom was present, given that the site was involved. Specificity was defined as the probability of an absence of the symptom, given the absence of the disease.

ent, given the involvement of the associated metastatic site. For instance, hepatic symptoms had a sensitivity of 52% with respect to presence of liver metastases (52% of patients with hepatic metastases were found to have hepatic symptoms). A symptom was defined as having a high specificity only if it tended to occur in conjunc- tion with the associated site involved. The specificity was defined as the probability that a patient without a

Survival

P

B A 0 . 6

B 0.5 I L 0 . 4

from Study Entry

I T Y :::I \ ; , :, : , .

0 . 0 0 12 24 36 4 8 60 72 84

MONTES

ALIVE DEAD TOTAL a D I A N

24 612 636 5 . 6

Figure 2. Survival from study entry.

3000 CANCER May 15,1993, Volume 71, No. 10

Table 4. Patient Characteristics and Survival From Study Entry

Overall Sex

Male Female

< 39 40-59 60-79

Age (yr)

> 80 Location of primary

Head and neck Upper limb Lower limb TrUnk Other or unknown

Primary surgery None Primary alone Primary and

lymphad- enectomy

Other or unknown Surgical excision for

recurrence No Yes, superficial Yes, primary

and/or lympha- denopathy

Other Unknown

Prior immunotherapy Prior radiation therapy Prior chemotherapy Initial diagnosis

to on- study (yr)

0 1 2 3 4 5+ Median (maximum)

Recurrence to on-study (Yr)

0-1 1-2 2+ Unknown Median (maximum)

No. of Stratified No. of Stratified patients Median Survival log-rank patients Median Survival log-rank (Oh) (wk) (12 mo) Pvalue (Oh) (wk) (12mo) Pvalue

635

390 (61) 245 (39)

115 (18) 273 (43) 234 (37)

10 (2)

80 (11)

91 (13) 164 (23) 259 (36)

64 (10) 331 (52)

41 (6)

166 (26) 74 (12)

164 (26) 109 (17)

111 (17) 169 (27) 82 (13) 91 (14) 84 (13) 40 (6)

142 (22) 166 (26) 91 (14) 73 (11) 37 (6)

114 (18) 20 mo

(35)

405 (64) 85 (13)

109 (17) 4 wk

36 (6)

(10 yr)

24

22 26

25 24 23 12

26 25 28 25 20

23 24

22 20

20 28

26 26 20 30 21 20

22 18 29 25 27 25

21 29 30 22

0.19

0.17 0.23

0.16 0.22 0.22 0.20

0.21 0.15 0.33 0.17 0.19

0.15 0.19

0.24 0.17

0.13 0.23

0.26 0.19 0.17 0.30 0.21 0.10

0.18 0.18 0.27 0.19 0.22 0.16

0.19 0.26 0.32 0.20

0.223

0.659

0.009

0.103

0.010

0.008 0.615 0.090

0.139

0.026

Clinical data at study

Performance status entry

0 1 2 3

Systemic symptoms Reduced appetite Aversion to protein Nausea/vomiting Fever Night sweats Other

Weight loss (%) None < 5 5-10 > 10

Metastatic disease symptoms

Central nervous system

Bone pain or fracture Respiratory Hepatic Gastrointestinal Hema tologic Palpable nodule Other

Distant metastases Lung Pleura Liver Brain Bone (or bone marrow) Skin/subcutaneous Gastrointestinal Palpable lymph node Other

Most clinically significant metastatic site

Central nervous system

Liver Lung, bone, viscera Soft tissue or nodes

No. of metastatic sites only

0 1 2 3 f

289 (45) 253 (40)

70 (11)

24 (4)

155 (24)

27 (4) 92 (14) 38 (6) 34 (5) 94 (15)

446 (70) 76 (12) 36 (6) 29 (5)

37 (6) 77 (12)

124 (20) 93 (15) 62 (10) 21 (3)

357 (56) 108 (17)

321 (51)

163 (26)

108 (17) 269 (42)

270 (43) 110 (17)

36 (6)

41 (6)

40 ( 6 )

32 (5) 121 (19) 289 (46)

193 (30)

20 (3) 189 (30) 215 (34) 211 (33)

33 20 12 6

12 12 12 9

10 15

27 21 13 9

17 19 15 12 12 20 21 20

22 12 13 17 20 20 13 23 21

18 12 25

31

3 1 35 22 13

0.30 0.14 0.10 0.00

0.10 0.03 0.06 0.02 0.08 0.14

0.24 0.11 0.11 0.03

0.04 0.18 0.14 0.14 0.07 0.13 0.19 0.14

0.17 0.06 0.14 0.21 0.15 0.17 0.05 0.02 0.15

0.14 0.12 0.18

0.32

0.40 0.32 0.15 0.10

< 0.001

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

0.001

< 0.001

< 0.001 0.056

< 0.001 < 0.001 < 0.001

0.098 0.171

< 0.001

< 0.001 < 0.001 < 0.001

0.044 0.131 0.011

< 0.001 0.739 0.391

< 0.001

< 0.001

Metastatic Melanoma/Ryan et al. 3001

particular metastatic site was also without associated symptoms. For example, of the patients without hepatic metastases, only 2% had hepatic symptoms (Table 3); therefore, hepatic symptoms had a specificity of 98%.

Survival From Study Entry

The overall median survival from the time of study entry was 24 weeks (Fig. 2). At the time of analysis, the longest surviving patients was still alive after 15 years and 8 months. Twenty percent of the patients survived longer than 1 year, but only 10 patients survived longer than 5 years. Because of the large number of patients analyzed, many characteristics were significantly associated with survival when analyzed with a univariate analysis (Table 4). Many of these associations disap- peared after performing a multivariate analysis based on the Cox proportional-hazards model. Many of the univariate associations were predictable, e.g, prior therapy, duration from primary disease to study entry, performance status, and symptoms and evidence of metastatic disease. The time from the initial diagnosis to recurrence did not significantly influence survival from the time of study entry, although the time from recurrence to study entry did.

In the multivariate model (Table 5 ) , patients who had poor ECOG performance status or systemic symptoms (reduced appetite, fever, or nausea and vomiting) a t the time of study entry had a worse prognosis. The primary disease history (site of primary, type of treatment, time to recurrence, and initial symptoms) had no significant association on survival from the patient’s entry into the study. Because of correlations between various sites, it was useful to consider summary measures of the extent of metastatic involvement. One par- ticularly useful measure was the physician’s assessment

Table 5. Favorable Prognostic Factors Identified From a Proportional-Hazards Model for Survival With Metastatic Melanoma

Normal appetite N o nausea/vomiting N o fever

Good performance status

Few (nonbone) metastatic sites

Soft tissue or nodes as most clinically significant site More than 1 yr since documented recurrence

Female gender

Chemotherapeutic response

Table 6. Response by Patient Characteristics

No. of Mantel- No. of responders Haensel patients (%) P value

Overall Performance status at start

of treatment 0 1 2 3

Location of primary Head and neck Upper limb Lower limb Trunk Unknown

Systemic symptoms Reduced appetite Aversion to protein Nausea/vomiting Fever Night sweats Other Weight loss

Lung Pleura Liver Brain Bone/marrow Skin/subcutaneous Gastrointestinal Palpable lymph node Other

Most clinically significant

Central nervous system Liver (not central nervous

Lung, bone, viscera

Distant metastases

metastatic site

system)

635

319 294 73 27

80 41 91

164 259

155 27 91 38 34 94

140

321 36

163 41

108 269 40

270 110

34

121 289

Soft tissue or nodes only 193 32 (17)

0.01

0.287

0.08 0.02 0.03 0.88 0.94 0.96 0.59

0.01 0.62 0.37 0.41 0.38 0.72 0.57 0.02 0.312

0.06

of the ”clinically most significant site.” Another useful summary was the number of nonbone metastatic sites of disease. Based on the multivariate model, patients classified as having liver or CNS as their clinically most significant site were found to have a relatively poorer prognosis than those with lung, other viscera, soft tissue, or nodal involvement. Those with soft tissue or node metastases had the best prognosis. The prognosis also tended to worsen in proportion to the number of nonbone metastatic sites, which included all soft tissue sites, nodes, and the skin. Patients with soft tissue or nodes as their most significant site of disease had a relatively good prognosis. Figures 3-7 show the survival


Survival by Performance Status

1.0-

MONTES

Perf. Status ALIVE DEAD TOTAL MEDIAN - 0 1 6 273 289 7 . 8

1 5 248 253 4 . 7 2 3 67 70 2 . 8 3 0 24 24 1 . 5

..-.

Figure 3. Survival from study entry by performance status

times with respect to some of the factors identified in the Cox model.

To interpret the results from the Cox model, we assessed the survival patterns predicted by various parameters. For example, an asymptomatic female patient entering the study with a good performance status and no liver involvement could expect a median survival of approximately 1 year. By contrast, a symptomatic man with a poor performance status, liver and other visceral metastatic involvement, who presented less than 1 year after the initial diagnosis could expect a median survival time of only approximately 2 months.

Response

Objective tumor response was an important end point for all three studies. Of the 635 analyzable patients, only 69 (1 1 YO) responded. The variables associated with response included performance status, the presence of systemic symptoms (reduced appetite, aversion to protein, and nausea/vomiting), and the sites of metastatic involvement. The strongest association with response occurred with the variable the ”clinically most significant metastatic site.” Patients classified as having soft

tissue or nodal metastases had a 17% response rate. After performing a multivariate logistic regression, the best predictors of response were good performance status and having soft tissue or nodes as the clinically most significant site.

Even though the response of metastatic melanoma was low, the large data set enabled us to address the important question of whether a response to chemotherapy increased the survival time. To do this, we used the proportional-hazards model, with the response as a time-varying covariate. When the response was included in the multivariate Cox model, it showed a significant association with survival (P < 0.0001). To display the association between response and survival graphi- cally, we performed a landmark analysis, taking the subset of patients who survived at least 92 days. The responders included only those who responded before 92 days. Figure 8 shows that the responders had a much better survival rate than did the nonresponders.

Conclusions

Using a proportional-hazards model stratified by treatment and study, we analyzed prognostic factors for sur-

Survival by Most Significant Sit0

I T Y

sig Site ALIVE DEAD TOTAL W D I A N

- a s 2 30 32 4 . 1

. . - - . Lung/Bone/Visc 9 280 289 5 . 9 Sft Tisa/Nodes 11 183 194 1.0

Liwr 2 119 1 2 1 2 . 8

Figure 4. Survival from study entry by the most significant metastatic site.

Metastatic MelanomalRyan e t al. 3003

Survival by reduced appetite

T

0 12 24 36 48 60 72 8 4

I 0.3. ’ T y 0.21

7 0 12 24 36 48 60 72 8 4

MONTRS

Red. Appetite? ALIVE DEAD TOTAL MEDIAN

- No 21 459 480 6.3 Y e 8 3 153 156 2.7

iigure 5. Survival from study entry by the presence of reduced appetite

viva1 among 635 patients with cutaneous metastatic melanoma. The disease characteristics at the initial diagnosis (symptoms and treatment) had no significant impact on the patient’s survival after entry into these advanced disease studies. However, a patient’s clinical status at the time of study entry had a strong impact. Poor survival rates occurred in patients with poor performance status (2 or greater) and in those with any of the following symptoms: fever, reduced appetite, or nausea/vomiting. Those who entered the study less than 1 year after a documented recurrence of melanoma had a poorer survival. The pattern and sites of metastatic involvement were also important prognostic factors for survival. A convenient summary was provided by the physician’s decision on the most clinically significant metastatic site. This variable was ordered in increasing order of severity from the CNS, liver, lung, bone or viscera, to soft tissue or nodes only. Patients classified as having liver or CNS involvement as the most clinically significant site had relatively poor survival times compared with all other patients. Although a very poor prognosis is expected for patients with CNS involvement, these patients in our series did not have a significantly worse survival rate than did patients with the liver as their most clinically significant metastatic

site (although the number of patients classified as having CNS metastases was small), A second convenient summary measure was number of nonbone metastases (soft tissues, nodes, and skin). The proportional-hazards model indicated that the prognosis worsened in proportion to the number of nonbone metastases.

Although the data available for analysis varied somewhat, certain commonalities emerged with the other two other multifactorial analyses of prognostic factors in metastatic melanoma that have been re- p ~ r t e d . ~ , ~ Performance status was identified in the Southeastern Cancer Study Group (SEG) analysis, as in our study, as the strongest parameter.6 It was not analyzed in the University of Alabama Melanoma Registry (UAMR) data.5 An increased number of metastatic sites was identified in the ECOG series and the UAMR analysis; hepatic involvement was the most adverse as identified by SEG. The UAMR analysis did not separate hepatic involvement but identified the negative impact of visceral involvement. A disease-free interval of less than 12 months was an adverse parameter in our series and that of UAMR, but this was not analyzed by SEG. Even after accounting for other parameters, women fared better than men in the ECOG series and the SEG study but not in the UAMR analysis. Of interest was the failure of any of these analyses to identify age as a

Survival by fever

I 0 12 24 36 48 60 12 8 4

MONTRS

Fever? ALIVE DEAD TOTAL MEDIAN

24 574 598 5.8 Yea 0 38 38 2.1

- No

Figure 6. Survival from study entry by fever.


prognostic parameter. Our analysis was unique in ana- lyzing clinical symptoms. Thus, in summary, a poor performance status, an increased number of metastatic sites, hepatic involvement, less than 1 year from the initial diagnosis to the identification of distant metastases, and male gender were identified as the most negative prognostic parameters in metastatic melanoma.

The median time to recurrence in the ECOG series was 19 months for the patients who had a documented recurrence (Table 1). Before entry into a subsequent clinical trial for metastatic melanoma, more than 80% of patients had recurrences by 4 years. However, 10% of recurrences took place after 7 years. These findings have implications for the frequency of clinical reevalua- tions after primary surgery for melanoma.

This large data base provided an opportunity to de- fine patient and disease factors associated with survival in those with metastatic melanoma. These results will be useful in stratification and analysis of future studies of metastatic melanoma. Included in those factors that had a positive impact on survival was the response to chemotherapy. Although we cannot eliminate the se- lection of a subset of patients who would have survived regardless of treatment, the use of the multivariate analysis of more than 20 independent predictors and the strong observed associations makes this unlikely. The

Survival by nausea/vomiting

1.0.

0.7 A 0 .6

0.5

B

I

P

L 0 .4

T

0 12 24 36 48 60 72 84 MONTES

N8uaaa/Vomiting ALIVE DEAD TOTAL MEDIAN

No 23 521 544 6.1 Yea 1 91 92 2.8

-

Figure 7. Survival from study entry by nausea/vomiting.

Survival by Reaponas: Landmark at 9 montha

I 0.3. 1 %

y 0 . 2 ' I_ T

- - - - + - - - - L - - 0.1 0.0 1

0 12 24 36 48 60 72 84 MONTES

Rmaponsm? ALIVE DEAD TOTAL MEDIAN

- No 21 374 395 7.3 50 12.3 Yea 3 47

Figure 8. A landmark analysis of responders versus nonresponderc (only patients who survived at least 92 days are included, and "responders" include those in whom a tumor response occurred before 92 days).

patients and disease characteristics can then also be used to provide a basis for identifying those who should be selected for treatment intervention. We recommend the use of the most clinically significant site of disease as a useful summary of the metastatic involvement and as a stratification factor in studies of advanced disease. Our findings suggest that patients can be most usefully classified in decreasing order of severity as (3) liver or CNS, (2) other viscera or bone, and (1) soft tissue or nodes.

References

1 . Gromet MA, Ominsky ST, Epstine WL, Blois MS. The thorax as the initial site for systemic relapse in malignant melanoma: a prospective survey of 324 patients. Cancer 1979; 44:776-84.

2. de la Monte SM, Moore WG, Hutchins GM. Patterned distribu- tion of metastases from malignant melanoma in humans. Cancer Res 1983; 43:3427-33.

3. Patel JK, Didolka MS, Pickren JW, Moore RH. Metastatic pattern of malignant melanoma. Am ] Surg 1978; 1355307-10.

4. Einhorn LH, Burgess MA, Vallejos C, Bodey GI' Sr., et al. Prog- nostic correlations and response to treatment in advanced metastatic malignant melanoma. Cancer Res 1974; 34:1995-2004.

Metastatic MelanomalRyan et al. 3005

5. Balch CM, Soong S-J, Murad TM, Smith JW, Maddox WA, Du- rant JR. A multifactorial analysis of melanoma: IV. Prognostic factors in 200 melanoma patients with distant metastases (stage Ill). Clin Oncol 1983; 1:126-34.

6. Presant CA, Bartolucci AA, the southeastern Cancer Study Group. Prognostic factors in metastatic malignant melanoma. Cancer 1982; 49:2192-6.

7. VonHoff DD, Amato DA, Kaufman JH, Falkson G, Cun- ningham TJ. Randomized trial of chlorozotocin, neocarzinosta- tin or methyl-CCNU in patients with malignant melanoma. Am J Clin Oiicol 1984; 7:135-9.

8. Amato DA, Bruckner H, Guerry D, Ash A, Falkson G, Borden EC, et al. Phase 11 evaluation of &bromodulcitol and actinomy- cin -D, hydroxyurea, and cyclophosphamide in previously un- treated patients with malignant melanoma. lnvest New Drugs 1987; 5:293-7.

9.

10.

11.

12.

13.

Nathanson L, Cunningham T, Kuperminc M, Falkson G, Schoenfeld D, Marsh J, et al. Combination chemoimmunother- apy of malignant melanoma. Proc Am Soc Clin Oncol 1979; 20:314. Kuperminc M, Amato D, May JT 111, Cunningham TJ. A prospective study of MGBG vs. meCCNU (phase 11) in patients with metastatic malignant melanoma. Proc Am Soc Clin Oncol 1984; 3:261. Arseneau JC, Schoenfeld DA, Borden EC. A phase I1 study of dihydroxyanthracenedione (DHAD, mitoxantrone, NCS 301 7939) in advanced malignant melanoma. Invest New Drugs 1986;

Mehta CR, Pate1 NR. A network algorithm for Fisher's exact test in r X c contingency tables. J A m Stat Assoc 1983; 78:427-34. Cox DR, Oakes D. Analysis of survival data. London: Chapman Hall, 1984.

4~53-6.

prognostic factors in metastatic melanoma

Documents