Prognostic Variables in Recurrent Limb Melanoma Treated With Hyperthermic Antiblastic Perfusion

FRANC0 DI FILIPPO, MD,* ANNAMARIA CALABRO, MD," DIANA GIANNARELLI, PHD,t SANDRO CARLINI, MD,' FRANCESCO CAVALIERE, MD,* FRANCESCO MOSCARELLI, MD,* AND RENATO CAVALIERE, MD'

Between October 1969 and December 1986, 136 patients with recurrent limb melanoma were treated with hyperthermic antiblastic perfusion (HAP). This retrospective analysis is aimed at identifying tumor- related and treatment-related variables likely to influence tumor response, locoregional control, disease- free survival, and overall survival. Independent factors predicting a complete response (CR) were the number of lesions (P < 0.0001) and the minimum tumor temperature (minT) (P = 0.03). Only a positive trend was observed for the drug dose (P = 0.08). However, the proportion of CR was significantly higher (57.7%; P = 0.02) in patients who had a minT of 41.5"C or greater and who were given a dose equal to or greater than the standard dose than in patients treated with lower temperatures and/or lower drug doses. The occurrence of a CR significantly increased the rates of locoregional control (77%; P = 0.007), disease-free survival (55.6%; P = 0.006), and overall survival (68.6%; P = 0.03). Treatment optimization may provide further therapeutic improvements by increasing the incidence of CR. However, the overall survival rates also were influenced by the number of lesions (P = 0.0014), sex (P = 0.04), and the number of previous relapses (P = 0.01). Therefore, tumor aggressiveness also is crucial in determining the outcome of the disease, and only early treatment with HAP can reduce the risk of distant metastases.

Cancer 63:2551-2561. 1989.

IMB melanoma with locoregional metastases is a very L challenging neoplasm to treat, especially when in- transit lesions are present. Surgery alone or combined with adjuvant chemo-immunotherapy has provided disap- pointing long term results. 1-8

Isolated limb perfusion has been shown to produce long-lasting remissions in a high number of patients. The method, originally designed to deliver high dosages of an- tineoplastic drugs regionally,' was radically modified in the early 1960s by heating the circulating blood and ex- posing the entire limb to the selective anti-cancer effect of a homogeneous and controllable hyperthermia."-'* As a result, the following three possible perfusion techniques became available: normothermic antiblastic perfusion, hyperthermic perfusion, and hyperthermic antiblastic perfusion.

From the *I11 Department of Surgery and the ?Department of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.

Supported in part by CNR grant no. 860063944, special project "Hy- perthermia" of the Italian Ministry of Health and the AIRC.

The authors thank V. Folino, G. Sanguigno, and R. Augeri for their assistance during the perfusional treatments and Gillian McIntire for the translation and preparation of the manuscript.

Address for reprints: Franco Di Filippo, MD, Istituto Regina Elena, Vide Regina Elena 29 1,OO 16 1 Rome, Italy.

Accepted for publication January 5 , 1989.

Retrospective and comparative analyses were then car- ried out and the results obtained provided evidence of the greater effectiveness of hyperthermic antiblastic perfu- sion (HAP).I2-l5

Currently,HAP represents the elective treatment for lo- cally advanced malignant melanomas of the extremities and is routinely carried out in the major oncologic insti- tutes. However, despite almost 20 years of experience and wide clinical implementation, the results have never been analyzed in terms of response rates for variances of re- gional heating or drug levels. Clarifications must still be made regarding drug schedule, level of hyperthermia, and tumor-related factors likely to influence the probability of success or failure of the treatment.

This retrospective analysis of our experience using HAP for treating recurrent limb melanoma was undertaken to investigate these problems on a continuous series of 136 patients. The prognostic influence of the treatment vari- ables was evaluated as a function of their observed vari- ability. Their predictive value was compared with that of clinical factors to identify the optimal treatment and define its effectiveness within groups of patients stratified ac- cording to risk factors.

Materials and Methods Between October 1969 and December 1986, a contin-

uous series of 136 patients with histologically confirmed

255 1

2552 CANCER June 15 1989 Vol. 63

TABLE 1. Variables Available for the Study of Therapeutic Results (1 16 Evaluable Patients)

Variable No. of patients

HAP, (2) review of recent literature in this field,4,5,'6-'8 and (3) availability of complete information relating the factors considered.

Sex Male Female

Age (yr) <40 240

Upper limb Lower limb

Thigh

Foot

Site

Leg

NL Single Multiple

NPR None 2 1

PDFI (mo) Absent 1-12 >12

Stages? 11 IIIA IlIB IIIAB IV node

Node status Negative Positive

LDFI (mo) Absent 1-12 > I2

<41.5"C 241.5"C

<41.5"C r41.5"C

Minimum temperature (mean, 4 1.3"C)

Maximum temperature (mean, 41.7"C)

Drug dose (mean, 0.97) <SD r S D

Drug schedule Bolus Fractionated

40 76

24 92

16 100 10 58 32

31 85

40* 76

40* 43 33

5 41 27 21 22

46 70

40" 48 28

37 79

21 95

53 63

46 70

NL: number of lesions; NPR: number of previous relapses; PDFI: prior disease-free interval; LDFI: last disease-free interval; SD: standard dose.

* Forty patients had a primary melanoma and synchronous locore- gional metastases.

t M. D. Anderson classification.

recurrent melanoma of the extremities was treated with HAP. Clinical charts and routine follow-up records were reviewed systematically. A retrospective-prospective computerized data base included potential variables likely to influence the clinical course of the disease.

Selection of the variables to be statistically analyzed was based on the following: (1) personal experience with

Patients

Only 1 16 patients were evaluated by statistical analysis. Their distribution according to clinical features has been summarized in Table 1. There were 40 men (34.5%) and 76 women (65.5%) with a mean age of 52 years (age range, 19 to 84 years). The lower limb was affected in 100 patients (86%) and the upper limb in 16 ( 1 4%). The median follow- up time was 68 months.

Stages: The M.D. Anderson Hospital and Tumor In- stitute staging system was adopted. l9 Twenty-two patients had in-transit recurrent melanoma but were subsequently classified as Stage IV because routine intraoperatory bi- opsy specimens of pelvic nodes showed metastatic in- volvement (Stage IV node).

Number of lesions (NL): On admission, 85 of 116 pa- tients (73.3%) had multiple lesions. Complete information regarding the number of lesions and their anatomic lo- cation (dermal or subcutaneous) was not available for all of these patients. Therefore, a further stratification could not be made. The second group included 31 patients (26.7%) with single nodules, although six had undergone excisional biopsy before HAP.

Lymph node status: Seventy patients (60.4%) had lymph node involvement that was regional in 48 patients and extraregional (pelvic nodes) in 22.

Number of previous relapses (NPR): Forty patients (34.5%) had an intact primary tumor and synchronous locoregional spreading of disease (NPR = 0). Forty-six patients (39.7%) were referred to because of their first re- lapse after definitive surgical treatment of the primary tumor; subsequent multiple recurrences developed in 30 patients (25.9%) after surgery alone (20 patients), surgery combined with radiotherapy (five patients), or systemic adjuvant chemotherapy (six patients) (NPR 2 1).

Time interval variables: The following two distinct time variables were calculated (months): ( 1) prior disease-free interval (PDFI) between the primary treatment and the first recurrence, and (2) last disease-free interval (LDFI) calculated from the date of the last treatment until the last relapse.

Both the PDFI and the LDFI were reported as contin- uous variables but the overall range was divided into 6- month to 24-month periods. The entire population was subdivided according to the resulting cut points and was analyzed preliminarily for differences in survival curves. The categories with similar results were then combined according to the arrangement that separated the subgroups with the highest statistical significance (Table 1).

Exclusion criteria: Twenty patients were excluded from the analysis of survival because of either postoperative

No. 12 PROGNOSTIC FACTORS IN PERFUSED RECURRENT MELANOMA - Di Filippo et al. 2553

death (eight cases) or the presence of distant metastases at the time of admission (12 cases).

Treatment

The surgical treatment of HAP has been reported pre- viously in detail,"-13 so only the major treatment variables will be described.

Melphalan was routinely used. Standard dosages were electively calculated on the basis of the actual body weight (0.8 and 1.5 mg/kg bw for the upper and lower limbs, respectively). However, a total dose of 80 mg for the upper limb and 120 mg for the lower limb was never exceeded. As a result, 24 obese patients received a lower pro kg dose of melphalan. In addition, the drug dose was decreased in six patients with a single lesion excised just before HAP, nine patients older than 70 years of age, four patients with a mild to moderate lymphedema after previous node dis- section, three patients with a history of thrombophlebitis, and seven patients with associated systemic diseases. Conversely, the dose of melphalan was increased in pa- tients with a high tumor burden or tumors resistant to previous radiotherapy and/or chemotherapy.

Overall, the dosages administered ranged between 0.6 and 1.3 mg/kg (mean, 0.9 mg/kg) for axillary perfusions and between 0.7 and 2.2 mg/kg (mean, 1.4 mg/kg) for lower limb perfusions.

For statistical purposes, the ratio between the actual and the standard dose was calculated and the patients were subgrouped according to the value obtained (Table 1). The total amount of the drug was administered non- randomly by bolus injection or in fractionated doses at 5-minute intervals.

Melphalan was injected directly into the oxygenator of the extracorporeal circuit when the entire limb reached a homogeneous temperature considered adequate to main- tain a steady state. The minimum tumor temperature (minT) and maximum tumor temperature (maxT) were monitored by multiple thermocouple probes inserted into the subcutaneous, muscular, and neoplastic tissues (mul- tichannel system; Data Logger Fluke Model 2.200 B, John Fluke Mfg. Co. Inc., Everett, WA). The range between 4 1.5"C and 4 12°C was considered optimal and was elec- tively used. However, a minT of 41.5"C or greater was achieved in only 68% of the patients (Table 1). There was no correlation between the temperature achieved and the site of the disease, either proximal (arm or thigh), inter- mediate (forearm or leg), or distal (hand or foot).

This observation suggests that variances in regional heating were likely to derive from differences in the per- fusional blood flow or in the vascular distribution within the limb, which was either natural or influenced by pre- vious surgical treatments.

Secondary debulking surgery was performed. Clinically involved nodes were always removed with axillary and

pelvic dissection at the time of the perfusion. whereas groin dissection occurred after 20 to 30 days. In-transit metastases were not excised if they completely disappeared macroscopically; otherwise, they were removed at the time of their presumed greatest reduction (approximately 20 to 30 days after HAP).

Systemic adjuvant chemotherapy was never adminis- tered.

Statistical Methods

The probability of a complete response (CR) after HAP according to tumor and treatment-related variables was initially analyzed by either the chi-square or Fisher's exact test. Selected variables with demonstrated predictivity were then evaluated for possible interrelationships using the multivariate logistic model2' (a stepwise selection based on the maximum likelihood ratio identified the most significant set of categoric variables influencing the proportion of CR).

The individual disease-free and overall survival intervals were calculated from the date of the HAP through De- cember 3 1, 1986. Four patients lost to follow-up and two patients who died of intercurrent disease were censored at the time of their last follow-up.

Survival curves were constructed according to the life table method" and the differences among categories within each variable were evaluated by means of the Lee- Desu test.22 None of the 69 patients evaluable for tumor response experienced a relapse or died within the first 30 postoperative days.23 Therefore, the survival rates in this group could be analyzed in relation to the observed re- sponse. A multifactorial analysis was then performed using the Cox proportional hazard with a stepwise method similar to that used for the logistic model with a tolerance value of P = 0.05.

Data were processed using the SPSSX (SPSSX Inc., Chicago, IL) and the BMDP (BMDP Statistical Software, Los Angeles, CA) statistical packages implemented on the Sperry 11 (Speny Corp., Blue Bell, PA)

Results Therapeutic results were evaluated in terms of tumor

response, locoregional control, disease-free survival, and overall survival. The incidence of local failure and distant metastases was referred to the site of the first relapse after HAP (these were distinctly reported to demonstrate the possible positive influence of locoregional control on the outcome of the disease). Treatment toxicity was then evaluated.

Tumor Response Tumor response, according to the World Health Or-

ganization (WHO) criteria2' and/or as a histologic per- centage of necrosis, was evaluated in 69 patients with

CANCER June 15 1989 Vol. 63

TABLE 2. Distribution of Patients According to the Degree of Response* and Stage of Disease

Total Total Stage CR PR S D DP (evaluable) (not evaluable) Total

II 4 0 0 0 4 1 5 IIIA 14 16 0 1 31 10 41 IIIB 1 7 0 0 8 19 27 IIIAB 4 6 3 1 14 7 21 IVnode 4 1 6 1 12 10 22

Total 27 30 9 3 69 47 116

Percent 39.1 43.5 13.0 4.4

CR: complete response; PR: partial response (regression > 50%); SD: stable disease (25% =s regressoin < 50%); DP: disease progression (regres- sion < 25%).

* According to World Health Organization criteria.

TABLE 3. Distribution of Complete Responses According to Clinical and Theraueutic Factors: Univariate Analvsis (69 Evaluable Patients)

No. of Variable Daticnts % CR P

Clinical Sex

Male Female

Age (yr) <40 240

Lower limb Upper limb

Single Multiple

Node status Negative Positive

Absent 1-12 >I2

NPR None 2 1

LDFI Absent 1-12 >12

Site

NL

PDFI

Treatment Minimum temperature

<41S°C r41S°C

<41.5"C r41.5"C

<SD 2SD

Schedule Bolus Fractionated

Maximum temperature

Dose

22 47

13 56

59 10

16 53

35 34

18 30 21

18 51

18 35 16

23 46

15 54

31 38

27 42

36.4 40.4

23.1 42.9

33.9 70.0

87.5 24.5

51.4 26.5

27.8 43.3 42.9

27.8 43.1

27.8 45.7 37.5

21.7 47.8

26.7 42.6

27.6 47.4

29.6 45.2

0.48 -

0.16 -

0.04 -

<O.o001 -

0.03 -

0.52 - -

0.19 -

0.44 - -

0.03 -

0.20 -

0.08 -

0. I4 -

CR: complete response; NL: number of lesions; PDFI: prior disease- free interval; NPR: number of previous relapses; LDFI: lost disease-free interval; S D standard dose.

measurable disease. Thirty-five patients had in-transit le- sions. The response of regional node metastases was eval- uated in 22 of 48 patients who underwent a delayed groin dissection. In addition, 12 patients with pelvic node in- volvement were examined for tumor response because of measurable in-transit lesions (Table 2).

A CR was observed in 27 patients (39.1%). A partial response occurred in 30 patients (43.5%). Nine patients (1 3.0%) had a tumor regression of less than 50% and only three patients (4.4%) had disease progression (Table 2).

The univariate analysis showed a strong correlation be- tween the number of lesions and the probability of tumor response (Table 3). In fact, 14 of 16 patients with a single nodule had a CR (87.5%), whereas this was achieved in only 13 of 53 patients (24.5%) with multiple lesions ( P < 0.00 1). Also, a lower but statistically significant predic- tive valut was observed for the site of the disease and the node status. Of the treatment-related variables, the minT was statistically significant. The percentage of CR was higher in patients with a minT of4 1.5"C or greater (47.8%; Y = 0.03), as compared with patients with a minT of less than 41.5"C (21.7%). A positive trend was observed for the drug dose ( P = 0.08), with 47.4% of CR in patients who received a dose greater than or equal to the standard dose versus 27.6% of CR in those who received a dose less than the standard dose (Table 3).

Possible correlations among these predictive factors were explored using the logistic model. Of the clinical variables, only the number of lesions maintained a sig- nificant predictive value (P < 0.000 1). Similarly, when the treatment variables were matched, only the min'1 (I' = 0.0 13) entered the model. This confirmed that the op- timal temperature should always exceed the threshold of 41.5"C for the entire period of the treatment.

To further investigate the influence of the antineoplastic drug, the proportion of CR was calculated within cate- gories defined by cross tabulating the minT and the mel- phalan dose (Fig. 1). The percentage of CR after treat- ments performed with a minT of less than 4 1.5"C and a dose less than the standard dose was 16.7%, which rose to 20.0% (+3.3%) in patients treated with a dose greater than the standard dose and to 35.3% (+l8.6%) in those treated with a minT of 41.5"C or greater. The proportion of CR was 57.7% (+41%) after treatments performed with a minT of 41.5"C or greater and a dose greater than or equal to the standard dose. The total improvement was significantly higher (P = 0.02) than that expected in the event of an additive relation (+3.3% and +18.6%; i.e., 21.9%), suggesting the presence of a synergistic effect (Fig. 1).

When the two sets of clinical and treatment variables were combined, the final model showed that both the number of lesions and the minT maintained their indi- vidual predictive values (P < 0.0001 and P = 0.04, re- spectively). This indicated that in groups of patients ho-

No. 12 PROGNOSTIC FACTORS IN PERFUSED RECURRENT MELANOMA * Di Filippo et al. 2555

c Q Q -

3 0 -

10-

0 u

0

8 L. 50 - A*= 186

4 3 3 -

A =41

10-

n

- A NL.32 NL=l -

1 1 1 I I I

minT c41.5 = 41.5 3 41.5 a41.5 d m cS.D 3 S . D c S.D 3 S . D

FIG. 1. Proportion of complete responses according to treatment factors (minimum temperature and dru! dose).

mogeneous for the number of lesions, the higher temper- ature significantly increases the probability of a CR. The predicted proportion for patients with a single lesion was 74.2% using a minT of less than 41.5"C versus 91.9% with a minT of 4 1.5"C or greater. The corresponding fig- ures for patients with multiple lesions were 10.7% versus 32.3% (Fig. 2). The goodness of fit test for the final model gave a value of P = 0.056, which could be considered satisfactory given that the limited number of cases deter- mined a low frequency (4) in four of the eight categoric cells.

Locoregional Control

The first site of relapse after completion of treatment was locoregional in 32 of 116 evaluable patients (27.6%) (Table 4). One patient had a local recurrence, 2 1 patients had in-transit metastases, and ten patients had femoral node relapses. All of the recurrences occurred within 36 months after HAP (Fig. 3). For the entire series, the 5- year actuarial rate for the disease-free interval was 6 1 .O%. The influence of each categoric variable was statistically evaluated by means of the Lee-Desu test.

Of the clinical factors considered, only the number of lesions had a significant predictive value, with a 5-year local control rate that was higher in patients with a single lesion (87%; P = 0.001) than in patients with multiple lesions (49.7%) (Table 5 ) . No direct correlation was found between the treatment-related variables and locoregional control (Table 5). However, the 5-year rate was signifi- cantly higher in patients who had a complete tumor re- sponse (77%; P = 0.007), compared with those who did

10 30 50 70 90 Predicted

FIG. 2. Results of the logistic model matching clinical and treatment factors in relation to observed and predicted complete tumor response. A: minT of41.5"C and multiple lesions; B: minT of41.5"C and multiple lesions; C: minT of 41.5"C and a single lesion; D: minT of 41.5"C and a single lesion.

not (37.7%). This provided indirect evidence of the role of the treatment (i.e., the minT and drug dose), together with the number of lesions, in significantly and indepen- dently influencing the proportion of CR (Fig. 4).

Distant Metastases

Distant metastases developed as the first site of relapse in 41 of 116 evaluable patients (35.3%) (Table 4). Almost 70% of these occurred within 12 months after HAP (Fig. 3), with a corresponding 5-year disease-free rate of 52.3%. In only one of 4 1 patients (2.4%) did regional metastasis develop after the systemic one. Despite excellent local control, that patient had a dismal prognosis most likely due to subclinical systemic disease at the time of the HAP.

The univariate analysis failed to show any predictive factor of distant failure among those evaluated. The only

TABLE 4. Distribution of Patients According to the Site of First Relapse and Stage of Disease

Local Distant No Stage recurrence metastasis recurrence Total

I1 0 1 4 5 IlIA 10 10 21 41 IIIB 6 12 9 21 IIIAB 10 6 5 21 IV node 6 12 4 22

Total 32 41 43 116

2556 CANCER June 15 1989 Vol. 63

A lqcal rocurrance distant metastasis

1 1 1 f i 1 1 1 1

10 30 50 70 90 110 Postoperative time (months)

FIG. 3. Timing of local recurrences (32 patients) and distant metastases (4 I patients) after HAP.

variables with a positive trend were the node status and the number of previous relapses. The 5-year distant dis- ease-free rate was 40.8% for patients with node involve- ment, as opposed to 69.5% for those without node in- volvement (P = 0.08). The corresponding figures were 33.9% for patients with synchronous metastases and 59.7% for those with metachronous recurrences ( P = 0.07).

Survival

Table 5 reports the following results of the univariate

1. Women had a higher overall survival rate than men

2. The presence of multiple lesions negatively affected both the disease-free survival (P = 0.001) and the overall survival (P = 0.006) rates, confirming the greater impor- tance of this prognostic factor.

3. Patients with node metastases had both a shorter disease-free survival (P = 0.03) and overall survival (P = 0.01) rate, as compared with the other group.

4. The general test on the differences between stages demonstrated a significant predictivity for both overall survival (P = 0.04) and disease-free interval (P = 0.03). These figures were stressed by matching the Stage IIIA and Stage IV nodes for both disease-free survival (P = 0.01) and overall survival (P = 0.003) rates, whereas only the disease-free interval was significantly longer for Stage IIIB as compared with Stage IV (P = 0.02);

5. Patients perfused for primary melanomas with si- multaneous locoregional spreading had shorter survival

analysis, as far as clinical factors are concerned:

(P = 0.01).

rates than those with a metachronous recurrence (P = 0.07 and P = 0.002 for disease-free survival and overall survival, respectively).

6. The PDFI and the LDFI were found to be predictive for the overall survival ( P = 0.004 and P = 0.001, re- spectively). The differences were stressed by comparing the groups with absent intervals (synchronous metastases) with those with intervals of nore than 12 months (meta- chronous relapses), with P = 0.001 and P = 0.003 for the PDFI and the LDFI, respectively. All of the other pairwise comparisons showed significant differences, with the ex- ception of the group with a PDFI of greater than 12 months as opposed to the group with a PDFI of less than 12 months. Regarding disease-free survival, the general test was not significant for either the PDFI or the LDFI, although the differences between the first category (absent

TABLE 5. Univariate Analysis of Clinical Parameters: 5-Year Locoregional Control, Disease-Free Survival, and Overall Survival

Sex Male Female

Age (yr) <40 >40

Lower limb Upper limb

Single Multiple

Node status Negative Positive

Stage I1 IIIA IIlB IIlAB IV node

NPR None > I

PDFI

Site

NL

Absent 1-12 >I2

LDFI Absent 1-12 >12

55.3 (0.23) 63.9 -

58.0 (0.42) 61.7 -

61.9 (0.63) 57.8 -

87.0 (0.001) 49.7 -

70.0 (0.21) 54.3 -

100.0 (0.14) 65.7 - 65.8 - 38.2 - 58.5 -

46.3 (0.50) 66.4 -

46.3 (0.16) 56.6 - 79.9 -

46.3 (0.35) 58.7 - 78.7 -

25.4 (0.16) 29.3 35.1 - 51.2

21.9 (0.1 1) 39.1 34.4 - 44.4

30.7 (0.53) 39.3 37.0 - 62.2

55.7 (0.001) 70.5 22.5 - 32.1

48.5 (0.03) 58.2 22.0 - 33.9

80.0 (0.03) 80.0 43.7 - 54.5 26.6 - 47.3 23.8 - 35.4 14.6 - 15.9

15.6 (0.07) 21.9 39.4 - 54.6

15.6 (0.13) 21.9 36.1 - 47.8 43.9 - 64.4

15.6 (0.08) 21.9 36.7 - 48.5 44.0 - 67.3

(0.01) -

(0.41) -

(0.20) -

(0.006) -

(0.01) -

(0.04) - - - -

(0.002) -

(0.004) - -

(0.001) - -

LRC: locoregional control; DFS disease-free survival; OS overall sur- vival; NL: number of lesions; NPR number of previous relapses; PDFI: prior disease-free interval; LDFI: last disease-free interval.

* Either locoregional relapse or distant metastasis.

No. 12 PROGNOSTIC FACTORS IN PERFUSED RECURRENT MELANOMA - Di Filippo et al. 2557

gOl intervals) and the last category (intervals > 12 months) were significant (P = 0.05 and P = 0.03, respectively).

No direct correlation was found between therapeutic variables and long-term survival. However, the 5-year disease-free survival rate was significantly higher in pa- tients who had a CR after HAP (55.6%; P = 0.006), as compared with those who did not (16.9%) (Fig. 5) . Sim- ilarly, the 5-year overall survival rate was significantly higher in patients who had a CR (68.6%; P = 0.03), as compared with patients who did not (32.8%) (Fig. 6).

The impact of locoregional control on survival was in- vestigated in the group of 80 patients with a follow-up period of longer than 36 months. Of course, the survival intervals were calculated from the time of the HAP. The survival rate was significantly higher in 56 patients who did not have regional failure after HAP (5-year rate, 55%; P = 0.03), as compared with 24 patients who experienced a relapse (5-year rate, 15.6%). This indicated that locore- gional control positively affected prognosis (Fig. 7).

-5 77.0

Multivariate Analysis

Two distinct regressions were carried out (Cox model), including the entire series of 1 16 patients and the subgroup of 69 patients evaluable for tumor response. Table 6 pre- sents the relative importance of single factors on the dis- ease-free survival and overall survival before adjustments for the other factors, the improvement given by each vari- able on entering the model, and the global goodness of fit.

Disease-Free Survival

As far as the basic series is concerned, the initial step analysis confirmed the predictive value of the variables selected by the univariate analysis. Moreover, the LDFI (considered here as a continuous variable) and the number of previous relapses became statistically significant. How- ever, the number of lesions remained the most predictive factor and when it entered the model, all of the other variables lost their significance.

The initial step analysis in the subgroup of 69 patients evaluable for tumor response showed similar results. However, tumor response (the additional variable) had the lowest P value. When it entered the model, the number of lesions and all of the other factors lost their significance (Table 6).

Overall Survival

At the initial step analysis rather overlapping results were found within the basic series and the subgroup of 69 patients, despite discrepancies in the P values of some predictive variables, determining a different order for the stepwise selection. When the entire series was considered, the set of variables, independently related to overall sur-

14

complae I

37.1

non complete

" P E 0.007 A 10

I I I 1 I 1 I 1

12 36 60 84 100 Time tmont hs)

FIG. 4. Actuarial curves showing locoregional control according to tumor response (complete versus noncomplete).

vival, included sex, the number of lesions, and the number of previous relapses. In contrast, only sex and tumor re- sponse entered the final model that evaluated the subgroup of 69 patients.

It should be emphasized that the number of lesions entered the final model for both disease-free survival and overall survival when the tumor response was not avail-

: 50

?! 30 a

I

complete

16.9 non complete

I I I I I I I I 1

12 36 60 a4 100 Time (months)

FIG. 5 . Actuarial curves of disease-free survival according to tumor response (complete versus noncomplete).

2558

~ ~ 0 . 0 3

CANCER June 15 1989 Vol. 63

70

aJ c E 50-

2 * 3 3 0 -

- a w .-

10

g0157- 70

.. - -

..

. =

non complete I

able. When the two variables were considered simulta- neously, the Cox model selected tumor response rather than the number of lesions as the dominant prognostic factor. Because it was demonstrated that the number of lesions and the treatment independently influenced the tumor response, these results indicated that the optimal treatment (minT 2 41.5"C and drug dose 2 standard

g°Fb,

I I I I I I I I 1 1

12 36 60 84 100 Time tmont hs)

FIG. 7. Actuarial curves of overall survival according to locoregional control after HAP in the series of patients with a follow-up of longer than 36 months.

TABLE 6. Multivariate Analysis of Prognostic Factors on Disease- Free Survival and Overall Survival.

Disease-free Overall

Single Single term term

Set of parameters P value ment P value ment Step 0 improve- Step 0 improve-

Basic series ( I 16 patients) Sex Age (yr) Site NL Node status NPR PDFl LDFI Goodness of fit

Subgroup with evaluable response (69 patients)

Sex

Site NL Node status NPR PDFl LDFI Tumor response Goodness of fit

Age (yr)

0.1971 0.1831 0.5679 0.0011 0.0011 0.0121 0.0392 0.1136 0.035 I

0.002

0.0149 0.0488 0.4877 0.1454 0.0014 0.0014 0.0147 0.0019 0.0101 0.0648 0.0103

o.Oo01

0.1479 0.0033 0.0033 0.0925 0.1045 0.1882 0.0407 0.0142 0.0402 0.0324 0. I392 0.0958 0.0 I08 0.0738 0.0723 0.075 I 0.0295 0.0034 0.0034 0.0148 0.0207

0.004 0.001

N L number of lesions: NPR: number of previous relapses; PDFI: prior disease-

Tolerance value of P = 0.05. free interval: LDFI: last disease-free interval.

dose) influenced the overall survival by providing the highest rate of CR within categories of patients stratified according to the lesions.

Toxicity

Eight of 136 patients (6%) died postoperatively (five of cardiovascular failure, two of acute hepato-renal failure, and one of septicemia). All of these patients had been treated previously with chemotherapy for either Stage IIIAB melanoma (four cases) or Stage IV melanoma (four cases). Of the remaining patients, both systemic and local side effects were infrequent and mostly mild to moderate in grade (Table 7). Severe but transient hemopoietic tox- icity occurred in only 16 patients (12%), despite the high dosages of melphalan used, since leakage during perfusion was always in the 0% to 9% range.

Arterial thrombosis requiring amputation occurred in four patients (3%) (Stage IIIA, two cases; Stage IIIAB, two cases). Twelve patients (9.3%) who had thrombophlebitis or venous thrombosis recovered within 15 to 20 days. Wound infection was observed in 16 patients (12%), with dehiscence in only seven (Table 7). The incidence of both systemic and local side effects was similar in groups of patients stratified according to treatment variables, indi-

No. 12 PROGNOSTIC FACTORS IN PERFUSED RECURRENT MELANOMA - Di Filippo et a/. 2559

TABLE 7. Local and Systemic Complications

Temperature Dose Schedule No. of

patients <41.5"C r41.5"C <SD rSD Bolus Fractionated Complication (128) (n = 39) (n = 89) (n = 59) (n = 69) (n = 48) (n = 80)

Local toxicity Acute reaction*

Grade 1 Grade I1 Grade I11 Grade IV Grade V

Thrombophlebitis Venous thrombosis Arterial thrombosis

Infection Deiscence

Vascular

Wound

Systemic toxicity Hemopoietic

3 4 5

Grade WHO

Cardiac Symptomatic

Renal disfunction Mild Moderate

Broncho-pneumonia Infection HeDatitis

2 108

15 2 1 (1)t

11 1 4 (4)t

16 1

29 15

1

3

4 1

6 6 1

2.1% 15.1% 18.9% 2.7% -

10.3% 2.6% 2.6%

17.9% 5.1%

20.6% 1.7% 2.6%

-

2,6% - 2.6% 1.1% -

1.2% 87.4% 9.0% 1.2% I .2%

1.3%

3.4% -

10.1% 5.6%

23.6% 13.5% -

3.4%

3.4% I .2%

5.6% 3.4% I .2%

- 9 1.5%

8.5% - -

6.8%

3.4% -

13.6% 6.8%

22.0% 11.9% -

-

- - 3.4% 3.4% -

3.0% 2.1% 18.0% 81.2% 14.5% 14.6% 3.0% 2.1% 1.5% -

8.7% 16.7% 1.5% 2.1% 2.9% 4.2%

10.1% 16.7% 4.3% 10.4%

17.4% 22.9% 1.3% 6.3% 1.5% 2.1%

3.0% -

4.3% - 1.5% - 5.8% 2.1% 4.3% 2.1% 1.5% -

1.3% 87.3%

8.8% 1.3% 1.3%

2.5%

2.5% -

8.8% 2.5%

20.0% 12.5% -

2.5%

5.0% 1.3%

6.3% 5.0% 1.3%

SD: standard dose; WHO: World Health Organization. * According to Wieberdink's classification.

cating that the higher temperatures and drug dosages did not increase treatment complications. Conversely, the in- cidence of moderate to severe acute limb reaction (Wie- berdink's criteria2') was higher in Stage IIIAB patients (33%; P = 0.01), as compared with all of the other groups ( 1 1 %).

Discussion

During the last 20 years, numerous prospective clinical trials using HAP with melphalan have been camed out. Results have confirmed the therapeutic effectiveness of this technique, showing its superiority to conventional therapie~. '~ , '~-~~ The rates obtained using HAP, with re- gard to both local control and survival, are so much higher that surgical treatment alone might be considered uneth- ical, particularly in the presence of satellitosis or in-transit lesions.

Although the overall results obtained in several centers may be considered satisfactory, great differences in sur- vival rates have been reported. Stehlin et aL3' and Martijn

t Four amputated cases.

et al." obtained 5-year overall survival rates of 8 1 % and 50%, respectively, in patients at Stage IIIA, whereas the corresponding figures for Stage IIIB were 54% and 46%. The 5-year survival rates observed in our series were sim- ilar (54.5% and 47.3%, respectively). Conversely, Kre- mentz reported a less satisfactory survival rate for Stage IIIA (25%) patients than for Stage IIIB (50%) patients.32

The reasons for these discrepancies have never been investigated. Differences might derive from either heter- ogeneity in patient populations or substantial differences in the treatment protocol.

Controlled clinical trials exploring potential ways to optimize the association of hyperthermia and drugs have not yet been performed. Some authors claimed that per- fusate and tissue temperature must be kept in the range of 39°C to 40°C to avoid major local complications and drug inact ivat i~n.~ ' .~~ In our experience, temperatures of greater than 41.5"C did not increase the incidence of toxic effects (Table 7). Moreover, Briele et al. reported that al- though hydrolysis of melphalan proceeded rapidly at el- evated temperatures, there was little difference in its half-

2560 CANCER June 15 1989 Vol. 63

life within the range of 39°C to 43"C.35 For clinical pur- poses, the range between 41.5"C and 41.8"C could be regarded as preferable (in vitro experimental studies have shown that the cytotoxicity potentiation of alkylating agents such as melphalan is directly correlated to the tem- p e r a t u r e ~ . ~ ~ - ~ ~

Moreover, in vivo studies have shown that a tempera- ture of greater than 4 1 "C gives the double advantage of permitting both the enhancement of drug cytotoxicity (direct action) and the microenvironmental phenomena after the local heating of neoplastic tissues (indirect action; i. e., tumor vasoparalysis and c ~ l l a p s e ) . ~ ~ , ~ '

Despite these experimental data, there is still consid- erable uncertainty regarding the clinical use of tempera- tures greater than 41°C to 41.5"C. The only study ex- ploring the therapeutic impact of variances in regional heating was reported by Mikhail et aL4* Their results failed to show a significant correlation between the maximum temperature applied (92°F to 106°F) and the survival rates of locoregional control in 156 patients with Stage I limb melanoma.

The main purpose of our retrospective study was to analyze the response of recurrent melanomas to the HAP treatment as a function of the minimum and maximum temperatures achieved, the drug dosage, and the admin- istration technique. Both the univariate and multivariate analyses showed that the minimum temperature was in- dependently predictive of tumor response. The drug dos- age was marginally significant. However, a significant in- crease in the number of CR was found in the group of patients treated simultaneously with a minT of 41.5"C or greater and a drug dose equal to or greater than the standard dose, as compared with the other groups treated with different combinations. This increase was higher than that expected from an additive action of hyperthermia and melphalan, suggesting the presence of a synergistic effect.

Because tumor aggressiveness also is crucial in deter- mining the outcome of the disease, the potential prog- nostic value of available clinical variables was explored. Different sets of variables were statistically predictive, de- pending on the end point considered.

The number of lesions was the most significant factor for both tumor response ( P < 0.0001) and long-term lo- coregional control ( P = 0.00 1). However, when treatment and clinical variables were matched, the minimum tem- perature maintained its predictive value for tumor re- sponse. Although the minimum temperature did not di- rectly influence the long-term results, a CR was highly predictive for locoregional control (P = 0.007), disease- free survival (P = 0.006), and overall survival (P = 0.03). Moreover, locoregional control positively affected (P = 0.03) the overall survival.

Overall survival appeared to be influenced by all of the other clinical variables examined. However, the multi-

variate analysis demonstrated that only some factors had an independent predictive value: (1) sex, the number of lesions, and the number of previous relapses in the entire series; and (2) sex and tumor response in the subgroup evaluated for immediate regression.

In conclusion, complete tumor response positively af- fected both locoregional control and long-term survival. Therefore, treatment optimization may provide further therapeutic improvements by increasing the probability of tumor regression. In our experience, a temperature of greater than 41.5"C and a higher than standard drug dos- age strongly correlated with a higher proportion of CR.

Tumor aggressiveness also was crucial in determining the outcome of the disease. The earlier the locoregional treatment was initiated, the better the prognosis because of a lesser probability of distant subclinical disease. There was no significant predictive factor for distant metastases among those evaluated, indicating that other variables are responsible for systemic dissemination. Unfortunately, we could not evaluate the relevance of other potential prog- nostic factors such as tumor u l~era t ion ,~"~ the number of positive node^$^^'^,'' and dermal or subcutaneous location of in-transit meta~tases .~~ In addition, a further stratifi- cation of patients according to the number and size of the lesions would have provided additional information.

Due to the obvious limitations of a retrospective study, definitive conclusions cannot be made. However, our re- sults demonstrate that patients who did not have a CR to HAP had the worst prognosis. Prospective clinical trials must be conducted to define treatment optimization (by exploring drug-hyperthermia dosimetry, duration, and scheduling more extensively) and evaluate the impact of treatment optimization on the survival of patients ho- mogeneously stratified according to clinical prognostic factors.

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