The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion

The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with... Ann Surg Oncol (2018) 25:1836–1842 https://doi.org/10.1245/s10434-018-6459-9 O R I G IN AL ARTI CL E – MELA NO MA S The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion Dimitrios Katsarelias, MD, PhD, Erik Ra˚dbo, MD, Ilan Ben-Shabat, MD, Jan Mattsson, MD, and Roger Olofsson Bagge, MD, PhD Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden ABSTRACT Conclusions. Modern ILP uses diminished perfusion time Background. Isolated limb perfusion (ILP) is used to treat and lower temperature, leading to a decrease in toxicity. in-transit metastases of melanoma of the extremities when However, our data also show a decrease in response, which surgical excision is not possible. The optimal setting con- indicates that optimal perfusion time and temperature cerning temperature and perfusion time is unknown. The regimen remain to be determined. purpose of this study was to analyze these factors con- cerning their effects on response, toxicity, and survival. Methods. A retrospective analysis of 284 consecutive BACKGROUND stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period Approximately 5–10% of patients with recurrence of (July 1986–May 2017), was performed. Our series was malignant melanoma develop lymphatic dissemination divided in four time periods, according to perfusion tem- manifested as in-transit metastasis. The initial treatment perature and duration. Demographical data, stage, number, option is surgical excision; however, in case of numerous and size of lesions were retrieved from our prospective lesions or short intervals between the appearances of new database. lesions, alternative treatment modalities should be Results. Overall response (OR) rate 83% and a complete considered. response (CR) rate of 59%. Significant predictive factors The technique of isolated limb perfusion (ILP) was for CR in multivariate analysis were non-bulky tumor, pioneered in the 1950s by Creech and Krementz. Com- fewer metastases, and a perfusion time of 120 min. Pre- pared with systemic administration, ILP achieves very high dictive factors for increased local toxicity were femoral tissue concentrations of the alkylating agent melphalan. An ILP and higher perfusion temperatures. The median overall early pharmacokinetic study using melphalan in an ILP survival was 30 months, and the independent negative setting showed that high peak perfusate concentrations prognostic factors were lymph-node status, bulky tumors, were achieved (6–115 mg/ml) and that these levels could response, upper limb perfusion, and 120 min perfusion at be 20–100 times higher than the peak levels achieved with 39–40 C. the usual intravenous doses of melphalan. In 1967, Cavaliere reported the effects of ILP using only hyper- thermia in 22 patients with recurrent extremity tumors. The duration of hyperthermia ([ 40 C) ranged from 50 min to Dimitrios Katsarelias and Erik Radbo have contributed equally to this almost 7 h. Twelve of the patients were alive without work. evidence of disease at 3–28 months of follow-up. In 1969, Stehlin increased perfusion time from 45 to 120 The Author(s) 2018. This article is an open access publication min and heated the perfusate to 46.1 C. Together with First Received: 19 February 2018; externally applied heat and wrapping, they reached skin Published Online: 15 May 2018 temperatures of 42.2 C. These changes resulted in higher R. Olofsson Bagge, MD, PhD tumor response but also increased complication rates. The e-mail: roger.olofsson@surgery.gu.se Temperature and Perfusion Time in ILP 1837 method has since then been refined and current results for approach for the lower extremity (Table 1). Limb isolation ILP with melphalan (M-ILP) show overall response rates was achieved through clamping and cannulation of the (ORR) ranging between 65 and 100%, with a complete major artery and vein for the extremity under treatment. response (CR) rate between 25 and 76%. The cannulas were connected to an oxygenated extracor- In Sweden, ILP treatment was initiated in the 1970s. poreal circuit. From October 2000, continuous leakage Initially, the perfusion time was 120 min with a tissue monitoring was performed using a precordial scintillation temperature of 41–41.5 C (true hyperthermia), which in probe (Medic View, Sweden) to detect and measure leak- 2002 was lowered to 39–40 C. The perfusion time was age of technetium-99m labelled human serum albumin lowered to 90 min in 2006 and then finally to 60 min in (Vasculosis, Cis-Bio International, Gif-sur-Yvette, France), 2012 keeping perfusions temperature between 39 and which was injected into the perfusion circuit. The dose of 40 C (mild hyperthermia). The administration of mel- melphalan was calculated as 13 mg/L perfused tissues for phalan was also changed, from three bolus doses, in the upper limb and 10 mg/L perfused tissues for lower limb. earlier periods, to 20 min infusion in 2012, and this is still in use in our practice. Time Periods The purpose of this study was to analyze retrospectively the effect of temperature lowering and diminishing of Between 1986 and 2002, the perfusion time and the perfusion time on response, toxicity, and survival for highest tissue target temperature was 120 min and melanoma patients with in-transit metastases treated with 41–41.5 C respectively. In 2002, this was changed to 120 melphalan-only ILP in our institution. min at 39–40 C, and this temperature was then used onward. In 2006, the total perfusion time was decreased to PATIENTS AND METHODS 90 min, and in 2012, the perfusion time was further decreased to 60 min. Before 2012, the melphalan was given Patients as three bolus doses, with 50% of the total dose adminis- tered initially and the remaining 50% administered in two Over a 31-year period (July 1986–May 2017), a total of equivalent doses at 30-min intervals (total 60 min). In 2012, the administration of melphalan was changed into a 284 consecutive patients with in-transit metastases of malignant melanoma (stage III), were treated with ILP for 20-min infusion in the perfusate, followed by 40-min the first time in our institution. In the beginning of this perfusion. study period, TNF-alpha was not available, and patients who later received TNF-alpha due to bulky melanoma were Response excluded not to induce a further bias between the treatment groups. There were 166 females and 118 males with a Clinical responses were evaluated and reported as the response at 3 months using the WHO criteria. For a median age of 70 years (range 23–95). A total of 171 patients (60.2 %) had in-transit metastases only (N2c), and response to be considered as a complete response (CR), all lesions should have been clinically not detectable at the 113 patients (39.8 %) had lymph node metastases (N3) before or at the time of ILP. Bulky melanoma (lesions[ 3 time of clinical examination. Partial response (PR) was defined as a clinical decrease of more than 50% of the total cm) was present in 36 patients (12.7%), and 88 patients (31.0%) had 10 or more lesions (Table 1). No patients tumor burden both in terms of number of lesions or received any adjuvant systemic therapies. diameter. Progressive disease (PD) was defined as an Baseline data, as well as data concerning response and increase of more than 25% in existing lesions or the toxicity, were retrieved from a prospectively kept database, appearance of new lesions not previously present. further completed with data from patient medical records. Stable disease (SD) was defined as a result where none of Data concerning survival was retrieved from the Swedish the abovementioned criteria for CR, PR, or PD were met. National Cause of Death Register. The study was approved by the Regional Ethical Review Board at the University of Local Toxicity Gothenburg (Dnr 721-08). Local toxicity was measured according to Wieberdink and classified from I to V, where I is no reaction, II slight ILP Technique erythema and/or edema, III is considerable erythema and/or The patients underwent ILP via an axillary, brachial, or edema with some blistering, IV is extensive epidermolysis subclavian vascular approach for upper extremity (n = 34) and/or obvious damage to deep tissues, and V induces a and via the external iliac (n = 99) or femoral (n = 151) reaction that may necessitate amputation. 1838 D. Katsarelias et al. TABLE 1 Patient and tumor characteristics perfusion time (120 min) under mild hyperthermia (39–40 C). In the multivariate analysis, both the number Sex of metastases, as well as longer perfusion time (120 min) at Female 166 (58.5%) 39–40 C, were proven statistically significant (Table 2). Male 118 (41.5%) For overall response, the only significant predictive factor Age. median (range), years 70.5 (23–95) was gender; males had a lower response (odds ratio = 0.43; N-stage (%) p = 0.02). N2c 171 (60.2%) N3 113 (39.8%) Toxicity Vessel (%) Upper extremity 34 (12.0%) Data on local toxicity was available in 270 patients Femoral 151 (53.2%) (95%). Reliable data were missing for 14 patients, and they External iliac 99 (34.9%) were excluded from the analysis. The distribution between Perfusion time/temp (%) Wieberdink grades through the entire 31-year period were: 60 min/ 39–40 C 91 (32.0%) grade I 4.4%, grade II 62.6%, grade III 24.4%, grade IV 90 min/ 39–40 C 86 (30.3%) 8.1%, and grade V 0.4%. In multivariate analysis com- 120 min/ 39–40 C 17 (6.0%) paring Wieberdink I–III versus IV–V, perfusion at 120 min/ 41–41.5 C 90 (31.7%) 41–41.5 C for 120 min (1986–2002) had a higher rate of Number of metastases (%) severe toxicity (grade III–V) with an odds ratio of 3.9 (p = 1 39 (13.7%) 0.04), whereas external iliac perfusions had a significantly 2–3 69 (24.3%) lower rate (OR 0.25; p = 0.03; Table 3). Similar results 4–10 81 (28.5%) were obtained in the multivariate analysis comparing [ 10 88 (31.0%) Wieberdink I–II versus III, where higher temperature Missing 7 (2.5%) (41.5 C at 120 min) had more grade III toxicity (OR 2.59, Largest metastasis (%) p = 0.05), whereas both external iliac and brachial perfu- Nodular (\ 3 cm) 237 (83.5%) sions had lower rates of grade III toxicity (brachial OR 0.22 Bulky ([ 3 cm) 36 (12.7%) p = 0.01; external iliac OR 0.23, p = 0.001) compared with Missing 11 (3.9%) femoral perfusions. Survival Statistical Evaluation Survival data were available for all 284 patients inclu- ded in the study. The 2, 5, and 10-year overall survival Overall survival (OS) was defined as the time from ILP (OS) was 64, 36, and 19% respectively, with a median OS to death or last follow-up. Survival estimates were made of 38 months. The median OS was 44 months in the 60-min according to the Kaplan-Meier method and prognostic ILP at 39–40 C group (2012–2017), 36 months for the factors for OS were analyzed using Cox regression. Pre- 90-min ILP at 39–40 C group (2006–2012), 47 months for dictive factors for response and toxicity were analyzed the 120-min ILP at 39–40 C group (2002–2006), and 30 using logistic regression. A p value\ 0.05 was considered months for the 120-min ILP at 41–41.5 C group statistically significant. All data were analyzed by using (1986–2002; p = 0.06; Fig. 1). In multivariate analysis, SPSS version 22 (SPSS, Chicago, IL). significant negative prognostic factors were increasing age, positive lymph-node status, bulky disease, brachial ILP, RESULTS and response after ILP and ILP for 120 min at 41–41.5 C (Table 4). When excluding response and toxicity from the Response survival analysis, the significant prognostic factors were age (HR 1.02, p = 0.047), positive lymph-node status (HR Clinical response was evaluable in 268 patients (94.4%). 1.52, p = 0.01), presence of bulky disease (HR 2.06, p = Two patients were not included due to early death (earlier 0.002), more than ten metastases (HR 1.85, p = 0.02), and than 3 months), and 14 patients were excluded due to lack ILP for 120 min at 41–41.5 C (HR 1.84, p = 0.02). of reliable response records. In total, 223 patients (83.2%) had an ORR, of which 167 patients (58.8%) had a CR. Significant predictive factors for CR in univariate analysis were a total number of metastases less than ten and a longer Temperature and Perfusion Time in ILP 1839 TABLE 2 Univariate and multivariate logistic regression of clinical predictive factors for complete response after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (year) 1.01 0.99–1.03 0.24 1.02 1.00–1.04 0.09 Gender (female vs. male) 0.86 0.58–1.58 0.86 0.82 0.46–1.47 0.51 N-stage (N2c vs. N3) 0.80 0.48–1.32 0.37 0.94 0.53–1.67 0.83 Size (nonbulky vs. bulky) 0.83 0.40–1.73 0.62 0.57 0.24–1.35 0.20 Number of lesions 11 1 2–3 0.56 0.20–1.59 0.28 0.54 0.18–1.63 0.28 4–10 0.38 0.14–1.03 0.06 0.32 0.11–0.93 0.04 [ 10 0.13 0.05–0.33 \ 0.0001 0.10 0.03–0.30 \ 0.0001 Vessel Femoral 1 1 Upper extremity 1.44 0.62–3.37 0.40 0.89 0.35–2.30 0.81 External iliac 0.88 0.52–1.50 0.63 0.74 0.35–1.55 0.42 Perfusion time/temp 60 min /39–40 C1 1 90 min /39–40 C 1.75 0.93–3.29 0.08 1.84 0.91–3.61 0.09 120 min /39–40 C 4.16 1.12–15.5 0.03 4.85 1.19–19.8 0.03 120 min /41–41.5 C 1.69 0.92–3.12 0.09 1.50 0.64–3.48 0.35 TABLE 3 Univariate and multivariate logistic regression of clinical predictive factors for local toxicity (Wieberdink I–III vs. IV–V) after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (year) 1.00 0.97–1.03 0.83 0.98 0.95–1.02 0.29 Gender (female vs. male) 0.76 0.31–1.86 0.54 0.95 0.36–2.52 0.92 N-stage (N2c vs. N3) 0.53 0.20–1.39 0.19 0.53 0.19–1.47 0.22 Size (nonbulky vs. bulky) 1.09 0.30–3.88 0.90 0.96 0.23–4.06 0.96 Number of lesions 11 1 2–3 0.39 0.10–1.55 0.18 0.45 0.10–2.01 0.30 4–10 0.44 0.12–1.62 0.22 0.48 0.11–2.05 0.32 [ 10 0.64 0.20–2.12 0.47 0.85 0.21–3.49 0.82 Vessel Femoral 1 1 Upper extremity 0.56 0.12– 2.60 0.46 0.51 0.10–2.73 0.43 External iliac 0.56 0.21–1.51 0.26 0.25 0.07–0.87 0.03 Perfusion time/temp 60 min /39–40 C1 1 90 min /39–40 C 0.47 0.12–1.88 0.29 0.61 0.15–2.54 0.50 120 min /39–40 C 0.72 0.08–6.29 0.77 0.94 0.10–8.78 0.95 120 min /41–41.5 C 1.83 0.68–4.88 0.23 3.90 1.08–14.1 0.04 1840 D. Katsarelias et al. DISCUSSION severe cases, other side effects of the treatment can occur, such as temporary loss of nails and hair, blistering, The purpose of this study was to perform a retrospective impermanent neuralgia, rhabdomyolysis, and compartment analysis on the effect of temperature and perfusion time on syndrome. Several factors have been shown to be asso- response, toxicity, and survival after first-time ILP with ciated with local toxicity. melphalan only for melanoma in-transit metastases. The It has already been demonstrated that perfusion tem- major limitation of this study was its retrospective design. peratures more than 40 C increase toxicity, a finding that However, it comprises a single-institution experience with also could be confirmed in this series for patients treated 13–16 few involved surgeons and standardized technique during with a 120-min perfusion at 41–41.5 C. It has been the period under examination. To answer the research demonstrated that hyperthermia mediates an increased question, the consecutive material at our center was divi- uptake of chemotherapeutics through changes in tumour ded into four distinct time periods, with changes in blood flow and cellular permeability. During ILP, an perfusion time, perfusion temperature, and way of mel- increase in temperature from 37 to 39.5 C doubles the phalan administration (bolus doses vs. 20 min infusion). concentration of cisplatin in tumours while at the same Concerning response, there was an increased response time decreasing the concentration in surrounding healthy rate associated to longer perfusion time (120 min). When tissue. Hyperthermia also acts synergistically with mel- comparing 60 min perfusion at 39–40 C (mild hyper- phalan leading to an increased toxicity in human melanoma thermia) to the 90 min perfusion, there was a trend towards cell lines. Previous reports showed that tissue tempera- better response in the longer perfusion group with an odds tures of 41.5 or more generates a high response rate, but ratio of 1.84 (p = 0.09), and this became significant when this could not be confirmed in this material. As a com- 60-min perfusion was compared with 120-min perfusion promise between response rate and toxicity, our current under mild hyperthermia with an odds ratio of 4.85 (p = standard is to use tissue temperatures of mild hyperthermia 0.03). Interestingly, a 120-min perfusion at 41–41.5 C (39–40 C). (true hyperthermia) did not achieve a higher response rate. It has previously been shown that a more proximal Why higher temperature perfusion did not result in the isolation for both upper and lower extremity gave a higher same or higher response rate can only be speculated upon, rate of local toxicity. However, in our series, iliac ILP but it might have been due to factors that changed through was an independent predictive factor for lower toxicity. the years that were not accounted for in this analysis. This might be due to differences in melphalan concentra- Alternatively, we have previously shown that immuno- tion between the different levels of isolation. One could logical factors are important for response after ILP, and it speculate that iliac ILPs received a lower dose of mel- might be that true hyperthermia is not as effective to phalan, because it has previously been shown that 9–11 activate the immune system. We currently use a 60-min melphalan concentration, both peak and area under the perfusion protocol, but data from this study point towards a curve (AUC), affects toxicity. better response rate using mild hyperthermia for a longer Negative independent prognostic factors for survival perfusion duration. The effect could be partly due to the were age, the presence of lymph node metastases, bulky changes from a divided bolus administration to a continu- tumors, brachial ILPs, 120-min perfusion at 41–41.5 C, ous infusion for 20 min. and not achieving a CR. Although not statistically signifi- Following ILP, local toxicity often is evident. Common cant, there was an improvement in survival over time in signs of local toxicity are discomfort, erythema, and univariate analysis (Fig. 1). However, only the earliest edema, which occurs in most of the patients. In some, more group (120 min at 41–41.5 C) was significant in multi- variate analysis. This phenomenon is probably because patients are receiving more effective systemic therapies in recent years, which has an impact on overall survival. Although only stage III patients were included in the analysis, some of them have received immunotherapy or BRAF, MEK inhibitors in the later stage of their disease. This has probably contributed to a better overall survival in the later periods. The results from this retrospective study point toward that prolonged perfusion time increases the response rates without an increase in local toxicity, whereas increased temperature increases the toxicity but not response rate. However, considering the retrospective design of this FIG. 1 Overall survival after isolated limb perfusion Temperature and Perfusion Time in ILP 1841 TABLE 4 Univariate and multivariate Cox analysis of clinical predictive factors for overall survival after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (years) 1.02 1.01–1.03 0.007 1.02 1.00–1.03 0.03 Gender (female vs. male) 1.24 0.93–1.66 0.14 1.12 0.79–1.71 0.52 N-stage (N2c vs. N3) 1.50 1.13–2.00 0.005 1.99 1.41–2.61 \ 0.0001 Size (Non-bulky vs. bulky) 1.80 1.20–2.70 0.005 2.56 1.59–4.10 0.0001 Number of lesions 11 1 2–3 0.93 0.57–1.51 0.76 1.24 0.71–2.03 0.45 4–10 1.13 0.71–1.79 0.61 1.44 0.85–2.23 0.18 [ 10 1.43 0.90–2.28 0.13 1.55 0.87–2.59 0.12 Vessel Femoral 1 1 Upper extremity 1.18 0.74–1.88 0.49 1.78 1.01–2.89 0.046 External iliac 1.30 0.96–1.75 0.09 1.24 0.83–1.82 0.29 Perfusion time / temp 60 min /39–40 C1 1 90 min /39–40 C 1.24 0.82–1.87 0.32 1.24 0.73–2.11 0.43 120 min /39–40 C 0.79 0.40–1.57 0.51 1.24 0.57–2.51 0.59 120 min /41–41.5 C 1.55 1.04–2.32 0.03 2.03 1.16–3.36 0.01 Response CR 1 1 PR 1.52 1.05–2.21 0.03 1.69 1.12–2.81 0.01 SD 1.73 1.08–2.77 0.02 1.51 0.88–2.72 0.13 PD 3.04 1.66–5.57 \ 0.001 4.39 2.04–9.66 0.0001 Local toxicity Wieberdink I 1 1 Wieberdink II 1.06 0.49–2.29 0.88 0.96 0.38–2.38 0.92 Wieberdink III 1.20 0.54–2.67 0.65 1.26 0.48–3.29 0.64 Wieberdink IV 0.82 0.33–2.05 0.68 0.80 0.27–2.34 0.68 study, these results must be interpreted with caution. At our together with other locoregional interventions, need to be institution, we have discussed this and decided not to further investigated to obtain better response rates, lower change our current protocol at this time, maintaining a toxicity, and why not better survival. 60-min perfusion under mild hyperthermia with melphalan OPEN ACCESS This article is distributed under the terms of the infusion for 20 min. The optimal temperature and perfusion Creative Commons Attribution 4.0 International License (http://crea time will probably not be analyzed in prospective, ran- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, domized trials, and it would take many years and multiple distribution, and reproduction in any medium, provided you give centers to verify the results. More important might be to appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were include the current results in future trial designs, where made. more urgent research questions can be analyzed. Future research will most probably not just try to maximize REFERENCES response rates, which already are superior to other treat- ment options, but rather to study combinatorial treatments 1. Pawlik TM, et al Predictors and natural history of in-transit ultimately leading to cure in this patient population. A very melanoma after sentinel lymphadenectomy. Ann Surg Oncol. interesting development is the synergistic effect of ipili- 2005;12(8):587–96. 2. Creech O Jr, et al. Chemotherapy of cancer: regional perfusion mumab and isolated limb infusion that was shown in a 21 utilizing an extracorporeal circuit. Ann Surg. recent publication. This kind of combined approaches, 1958;148(4):616–32. 1842 D. 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The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion

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Abstract

Ann Surg Oncol (2018) 25:1836–1842 https://doi.org/10.1245/s10434-018-6459-9 O R I G IN AL ARTI CL E – MELA NO MA S The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion Dimitrios Katsarelias, MD, PhD, Erik Ra˚dbo, MD, Ilan Ben-Shabat, MD, Jan Mattsson, MD, and Roger Olofsson Bagge, MD, PhD Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden ABSTRACT Conclusions. Modern ILP uses diminished perfusion time Background. Isolated limb perfusion (ILP) is used to treat and lower temperature, leading to a decrease in toxicity. in-transit metastases of melanoma of the extremities when However, our data also show a decrease in response, which surgical excision is not possible. The optimal setting con- indicates that optimal perfusion time and temperature cerning temperature and perfusion time is unknown. The regimen remain to be determined. purpose of this study was to analyze these factors con- cerning their effects on response, toxicity, and survival. Methods. A retrospective analysis of 284 consecutive BACKGROUND stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period Approximately 5–10% of patients with recurrence of (July 1986–May 2017), was performed. Our series was malignant melanoma develop lymphatic dissemination divided in four time periods, according to perfusion tem- manifested as in-transit metastasis. The initial treatment perature and duration. Demographical data, stage, number, option is surgical excision; however, in case of numerous and size of lesions were retrieved from our prospective lesions or short intervals between the appearances of new database. lesions, alternative treatment modalities should be Results. Overall response (OR) rate 83% and a complete considered. response (CR) rate of 59%. Significant predictive factors The technique of isolated limb perfusion (ILP) was for CR in multivariate analysis were non-bulky tumor, pioneered in the 1950s by Creech and Krementz. Com- fewer metastases, and a perfusion time of 120 min. Pre- pared with systemic administration, ILP achieves very high dictive factors for increased local toxicity were femoral tissue concentrations of the alkylating agent melphalan. An ILP and higher perfusion temperatures. The median overall early pharmacokinetic study using melphalan in an ILP survival was 30 months, and the independent negative setting showed that high peak perfusate concentrations prognostic factors were lymph-node status, bulky tumors, were achieved (6–115 mg/ml) and that these levels could response, upper limb perfusion, and 120 min perfusion at be 20–100 times higher than the peak levels achieved with 39–40 C. the usual intravenous doses of melphalan. In 1967, Cavaliere reported the effects of ILP using only hyper- thermia in 22 patients with recurrent extremity tumors. The duration of hyperthermia ([ 40 C) ranged from 50 min to Dimitrios Katsarelias and Erik Radbo have contributed equally to this almost 7 h. Twelve of the patients were alive without work. evidence of disease at 3–28 months of follow-up. In 1969, Stehlin increased perfusion time from 45 to 120 The Author(s) 2018. This article is an open access publication min and heated the perfusate to 46.1 C. Together with First Received: 19 February 2018; externally applied heat and wrapping, they reached skin Published Online: 15 May 2018 temperatures of 42.2 C. These changes resulted in higher R. Olofsson Bagge, MD, PhD tumor response but also increased complication rates. The e-mail: roger.olofsson@surgery.gu.se Temperature and Perfusion Time in ILP 1837 method has since then been refined and current results for approach for the lower extremity (Table 1). Limb isolation ILP with melphalan (M-ILP) show overall response rates was achieved through clamping and cannulation of the (ORR) ranging between 65 and 100%, with a complete major artery and vein for the extremity under treatment. response (CR) rate between 25 and 76%. The cannulas were connected to an oxygenated extracor- In Sweden, ILP treatment was initiated in the 1970s. poreal circuit. From October 2000, continuous leakage Initially, the perfusion time was 120 min with a tissue monitoring was performed using a precordial scintillation temperature of 41–41.5 C (true hyperthermia), which in probe (Medic View, Sweden) to detect and measure leak- 2002 was lowered to 39–40 C. The perfusion time was age of technetium-99m labelled human serum albumin lowered to 90 min in 2006 and then finally to 60 min in (Vasculosis, Cis-Bio International, Gif-sur-Yvette, France), 2012 keeping perfusions temperature between 39 and which was injected into the perfusion circuit. The dose of 40 C (mild hyperthermia). The administration of mel- melphalan was calculated as 13 mg/L perfused tissues for phalan was also changed, from three bolus doses, in the upper limb and 10 mg/L perfused tissues for lower limb. earlier periods, to 20 min infusion in 2012, and this is still in use in our practice. Time Periods The purpose of this study was to analyze retrospectively the effect of temperature lowering and diminishing of Between 1986 and 2002, the perfusion time and the perfusion time on response, toxicity, and survival for highest tissue target temperature was 120 min and melanoma patients with in-transit metastases treated with 41–41.5 C respectively. In 2002, this was changed to 120 melphalan-only ILP in our institution. min at 39–40 C, and this temperature was then used onward. In 2006, the total perfusion time was decreased to PATIENTS AND METHODS 90 min, and in 2012, the perfusion time was further decreased to 60 min. Before 2012, the melphalan was given Patients as three bolus doses, with 50% of the total dose adminis- tered initially and the remaining 50% administered in two Over a 31-year period (July 1986–May 2017), a total of equivalent doses at 30-min intervals (total 60 min). In 2012, the administration of melphalan was changed into a 284 consecutive patients with in-transit metastases of malignant melanoma (stage III), were treated with ILP for 20-min infusion in the perfusate, followed by 40-min the first time in our institution. In the beginning of this perfusion. study period, TNF-alpha was not available, and patients who later received TNF-alpha due to bulky melanoma were Response excluded not to induce a further bias between the treatment groups. There were 166 females and 118 males with a Clinical responses were evaluated and reported as the response at 3 months using the WHO criteria. For a median age of 70 years (range 23–95). A total of 171 patients (60.2 %) had in-transit metastases only (N2c), and response to be considered as a complete response (CR), all lesions should have been clinically not detectable at the 113 patients (39.8 %) had lymph node metastases (N3) before or at the time of ILP. Bulky melanoma (lesions[ 3 time of clinical examination. Partial response (PR) was defined as a clinical decrease of more than 50% of the total cm) was present in 36 patients (12.7%), and 88 patients (31.0%) had 10 or more lesions (Table 1). No patients tumor burden both in terms of number of lesions or received any adjuvant systemic therapies. diameter. Progressive disease (PD) was defined as an Baseline data, as well as data concerning response and increase of more than 25% in existing lesions or the toxicity, were retrieved from a prospectively kept database, appearance of new lesions not previously present. further completed with data from patient medical records. Stable disease (SD) was defined as a result where none of Data concerning survival was retrieved from the Swedish the abovementioned criteria for CR, PR, or PD were met. National Cause of Death Register. The study was approved by the Regional Ethical Review Board at the University of Local Toxicity Gothenburg (Dnr 721-08). Local toxicity was measured according to Wieberdink and classified from I to V, where I is no reaction, II slight ILP Technique erythema and/or edema, III is considerable erythema and/or The patients underwent ILP via an axillary, brachial, or edema with some blistering, IV is extensive epidermolysis subclavian vascular approach for upper extremity (n = 34) and/or obvious damage to deep tissues, and V induces a and via the external iliac (n = 99) or femoral (n = 151) reaction that may necessitate amputation. 1838 D. Katsarelias et al. TABLE 1 Patient and tumor characteristics perfusion time (120 min) under mild hyperthermia (39–40 C). In the multivariate analysis, both the number Sex of metastases, as well as longer perfusion time (120 min) at Female 166 (58.5%) 39–40 C, were proven statistically significant (Table 2). Male 118 (41.5%) For overall response, the only significant predictive factor Age. median (range), years 70.5 (23–95) was gender; males had a lower response (odds ratio = 0.43; N-stage (%) p = 0.02). N2c 171 (60.2%) N3 113 (39.8%) Toxicity Vessel (%) Upper extremity 34 (12.0%) Data on local toxicity was available in 270 patients Femoral 151 (53.2%) (95%). Reliable data were missing for 14 patients, and they External iliac 99 (34.9%) were excluded from the analysis. The distribution between Perfusion time/temp (%) Wieberdink grades through the entire 31-year period were: 60 min/ 39–40 C 91 (32.0%) grade I 4.4%, grade II 62.6%, grade III 24.4%, grade IV 90 min/ 39–40 C 86 (30.3%) 8.1%, and grade V 0.4%. In multivariate analysis com- 120 min/ 39–40 C 17 (6.0%) paring Wieberdink I–III versus IV–V, perfusion at 120 min/ 41–41.5 C 90 (31.7%) 41–41.5 C for 120 min (1986–2002) had a higher rate of Number of metastases (%) severe toxicity (grade III–V) with an odds ratio of 3.9 (p = 1 39 (13.7%) 0.04), whereas external iliac perfusions had a significantly 2–3 69 (24.3%) lower rate (OR 0.25; p = 0.03; Table 3). Similar results 4–10 81 (28.5%) were obtained in the multivariate analysis comparing [ 10 88 (31.0%) Wieberdink I–II versus III, where higher temperature Missing 7 (2.5%) (41.5 C at 120 min) had more grade III toxicity (OR 2.59, Largest metastasis (%) p = 0.05), whereas both external iliac and brachial perfu- Nodular (\ 3 cm) 237 (83.5%) sions had lower rates of grade III toxicity (brachial OR 0.22 Bulky ([ 3 cm) 36 (12.7%) p = 0.01; external iliac OR 0.23, p = 0.001) compared with Missing 11 (3.9%) femoral perfusions. Survival Statistical Evaluation Survival data were available for all 284 patients inclu- ded in the study. The 2, 5, and 10-year overall survival Overall survival (OS) was defined as the time from ILP (OS) was 64, 36, and 19% respectively, with a median OS to death or last follow-up. Survival estimates were made of 38 months. The median OS was 44 months in the 60-min according to the Kaplan-Meier method and prognostic ILP at 39–40 C group (2012–2017), 36 months for the factors for OS were analyzed using Cox regression. Pre- 90-min ILP at 39–40 C group (2006–2012), 47 months for dictive factors for response and toxicity were analyzed the 120-min ILP at 39–40 C group (2002–2006), and 30 using logistic regression. A p value\ 0.05 was considered months for the 120-min ILP at 41–41.5 C group statistically significant. All data were analyzed by using (1986–2002; p = 0.06; Fig. 1). In multivariate analysis, SPSS version 22 (SPSS, Chicago, IL). significant negative prognostic factors were increasing age, positive lymph-node status, bulky disease, brachial ILP, RESULTS and response after ILP and ILP for 120 min at 41–41.5 C (Table 4). When excluding response and toxicity from the Response survival analysis, the significant prognostic factors were age (HR 1.02, p = 0.047), positive lymph-node status (HR Clinical response was evaluable in 268 patients (94.4%). 1.52, p = 0.01), presence of bulky disease (HR 2.06, p = Two patients were not included due to early death (earlier 0.002), more than ten metastases (HR 1.85, p = 0.02), and than 3 months), and 14 patients were excluded due to lack ILP for 120 min at 41–41.5 C (HR 1.84, p = 0.02). of reliable response records. In total, 223 patients (83.2%) had an ORR, of which 167 patients (58.8%) had a CR. Significant predictive factors for CR in univariate analysis were a total number of metastases less than ten and a longer Temperature and Perfusion Time in ILP 1839 TABLE 2 Univariate and multivariate logistic regression of clinical predictive factors for complete response after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (year) 1.01 0.99–1.03 0.24 1.02 1.00–1.04 0.09 Gender (female vs. male) 0.86 0.58–1.58 0.86 0.82 0.46–1.47 0.51 N-stage (N2c vs. N3) 0.80 0.48–1.32 0.37 0.94 0.53–1.67 0.83 Size (nonbulky vs. bulky) 0.83 0.40–1.73 0.62 0.57 0.24–1.35 0.20 Number of lesions 11 1 2–3 0.56 0.20–1.59 0.28 0.54 0.18–1.63 0.28 4–10 0.38 0.14–1.03 0.06 0.32 0.11–0.93 0.04 [ 10 0.13 0.05–0.33 \ 0.0001 0.10 0.03–0.30 \ 0.0001 Vessel Femoral 1 1 Upper extremity 1.44 0.62–3.37 0.40 0.89 0.35–2.30 0.81 External iliac 0.88 0.52–1.50 0.63 0.74 0.35–1.55 0.42 Perfusion time/temp 60 min /39–40 C1 1 90 min /39–40 C 1.75 0.93–3.29 0.08 1.84 0.91–3.61 0.09 120 min /39–40 C 4.16 1.12–15.5 0.03 4.85 1.19–19.8 0.03 120 min /41–41.5 C 1.69 0.92–3.12 0.09 1.50 0.64–3.48 0.35 TABLE 3 Univariate and multivariate logistic regression of clinical predictive factors for local toxicity (Wieberdink I–III vs. IV–V) after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (year) 1.00 0.97–1.03 0.83 0.98 0.95–1.02 0.29 Gender (female vs. male) 0.76 0.31–1.86 0.54 0.95 0.36–2.52 0.92 N-stage (N2c vs. N3) 0.53 0.20–1.39 0.19 0.53 0.19–1.47 0.22 Size (nonbulky vs. bulky) 1.09 0.30–3.88 0.90 0.96 0.23–4.06 0.96 Number of lesions 11 1 2–3 0.39 0.10–1.55 0.18 0.45 0.10–2.01 0.30 4–10 0.44 0.12–1.62 0.22 0.48 0.11–2.05 0.32 [ 10 0.64 0.20–2.12 0.47 0.85 0.21–3.49 0.82 Vessel Femoral 1 1 Upper extremity 0.56 0.12– 2.60 0.46 0.51 0.10–2.73 0.43 External iliac 0.56 0.21–1.51 0.26 0.25 0.07–0.87 0.03 Perfusion time/temp 60 min /39–40 C1 1 90 min /39–40 C 0.47 0.12–1.88 0.29 0.61 0.15–2.54 0.50 120 min /39–40 C 0.72 0.08–6.29 0.77 0.94 0.10–8.78 0.95 120 min /41–41.5 C 1.83 0.68–4.88 0.23 3.90 1.08–14.1 0.04 1840 D. Katsarelias et al. DISCUSSION severe cases, other side effects of the treatment can occur, such as temporary loss of nails and hair, blistering, The purpose of this study was to perform a retrospective impermanent neuralgia, rhabdomyolysis, and compartment analysis on the effect of temperature and perfusion time on syndrome. Several factors have been shown to be asso- response, toxicity, and survival after first-time ILP with ciated with local toxicity. melphalan only for melanoma in-transit metastases. The It has already been demonstrated that perfusion tem- major limitation of this study was its retrospective design. peratures more than 40 C increase toxicity, a finding that However, it comprises a single-institution experience with also could be confirmed in this series for patients treated 13–16 few involved surgeons and standardized technique during with a 120-min perfusion at 41–41.5 C. It has been the period under examination. To answer the research demonstrated that hyperthermia mediates an increased question, the consecutive material at our center was divi- uptake of chemotherapeutics through changes in tumour ded into four distinct time periods, with changes in blood flow and cellular permeability. During ILP, an perfusion time, perfusion temperature, and way of mel- increase in temperature from 37 to 39.5 C doubles the phalan administration (bolus doses vs. 20 min infusion). concentration of cisplatin in tumours while at the same Concerning response, there was an increased response time decreasing the concentration in surrounding healthy rate associated to longer perfusion time (120 min). When tissue. Hyperthermia also acts synergistically with mel- comparing 60 min perfusion at 39–40 C (mild hyper- phalan leading to an increased toxicity in human melanoma thermia) to the 90 min perfusion, there was a trend towards cell lines. Previous reports showed that tissue tempera- better response in the longer perfusion group with an odds tures of 41.5 or more generates a high response rate, but ratio of 1.84 (p = 0.09), and this became significant when this could not be confirmed in this material. As a com- 60-min perfusion was compared with 120-min perfusion promise between response rate and toxicity, our current under mild hyperthermia with an odds ratio of 4.85 (p = standard is to use tissue temperatures of mild hyperthermia 0.03). Interestingly, a 120-min perfusion at 41–41.5 C (39–40 C). (true hyperthermia) did not achieve a higher response rate. It has previously been shown that a more proximal Why higher temperature perfusion did not result in the isolation for both upper and lower extremity gave a higher same or higher response rate can only be speculated upon, rate of local toxicity. However, in our series, iliac ILP but it might have been due to factors that changed through was an independent predictive factor for lower toxicity. the years that were not accounted for in this analysis. This might be due to differences in melphalan concentra- Alternatively, we have previously shown that immuno- tion between the different levels of isolation. One could logical factors are important for response after ILP, and it speculate that iliac ILPs received a lower dose of mel- might be that true hyperthermia is not as effective to phalan, because it has previously been shown that 9–11 activate the immune system. We currently use a 60-min melphalan concentration, both peak and area under the perfusion protocol, but data from this study point towards a curve (AUC), affects toxicity. better response rate using mild hyperthermia for a longer Negative independent prognostic factors for survival perfusion duration. The effect could be partly due to the were age, the presence of lymph node metastases, bulky changes from a divided bolus administration to a continu- tumors, brachial ILPs, 120-min perfusion at 41–41.5 C, ous infusion for 20 min. and not achieving a CR. Although not statistically signifi- Following ILP, local toxicity often is evident. Common cant, there was an improvement in survival over time in signs of local toxicity are discomfort, erythema, and univariate analysis (Fig. 1). However, only the earliest edema, which occurs in most of the patients. In some, more group (120 min at 41–41.5 C) was significant in multi- variate analysis. This phenomenon is probably because patients are receiving more effective systemic therapies in recent years, which has an impact on overall survival. Although only stage III patients were included in the analysis, some of them have received immunotherapy or BRAF, MEK inhibitors in the later stage of their disease. This has probably contributed to a better overall survival in the later periods. The results from this retrospective study point toward that prolonged perfusion time increases the response rates without an increase in local toxicity, whereas increased temperature increases the toxicity but not response rate. However, considering the retrospective design of this FIG. 1 Overall survival after isolated limb perfusion Temperature and Perfusion Time in ILP 1841 TABLE 4 Univariate and multivariate Cox analysis of clinical predictive factors for overall survival after isolated limb perfusion Variables Univariate analysis Multivariate analysis OR 95% CI p value OR 95% CI p value Age (years) 1.02 1.01–1.03 0.007 1.02 1.00–1.03 0.03 Gender (female vs. male) 1.24 0.93–1.66 0.14 1.12 0.79–1.71 0.52 N-stage (N2c vs. N3) 1.50 1.13–2.00 0.005 1.99 1.41–2.61 \ 0.0001 Size (Non-bulky vs. bulky) 1.80 1.20–2.70 0.005 2.56 1.59–4.10 0.0001 Number of lesions 11 1 2–3 0.93 0.57–1.51 0.76 1.24 0.71–2.03 0.45 4–10 1.13 0.71–1.79 0.61 1.44 0.85–2.23 0.18 [ 10 1.43 0.90–2.28 0.13 1.55 0.87–2.59 0.12 Vessel Femoral 1 1 Upper extremity 1.18 0.74–1.88 0.49 1.78 1.01–2.89 0.046 External iliac 1.30 0.96–1.75 0.09 1.24 0.83–1.82 0.29 Perfusion time / temp 60 min /39–40 C1 1 90 min /39–40 C 1.24 0.82–1.87 0.32 1.24 0.73–2.11 0.43 120 min /39–40 C 0.79 0.40–1.57 0.51 1.24 0.57–2.51 0.59 120 min /41–41.5 C 1.55 1.04–2.32 0.03 2.03 1.16–3.36 0.01 Response CR 1 1 PR 1.52 1.05–2.21 0.03 1.69 1.12–2.81 0.01 SD 1.73 1.08–2.77 0.02 1.51 0.88–2.72 0.13 PD 3.04 1.66–5.57 \ 0.001 4.39 2.04–9.66 0.0001 Local toxicity Wieberdink I 1 1 Wieberdink II 1.06 0.49–2.29 0.88 0.96 0.38–2.38 0.92 Wieberdink III 1.20 0.54–2.67 0.65 1.26 0.48–3.29 0.64 Wieberdink IV 0.82 0.33–2.05 0.68 0.80 0.27–2.34 0.68 study, these results must be interpreted with caution. At our together with other locoregional interventions, need to be institution, we have discussed this and decided not to further investigated to obtain better response rates, lower change our current protocol at this time, maintaining a toxicity, and why not better survival. 60-min perfusion under mild hyperthermia with melphalan OPEN ACCESS This article is distributed under the terms of the infusion for 20 min. The optimal temperature and perfusion Creative Commons Attribution 4.0 International License (http://crea time will probably not be analyzed in prospective, ran- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, domized trials, and it would take many years and multiple distribution, and reproduction in any medium, provided you give centers to verify the results. More important might be to appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were include the current results in future trial designs, where made. more urgent research questions can be analyzed. Future research will most probably not just try to maximize REFERENCES response rates, which already are superior to other treat- ment options, but rather to study combinatorial treatments 1. Pawlik TM, et al Predictors and natural history of in-transit ultimately leading to cure in this patient population. A very melanoma after sentinel lymphadenectomy. Ann Surg Oncol. interesting development is the synergistic effect of ipili- 2005;12(8):587–96. 2. Creech O Jr, et al. Chemotherapy of cancer: regional perfusion mumab and isolated limb infusion that was shown in a 21 utilizing an extracorporeal circuit. Ann Surg. recent publication. This kind of combined approaches, 1958;148(4):616–32. 1842 D. 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Annals of Surgical OncologySpringer Journals

Published: May 15, 2018

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