Phosphorylated CXCR4 expression has a positive prognostic impact in colorectal cancer.

BACKGROUND: The CXCL12-CXCR4 chemokine axis plays an important role in cell trafficking as well as in tumor progression. In colorectal cancer (CRC), the chemokine receptor CXCR4 has been shown to be an unfavorable prognostic factor in some studies, however, the role of its activated (phosphorylated) form, pCXCR4, has not yet been evaluated. Here, we aimed to investigate the prognostic value of CXCR4 and pCXCR4 in a large cohort of CRC patients. PATIENTS AND METHODS: A tissue microarray (TMA) of 684 patient specimens of primary CRCs was analyzed by immunohistochemistry (IHC) for the expression of CXCR4 and pCXCR4 by tumor cells and tumor-infiltrating immune cells (TICs). RESULTS: The combined high expression of CXCR4 and pCXCR4 showed a favorable 5-year overall survival rate (68%; 95%CI = 59-76%) compared to tumors showing a high expression of CXCR4 only (48%; 95%CI = 41-54%). High expression of pCXCR4 was significantly associated with a favorable prognosis in a test and validation group (p = 0.015 and p = 0.0001). Moreover, we found that CRCs with a high density of pCXCR4+ tumor-infiltrating immune cells (TICs) also showed a favorable prognosis in a test and validation group (p = 0.054 and p = 0.004). Univariate Cox regression analysis for TICs revealed that a high density of pCXCR4+ TICs was a favorable prognostic marker for overall survival (HR = 0.97,95%CI = 0.96-1.00; p = 0.01). In multivariate Cox regression survival analyses a high expression of pCXCR4 in tumor cells lost its association with a better overall survival (HR = 0.99; 95%CI = 0.99-1.00, p = 0.098). CONCLUSION: Our results show that high densities of CXCR4 and pCXCR4 positive TICs are favorable prognostic factors in CRC.

Surgical treatment of uncomplicated diverticulitis in Switzerland: comparison of population-based data over two time periods.

AIM: The standard of care for acute uncomplicated diverticulitis used to be an elective colon resection after the second or third episode. This practice was replaced by a more conservative and individualized approach. This study investigates current surgical practice in the treatment of acute uncomplicated diverticulitis in Switzerland. METHOD: Retrospective cross-sectional analysis of all hospital admissions due to uncomplicated diverticulitis in Switzerland using prospectively collected data from the Swiss Federal Statistical Office in two periods: 2004/2005 and 2010/2011. Treatment options were compared between the two periods with adjustment for baseline characteristics of patients and treating institutions. RESULTS: A total of 24 497 patients (11 835 in 2004/2005; 12 662 in 2010/2011) were admitted to Swiss hospitals for uncomplicated diverticulitis. Between periods, the incidence increased from 81 to 85 admissions per 105 inhabitants per year. Elective admissions decreased from 46% (n = 5490) to 34% (n = 4294). The unadjusted resection rate decreased from 40% (n = 4730) to 34% (n = 4308). In the adjusted analysis, inpatients were more likely to have a resection in 2010/2011 than in 2004/2005 [odds ratio of 1.38 (95% confidence interval 1.25-1.54)]. In addition, private insurance, elective mode of admission and younger age increased the odds for resection while there was no evidence of an association between resection and either gender or comorbidities. CONCLUSION: The probability of colon resection for patients hospitalized with acute uncomplicated diverticulitis increased between periods while the overall number of colon resections declined. A change of practice expected given the paradigm shift towards conservative treatment could not be confirmed in this analysis.

Reversal after Hartmann's procedure in patients with complicated sigmoid diverticulitis.

AIM: Hartmann's procedure (HP) is commonly used for the emergency treatment of complicated sigmoid diverticulitis (CSD). It is intended to restore intestinal continuity; however, in practice, reversal is not carried out in all patients. It is important to know the frequency of reversal and the impact of patient-related factors on the decision for reversal. METHOD: A retrospective study was conducted on all patients who underwent HP for CSD at a tertiary referral hospital between 1 May 2005 and 31 December 2010. We assessed the frequency of reversal over time and the prognostic factors affecting the decision for reversal. RESULTS: Of 67 patients [median age 76 (interquartile range: 68-81) years] who had HP for CSD, 28 (42%) underwent reversal. The cumulative incidence of reversal after 48 weeks was 48% (95% CI: 36-62%). Reversal was less likely in elderly patients [hazard ratio (HR) per decade increase = 0.43; 95% CI: 0.26-0.71], with cardiac insufficiency or coronary heart disease (HR = 0.60; 95% CI: 0.26-1.40) and with preoperative immunosuppression or chemotherapy (HR = 0.31; 95% CI: 0.07-1.33). There was no apparent effect of these factors on mortality. CONCLUSION: Approximately half of the patients having HP for CSD undergo reversal within 48 weeks of the initial operation. The finding that age, cardiac or coronary heart disease and preoperative immunosuppression or chemotherapy have an impact on the decision for reversal is relevant to healthcare professionals and patients.

[Endoprosthesis in the operative treatment of bone tumours of the pelvis]. / Stellenwert der Beckenendoprothetik in der operativen Therapie von Tumoren des knöchernen Beckens.

AIM: Limb salvage procedures in cases of bone tumours of the pelvis are established. In this retrospective study the clinical results after implantation of megaprostheses of the pelvis are reported. METHODS: Between November 1994 and September 2004 an endoprosthetic replacement of the pelvis was performed in 24 consecutive patients, fourteen females and ten males. The mean age was 49.3 years (range: 17-64 years). In ten cases a complete and in fourteen an incomplete internal hemipelvectomy was done. Thirteen patients presented with a primary bone tumour and eleven with a bone metastasis. The tumour volume ranged between 50 and 1315 ml (median: 352 ml). The mean follow-up was 98 months. RESULTS: In 23 of the 24 patients an R0 resection was achieved. Local recurrences were observed in five patients (20.8%). Deep infections developed in ten patients (41.7%) postoperatively. In two of these ten patients a secondary external hemipelvectomy was necessary. Eight patients (33.3%) developed a paralysis of the femoral and/or sciatic nerve, and a loosening of the endoprosthesis was observed in four cases (16.7%). Two patients died within 30 days postoperatively (pulmonary embolism, dissection of the abdominal aorta). Eight of the 24 patients are still alive, two of them after secondary hemipelvectomy and another after removal of the endoprosthesis due to infection. The functional results of the five surviving patients with an endoprosthesis, according to the MSTS scoring system, are good in two and poor in three patients. CONCLUSION: Internal hemipelvectomy and reconstruction of the pelvic girdle with endoprostheses is associated with a high rate of complications. Each single case should be critically evaluated and alternative procedures should be considered.

Hepatic arterial Fotemustine chemotherapy in patients with liver metastases from cutaneous melanoma is as effective as in ocular melanoma.

AIM: Hepatic metastases from melanoma are associated with poor prognosis. Systemic chemotherapy and biological treatments remain unsatisfactory. This study investigated the impact of hepatic arterial chemotherapy in patients with ocular and cutaneous melanoma. METHODS: In a retrospectively analysed observational study, 36 consecutive patients with hepatic metastases from ocular or cutaneous melanoma were assigned for surgical hepatic port-catheter implantation. Fotemustine was delivered weekly for a 4-week period, followed by a 5-week rest and a maintenance period every 3 weeks until progression. Overall survival, response and toxicity were analysed and compared. RESULTS: After port-catheter implantation 30/36 patients were finally treated (18 with ocular and 12 with cutaneous melanoma). A median of 8 infusions per patient were delivered (range 3-24). 30% thrombocytopenia grade >or=3, 7% neutropenia grade >or=3 but no nausea or vomiting grade >or=3 were encountered. Nine out of 30 patients achieved partial remission, 10/30 stable disease; 11/30 patients were progressive. Median survival for all treated patients was 14 months. Partial remission and stable disease were associated with a survival advantage compared to progressive disease (19 vs. 5 months). No significant difference in survival was observed for ocular versus cutaneous melanoma. Serum LDH was a significant predictor of both response and survival. CONCLUSIONS: Hepatic arterial Fotemustine chemotherapy was well tolerated. Meaningful response and survival rates were achieved in ocular as well as cutaneous melanoma. Careful patient selection in consideration of extra-hepatic involvement is crucial for the effectiveness of this treatment. Independent from the primary melanoma site, it is debatable if patients with highly elevated serum-LDH may benefit from this approach.

[Synovial sarcoma of the extremities. Results of surgical and multimodal therapy]. / Synovialsarkome der Extremitäten. Ergebnisse chirurgischer und multimodaler Therapie.

BACKGROUND: Synovial sarcoma is a rare tumor frequently occurring in adolescents and young adults. The preferred location, at the distal parts of the extremities, and the high incidence of distant metastases represent major challenges for treatment. The purpose of this study is to analyze the indications for surgery in the context of a multimodal therapy. PATIENTS AND METHODS: Between October 1992 and December 2000, 41 patients were treated surgically for synovial sarcoma of the extremities. Their mean age was 35 years (range: 11-75 years). Extracompartmental tumor growth was present in more than 90% of the patients. Fourteen patients (34%) presented with a tumor size of less than 5 cm (T1) while 27 patients (66%) showed lesions greater than 5 cm (T2). At the time of presentation, seven patients had distant metastases; three located in the lung and four in lymph nodes. RESULTS: Due to a locally unresectable tumor or synchronous distant metastases, 28 patients (68%) underwent preoperative systemic chemotherapy (n=9) or isolated limb perfusion (n=18) or both (n=1). In 29 patients, limb-conserving surgery was possible. Of the 12 patients (29%) who required amputation, 85% had a distal tumor. Sixteen patients received additional postoperative radio- and/or chemotherapy. After a median follow-up of 30 months, only two patients (7%) had developed a local recurrence, while seven patients (20%) suffered from new, distant metastases. The 5-year overall survival rate was 82%. CONCLUSION: With a combined modality treatment, it is possible to achieve excellent local control rates and long-term survival in patients with synovial sarcoma of the extremities. Neoadjuvant treatment can enable limb-sparing surgery in most patients, even if the tumors are located in anatomically difficult areas.

Surgical oncology in the interplay of surgical and nonsurgical disciplines.

Advances in surgical tumor therapy are founded on a very close interaction between different surgical subspecialties as well as the inclusion of surgical into modern multimodality treatment concepts. The ongoing development of surgical techniques, e.g. microsurgical flap transfers or pouch reconstructions of intestinal reservoirs, has increasingly enabled organ- and function-preserving surgery. In addition, new materials (e.g. modular tumor endoprosthesis) has supported this development. The broad application of the sentinel node technique in melanoma and breast cancer and also in gastrointestinal tract cancers opens new concepts of diagnosis and therapy for lymphatic metastasized tumors. Locally advanced tumors can be treated in neoadjuvant protocols to increase the resectability rate and the probability for local control as a prerequisite for long-term survival. Especially for metastatic disease, interventional treatment techniques such as laser-induced thermotherapy (LITT) or photodynamic therapy have added valuable options to surgical treatment.

[Therapeutic strategies in malignant soft tissue tumors. Results of the soft tissue tumor register study of the Surgical Oncology Working Group]. / Therapeutische Strategien bei malignen Weichteiltumoren. Ergebnisse der Weichteiltumor-Registerstudie der CAO.

INTRODUCTION: This study, carried out by the Surgical Oncology Working Group (CAO) of the German Society for Surgery, was performed to analyse the strategies in the treatment of soft tissue sarcomas in adults. METHODS: In a period of 19 months the data on 292 patients suffering from soft tissue sarcomas, treated in 99 surgical departments in Germany, were analysed prospectively. A special questionnaire was developed including pretherapeutic biopsy, previous treatment, definitive surgical treatment, combined modality approach and histopathological results. RESULTS: Thirty-nine per cent of the tumours were treated in university hospitals, 36% in medical centres, 24% in regional hospitals. During the observation period two patients were treated on average (median) by each hospital. Limb-sparing treatment was performed in 96% of the extremity tumours. There was no significant difference in the frequency of R0 resections between the different hospitals. At the university hospitals local extended operations and additive measures were used more often. The indication for adjuvant radiotherapy differed: after compartmental resection, adjuvant radiotherapy was performed in 39% of cases (19/49); after wide-excision of high-grade tumours, in 45% of cases (20/44) no adjuvant radiotherapy was necessary. In spite of less radical treatment in tumours of the trunk, additional radiotherapy was not more frequently performed. CONCLUSION: To improve the quality in the treatment of soft tissue sarcomas it seems to be of great importance to avoid inadequate initial treatment (18%), to respect the rules of oncological surgery (tumour rupture in 7% of cases), to improve the histopathological examination (no R classification in 5-12%) and to develop guidelines for multimodality treatment.

["Sentinel" lymph node biopsy in breast carcinoma. Current experiences]. / "Sentinel"-Lymphknotenbiopsie beim Mammakarzinom. Aktuelle Erfahrungen.

Recent studies show the sentinel lymph node biopsy (SNB) as a reliable method for the determination of the nodal status in patients with breast cancer. We present our experience with this method during 3 years and discuss its potential and limitations. From 11/95 to 3/99 we performed a sentinel node detection in 146 patients with breast cancer stage I to III. We used the raionuclide method including preoperative lymphscintigraphy and intraoperative gamma.probe detection. The detection rate varied with the tumor size between 94% for tumors with a diameter < 1 cm, 85% (1-3 cm), 70% (3-5 cm) and 63% (> 5 cm). The accuracy of the SNB in the prediction of the nodal status varied also with the tumor diameter between 100% for very small tumors (< 1 cm), 97% (1-3 cm), 88% (3-5 cm) and 67% (> 5 cm). In the subgroup of patients restricted to T1-2-tumors (n = 106), 57 patients (53%) showed true negative, 4 (4%) false negative SNB. 38 (36%) revealed tumor cells in the HE-staining and an additional 7 patients (7%) solely in the immunohistochemical staining. The presented results show, that SNB is a reliable method for the evaluation of the nodal status in early breast cancer patients with a tumor size up to ca. 3 cm. While in about 50% of these patients a surgical intervention could be avoided after a negative SNB, an additional 5-10% of conventionally nodal negative patients can be found by the immunohistochemical examination of the sentinel node. The sn-concept can also identify parasternal metastasis and can be applied in patients after neoadjuvant therapy and patients with recurrent tumor. Indications and contraindications of this method, however, still remain to be determined.

Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan.

OBJECTIVES: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP. SETTING: University surgical oncology division with an integrated eight-bed intensive care unit. PATIENTS: Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma. INTERVENTIONS: The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel. MEASUREMENTS AND MAIN RESULTS: PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes. CONCLUSIONS: Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.

[Strategy for multimodal therapy of soft tissue sarcomas of the trunk and extremities]. / Strategie multimodaler Therapie bei Weichgewebssarkomen des Stammes und der Extremitäten.

The aim of surgical therapy for soft tissue sarcoma is local tumor control with the best possible functional result. Only small, superficial, well-differentiated or strictly intracompartmental lesions should be treated by surgery alone. In all other cases, especially for recurrent lesions, multimodality treatment strategies should be applied. For locally advanced lesions, neoadjuvant therapy can achieve tumor response. Aside from systemic chemotherapy and preoperative radiation therapy, isolated limb perfusion with tumor necrosis factor and melphalan can aid local control, and thus enable limb-sparing resection. The application of adjuvant systemc chemotherapy must be further investigated in prospective trials before a general recommendation can be given. If the patient has distant metastases, decisions regarding treatment of the local lesion must take into account quality-of-life aspects. Should complete resection not be possible, multimodality strategies may be able to control the tumor for a longer period.

Clinical management and current research in isolated limb perfusion for sarcoma and melanoma.

Currently, isolated limb perfusion (ILP) attracts major interest in the treatment of soft tissue sarcoma and melanoma confined to the limb. The procedure combines innovative approaches such as hyperthermia, the use of cytokines, as well as the administration of high-dose chemotherapy. Although used since more than 40 years, the basic knowledge on the mode of action of ILP is still limited. Besides regional toxicity, systemic effects following the application of rhTNF in the perfusion circuit have to be taken into account. Furthermore, WHO criteria of tumor response are rarely met after perfusion of sarcomas. To overcome this, new modalities based on tumor metabolism are currently under investigation. Also the clinical decision on how to proceed after a successful ILP is discussed.

Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma.

BACKGROUND: The possible immunosuppressive effect of blood transfusion and its influence on survival after surgery for cancer makes it worthwhile to seek methods to avoid transfusion wherever possible. Patients with right-sided colonic cancer are frequently anaemic. Such patients were entered into a study that employed erythropoietin to avoid homologous transfusion. METHODS: In a prospectively randomized double-blind placebo-controlled multicentre trial, patients with moderate anaemia (haemoglobin concentration greater than 8.5 g/dl and less than or equal to 13.5 g/dl) presenting with right-sided colonic cancer and scheduled for hemicolectomy were treated with recombinant human erythropoietin (epoetin beta) 20,000 units/day subcutaneously or placebo for at least 10 days over the operative period. RESULTS: Perioperative treatment with epoetin beta was well tolerated and there were no significant differences in morbidity and mortality. Following hemicolectomy, median cumulative blood loss in the two groups was similar (epoetin beta 440 ml versus placebo 345 ml). Sixteen (33 per cent) of 48 patients treated with epoetin beta and 15 (28 per cent) of 54 in the placebo group received perioperative blood transfusions (P not significant). The increase in reticulocyte count between baseline and the last preoperative value was more pronounced in the epoetin beta group than in those receiving placebo (P = 0.036). CONCLUSION: Despite the perioperative administration of 20,000 units erythropoietin per day for at least 10 days, it was not possible to reduce the intraoperative and postoperative transfusion need. None the less, a positive change in the haematological variables of treated patients was clearly discernible. The negative result may be due to the short treatment interval and to iron deficiency, which was present in the majority of patients. The general change of attitude towards allogeneic blood transfusion is demonstrated by the overall low frequency of blood transfusion in this study.

[Procalcitonin as marker of systemic inflammatory reaction after isolated extremity perfusion]. / Procalcitonin als Marker der systemischen inflammatorischen Reaktion nach isolierter Extremitätenperfusion.

The systemic side effects of isolated limb perfusion (ILP) with rhTNF alpha and melphalan are characterised by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after TNF-ILP. Serum-PCT was analysed in 24 patients (12 male, 12 female), who treated by ILP for regionally metastasized melanoma (n = 8) or locally advanced soft tissue sarcoma (n = 16). Serum samples were analysed pre- and intraoperatively, and at defined intervals after reperfusion of the limb. In addition to PCT, serum IL-6 and IL-8 were analysed in 11 patients. PCT was significantly elevated over baseline after ILP with a maximum between 8 and 36 hours (p < 0.001). Even 96 hours after reperfusion, PCT was still significantly elevated as compared to baseline levels (p = 0.005). There was no correlation to the systemic leakage rate during the perfusion. IL-6 and IL-8 were also significantly increased after ILP (p = 0.001), but the maximum peaks of both cytokines were reached much earlier than for PCT (IL-8 max. at 1 hour and IL-6 max. at 4 hours after reperfusion). Serum procalcitonin is induced as part of the specific SIRS after ILP with rhTNF alpha and melphalan. It may be induced directly by rhTNF alpha or by different cytokines, as serum peaks of IL-6 and IL-8 are reached well before the peak of PCT. Determination of PCT prior to and after ILP with TNF might be useful to assess patients at risk of developing hyperdynamic shock.

[Assessment of regional and systemic toxicity of isolated hyperthermic extremity perfusion with tumor necrosis factor-alpha and melphalan]. / Erfassung regionaler und systemischer Toxizität der isolierten, hyperthermen Extremitätenperfusion mit Tumor-Nekrose-Faktor alpha und Melphalan.

Following isolated limb perfusion (ILP) with TNF alpha and melphalan the damage to muscle tissue and its systemic consequences in terms of myoglobinemia and myoglobinuria as well as the activation of the cytokine cascade were investigated. We measured the compartmental pressure of the limb during and after perfusion and determined the serum changes of myoglobin, creatine kinase (CK), interleukin (IL)-6, IL-1, s-IL-2-receptor, TNF-receptor, and ICAM-1 levels. The compartmental pressure rose significantly during ILP and decreased after reperfusion. Following its course, the decision whether to perform a fasciotomy or not can be more reliably made. Serum myoglobin levels exceeded 200 times normal values and the increase occurred significantly earlier than that of CK, thus enabling judgement of the risk of renal failure (crush kidney syndrome). The elevation of serum IL-1 and IL-6 values correlated with the frequency of cardiopulmonary problems (hyperdynamic shock) and facilitated counter-maneuvers. Our data, although obtained from ILP with TNF alpha, could be used to monitor toxicity also when other drug regimens are administered.

[Isolated hyperthermic limb perfusion with melphalan and tumor necrosis factor in malignant melanoma]. / Die isolierte hypertherme Extremitätenperfusion beim malignen Melanom mit Melphalan und Tumornekrosefaktor.

OBJECTIVE: To analyse a personal series of cases of malignant melanoma of a limb with regional metastasis treated by isolated cytostatic perfusion of both recombinant human tumour necrosis factor (rhTNF-alpha) and melphalan, reported to produce a response rate of up to 100%. PATIENTS AND METHODS: 23 isolated hyperthermic regional perfusions were performed between 1993 and 1995 in 21 patients (17 women, four men) with proven regionally metastatic malignant melanoma of the limb, using rhTNF-alpha and melphalan in combination. Perfusion time was 90 min, at a tissue temperature of 38 degrees to 40 degrees C and a perfusion pressure 10-15 mm Hg below mean arterial. RESULTS: All systemic effects of the limb perfusions were easily manageable under intensive care monitoring. There were no severe disturbances (WHO grade 3/4) of cardiovascular or pulmonary functions. One patient, who had sustained a marked leak during the perfusion, died two days after the perfusion of severe pneumonia and pulmonary emboli from a femoral vein thrombosis. Two further perfusions were terminated because of a leakage rate of more than 10%. A rise in bilirubin and the transaminases occurred in 11 of the 23 perfusions up to WHO grade 2 (n = 9) and 3 (n = 2). Renal functions were temporarily impaired in three of the 21 patients (WHO grade 1). Complete tumour regression was obtained in 13 patients, a partial one in three (response rate 80%). After a median follow-up period of 15 months five of the 13 patients developed a regional recurrence. CONCLUSION: The observed response rate is higher than that with melphalan alone as reported in the literature. To clarify this difference a randomized phase III study comparing the two methods has been initiated.

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.

OBJECTIVE: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. SUMMARY BACKGROUND DATA: To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. METHODS: In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. RESULTS: A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. CONCLUSIONS: In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

[Isolated hyperthermic perfusion of extremities in malignant melanoma with melphalan and tumor necrosis factor]. / Die isolierte hypertherme Extremitätenperfusion beim Malignen Melanom mit Melphalan und Tumornekrosefaktor.

Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan was carried out in 21 patients with regionally metastatic malignant melanoma of the limbs. The observed response rate was 65% complete and 15% partial remission. These results warrant further investigation of ILP with TNF and melphalan vs ILP with melphalan alone in a prospective randomised multicenter trial.