EMA vs EMACO in the treatment of gestational trophoblastic neoplasia.

OBJECTIVE: To compare experiences with EMA versus EMACO in the treatment of gestational trophoblastic neoplasia. METHODS: The medical records of women diagnosed with GTN at the New England Trophoblastic Disease Center from 1986 to 2019 were reviewed, and women receiving EMA or EMACO as their first multiagent regimen were eligible. Clinical characteristics, treatment, outcomes, and adverse events were compared between the two groups. RESULTS: We identified 44 and 39 patients who received EMA and EMACO, respectively. The complete remission rate was significantly higher in the EMA group (97.7%) than in the EMACO group (71.8%) (p = 0.001). However, patients receiving EMACO were more likely to have adverse prognostic factors such as higher median prognostic risk score (8 vs 4, p < 0.001), non-molar antecedent pregnancy (59 vs 27.3%, p = 0.014) and distant metastasis (64.1 vs 47.7%, p = 0.017). Time to complete remission was also similar (p = 0.947) with a median of 12 weeks with EMA and 13.1 weeks with EMACO. There was no significant difference in treatment delays or use of adjuvant surgery. After multivariate analysis, chemotherapy regimen (EMA or EMACO) did not retain prognostic significance for remission. Overall toxicities were more frequent in EMA (60.2 vs 32.7%, p < 0.001), especially neutropenia, but this did not delay treatment and likely resulted from less growth factor support (18.2 vs 48.7%, p = 0.003). CONCLUSIONS: When controlling for other prognostic factors, outcomes with EMA appear similar to EMACO. It may be worthwhile to investigate whether EMA, a simpler and less costly regimen, may be as effective as EMACO in the treatment of GTN.

Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6months after uterine evacuation?

OBJECTIVE: To compare the outcomes of Brazilian patients with molar pregnancy who continue human chorionic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6months after uterine evacuation. METHODS: Retrospective chart review of 12,526 patients with hydatidiform mole treated at one of nine Brazilian reference centers from January 1990 to May 2016. RESULTS: At 6months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients were managed expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) developed postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectant management required more time for remission (11 versus 8months; p=0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6months; p<0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p=0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/16 patients, p=0.60). None of the women relapsed, and no deaths occurred in either group. CONCLUSION: In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients.

Isolated limb infusion with hyperthermia and chemotherapy for advanced limb malignancy: factors influencing toxicity.

BACKGROUND: The isolated limb infusion (ILI) technique is a simpler and less invasive alternative to isolated limb perfusion, which allows regional administration of high-dose chemotherapy to patients with advanced melanoma and other malignancies restricted to a limb. METHODS: Patients from two institutions, treated by ILI between 1998 and 2009 for extensive disease restricted to a limb, were included. The cohort included 31 patients with melanoma who presented with in-transit metastases or an extensive primary lesion, one patient with squamous cell carcinoma and another with epithelioid sarcoma not suitable for local surgical treatment. RESULTS: A complete response was achieved in 26.3% of patients and a partial response in 52.6%. Toxicity was assessed according to the Wieberdink limb toxicity scale. Grade II toxicity was noted in 39.5% of patients, grade III in 50% and grade IV in 10.5%. Toxicity was correlated with the results of a number of clinical and laboratory tests. The toxicity of melphalan and actinomycin D was dose-dependent. For melphalan, the relationship between toxicity and mean dose was as follows: grade II--34.7 mg; grades III and IV--47.5 mg (P = 0.012). The relationship between toxicity and maximum serum creatine phosphokinase (CPK) was as follows: grade II--431.5 U/L; grades III and IV--3228 U/L (P = 0.010). CONCLUSION: Toxicity after ILI is dose-dependent and serum CPK correlates with toxicity.

Clinical epidemiology and management of gestational trophoblastic neoplasia in Hungary in the past 34 years.

OBJECTIVE: To review our clinical experience in the treatment of patients with gestational trophoblastic neoplasia (GTN) over the past 34 years in our national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2010, 331 patients with low-risk GTN and 174 patients with high-risk GTN (altogether 505) were treated. The patients were directed to the national trophoblastic disease center from all parts of Hungary. The patients were between 14 and 54 years of age, with an average age of 28.7 years. Primary chemotherapy was selected based upon the patient's stage and prognostic score of GTN. RESULTS: Among 237 low-risk patients, 228 (96.2%) achieved remission as a result of primary methotrexate (MTX) therapy. Out of 94 low-risk patients 90 (95.7%) achieved remission as a result of primary actinomycin-D (Act-D) therapy. MTX, Act-D and cyclophosphamide (MAC) as a primary therapy was used in 118 high-risk cases, and 110 (93.2%) patients achieved complete remission. A total of 32 high-risk patients were treated with the etoposide, high-dose MTX/folinic acid, Act-D, cyclophosphamide and vincristine (EMA-CO) regimen, and of 26 primary therapies complete remission was achieved in 21 (80.8%) cases. Primary cisplatin, etoposide and bleomycin (CEB) therapy was successful in 16 of 17 high-risk cases (94.1%). Metastases were found in 47.3% (239/505) of the patients. Hysterectomy was performed in 68 of 505 (13.5%) cases. Chemotherapy, surgical intervention or other supplementary treatments resulted in 100% remission in cases of nonmetastatic and metastatic low-risk disease. Comparison of mean prognostic scores resulted in significant differences between CEB and MAC, CEB and EMA-CO, and MAC and EMA-CO. CONCLUSION: Our data indicate that MTX/folinic acid or Act-D should be the primary treatment in patients with nonmetastatic or metastatic low-risk GTN. Patients with high-risk metastatic GTN should be treated primarily with combination chemotherapy. Our data support the effectiveness of MAC, EMA-CO and CEB regimens. Results also show that patient care under the direction of experienced clinicians serves to optimize the opportunity for cure and minimize morbidity.

Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia.

OBJECTIVE: To assess the value of secondary therapy in the management of high-risk gestational trophoblastic neoplasia (GTN) after failure of initial multiagent chemotherapy. STUDY DESIGN: Forty-nine women with high-risk GTN, including 29 who were treated primarily and 20 who were treated secondarily, completed treatment at the Brewer Trophoblastic Disease Center between 1986 and 2010. Initial chemotherapy consisted of etoposide, high-dose methotrexate with folinic acid, actinomycin D, cyclophosphamide and vincristine (EMA-CO) in 29 patients who were treated primarily and in 10 patients who had received single-agent chemotherapy before being treated at our center. Patients who had incomplete responses or developed resistance to EMA-CO or had previously received EMA-CO were treated with drug combinations employing etoposide and a platinum agent with methotrexate and actinomycin D (EMA-EP), bleomycin (BEP), ifosfamide (VIP, ICE) or paclitaxel (TP/TE). Adjuvant surgery and brain radiation were used in selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: Twenty-eight (57%) of the 49 patients developed resistance to EMA-CO: 13 (45%) of 29 treated primarily and 15 (75%) of 20 treated secondarily. Of the 13 patients who failed primary treatment with EMA-CO, 10 (77%) had lasting complete responses to EMA-EP (4), BEP (3), VIP (1), ICE (1) or TP/TE (1). Of the 15 patients who failed EMA-CO used as secondary therapy, 13 (87%) had lasting complete responses to EMA-EP (5), BEP (6) or ICE (2). Brain irradiation was given to 4 patients who developed brain metastases during treatment, 3 of whom survived. Operative procedures were performed to remove resistant foci of disease in the lungs (9) or uterus (2) in 11 (39%) of the 28 patients, 9 (82%) of whom survived. Survival was significantly influenced by hCG level at the start of salvage therapy (p<0.001), number of metastatic sites (p <0.02) and metastases to sites other than the lung and vagina (p<0.05). CONCLUSION: Salvage therapy with platinum/etoposide-based drug regimens, often in conjunction with surgery and brain radiation, was successful in achieving cure in 82% of 28 high-risk GTN patients who failed initial multiagent chemotherapy and was ultimately responsible for survival in 53% of the 43 patients (88%) with high-risk GTN who were cured.

Patterns of recurrence following complete response to regional chemotherapy for in-transit melanoma.

BACKGROUND: Even after complete response (CR) to regional chemotherapy for in-transit melanoma, many patients develop recurrence. Understanding the probability, location, and timing of recurrences can optimize management strategies for this patient population. METHODS: A prospective database identified patients who underwent 81 first-time hyperthermic isolated limb perfusions (HILPs) and 133 first-time isolated limb infusions (ILIs). Response was defined using the response evaluation criteria in solid tumors; recurrence was defined as development of new disease after in-field CR. RESULTS: HILP exhibited a significantly higher CR rate than ILI (44 vs. 28 %, p = .01). Among 36 HILP-CRs and 37 ILI-CRs, the 3-year recurrence rate was 65 % (95 % confidence interval [95 % CI]: 43-79 %) and 85 % (95 % CI: 63-94%), respectively. Median time to first recurrence was longer for HILP-CR than ILI-CR (23 vs. 8 months, p = .02). There was no statistically significant difference in median time to in-field recurrence between HILP-CR and ILI-CR (46 vs. 25 months, p = .15), but HILP-CR showed a longer median time to out-of-field recurrence (42 vs. 14 months, p = .02). Finally, the overall survival (OS) difference between HILP-CR and ILI-CR (3-year survival: 77 vs. 54 %) did not achieve statistical significance (p = .10). CONCLUSIONS: In the largest series comparing patterns of recurrence, we demonstrate that out-of-field recurrence after CR to HILP occurs later than after CR to ILI, though control of in-field disease remains similar. There remains no statistically significant difference in overall survival after CR to the 2 procedures.

A retrospective study of the preoperative treatment of advanced Wilms tumor in children with chemotherapy versus transcatheter arterial chemoembolization alone or combined with short-term systemic chemotherapy.

PURPOSE: To evaluate the therapeutic effect of preoperative transcatheter arterial chemoembolization (TACE) combined with short-term systematic chemotherapy in the treatment of advanced Wilms tumor. MATERIALS AND METHODS: This was a retrospective study on 66 patients with unilateral advanced Wilms tumor, age 5 months to 11 years (median, 2.9 years; 30 boys and 36 girls), treated at our institution between 1995 and 2007. Characteristics of the patient population were maximal tumor diameter > 10 cm, or involvement of periaortic lymph nodes, or inferior vena cava invasion, or distal metastasis, or tumor with anaplastic histology. Patients were divided into three groups. Twenty patients were treated with conventional preoperative chemotherapy (PC group) using vindesine, actinomycin D, and pirarubicin for 4 weeks; 21 patients were treated in the TACE group with preoperative renal arterial chemoembolization using Lipiodol-pirarubicin-vindesine emulsion; and 25 patients were treated with preoperative chemoembolization combined with short-term systematic chemotherapy (T+S) for 2 weeks. RESULTS: No drug-induced cardiotoxicity, nephrotoxicity, or hepatic dysfunction was observed. Complete surgical removal of the tumor was achieved in 12 (65.0%), 17 (80.9%), and 22 (88.0%) patients in the PC, TACE, and T+S groups, respectively (T+S group vs PC group, P = .030). The 2-year relapse-free survival rates were 65.0%, 80.9%, and 100.0% in the PC, TACE, and T+S groups, respectively (T+S vs PC, P = .001). CONCLUSIONS: From our experience, preoperative chemoembolization combined with short-term systematic chemotherapy is able to achieve higher rates of complete tumor resection and relapse-free survival in the treatment of advanced Wilms tumor.

Long-term survivals of stage IIb osteosarcoma: a 20-year experience in a single institution.

BACKGROUND: The purpose of this study is to evaluate the disease-free survival (DFS) and overall survival (OS) of patients with stage IIB osteosarcoma at a single institution for 20 years and to compare the results according to the chemotherapy protocols. METHODS: From Jan 1988 to Nov 2008, 167 patients with osteosarcoma were treated at our hospital and among them, 117 patients (67 males and 50 females) with stage IIB osteosarcoma were evaluable. Their mean age was 22.6 years (range, 8 months to 71 years). Seventy-eight cases underwent the modified T10 (M-T10) protocol (group 1), 23 cases underwent the T20 protocol (group 2) and 16 cases underwent the T12 protocol (group 3). The DFS and OS were calculated and compared according to the chemotherapy protocols. RESULTS: At a mean follow-up of 78.9 months, 63 patients were continuously disease-free (63/117), 6 patients were alive after having metastatic lesions, 7 patients died of other cause and 41 patients died of their disease. The 5- and 10-year OS rates were 60.2% and 44.8%, respectively and the 5- and 10-year DFS rates were 53.5% and 41.4%, respectively. There was no significant difference of the OS and DFS between the chemotherapy protocols (p = 0.692, p = 0.113). CONCLUSIONS: At present, we achieved success rates close to the internationally accepted DFS and OS. We were able to achieve the higher survival rates using the M-T10 protocol over the 20 years. However, there was no significant difference of results between the chemotherapy protocols. We think the M-T10 protocol will achieve more favorable results in the near future.

Long-Term Survivals of Stage IIB Osteosarcoma: A 20-Year Experience in a Single Institution

BACKGROUND: The purpose of this study is to evaluate the disease-free survival (DFS) and overall survival (OS) of patients with stage IIB osteosarcoma at a single institution for 20 years and to compare the results according to the chemotherapy protocols. METHODS: From Jan 1988 to Nov 2008, 167 patients with osteosarcoma were treated at our hospital and among them, 117 patients (67 males and 50 females) with stage IIB osteosarcoma were evaluable. Their mean age was 22.6 years (range, 8 months to 71 years). Seventy-eight cases underwent the modified T10 (M-T10) protocol (group 1), 23 cases underwent the T20 protocol (group 2) and 16 cases underwent the T12 protocol (group 3). The DFS and OS were calculated and compared according to the chemotherapy protocols. RESULTS: At a mean follow-up of 78.9 months, 63 patients were continuously disease-free (63/117), 6 patients were alive after having metastatic lesions, 7 patients died of other cause and 41 patients died of their disease. The 5- and 10-year OS rates were 60.2% and 44.8%, respectively and the 5- and 10-year DFS rates were 53.5% and 41.4%, respectively. There was no significant difference of the OS and DFS between the chemotherapy protocols (p = 0.692, p = 0.113). CONCLUSIONS: At present, we achieved success rates close to the internationally accepted DFS and OS. We were able to achieve the higher survival rates using the M-T10 protocol over the 20 years. However, there was no significant difference of results between the chemotherapy protocols. We think the M-T10 protocol will achieve more favorable results in the near future.

Isolated limb infusion with melphalan and actinomycin D in melanoma patients: factors predictive of acute regional toxicity.

IMPORTANCE OF THE FIELD: Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%. AREAS COVERED IN THIS REVIEW: Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects. WHAT THE READER WILL GAIN: An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb. TAKE HOME MESSAGE: ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities.

OBJECTIVE: The aim is to analyse a modified standardised HILP procedure regarding the response rates, local recurrences and complication rates. PATIENTS AND METHODS: 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using melphalan and dactinomycin between 1992 and 2007. Using M.D. Anderson's classification at the time of the perfusion 51 patients presented in stage IIIA, 43 patients in stage IIIAB and 58 patients in stage IV. If indicated, lymph node dissection was performed simultaneously just before perfusion of the extremity. RESULTS: Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (17.9%) patients. 28 (19.3%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). Severe complications (Wieberdink IV/V) were seen in eight cases. The average recurrence-free survival was 17 months. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease. CONCLUSION: HILP is an efficient therapy for multiple or recurrent in-transit metastases of malignant melanoma of the lower extremities. The efficiency increased by improving the technique of the perfusion. Long-term survival can be observed in patients without regional lymph node metastases or distant metastases.

Acute malnutrition is common in Malawian patients with a Wilms tumour: A role for peanut butter.

BACKGROUND: Children with cancer in resource limited countries are often malnourished at diagnosis. Acute malnutrition is associated with more infectious complications and an increased risk of morbidity and mortality in major surgery. METHODS: All new patients with the clinical diagnosis of a Wilms tumour admitted in the Queen Elizabeth Central Hospital, Blantyre, Malawi from January 2007 until June 2008 were included. We documented anthropometric parameters, tumour size and serum levels of micronutrients at diagnosis. Corrected weight (body weight - tumour weight) was repeated after 4 weeks of preoperative chemotherapy. During therapy oral feeds were encouraged and a locally made ready to use therapeutic peanut butter-based food (chiponde) supplied. RESULTS: A high rate of acute malnutrition was found in patients with Wilms tumour at diagnosis (45-55%), much higher than in community controls (11%). Patients (40%) and community controls (37%) had a similar, high rate of stunting (low height for age), a sign of chronic malnutrition. Tumour size at diagnosis and the degree of acute malnutrition at diagnosis was correlated; patients with a larger tumour had more severe acute malnutrition (r = -0.88, P < 0.01). With a supply of chiponde, 7 of 18 patients had a >5% increase in corrected weight during preoperative chemotherapy. Patients with a more positive nutritional course had a better tumour response to chemotherapy (r = 0.52, P < 0.05). Surprisingly, few micronutrient deficiencies were found, except for low serum levels of vitamin A (44% of patients). CONCLUSION: Acute malnutrition, superimposed on chronic malnutrition, is common in patients with Wilms tumour in Malawi. Earlier presentation needs to be encouraged. Chiponde, a peanut butter based ready-to-use-therapeutic-food, is an attractive means of nutritional support which needs further study.

Alveolar rhabdomyosarcoma of the extremity and nodal metastasis: Is the in-transit lymphatic system at risk?

Alveolar rhabdomyosarcoma (RMS) of the extremity is not infrequently associated with regional node metastasis. Knowledge of lymphatic drainage of extremity RMSs is important to determine radiotherapy fields. In this report we describe two patients with alveolar RMS of the lower extremity with inguinal metastasis at presentation. Both the distal lower extremity and inguinal region received local therapy consisting of surgery and postoperative radiotherapy. Both patients later developed in-transit lymphatic metastasis outside of the irradiated field. The in-transit lymphatics can be a site of failure in children with alveolar RMS of the extremity and nodal involvement.

A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive approach for treating in-transit extremity melanoma, with only two US single-center studies reported. Establishing response and toxicity to ILI as compared with hyperthermic isolated limb perfusion is important for optimizing future regional chemotherapeutic strategies in melanoma. STUDY DESIGN: Patient characteristics and procedural variables were collected retrospectively from 162 ILIs performed at 8 institutions (2001 to 2008) and compared using chi-square and Student's t-test. ILIs were performed for 30 minutes in patients with in-transit melanoma. Melphalan dose was corrected for ideal body weight (IBW) in 42% (n = 68) of procedures. Response was determined at 3 months by Response Evaluation Criteria in Solid Tumors; toxicity was assessed using the Wieberdink Limb Toxicity Scale. RESULTS: In 128 evaluable patients, complete response rate was 31%, partial response rate was 33%, and there was no response in 36% of patients. For all patients (n = 162), 36% had Wieberdink toxicity grade >or=3 with one toxicity-related amputation. On multivariate analysis, smaller limb volumes were associated with better overall response (p = 0.021). Use of papaverine in the circuit to achieve cutaneous vasodilation was associated with better response (p < 0.001) but higher risk of grade >or=3 toxicity (p = 0.001). Correction of melphalan dose for ideal body weight did not alter complete response (p = 0.345), but did lead to marked reduction in toxicity (p < 0.001). CONCLUSIONS: In the first multi-institutional analysis of ILI, a complete response rate of 31% was achieved with acceptable toxicity demonstrating this procedure to be a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma.

Isolated limb infusion as palliative treatment for advanced limb disease in patients with AJCC stage IV melanoma.

INTRODUCTION: In the treatment of patients with advanced limb melanoma a major treatment dilemma can arise when distant metastases are present also. Isolated limb infusion (ILI) has proved to be a useful limb-saving treatment and could potentially be of palliative value in patients with American Joint Committee on Cancer (AJCC) stage IV melanoma. METHODS: We identified 37 patients with advanced symptomatic limb disease as well as documented distant metastases at the time of their ILI. In all patients a drug combination of melphalan and actinomycin D was used. RESULTS: Fifty one percent had visceral distant metastases and 49% had cutaneous distant metastases only. The overall response rate in the treated limb was 76% [complete response (CR) rate 22%, partial response (PR) rate 54%]. Median response duration was 11 months (28 months for patients with CR; p = 0.08). Median survival after CR was 22 months, 17 months after PR, and only 4 months for those with stable or progressive disease (p = 0.002). Patients with visceral distant metastases had a significantly decreased survival compared with those with cutaneous distant metastases only (8 and 21 months, respectively; p = 0.03). Limb salvage was achieved in 86% of the patients. The procedure was well tolerated, with only one patient developing Wieberdink grade IV toxicity (threatened/actual compartment syndrome) and none requiring amputation as a result of the procedure (grade V toxicity). CONCLUSIONS: Minimally invasive ILI can effectively be used as palliative treatment to provide local tumor control and limb salvage in stage IV melanoma patients with advanced, symptomatic limb disease.

Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients.

INTRODUCTION: Isolated limb infusion (ILI) with cytotoxic drugs is a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation to treat metastatic melanoma confined to a limb. Response rates and duration of response following ILI are similar to those after ILP. Previously we have shown that more significant limb toxicity is not associated with a higher response rate or improved patient outcome. In this study we sought to determine factors predicting toxicity following ILI. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). Limb toxicity was assessed using the Wieberdink scale. RESULTS: The average patient age was 74 years (range 29-93 years) and 62% were female. Most patients (134/185) had MD Anderson stage III disease (satellites and in-transit metastases). Toxicity grade I (no reaction) occurred in 3 patients, grade II (slight erythema and edema) in 105 patients, grade III (considerable erythema and edema +/- blistering) in 72 patients, and grade IV (threatened or actual compartment syndrome) in 5 patients. No patient developed grade V toxicity (requiring amputation). On univariate analysis high peak and high final melphalan concentrations were found to be predictive factors for grade III/IV limb toxicity as well as the area under the curve of the melphalan concentration. Surprisingly, a greater rise in the CO(2) level during the procedure was associated with lower toxicity in the univariate analysis. Increased serum creatine phosphokinase (CK) postoperatively was related to higher toxicity score. In the multivariate analysis high final melphalan concentration and shorter tourniquet time were independent predictive risk factors for developing grade III/IV limb toxicity. CONCLUSIONS: ILI is a safe alternative to the more invasive and laborious ILP technique to treat melanoma confined to a limb. Regional acute toxicity following ILI is mild to moderate in most patients. Based on the predictive factors found in this series, altering melphalan dose and tourniquet time may allow further reductions in post-ILI toxicity without compromising effectiveness.

Isolated limb infusion for in-transit malignant melanoma of the extremity: a well-tolerated but less effective alternative to hyperthermic isolated limb perfusion.

BACKGROUND: Isolated limb infusion (ILI) is a recently described minimally invasive technique developed in Australia for delivering regional chemotherapy. This study examined the efficacy and toxicity of ILI, compared to hyperthermic isolated limb perfusion (HILP), in treating extremity in-transit melanoma. METHODS: Variables from a prospective single institution database of 120 regionally treated melanoma patients (1995-2007) were compared using chi-square analysis. This included 61 consecutive ILI treatments in 58 patients and 59 HILP treatments in 54 patients. Response was defined at 3 months using the response evaluation criteria in solid tumors (RECIST). ILI was performed using melphalan (LPAM) and dactinomycin for 30 min after limb temperature reached 37 degrees C. HILP was performed using LPAM for 60 min after limb temperature reached 38.5 degrees C. RESULTS: For ILI (n = 61), the complete response (CR) rate was 30%, the partial response (PR) rate was 14%, and there was no response (NR) in 56% of patients. The median duration of CR was 12 months and 18% of patients experienced (grade >or=3) toxicity. HILP (n = 59) was associated with a better (P < 0.001) response rate (CR 57%, PR 31%, and NR 12%) however, more patients (32%) experienced grade >or=3 toxicity (P = 0.037). The dose of LPAM was corrected for ideal body weight (IBW) in 40 out of 61 ILI procedures, and 13 of 59 HILP procedures. This dosing modification was associated with decreased toxicity (P = 0.024) without diminishing response. CONCLUSION: ILI was found to be a well-tolerated alternative to HILP. While ILI does not appear to be as effective as HILP, it does seem to be associated with less morbidity.

Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology.

PURPOSE: To review the long-term duration of limb tumor complete remission (CR) and patient survival following therapeutic hyperthermic isolated limb perfusion (ILP) with cytotoxic drugs for melanoma. METHODS: A retrospective case series of 124 ILPs performed in 111 patients. RESULTS: There were 120 assessable ILPs. Patient staging (M.D. Anderson system) was stage II 11.7%, stage IIIA 44.2%, stage IIIAB 33.3%, and stage IV 10.8%. CR was initially attained after 83 ILPs (69.2%) and partial remission (PR) after 19 ILPs (15.8%). Limb CR was maintained in 28 (33.7%) of the 83 cases. Disease recurred in the perfused limb after an initial CR in the remaining 55 cases (median time to recurrence, 11 months); in 19 of these cases, the limb was disease-free at last follow-up after further locoregional treatment. A long-term CR was achieved, with or without further treatment, in 47 (56.6%) of the 83 cases in which an initial CR had occurred (mean follow-up, 97 months; median, 65 months). There was no significant difference in long-term local remission for stage IIIA and IIIAB patients. Five-year survival for those who had a partial or no response to ILP was 7%. Ten-year survival for those who had a long-term CR was 49%. CONCLUSIONS: ILP, with or without further locoregional treatment, achieved long-term control of recurrent and metastatic limb disease in 56.6% of cases in which an initial CR was achieved. A complete response to ILP was a positive prognostic indicator for survival, probably reflecting more favorable tumor biology in this subset of patients.

Cisplatin-induced hypomagnesemia and cardiac dysrhythmia.

We describe a case of a patient with cisplatin-induced hypomagnesemia who suffered brief asystole during an episode of gastroenteritis. Structural heart disease was excluded. The patient achieved complete clinical recovery after short-term administration of intravenous magnesium supplementation. Cisplatin should be considered a cause of hypomagnesemic-related cardiac dysrhythmia. Magnesium deficit may increase myocardial electrical instability and thus, the risk of life-threatening arrhythmias and sudden death. Long-term serum electrolyte measurement and appropriate replacement of magnesium are recommended.

High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients.

PURPOSE: To report our recent experience managing four patients with brain metastases of gestational trophoblastic neoplasia (GTN), coordinating systemic chemotherapy with early neurosurgical intervention or stereotactic radiosurgery and intensive supportive care during initial therapy to prevent early mortality. MATERIALS AND METHODS: A series of four consecutive patients with brain metastases from high-risk Stage IV GTN managed at our institution in 2003 and 2005. Patients were assigned FIGO stage and risk score prospectively. Because of concern for chronic toxicity resulting from concurrent moderate dose methotrexate and whole brain radiation, an individualized multidisciplinary approach was used to manage patients. RESULTS: All four women presented with brain and pulmonary metastases; one had multiple liver metastases. Neurological symptoms at presentation included grand mal seizures in 2 patients, left upper extremity hemiparesis and headache each in 1 patient, while 1 patient was asymptomatic. Index pregnancies were term pregnancies in all patients with interval from prior delivery ranging from 2 weeks to 4 years. Two had received prior chemotherapy for postmolar GTN prior to the index pregnancy with incomplete follow-up. Initial hCG values ranged from 26,400 to 137,751 mIU/ml; FIGO risk scores were > or =16 for all patients. Systemic combination chemotherapy was initiated with etoposide and cisplatin followed by moderate/high-dose (500-1000 mg/m(2)) methotrexate combinations. Craniotomy was used before or during the first chemotherapy cycle to extirpate solitary lesions in 3 patients, while stereotactic radiosurgery was administered after the first cycle to treat two brain lesions in the remaining patient. None received whole brain radiation or intrathecal methotrexate. In one patient, selective angiographic embolization was used to control hemorrhage from multiple liver metastases. Two patients required ventilator support early in treatment to allow stabilization from intrathoracic hemorrhage and neutropenic sepsis with respiratory distress syndrome, respectively. Hysterectomy was performed in one patient after completion of salvage chemotherapy. All have completed maintenance chemotherapy and are in prolonged remission (12-24 months). Neurologic sequelae include persistent left upper extremity dyskinesia and weakness in one patient, and episodic grand mal seizures and pseudoseizures in a second patient with a pre-existing seizure disorder. CONCLUSION: This case series documents the utility for a multidisciplinary approach to the treatment of brain metastases from GTN. Using early craniotomy or stereotactic radiosurgery combined with etoposide-cisplatin and moderate/high-dose methotrexate combination chemotherapy, we were able to stabilize patients early in their treatment and avoid whole brain radiation therapy or intrathecal chemotherapy.