H. Schraffordt Koops

Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: A multicenter trial

PURPOSE To determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS). PATIENTS AND METHODS Among 55 patients with 30 primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade 1 sarcomas (very large, recurrent, or multiple). The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases. IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP. RESULTS A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases. Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC). Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and seven (13%) NC. Limb salvage was achieved in 84% (follow-up duration, 20+ to 50+ months). In 39 patients, resection of the tumor remnant (n = 31) or of two to eight tumors (n = 8) after ILP was performed; local recurrence developed in five (13%). When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease. Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths. Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels. CONCLUSION ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS. TNF is an active anticancer drug in humans in the setting of ILP.

Cardiovascular Morbidity in Long-Term Survivors of Metastatic Testicular Cancer

PURPOSE To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy. PATIENTS AND METHODS Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were </= 50 years at the time of analysis were evaluated for the occurrence of cardiovascular events. Sixty-two of 87 patients were additionally evaluated for cardiac damage and cardiovascular risk factors. Their cardiovascular risk profile was compared with that of 40 patients with comparable age and follow-up duration treated with orchidectomy only for stage I disease. RESULTS Major cardiac events were found in five (6%) of the 87 patients (age at time of event, 30 to 42 years; time after chemotherapy, 9 to 16 years): two with myocardial infarction and three with angina pectoris with proven myocardial ischemia. An increased observed-to-expected ratio of 7.1 (95% confidence interval, 1.9 to 18.3) for coronary artery disease, as compared with the general male Dutch population, was found. In addition, one patient experienced a cerebrovascular accident. Exercise ECG did not reveal cases of subclinical coronary artery disease. Echocardiography showed normal systolic left ventricular function in most patients, but diastolic left ventricular function was disturbed in 33% of the patients. Of 62 chemotherapy patients, 79% had hypercholesterolemia, 39% had hypertension, 25% still experienced Raynauds phenomenon, and 22% had microalbuminuria. Compared with patients with stage I disease, the chemotherapy patients had higher blood pressure and higher total cholesterol and triglyceride levels and were more insulin-resistant. CONCLUSION In long-term survivors of metastatic testicular cancer, we observed a significantly increased risk for occurrence of cardiac events accompanied by a persisting unfavorable cardiovascular risk profile. Accurate follow-up, focused on cardiovascular complications and aimed at intervention in these young cancer survivors, seems to be important.

Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro

Objectives: Procalcitonin (PCT) is a 13 kD protein of which plasma concentrations are strongly increased in inflammatory states. PCT concentrations are claimed to have a more powerful discriminatory value for bacterial infection than the acute phase proteins serum amyloid A (SAA) or C‐reactive protein (CRP). The source of production and its mechanism of induction are unknown. We investigated the inducibility of PCT both in vivo and in vitro and compared the behavior of PCT with those of SAA and CRP. Design: A prospective descriptive patient sample study and a controlled liver tissue culture study. Setting: A university hospital. Patients: Cancer patients who were treated with human tumor necrosis factor‐α (rhTNF‐α; 5 patients) or interleukin‐6 (rhIL‐6; 7 patients). Measurements and Main Results: Serial serum samples were collected for analysis of concentrations of PCT, SAA, and CRP. In the TNF‐α group, frequent sampling was performed on the first day to allow analysis of initial responses. In a human liver slice model, the release of PCT, SAA, and CRP was measured on induction with rhTNF‐α and rhIL‐6 for 24 hrs. We found that PCT displayed acute phase reactant behavior in vivo after administration of both rhTNF‐α and rhIL‐6. After rhTNF‐α‐administration, PCT reached half‐maximal concentrations within 8 hrs, 12 hrs earlier than either SAA or CRP did. PCT, SAA, and CRP were produced in detectable quantities by liver tissue in vitro. PCT production by liver slices was enhanced after stimulation with rhTNF‐α or rhIL‐6; SAA and CRP concentrations were elevated after stimulation with rhTNF‐α. Conclusions: We found that PCT and acute phase proteins such as CRP are induced by similar pathways. The liver appears to be a major source of PCT production. Thus, PCT may be considered an acute phase protein. The different kinetics of PCT, rather than a fundamentally different afferent pathway, may explain its putative diagnostic potential to discriminate bacterial infection from other causes of inflammation.

Detection of recurrence in patients with clinical stage I nonseminomatous testicular germ cell tumors and consequences for further follow-up: a single-center 10-year experience

PURPOSE A wait-and-see policy for patients with stage I nonseminomatous testicular germ cell tumors (NSTGCT) was evaluated in a prospective study. The frequency and time of recurrence, detection of recurrence, and presence of unfavorable prognostic factors were investigated. PATIENTS AND METHODS During the period 1982 to 1992, 154 patients with stage I NSTGCT (median age, 29 years) underwent orchidectomy and were monitored at follow-up evaluation with physical examinations, alfafetoprotein (AFP) and beta-human choriogonadotropin (hCG) levels, chest x-rays (CXR), and computed tomographic (CT) scans of the abdomen and chest. Multivariate logistic regression analyses were performed to identify prognostic factors. RESULTS During a median follow-up period of 7 years (range, 2 to 12), recurrence was found in 42 patients (27.3%). All cases of recurrence were detected within 2 years, 90% in the first year after orchidectomy. In 29 patients (69.0%), recurrence was detected in the abdominal lymph nodes. Nine patients (21.4%) had metastases in the retroperitoneum and mediastinum and/or lungs, and four patients (9.6%) had metastases only in the mediastinum or lungs. The majority of recurrences (97.6%) were detected by tumor markers and CT scans. Recurrence was related to the presence of vascular invasion, embryonal carcinoma (E), elevated preoperative hCG level, and absence of mature teratoma (M). Only vascular invasion was an independent risk factor. After polychemotherapy treatment for recurrence, the survival rate for the total group was 98.7%. CONCLUSION The wait-and-see policy is a reliable method for follow-up monitoring of patients with stage I NSTGCT. Even in patients with unfavorable prognostic factors, it is justified to await the possible appearance of metastases. For the future, it is recommended that CXR be omitted from the schedule, and it might be feasible to discontinue follow-up evaluations after 5 years.

Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases : a multicentre randomized Phase II study

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.

Detection of local recurrence of soft-tissue sarcoma with positron emission tomography using [18F]fluorodeoxyglucose

AbstractBackground: It is often difficult to detect a local recurrence of soft-tissue sarcomas due to disturbance of the normal anatomy by previous surgery and radiotherapy. The aim of this study was to assess the value of positron emission tomography (PET) with [18F]fluoro-2-deoxy-d-glucose (FDG) for detecting local recurrences. Methods: In the period 1992–1995, 17 patients with proven or suspected local recurrence of soft-tissue sarcoma were examined using FDG-PET. Fifteen of these patients were ultimately proven to have a recurrence. Results: Recurrence was visualized in 14 patients (93%). Small tumors (maximum diameter 0.5 cm) were as easily visible as large lesions (maximum diameter 20 cm). In one patient the PET scan was positive, but the recurrence could not be proven histologically. Recurrence was proven 1 year later. A recurrent low-grade liposarcoma was not visualized. The two patients with benign lesions had a negative PET scan. The mean glucose metabolic rate was calculated to be 13.2 µmol/100 g/min (range 1.9–28.4). A correlation was found between the histological malignancy grade and the metabolic rate (p<0.05; Kruskal-Wallis). Conclusion: PET with FDG is a useful addition to the diagnostic armamentarium for detecting local recurrence of soft-tissue sarcomas and provides an indication of the malignancy grade of the recurrent lesion.

Limb salvage surgery for primary bone sarcoma of the lower extremities : Long-term consequences of endoprosthetic reconstructions

AbstractBackground: Adjuvant chemotherapy and endoprosthetic replacement for bone sarcomas of the lower extremity is well established. The specific long-term consequences of these endoprosthetic reconstructions for the patients affected limb are unknown. Method: The oncologic results and the survival of the endoprostheses were reviewed in 32 patients with primary bone sarcoma of the femur or proximal tibia. There were 26 high-grade sarcomas, and 6 low-grade sarcomas. A proximal femoral endoprosthesis was used for reconstruction in 4 patients, a total or push-through femoral endoprosthesis in 11 patients, a distal femoral endoprosthesis in 15 patients, and a proximal tibial endoprosthesis in two patients. Results: Median survival was 10 years (range, 1.1 to 18.9 years) for patients with high-grade sarcoma, and 8.1 years (range, 7.1 to 10 years) for patients with low-grade sarcomas. Distant metastases developed in seven patients (22%), all with stage IIB sarcoma, with concomitant local recurrence in 3 patients (9%). Five-year overall and disease-free survival rates for high-grade sarcomas were 81% and 73%, respectively. The overall endoprosthetic survival rate was 87% at 5 years, 80% at 10 years, and 56% at 15 years. Median follow-up of the original endoprostheses was 8.3 years (range, 0.6 to 18.7 years). Endoprosthesis-related complications occurred in 13 patients (41%); most complications were mechanical failures. The highest complication rate was found in distal femoral replacements (60%); amputation was necessary in both patients treated with a proximal tibial endoprosthesis. Five endoprostheses (16%) were revised. An amputation of the involved limb was performed in four patients (13%): in two patients because of local recurrence and in the other two patients because of infection. For patients alive at follow-up, the median functional Enneking evaluation score was 22 points (range, 12 to 28 points), with the highest functional scores in patients with a distal femoral endoprosthesis, and the lowest functional scores in patients with total or push-through femoral replacements. Conclusion: Endoprosthetic reconstructions gave satisfying functional results in most patients after long-term survival. However, the proximal tibial and distal femoral endoprosthesis are particularly at risk for long-term endoprosthetic complications requiring additional surgical procedures.

Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors.

The gonadal functions were studied in 54 patients with disseminated nonseminomatous testicular tumors who had been subjected to combination chemotherapy (cisplatin, vinblastine, and bleomycin [PVB]) and surgery (hemiorchiectomy, retroperitoneal lymph node dissection or removal of retroperitoneal residual tumor after chemotherapy) and in 17 patients with a stage I tumor subjected to hemiorchiectomy exclusively. In the patients treated with chemotherapy, the plasma testosterone levels remained at the lower limit of normal and the luteinizing hormone (LH) levels remained elevated for 2 years after completion of treatment. The follicle-stimulating hormone (FSH) levels also remained significantly elevated, but showed a tendency to decrease after 2 years. Semen analysis was performed in 25 patients; of the other patients, 18 had no antegrade ejaculation, eight had undergone a vasectomy and three patients did not cooperate. Before treatment, 72% of the patients showed azoo- or oligozoospermia; 2 years after discontinuation of the chemotherapy, 48% had azoo- or oligozoospermia while 28% had more than 60 X 10(6) spermatozoa/mL. However, interestingly the proportion of patients with azoospermia had increased from 4% to 28%. In the course of this study, eight pregnancies occurred; one ended in an early spontaneous abortion; the other seven pregnancies ran an uncomplicated course. Seven healthy children were born. In 17 patients with a stage I tumor treated by hemiorchiectomy only, the testosterone, LH and FSH levels were also observed for 2 years; until 2 years after treatment, the testosterone levels remained lower and the FSH levels remained higher than normal. Insufficiency of the Leydigs cells in the unaffected gonad appeared to be responsible for the altered hormone concentrations in the blood.

Angiographic response of locally advanced soft-tissue sarcoma following hyperthermic isolated limb perfusion with tumor necrosis factor

AbstractBackground: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target. The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma. Patients and Methods: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18–80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4–14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined. The changes in tumor vascularization after treatment were scored and compared with the pathological response. Results: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with >90% necrosis of the tumor. Of seven patients with an AA, pathological examination showed a pCR in one patient, 10–50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p<0.001). Conclusion: An angiography performed after hyperthermic isolated limb perfusion with TNF-α and melphalan provides a good indication, regardless of whether a good pathological response is expected.

Sexual functioning after treatment for testicular cancer

This retrospective study evaluates changes in sexual functioning after treatment for testicular cancer and investigates whether there is a relationship with different treatment modalities.