Wilfried J. Graveland

Factors affecting cytochrome P-450 3A activity in cancer patients

Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients Experimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). Results: CYP3A activity (AUC0–40min) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by ∼50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, α-1 acid glycoprotein, explained ∼18% of overall variation in CYP3A activity (P < 0.001). Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.

One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases

Objective:The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. Methods:One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. Results:Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. Conclusions:TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.

Prospective Evaluation of the Pharmacokinetics and Toxicity Profile of Docetaxel in the Elderly

PURPOSE To prospectively study the pharmacokinetics and toxicity profile of docetaxel in elderly patients with cancer. PATIENTS AND METHODS Docetaxel was administered at a dose 75 mg/m(2) once every 3 weeks to 25 elderly cancer patients aged >/= 65 years and 26 cancer patients aged younger than 65 years. Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy. RESULTS Of 51 patients treated, 20 aged >/= 65 years (median, 71 years; range, 65 to 80 years) and 20 aged younger than 65 years (median, 53 years; range, 26 to 64 years) were assessable for pharmacokinetic studies, and 39 were assessable for toxicity. Patient characteristics were similar (P >/= .15) between the two cohorts. Mean docetaxel clearance was not altered in the elderly versus younger patients: 30.1 L/h (standard deviation [SD] 18.3 L/h) v 30.0 L/h (SD, 14.8 L/h; P = .98). The percentage of patients with grade 4 and febrile neutropenia was higher in the elderly (63% and 16%, respectively) versus younger (30% and 0%, respectively) cohort, although this observation did not reach a level of statistical significance (P = .056). From logistic regression analysis, the odds ratio for a patient aged 65 years was 1.98 for developing grade 4 neutropenia compared with a patient aged 50 years (P = .091). CONCLUSION Docetaxel plasma pharmacokinetics are unaltered in elderly patients. Patients aged >/= 65 years appear to be more sensitive to docetaxel-induced neutropenia.

High-dose-rate intraoperative radiotherapy for close or positive margins in patients with locally advanced or recurrent rectal cancer.

PURPOSE A high-dose-rate intraoperative radiotherapy (HDR-IORT) technique for rectum cancer was developed and the technique, local failure, and survival were analyzed. METHODS AND MATERIALS After the exclusion of metastatic patients, 37 patients were treated with external beam RT, surgery, and HDR-IORT between 1997 and 2000. Primary locally advanced rectum cancer was found in 18 patients and recurrent disease in 19. HDR-IORT was only administered if the resection margins were < or =2 mm. The flexible intraoperative template is a 5-mm-thick pad with 1-cm-spaced parallel catheters. Clips were placed during surgery to define the target area. A dose of 10 Gy was prescribed at a 1 cm depth from the template surface and calculated using standard plans. After treatment, the dose at the clips was calculated using the reconstructed template geometry and the actual treatment dwell times. The median follow-up of surviving patients was 3 years. No patients were lost to follow-up. RESULTS Overall, 12 patients (32%) had local recurrence, 5 (14%) of which were in the HDR-IORT field. The 3-year local failure rate for primary tumors and recurrent tumors was 19% and 52%, respectively (p = 0.0042). The 3-year local failure rate was 37% for negative margins and 26% for positive margins (p = 0.51). A high mean dose at the clip (17.3 Gy) was found. The overall survival was significantly different for primary vs. recurrent tumors, stage, and grade. CONCLUSION Because of the HDR technique, a high dose at the clips was found, with good local control. More out-of-field than in-field failures were seen. The local failure rate was significantly different for primary vs. recurrent disease.

Has 3-D conformal radiotherapy (3D CRT) improved the local tumour control for stage I non-small cell lung cancer?

AIMS AND BACKGROUND The high local failure rates observed after radiotherapy in stage I non-small cell lung cancer (NSCLC) may be improved by the use of 3-dimensional conformal radiotherapy (3D CRT). MATERIALS AND METHODS The case-records of 113 patients who were treated with curative 3D CRT between 1991 and 1999 were analysed. No elective nodal irradiation was performed, and doses of 60Gy or more, in once-daily fractions of between 2 and 3Gy, were prescribed. RESULTS The median actuarial survival of patients was 20 months, with 1-, 3- and 5-year survival of 71, 25 and 12%, respectively. Local disease progression was the cause of death in 30% of patients, and 22% patients died from distant metastases. Grade 2-3 acute radiation pneumonitis (SWOG) was observed in 6.2% of patients. The median actuarial local progression-free survival (LPFS) was 27 months, with 85 and 43% of patients free from local progression at 1 and 3 years, respectively. Endobronchial tumour extension significantly influenced LPFS, both on univariate (P=0.023) and multivariate analysis (P=0.023). The median actuarial cause-specific survival (CSS) was 19 months, and the respective 1- and 3-year rates were 72 and 30%. Multivariate analysis showed T2 classification (P=0.017) and the presence of endobronchial tumour extension (P=0.029) to be adverse prognostic factors for CSS. On multivariate analysis, T-stage significantly correlated with distant failure (P=0.005). CONCLUSIONS Local failure rates remain substantial despite the use of 3D CRT for stage I NSCLC. Additional improvements in local control can come about with the use of radiation dose escalation and approaches to address the problem of tumour mobility.

Preoperative Radiotherapy Improves Outcome in Recurrent Rectal Cancer

PURPOSEWhen local recurrent rectal cancer is diagnosed without signs of metastases, a potentially curative resection can be performed. This study was designed to compare the results of preoperative radiotherapy followed by surgery with surgery only.METHODSBetween 1985 and 2003, 117 patients with recurrent rectal cancer were prospectively entered in our database. Ninety-two patients were suitable for resection with curative intent. Preoperative radiation with a median dosage of 50 Gy was performed in 59 patients; 33 patients did not receive preoperative radiotherapy. The median age of the patients was respectively 66 and 62 years.RESULTSThe median follow-up of patients alive for the total group was 16 (range, 4–156) months. Tumor characteristics were comparable between the two groups. Complete resections were performed in 64 percent of the patients who received preoperative radiation and 45 percent of the nonirradiated patients. A complete response after radiotherapy was found in 10 percent of the preoperative irradiated patients (n = 6). There were no differences in morbidity and reintervention rate between the two groups. Local control after preoperative radiotherapy was statistically significantly higher after three and five years (P = 0.036). Overall survival and metastases-free survival were not different in both groups. Complete response to preoperative radiotherapy was predictive for an improved survival.CONCLUSIONSPreoperative radiotherapy for recurrent rectal cancer results in a higher number of complete resections and an improved local control compared with patients treated without radiotherapy. Preoperative radiotherapy should be standard treatment for patients with recurrent rectal cancer.

Efficacy of Repeat Isolated Limb Perfusions With Tumor Necrosis Factor α and Melphalan for Multiple In-Transit Metastases in Patients with Prior Isolated Limb Perfusion Failure

BackgroundIsolated limb perfusion (ILP) is an effective treatment modality for multiple in-transit melanoma metastases confined to the limb. Recurrences after ILP, however, occur in approximately 50% of patients and are a challenge for further treatment. The efficacy of repeat ILPs to prolong local control in this patient category is evaluated in this article.MethodsWe used a prospective database in a tertiary referral center. Out of 100 tumor necrosis factor (TNF)-based ILPs with TNF and melphalan (TM-ILPs) in melanoma patients between March 1991 and July 2003, 25 repeat ILP procedures were performed in 21 patients in whom prior ILP treatment failed. All patients had bulky and/or numerous lesions and were treated with mild hyperthermic TM-ILP by using 2 to 4 mg of TNF and 10 to 13 mg/L of limb volume for the leg and arm, respectively.ResultsThe complete response rate was 76%, a partial response occurred in 20%, and no change was recorded in 4%. There was no difference in the complete response rate or local toxicity between first and repeat perfusions. Local recurrence occurred in 72%; the median time to local progression was 14 months. The 5-year survival rate was 47%, which compares favorably with known survival rates of stage IIIA/AB patients. The median follow-up of the patients was 26 months.ConclusionsPatients who experience treatment failure after previous ILP treatment respond very well to repeat perfusion, and prolonged local control can thus be obtained. The subgroup of patients qualifying for repeat ILP represents a relatively favorable biological behavior of the melanoma.

Isolated Limb Perfusion With Tumor Necrosis Factor and Melphalan Prevents Amputation in Patients With Multiple Sarcomas in Arm or Leg

BackgroundTreatment for extremity soft tissue sarcoma (STS) has shifted in recent years from amputation to local wide excision combined with irradiation. For multiple sarcomas, this limb-sparing approach is often not possible. To avoid amputations, isolated limb perfusion (ILP) with tumor necrosis factor and melphalan is an attractive treatment option for patients with multiple extremity sarcomas.MethodsWe investigated a prospective database at a tertiary referral institute. From July 1991 to July 2003, out of 217 ILPs, 64 ILPs were performed for either multifocal primary sarcomas or multiple sarcoma recurrences in 53 patients. All ILPs were performed under mild hyperthermic conditions by using 1 to 4 mg of tumor necrosis factor and 10 to 13 mg/L of limb volume for leg and arm perfusions, respectively.ResultsThe overall response was 88%, with 42% complete response, 45% partial response, 11% no change, and 2% progressive disease. This response rate is significantly better than our experience in 153 locally advanced single-STS cases (88% vs. 69%). The toxicity of the procedure was mild to moderate in almost all cases; no treatment-related amputation had to be performed. The time to local recurrence was 29 months and differed significantly between multiple primary and multiple recurrent STS. The 5-year survival rate was 39%. Limb salvage was achieved in 45 (82%) of 55 treated limbs.ConclusionsIn a group of patients who are uniformly candidates for amputation, ILP can achieve limb salvage in approximately four out of five patients. Because this treatment option provides excellent local control, it should be considered before an amputation is planned.

Prognostic factors after cervical lymph node dissection for cutaneous melanoma metastases.

Cervical lymph node dissection (CLND) is the surgical therapy used for the local control of regionally metastasized cutaneous head and neck melanoma. This study evaluated the outcome of patients undergoing CLND at our institution in order to determine the prognostic factors for recurrence-free survival and overall survival after this procedure. The hospital records of 66 patients with histologically proven lymph node metastases who underwent curative or palliative CLND between 1982 and 2004 were analysed. The characteristics of the patients, the primary tumour and the surgical procedure were recorded. During follow-up, the incidence of local or distant recurrences was recorded and the survival was determined. Of the 66 patients, a (modified) radical neck dissection was performed in 20 and a selective procedure in 46. The 5-year actuarial overall survival was 26% and the recurrence-free survival was 22%. Neither the primary tumour characteristics nor the extent of surgery was of prognostic value; the number of positive nodes affected both the overall survival (P=0.046) and overall recurrence-free survival (P<0.001). Selective CLND is the recommended procedure for patients with cervical metastases of cutaneous melanoma. The number of positive lymph nodes significantly affects the outcome of the patients.

Präoperative Strahlentherapie verbessert das Ergebnis bei Rezidiven eines Rektumkarzinoms

ZusammenfassungZiel:Wenn Lokalrezidive eines Rektumkarzinoms ohne Zeichen von Metastasen diagnostiziert werden, kann eine potenziell kurative Resektion durchgeführt werden. Diese Studie wurde durchgeführt, um die Ergebnisse von präoperativer Strahlentherapie plus nachfolgender Operation mit denen von ausschließlicher Operation zu vergleichen.Methodik:Zwischen 1985 und 2003 wurden 117 Patienten mit Rezidiv eines Rektumkarzinoms prospektiv in unserer Datenbank geführt. 92 Patienten kamen für eine Resektion mit kurativer Zielsetzung in Frage. Eine präoperative Bestrahlung mit einer mittleren Dosierung von 50 Gy wurde bei 59 Patienten durchgeführt; 33 Patienten erhielten keine präoperative Radiotherapie. Das mittlere Alter der Patienten war 66 bzw. 62 Jahre.Ergebnisse:Das mittlere Follow-up von überlebenden Patienten war für die Gesamtgruppe 16 (4–156) Monate. Tumorcharakteristika waren zwischen den beiden Gruppen vergleichbar. Komplette Resektionen wurden bei 64% der Patienten mit präoperativer Bestrahlung und 45% der nicht bestrahlten Patienten durchgeführt. Ein vollständiges Ansprechen auf die Radiotherapie wurde bei 10% der präoperativ bestrahlten Patienten (n = 6) festgestellt. Es gab keine Unterschiede in der Morbiditäts- und Reinterventionsrate zwischen den beiden Gruppen. Lokale Tumorfreiheit nach der präoperativen Radiotherapie war statistisch signifikant höher nach drei und fünf Jahren (p = 0,036). Es gab keinen Unterschied im Gesamtüberleben und metastasenfreien Überleben in beiden Gruppen. Das vollständige Ansprechen auf die präoperative Radiotherapie war entscheidend für die Prognose eines verbesserten Überlebens.Schlussfolgerung:Präoperative Radiotherapie beim Lokalrezidiv eines Rektumkarzinoms resultiert in einer höheren Anzahl kompletter Resektionen und einer verbesserten lokalen Tumorfreiheit verglichen mit Patienten, die ohne Bestrahlung behandelt wurden. Präoperative Radiotherapie sollte die Standardbehandlung für Patienten mit Lokalrezidiv eines Rektumkarzinoms sein.AbstractPurpose:When local recurrent rectal cancer is diagnosed without signs of metastases, a potentially curative resection can be performed. This study was designed to compare the results of preoperative radiotherapy followed by surgery with surgery only.Methods:Between 1985 and 2003, 117 patients with recurrent rectal cancer were prospectively entered in our database. Ninety-two patients were suitable for resection with curative intent. Preoperative radiation with a median dosage of 50 Gy was performed in 59 patients; 33 patients did not receive preoperative radiotherapy. The median age of the patients was 66 and 62 years, respectively.Results:The median follow-up of patients alive for the total group was 16 (range, 4–156) months. Tumor characteristics were comparable between the two groups. Complete resections were performed in 64% of the patients who received preoperative radiation and 45% of the nonirradiated patients. A complete response after radiotherapy was found in 10% of the preoperatively irradiated patients (n = 6). There were no differences in morbidity and reintervention rate between the two groups. Local control after preoperative radiotherapy was statistically significantly higher after three and five years (p = 0,036). Overall survival and metastases-free survival were not different in both groups. Complete response to preoperative radiotherapy was predictive for an improved survival.Conclusions:Preoperative radiotherapy for recurrent rectal cancer results in a higher number of complete resections and an improved local control compared with patients treated without radiotherapy. Preoperative radiotherapy should be standard treatment for patients with recurrent rectal cancer.