A.M.M. Eggermont

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.

Total pelvic exenteration for primary and recurrent malignancies.

IntroductionComplete resection is the most important prognostic factor in surgery for pelvic tumors. In locally advanced and recurrent pelvic malignancies, radical margins are sometimes difficult to obtain because of close relation to or growth in adjacent organs/structures. Total pelvic exenteration (TPE) is an exenterative operation for these advanced tumors and involves en bloc resection of the rectum, bladder, and internal genital organs (prostate/seminal vesicles or uterus, ovaries and/or vagina).MethodsBetween 1994 and 2008, a TPE was performed in 69 patients with pelvic cancer; 48 with rectal cancer (32 primary and 16 recurrent), 14 with cervical cancer (1 primary and 13 recurrent), 5 with sarcoma (3 primary and 2 recurrent), 1 with primary vaginal, and 1 with recurrent endometrial carcinoma. Ten patients were treated with neoadjuvant chemotherapy and 66 patients with preoperative radiotherapy to induce down-staging. Eighteen patients received IORT because of an incomplete or marginal complete resection.ResultsThe median follow-up was 43 (range, 1–196) months. Median duration of surgery was 448 (range, 300–670) minutes, median blood loss was 6,300 (range, 750–21,000) ml, and hospitalization was 17 (range, 4–65) days. Overall major and minor complication rates were 34% and 57%, respectively. The in-hospital mortality rate was 1%. A complete resection was possible in 75% of all patients, a microscopically incomplete resection (R1) in 16%, and a macroscopically incomplete resection (R2) in 9%. Five-year local control for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 89%, 38%, and 64%, respectively. Overall survival after 5xa0years for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 66%, 8%, and 45%.ConclusionsTotal pelvic exenteration is accompanied with considerable morbidity, but good local control and acceptable overall survival justifies the use of this extensive surgical technique in most patients, especially patients with primary locally advanced rectal cancer and recurrent cervical cancer.

Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population‐based series

Aimu2002 The incidence, patterns of care and survival were determined in patients with stage IV colorectal cancer (CRC) in a population‐based series.

Optimizing the outcome of surgery in patients with rectal cancer and synchronous liver metastases

This study evaluated the outcome of patients treated for rectal cancer and synchronous hepatic metastases in the era of effective induction radiotherapy and chemotherapy.

Cancer patients seeking a second surgical opinion: results of a study on motives, needs, and expectations

PURPOSEnTo explore the sociodemographic and clinical characteristics of cancer patients seeking a second-opinion consultation and to analyze their second opinion-related motives, needs, and expectations.nnnPATIENTS AND METHODSnIn 212 consecutive patients seeking a second opinion at the Surgical Oncology Outpatient Clinic, satisfaction with the first specialist, motivation for the second opinion, need for information, preference for decision participation, and hope for and expectation of a different second opinion were assessed with a questionnaire.nnnRESULTSnThe mean age was 53 years. Most patients were women (82%), of whom 76% were diagnosed with breast cancer. Half of the patients (51%) had a low educational level. The majority of patients (62%) only had internal motives for second-opinion seeking associated with the need for reassurance and more certainty, whereas a substantial minority of patients (38%) also had external motives related to negative experiences or unfulfilled needs. The externally motivated patients had a higher anxiety disposition, were less satisfied with their first specialist, preferred a more active role in medical decision making, and more often hoped for and expected a different second opinion.nnnCONCLUSIONnMotives for second-opinion consultations differ greatly. Understanding the difference between internal and external motivation is necessary to develop strategies to prevent unnecessary second-opinion seeking. Additional studies are warranted to evaluate the objective and subjective outcomes of second-opinion consultations.

LOSS OF IMPRINTING OF IGF2 AND NOT H19 IN BREAST CANCER, ADJACENT NORMAL TISSUE AND DERIVED FIBROBLAST CULTURES

Insulin‐like growth factors are involved in the paracrine growth regulation of human breast tumor cells. IGF2 is imprinted in most tissues, and shows expression of the paternal allele only. To investigate whether disruption of this monoallelic IGF2 expression is involved in breast cancer development, a series of primary tumors and adjacent, histologically normal, breast tissue samples, as well as matched primary in vitro fibroblast cultures were studied. Biallelic expression (partial) of IGF2 was found in the majority of in vivo samples, and corresponding fibroblast cultures, while monoallelic expression was found in a normal breast sample. In contrast, H19, a closely apposed, but reciprocally imprinted gene, assumed to be regulated by a common control element, showed retention of monoallelic H19 expression in all in vivo and in the majority of in vitro samples. These data indicate that IGF2, but not H19, is prone to loss of imprinting in breast cancer.

Multivariable analysis comparing outcome after sentinel node biopsy or therapeutic lymph node dissection in patients with melanoma.

Sentinel node (SN) status is the most important prognostic factor for overall survival in stage I or II melanoma. Yet SN‐positive tumours with submicroscopic involvement of the SN (clusters of cells smaller than 0·1 mm) have shown a distant recurrence rate of only 9 per cent at 5 years, as good as that in SN‐negative patients. This study compared the outcome after completion lymph node dissection (CLND) in SN‐positive tumours with elective total lymph node dissection (TLND) in patients with palpable nodes.

Isolated Limb Perfusions With Tumor Necrosis Factor and Melphalan for Locally Recurrent Soft Tissue Sarcoma in Previously Irradiated Limbs

BackgroundRecurrent extremity soft tissue sarcoma (STS) in a previously operated and irradiated area can usually be managed only by amputation. Tumor necrosis factor (TNF)-α–based isolated limb perfusion (ILP) is an established alternative to achieve limb salvage but is assumed to require sufficient vasculature. Because radiotherapy is known to destroy vasculature, we wanted to evaluate retrospectively whether the outcome of ILP in patients with radiotherapy for their primary tumor nonetheless showed a benefit from TNF treatment.MethodsWe consulted a prospective database of TNF-based ILPs at the Erasmus MC–Daniel den Hoed Cancer Center in Rotterdam. Out of 342 TNF-based ILPs between 1991 and 2003, 30 ILPs were performed in 26 patients with recurrent STS in the irradiated field after prior surgery and radiotherapy. Eleven patients (42%) had multiple tumors (n = 2–20). All patients were candidates for amputation.ResultsWe observed 6 complete responses (20%), 15 partial responses (50%), no change in 8 patients (27%), and progressive disease in 1 patient (3%). The median duration of response was 16 months (range, 3–56 months) at a median follow-up of 22 months (range, 3–67 months). The local recurrence rate was 45% in patients with multiple tumors and 27% in patients with single tumors. Ten patients (35%) died of systemic metastases. Limb salvage was achieved in 17 patients (65%). Regional toxicity was limited and systemic toxicity minimal.ConclusionsTNF-based ILP can avoid amputations in most patients with recurrent extremity STS in a prior operated and irradiated field.

Rising trends in the incidence of and mortality from cutaneous melanoma in the Netherlands: a Northwest to Southeast gradient?

The aim of this study was to determine characteristics of the trends in incidence of and mortality from cutaneous malignant melanoma in The Netherlands. We used incidence data from the Netherlands Cancer Registry since 1989 and the causes of death registry of Statistics Netherlands since 1950. Data were age-adjusted and age-specific rates were calculated. Age-period-cohort modelling was applied to the mortality data. Between 1989 and 1998, age-adjusted incidence rates increased, mainly among those aged 45 years and older. Incidence rates were highest in the North-West and lowest in the South-East. Mortality rates increased in all age-categories, but more so among males than females. For women, an age-period model fitted the data, with decreasing relative risks after 1972. Age-period-cohort models were needed for males. The most likely explanation for the higher incidence is increasing intermittent over-exposure to ultraviolet (UV) radiation. The regional differences in melanoma incidence rates would correspond with host characteristics opportunities for and recreational exposure. Melanomas were detected at earlier stages in females, possibly explaining the flattening out of the female mortality rates.

Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs

OBJECTIVEnTo validate the methodology of isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques and to gain insight into the distribution of tumor necrosis factor-alpha (TNF), melphalan, and mitomycin C (MMC) through the regional and systemic blood compartments when applying these techniques.nnnSUMMARY BACKGROUND DATAnThere is no standard treatment for unresectable liver tumors. Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting. The magnitude and toxicity of the surgical procedure, however, have limited clinical applicability.nnnMETHODSnPigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously. After a 20-minute perfusion, a washout procedure was performed for 10 minutes, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the hepatic and systemic blood compartments and concentrations of perfused agents were determined.nnnRESULTSnDuring perfusion, locoregional plasma drug concentrations were 20- to 40-fold higher than systemic concentrations. Compared with systemic concentrations after intravenous administration, regional concentrations during IHHP were up to 10-fold higher. Regional MMC and melphalan levels steadily declined during perfusion, indicating rapid uptake by the liver tissue; minimal systemic concentrations indicated virtually no leakage to the systemic blood compartment. During isolation, concentrations of TNF in the perfusate declined only slightly, indicating limited uptake by the liver tissue; no leakage of TNF to the systemic circulation was observed. After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective.nnnCONCLUSIONSnComplete isolation of the hepatic vascular bed can be accomplished when performing IHHP using this balloon catheter technique. Thus, as in extremities, an ideal leakage-free perfusion of the liver can now be performed, and repeated, without major surgery. The effective washout allows the addition of TNF in this setting.