Lionel Duck

Phase I/II Study of Cetuximab in Combination With Cisplatin or Carboplatin and Fluorouracil in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

PURPOSE This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Treatment comprised cetuximab (initial dose 400 mg/m2 with subsequent weekly doses of 250 mg/m2) in combination with 3-week cycles of either cisplatin (100 mg/m2) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m2/d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity. RESULTS Fifty-three patients were enrolled onto the study. The incidence of dose-limiting toxicities in phase A was acceptable. The most common grade 3/4 adverse events in both groups were leucopenia (38%), asthenia (25%), vomiting (14%), and thrombocytopenia (15%), which are consistent with the known safety profiles of cetuximab, cisplatin/carboplatin, and FU. The overall response rate among patients was 36%, with no clear trend toward an increased efficacy at the highest dose of FU, and no impact of the concomitant chemotherapy regimens on cetuximab pharmacokinetics. CONCLUSION The combination of cetuximab, cisplatin/carboplatin, and FU was reasonably well tolerated and active in recurrent/metastatic SCCHN, and merits additional investigation. An FU dose of 1,000 mg/m2/d in combination with cisplatin or carboplatin can be recommended for additional studies.

Prospective Randomized Study Comparing Docetaxel, Estramustine, and Prednisone With Docetaxel and Prednisone in Metastatic Hormone-Refractory Prostate Cancer

PURPOSE To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. PATIENTS AND METHODS One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. RESULTS The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). CONCLUSION The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer

OBJECTIVE The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. METHODS Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. RESULTS At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2-6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P = 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P = 0.01). Neither treatment-related deaths nor significant toxicities were observed. CONCLUSION Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials.

Cancer and renal insufficiency results of the BIRMA study

Background:Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed.Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006.Results:A total of 1218 patients were included. The prevalence of elevated SCR (⩾1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min−1 per 1.73 m2. In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment.Conclusions:The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.

Primary combined squamous and small cell carcinoma of the larynx : Report of two cases and discussion of treatment modalities

Combined small cell carcinoma (SMCC) of the larynx consists of SMCC admixed with a component of squamous cell carcinoma or adenocarcinoma. These tumors are very rare and, to date, only a few cases have been fully described. This points out the lack of information available about the correct management of these patients. Here, we describe two additional cases of combined SMCC of the larynx that illustrate the difficulties that we can encounter to diagnose correctly these patients and, by consequence, to treat them adequately.

Acute cardiac failure after sunitinib

A 54-year-old male with cytokine-refractory metastatic renal cell carcinoma was admitted because of respiratory distress and hypotension. Five years earlier, he has been treated with alpha interferon (IFN) and interleukin-2 (two cycles of 6 weeks, s.c.) for bone, mediastinal lymph node and pulmonary metastases. Six months before admission, sunitinib (50 mg/day during 4 weeks followed by 2 weeks of rest) was initiated for disease progression and a partial response (according to Response Evaluation Criteria in Solid Tumors criteria) was obtained after 3 months. Sunitinib was well tolerated with a grade 2 fatigue (NCI—CTC version 2). As cardiovascular risks, only a well-controlled chronic hypertension (carvedilol 25 mg/day) was recorded and sunitinib did not worsen blood pressure. He did not have symptoms or past medical history of ischemic cardiomyopathy. At admission, the patient was still taking sunitinib. The symptoms appeared 1 week before and worsened gradually. Blood pressure was 75/48 mmHg and heart rate 104 beats per minute. The patient was admitted into the intensive care unit. Chest radiograph revealed diffuse interstitial pulmonary infiltrates consistent with pulmonary edema. ECG demonstrated ST-segment elevation in aVR, T-wave inversion and ST-segment depression in D1, aVL, V5 and V6. Cardiac enzymes were abnormal: CPK, 643 IU/l (normal value <400); myocardial band, 10 mg/l (normal value <3) and Troponin-I, 2 ng/ml (normal value <0.06). Echocardiogram showed left and right ventricular dilatation. Hemodynamic data on admission showed biventricular failure (cardiac index 1.3 l/min/m, capillary wedge pressure 10 mmHg, pulmonary artery mean pressure 17 mmHg and right atrial pressure 17 mmHg) with a predominantly right ventricular dysfunction. Dobutamine infusion did not improve the hemodynamic status (after 12 h infusion at 10 c/kg/min, cardiac index remains at 1.27 l/min/m) as well as Milrinone. This situation was thus consistent with refractory heart failure. Eight days after admission, despite optimal cardiac and respiratory supports, he died from cardiac and respiratory failure with renal and liver dysfunctions. Post-mortem examination revealed a heart that was soft with mildly dilated atrial and ventricular chambers. The coronary arteries were normal with neither luminal narrowing nor thrombosis. No macroscopic or microscopic sign of myocardial ischemia or infarction was found. The valves were normal. The pericardium was highly fibrous and adhered to the epicardium. Three metastases were found in the lungs. The lower pole of the right kidney contained a metastatic nodule. At histology, the heart revealed a diffuse loss of cellular mass (Figure 1). The myocardial muscle bundles were fragmented and dissected by loose fibrous tissue in association with edema depleted of lymphocytic infiltration. The cytoplasm of myocardial cells was observed to be occasionally eosinophilic or vacuolized with gross anisokaryosis. These histological and cytological changes in the absence of inflammatory infiltrate were in favor of a cardiomyopathy of toxic origin. Vascular endothelial growth factor (VEGF) has been incriminated in angiogenesis and revascularization after myocardial infarction indicating that VEGF could be an important growth factor for the cardiac tissue [1]. In addition, platelet-derived growth factor receptors (PDGFR) are also expressed on cardiomyocytes. Cardiotoxicity, however, has been rarely described with antiangiogenic therapy [2, 3]. Sunitinib is a tyrosine kinase inhibitor with a wide range of kinase inhibition, including KIT, PDGFRa/b, VEGF receptor 1–3, colony-stimulating factor 1, RET and FLT3. Sunitinib improves progression-free survival in metastatic renal cell carcinoma and imatinib-refractory gastrointestinal stroma tumors (GISTs) [2, 3]. In a large phase III trial randomizing renal cell carcinoma patients between IFN or sunitinib, decline in left ventricular ejection fraction (any grade) has been observed in 10% of sunitinib-treated patients [2]. Among them, only 2% had a grade 3 cardiotoxicity. This frequency was not statistically different than the one observed in the IFN group and all the patients recovered without sequelae. In the randomized trial comparing placebo versus sunitinib in imatinib-resistant GIST, cardiotoxicity was not found to be increased by sunitinib [3] although the prescribing information for sunitinib mentions that 11% of patients had declines in LVEF to below the lower limit of normal in this last study [4]. Two other cases of cardiac failure were identified in sunitinib dose-escalation study in acute myeloid leukemia patients [5]. One of these patients received a high daily dosage (75 mg, 4 weeks followed by 2 weeks of rest) and the other developed cardiac deficiency after myocardial infarction. Recently, Chu et al. [6] assessed the cardiovascular risk associated with sunitinib in 75 patients with GIST. Six patients (8%) had a nonfatal New York Heart Association class III–IV congestive heart failure. Left and ventricular dysfunction improved in five of these patients after sunitinib discontinuation. Mechanisms of cardiac dysfunction is incompletely understood [7] but has been recently investigated by the same group. Interestingly, they found that sunitinib had direct cardiomyocyte toxicity and induced mitochondrial injury in mice [6]. Incubation of rat le tt e r to

Prospective observational study of treatment pattern, effectiveness and safety of zoledronic acid therapy beyond 24 months in patients with multiple myeloma or bone metastases from solid tumors

PurposeTo study the treatment patterns, effectiveness and safety of zoledronic acid (ZOL) beyond 2 years of therapy, given the paucity of data on long-term treatment in daily clinical practice.MethodsPatients with multiple myeloma (MM) or solid tumor bone metastases (STM) and at least 24 months of regular q3-4w ZOL therapy were followed prospectively for an additional 18 months beyond the 24 months required for study entry. End-points included ZOL exposure, incidence of skeletal related events (SRE), and safety.ResultsIn all, 298 evaluable patients were enrolled. The mean continuation rate of ZOL was 90.6%. Exposure to ZOL decreased with time in all patients, but was lower (50.0% vs. 67.6%; p<0.001) and with higher discontinuation rates (incidence rate ratio [IRR]=1.95; p=0.002) in MM compared to the STM group. ZOL suppressed the rate of SREs similarly during the study as compared to before inclusion (0.12 vs. 0.13 events per person-year; p=0.7). At 18 months, 84.5% remained SRE-free. In STM patients, persistent ZOL therapy was associated with lower SRE risk (hazard ratio [HR]=0.42; p=0.01), but not in MM. Renal deterioration occurred in 3.7% and osteonecrosis of the jaw (ONJ) developed in 6.0%, with dental trauma increasing ONJ risk (HR=4.67; p=0.002).ConclusionsBeyond 2 years of therapy, treatment patterns of ZOL were heterogeneous and SRE rates were low. The safety profile of ZOL was acceptable, and interrupting ZOL in patients with solid tumors was associated with a higher risk of SREs.

A phase II study of preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with locally advanced rectal adenocarcinoma. : Abstract #3552

3552 Background: Local recurrence after surgery is a cause of treatment failure in pts with locally advanced rectal cancer (LARC). Preoperative RT decreases local recurrence but not distant spread. Oxaliplatin (OX) and capecitabine (CAP) are both highly active cancer drugs for advanced colorectal cancer and have radiosensitizing properties. Therefore, adding CAP and OX to preoperative RT should improve its efficacy in terms of local control and prevention of metastases. Methods: This study was designed to investigate the efficacy (based on pathological response rate) and safety of preoperative chemo-RT in patients with LACR (T3-T4 and/or N+ staged by endorectal ultrasound). RT was administered for 5 weeks, 5 days a week (1.8 Gy/fraction, total dose 45 Gy, 3D conformation technique) in combination with OX 50 mg/m2 intravenously, weekly for 5 weeks and oral CAP 825 mg/m2 twice a day, each day of radiation. Surgery was performed 6–8 weeks after completion of RT. Results: Since December 2002, 37 out of the 40...

Unusual metastatic features in a patient with concomitant malignant orbital melanoma and prostate carcinoma

A 73-year-old man with a history of malignant orbital melanoma and prostate carcinoma was admitted for progressive visual disturbance. Brain magnetic resonance imaging showed a suprasellar enhancing nodular lesion with major impingement on the anterior optical ways and sellar invasion. The extensive imaging work-up could not demonstrate with certainty its origin. Surprisingly, the transphenoidal biopsy of this patient revealed a prostate cancer metastasis outlining the importance of a histopathological diagnosis of cerebral metastases in patients with multiple malignancies when there is a doubt about the nature of the lesion.

A BELGIAN REGISTRY OF INTERLEUKIN-2 ADMINISTRATION FOR TREATMENT OF METASTATIC RENAL CELL CANCER AND CONFRONTATION WITH LITERATURE DATA

Abstract In an effort to map the use of interleukin-2 (IL-2) treatment in patients with clear cell renal cell cancer (RCC) in Belgian hospitals, 44 cases were registered from 9 hospitals between February 2003 and June 2006. It was demonstrated that the majority of these patients were treated with subcutaneous (SC) IL-2. Other methods such as the inhalation of the drug in case of intrathoracic disease or high dose intravenous (IV) administration were much less frequent (3 and 0 cases in this registry, respectively). The results of antitumour activity (around 16% partial response – absence of complete responses) and toxicity of this drug correlate with observations from the literature with the SC administration. In view of the poor results and tolerance with the currently used cytokines (IL-2 or interferon-alfa), much hope is directed towards the development of the novel targeted drugs like sunitinib or sorafenib used alone or in combination with cytokines in this disease.