First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: a multicenter study.

BACKGROUND: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). RESULTS: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. CONCLUSIONS: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

Safety of cisplatin after severe hypersensitivity reactions to carboplatin in patients with recurrent ovarian carcinoma.

BACKGROUND: Carboplatin is a milestone drug against ovarian carcinoma; it is used both in front-line and second-line chemotherapy. Hypersensitivity reactions to carboplatin may occur during the treatment as salvage therapy. The purpose of this study was to describe the feasibility of the replacing of carboplatin with cisplatin in patients presenting with severe hypersensitivity reactions to carboplatin. PATIENTS AND METHODS: Ten consecutive patients with platinum-sensitive, recurrent ovarian carcinoma, presenting with moderate/severe hypersensitivity reactions to carboplatin were treated with cisplatin 60 mg/m2 from January 2000 to December 2002. Hypersensitivity reactions consisted of respiratory distress (chest tightness, wheezing, dyspnea), urticaria/erythema with tachycardia, facial swelling and hypotension. RESULTS: The total number of cisplatin cycles given was 44 (range 2-5). The treatment with cisplatin was generally well tolerated. No serious allergic reactions occurred. A mild allergic reaction was recorded (urticaria) in only one case, after one cycle of cisplatin, and the patient was not rechallenged because of progressive disease. No reductions of chemotherapy doses were needed. CONCLUSION: To date, platinum-based regimens remain the most effective treatment in recurrent platinum-sensitive ovarian cancer with a high rate of objective responses. Although our experience is limited, we suggest that, under anesthesiologic surveillance and providing immunologic blockade, the replacement of carboplatin salvage therapy with cisplatin can be considered a safe therapeutic strategy in patients who cannot continue carboplatin due to allergic reactions.

Management of small-cell lung cancer in the elderly.

More than 50% of lung cancer patients are diagnosed over the age of 65 and about 30% over 70. Small-cell lung cancer (SCLC) accounts for 20-25% of lung carcinomas. Chemotherapy is the cornerstone of treatment for SCLC. Usually in the elderly it is difficult to administer the same chemotherapy administered to younger patients because elderly patients tolerate chemotherapy poorly. The empirical reduction of drug doses may be criticized. The best approach is to design specific trials in order to develop active and well-tolerated chemotherapy regimens for SCLC elderly patients. The standard therapy in limited disease is combined chemo-radiotherapy followed by prophylactic brain irradiation for patients achieving a complete response. In the elderly, the addition of radiotherapy to chemotherapy must be accurately evaluated, considering the slight survival improvement and the potential relevant toxicity.

Effect of chemotherapy with 5-fluorouracil on intestinal permeability and absorption in patients with advanced colorectal cancer.

5-Fluorouracil (5-FU), in association with leucovorin (LV), is the most used chemotherapy agent in the treatment of colorectal cancer. Response rate, as well as side-effect incidence, increases with the dose intensity of regimens that are used. The most common dose-limiting toxicity for 5-FU/LV modulation is diarrhea. To assess the modification of small intestinal function, we investigated the changes in intestinal permeability (IP) and intestinal absorption (IA) in 41 chemo-naive patients (21 men and 22 women; mean age, 61 +/- 9 years) with advanced colorectal cancer after treatment with the association of folinic acid and 5-FU. After chemotherapy administration, we found a marked increase in IP and a reduction in IA, measured as cellobiose-mannitol (CE-MA) ratio (p < 0.0001) and D-xylose absorption (p = 0.0001), respectively. Patients who experienced diarrhea have an increase in CE-MA ratio and a reduction in D-xylose absorption values, both statistically significant. Cellobiose-mannitol ratio and D-xylose absorption tests can be used for the assessment of toxic effect of 5-FU on mature intestinal epithelium and also for evaluating the role of cytoprotective agents.

Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial.

BACKGROUND: 5-Fluorouracil (FU) in association with folinic acid (FA) is the most frequently used chemotherapeutic agent in colorectal cancer but it often causes diarrhoea. Animal and human studies suggest that glutamine stimulates intestinal mucosal growth. AIM: To determine if oral glutamine prevents changes in intestinal absorption (IA) and permeability (IP) induced by FU/FA. METHODS: Seventy chemotherapy naive patients with colorectal cancer were randomly assigned to oral glutamine (18 g/day) or placebo before the first cycle of FU (450 mg/m(2)) and FA (100 mg/m(2)) administered intravenously for five days. Treatment was continued for 15 days, starting five days before the beginning of chemotherapy. IA (D-xylose urinary excretion) and IP (cellobiose-mannitol test) were assessed at baseline and four and five days after the end of the first cycle of chemotherapy, respectively. Patients kept a daily record of diarrhoea, scored using the classification system of the National Cancer Institute (Bethesda, Maryland, USA). Duration of diarrhoea was recorded and the area under the curve (AUC) was calculated for each patient. RESULTS: Baseline patient characteristics and basal values of IP and IA tests were similar in the two arms. After one cycle of chemotherapy, the reduction in IA (D-xylose absorption) was more marked in the placebo arm (7.1% v 3. 8%; p=0.02); reduction of IP to mannitol was higher in the placebo arm (9.2% v 4.5%; p=0.02); and urinary recovery of cellobiose was not different between the study arms (p=0.60). Accordingly, the cellobiose-mannitol ratio increased more in the placebo arm (0.037 v 0.012; p=0.04). Average AUC of diarrhoea (1.9 v 4.5; p=0.09) and average number of loperamide tablets taken (0.4 v 2.6; p=0.002) were reduced in the glutamine arm. CONCLUSIONS: Glutamine reduces changes in IA and IP induced by FU and may have a protective effect on FU induced diarrhoea.

Levovist-enhanced Doppler sonography versus spiral computed tomography to evaluate response to percutaneous ethanol injection in hepatocellular carcinoma.

The aim of the current study was to compare Levovist-enhanced power Doppler (PD) imaging with contrast-enhanced spiral computed tomography (CT) in the evaluation of intratumoral vascularity of hepatocellular carcinomas at diagnosis and after percutaneous ethanol injection (PEI). Nineteen patients with hepatocellular carcinoma (HCC) underwent PD with and without Levovist and spiral CT at diagnosis and 1 month after PEI treatment. Compared to spiral CT at baseline evaluation, the PD showed intratumoral vascularity in 36.8% of the cases; this percentage reached 78.9% after Levovist enhancement. One month after PEI, only 5 out of 19 treated HCCs appeared as hypodense areas at CT and showed no contrast enhancement. Only 3 of the 14 patients with a positive spiral CT scan were positive at the PD performed without the Levovist administration (sensitivity, 21.4%). The use of contrast-enhanced ultrasonography led to detection of residual signal in six other HCCs treated by ethanol injection (sensitivity, 64.2%). We confirm that spiral CT is the most sensitive and accurate technique in evaluating the effect of ethanol injection in HCC. It correctly identifies most cases of treatment failure as enhanced areas within the lesion. The lower rate of detection of tumoral vascularity by Doppler sonography was significantly increased by Levovist. The evidence of residual vascularity within HCC at Levovist Doppler sonography allows the targeting of additional ethanol injections.

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer.

BACKGROUND: Gemcitabine is active in patients with otherwise resistant or refractory ovarian cancer. As the drug is well tolerated, studies using gemcitabine combined with other antineoplastic agents are needed. The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with gemcitabine, with and without support of G-CSF. PATIENTS AND METHODS: Patients with platinum-resistant or refractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800 mg/m2 day 1 and 8; 200 mg/m2 escalation per level) and epirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2 escalation per level) were given every 21 days for four to six cycles. G-CSF (filgrastim 5 microg/kg/die) was given in case of grade 4 neutropenia (levels without support) or from day 9 up to leukocyte count > 10.000/mm3 after nadir (levels with support). Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. MTD was determined first without and then with G-CSF. RESULTS: Four levels were studied (G 800 + E 60; G 1000 + E 60; G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and three patients enrolled, respectively. DLT (grade 4 febrile neutropenia) was observed in two patients at level 3. Thus, G1000 + E 60 mg/m2 was the MTD without G-CSF. The addition of prophylactic G-CSF did not allow a further increase of the dose and grade 4 thrombocytopenia was the DLT at level 4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in four patients. Among the 13 patients with measurable or evaluable disease, 3 partial responses were observed for an overall response rate of 23.1%. CONCLUSIONS: The combination of gemcitabine 1000 mg/m2 (day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasible therapy. Grade 4 neutropenia is frequent and G-CSF support is often required. With prophylactic support of G-CSF, the DLT is thrombocytopenia.

Phase I study with weekly cisplatin-paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri.

BACKGROUND: Cisplatin and paclitaxel are active in cervical cancer and both are able to potentiate the effects of radiotherapy. In this study we evaluated the maximum-tolerated dose (MTD) of paclitaxel in combination with a fixed dose of cisplatin when given weekly concurrently with pelvic radiotherapy to patients with carcinoma of the cervix uteri. PATIENTS AND METHODS: Eighteen patients with cervical cancer were enrolled in this study. Cisplatin (30 mg/m2) and paclitaxel (starting dose 40 mg/m2; 5 mg/m2 escalation per level) were given on day 1 of radiotherapy and then weekly for six times. Radiotherapy was given to the pelvis with a four-field box technique for five days each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of three patients were enrolled at each level and three further patients were included if one or two dose-limiting severe adverse events (SAE) were recorded. SAE was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomiting and alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (> 1 week) neutropenia or thrombocytopenia. RESULTS: Four levels were studied (paclitaxel 40, 45, 50, 55 mg/m2) with three, five, four and six patients enrolled, respectively. The MTD of paclitaxel was found at 50 mg/m2/wk and cisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity. Thirteen patients were evaluable for response: seven complete and five partial responses were obtained with an overall response rate of 92.3%. CONCLUSIONS: The MTD of paclitaxel is 50 mg/m2/wk when associated to cisplatin 30 mg/m2/wk and concurrent pelvic radiotherapy. Diarrhea is the dose limiting side effect. Preliminary data suggest that concurrent chemoradiotherapy with paclitaxel and cisplatin could be a very active treatment for patients with locally advanced carcinoma of the cervix.

The role of chemotherapy in the management of gastric cancer.

Despite a marked decline in the incidence of gastric carcinoma in Western countries, the majority of patients presents with advanced inoperable tumors. In this setting, usually the aim of therapy is palliation, with the exception of chemotherapy administered in the attempt to downstage the tumor and to facilitate potentially curative surgery in patients with locally advanced nonmetastatic disease. This review will focus on the use of chemotherapy for advanced gastric cancer and after curative surgery, providing an overview of future directions for clinical research: preoperative (neoadjuvant) systemic chemotherapy, intraperitoneal treatment, and newer drugs.

Phase I clinical trial of liposomal daunorubicin in hepatocellular carcinoma complicating liver cirrhosis.

Chemotherapy has been proposed for patients with hepatocellular carcinoma (HCC) associated with well-compensated cirrhosis who are unsuitable for locoregional treatments. Anthracyclines are the most active agents against HCC, although their toxicity is often unpredictable; thus, there is a need for new active drugs with a safe toxicity profile. The liposomal formulation of the anthracycline daunorubicin has low systemic toxicity and is taken up strongly by the liver. We started a phase I study with liposomal daunorubicin (starting dose 80 mg/m2 every 21 days) in patients with hepatocellular carcinoma and Child-Pugh stage A or B liver cirrhosis. At the starting dose, we recorded dose-limiting toxicities (1 hyperbilirubinemia, 1 prolonged prothrombin time, 1 persisting grade 3 neutropenia) in 3 out of 4 patients. Thus, according to protocol, we went down to the dose level of 60 mg/m2 but still 2 out of 3 patients had unacceptable toxicity (1 hypertransaminasemia, 1 hyperbilirubinemia with encephalopathia). Finally, we treated 4 more patients at the dose level of 40 mg/m2 and again we recorded liver toxicity in three of them. Overall haematological toxicity was mild and significant non-haematologic toxicities, other than hepatic, were not recorded. The toxicity profile observed warns against further assessment of liposomal daunorubicin in patients with hepatocellular carcinoma and liver cirrhosis.

Endocrine treatment of hepatocellular carcinoma. Any evidence of benefit?

In the past 20 years, a number of studies have investigated the relationship between sex hormones and liver cancer. Experimental studies indicate that a dynamic process, with sequential modifications in the pattern of sex hormones in the serum and of sex hormone receptors in the liver, occurs progressively during hepatocarcinogenesis. Overall, it seems that both androgens and oestrogens may enhance liver carcinogenesis, while androgens may also support the growth of established liver tumours. Unfortunately, clinical studies of endocrine treatment of hepatocellular carcinoma (HCC) have not adequately tested the suggestions from biological studies. So far, no clinical trial has been performed to test the efficacy of endocrine manipulation for the chemoprevention of HCC in cirrhotic patients nor in preventing relapse after radical resection of primary HCC. Anti-oestrogens have been the most studied agents for the endocrine treatment of established HCC, although the rationale that supports their use is weaker than for anti-androgens. Studies with anti-androgens have produced prevalently negative results, due to either a lack of activity or excessive toxicity. The use of chemical castration, which theoretically could enhance the activity of antihormonal compounds, yielded no benefit at all. In summary, there is, as yet, no definitive evidence that endocrine treatment favourably affects the outcome of patients with HCC.

Power Doppler sonography to evaluate response to percutaneous ethanol injection in hepatocellular carcinoma.

BACKGROUND AND AIMS: The aim of the present study was to compare power Doppler imaging with traditional color Doppler imaging and with contrast enhanced computer tomography in the evaluation of intratumoral vascularity of hepatocellular carcinomas at diagnosis and in response to percutaneous ethanol injection. PATIENTS AND METHODS: Sixteen patients with hepatocellular carcinoma underwent colour Doppler, power Doppler and computed tomography at diagnosis. Seventeen patients were studied by the three techniques one month after percutaneous ethanol injection treatment. RESULTS: At baseline evaluation, power Doppler and color Doppler were always in agreement and, with the exception of one case, were also in agreement with the computerized tomography scan. On the contrary, power Doppler and computerized tomography are more sensitive than color Doppler in the evaluation of residual vascularized tumoral tissue after percutaneous ethanol injection. In 3 patients, residual vascularity was demonstrated only by computerized tomography while color and power Doppler were negative. In another 3 cases, a positive power Doppler signal, with a typical arterial Doppler spectrum, was observed while color Doppler and computerized tomography were negative. In these patients, cancer relapse was clinically evident after a few months and treatment was repeated to obtain complete necrosis. CONCLUSIONS: We conclude that only the integration of the results of all these techniques can reliably evaluate tumoral vascularity after percutaneous ethanol injection.