Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial.

BACKGROUND: We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases. METHODS: This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2-6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day. RESULTS: Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3-15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21-53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction. CONCLUSION: Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.

P53 and bcl-2 in colorectal cancer arising in patients under 40 years of age: distribution and prognostic relevance.

Young people (40 years of age) with colorectal cancer (CRC) represent a distinct subgroup with more aggressive disease behaviour compared to older patients. We evaluate whether p53 and bcl-2 could be useful in identifying young patients at higher risk of tumour progression. We reviewed 1340 CRC patients with 58 patients 40 years (4.2%). They had more frequent moderately or poorly differentiated mucinous adenocarcinomas (26% versus 12.3%, p=0.03); higher advanced stage at diagnosis; shorter 5-year overall survival (49.8% versus 71%; p=0.02); more frequent p53 positive (89.8% versus 72.6%, p<0.05) and bcl-2 negative (88.0% versus 66.2%, p<0.05) tumours; no difference in DNA content or proliferation indexes. Moreover, p53+ and bcl-2- resulted in being independent predictors of survival with shorter survival for the p53+/bcl-2- patients. Combining p53 and bcl-2, we could identify young CRC patients at higher risk of progression, who probably require development of a more sophisticated therapeutic approach based on identification of predictive factors.

A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates.

BACKGROUND: In patients locally progressing after two lines of chemotherapy, some locoregional approaches showed encouraging results in terms of local control of disease. The aim of our study was to evaluate toxicity, clinical response and quality of life in 48 patients with unresectable colorectal liver metastases submitted to selective internal radiotherapy (SIRT). MATERIALS AND METHODS: Up to now 35 patients with unresectable colorectal liver metastases, refractory to two lines of chemotherapy, underwent intra-arterial infusion of resin microspheres with yttrium-90 (SIR-spheres). Pre-treatment evaluation included a CT scan, blood tests, a PET scan and arteriography of celiac trunk, hepatic and superior mesenteric artery; extrahepatic uptakes and pulmonary shunts more than 10% were excluded by a Scinti-scan. The gastroduodenal artery was embolized before the SIR-spheres injection. Other exclusion criteria were liver dysfunction and anatomical vascular anomalies. The clinical response was evaluated by CT-scan following the RECIST criteria. Median follow-up was 4 months. RESULTS: Median number of metastases was 4 (range, 1-15), 38% of cases presenting hepatic involvement < 25%. The median SIRT dose delivered was 1.7 GBq. Median pulmonary shunt was 6%. No operative mortality occurred; early toxicity (within 48 hours) was 20.6%, shown as fever, acute pain and leucocytosis. The late toxicity was 24.1% with chronic pain, jaundice and nausea being the most frequent. All the toxic events were graded 2 or 3 according to the WHO scale. Preliminary results were available in terms of clinical response after 6 weeks: 12.5% had a partial response, 75% a stable disease, while progression of disease, was observed in 12.5% of the patients. CONCLUSION: SIRT is a safe treatment in terms of acute and late toxicity. Intra-arterial microspheres could represent a good therapeutic option for patients with progressing liver metastases only, after two lines of systemic chemotherapy.

Evaluation of hepatic metastases from colorectal carcinoma with MR-superparamagnetic iron oxide.

The purpose of this study was to compare the results obtained with superparamagnetic iron oxide-enhanced and unenhanced Magnetic Resonance at 1.5 T with that of spiral-computed tomography (CT) in order to select those patients suitable for liver resection; the intraoperative US (IOUS) comprised the gold standard. Thirty five candidates for liver resection with known colorectal neoplasm were studied; 26 patients underwent surgery, one patient underwent RF ablation and 8 of them were submitted to follow-up. MR examination was performed using a 1.5 T superconductive instrument, CT examination was performed on a Somatom-Plus (Siemens) scanner. Dimensions and number of the lesions were defined in all patients as well as the sensitivity of spiral CT and MR imaging, using either the plain technique or after Ferumoxides c.m.. In those patients submitted to surgery, results have been correlated to those of IOUS. From 26 patients, a total of 48 lesions were removed surgically. With CT, 34 lesions with 3 false positive cases were detected; 32 with plain MR imaging, while MR imaging with Ferumoxides detected 41 lesions. In the patients not submitted to surgery, MR iron-oxide imaging identified 15 lesions, while both plain MR imaging and CT showed 8 lesions. The smallest lesion was 6 mm. as shown by MR imaging with Ferumoxides. In the cases submitted to surgery, the CT sensitivity was 71%, plain MR imaging 66% and MR imaging with Ferumoxides 85%. In our experience, Ferumoxides-enhanced MR imaging of the liver shows increased sensitivity compared to plain and spiral-CT in the evaluation of hepatic metastases. We think that MR superparamagnetic iron oxide should be used in all patients selected for liver resection.

Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer.

BACKGROUND: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three chemotherapy-naïve patients were enrolled. Capecitabine 2500 mg/m(2)/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m(2) was administered as a 2-h infusion on day 1, repeated every 3 weeks. RESULTS: Forty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 12-28). CONCLUSIONS: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-naïve advanced colorectal cancer patients.

Ifosfamide and epirubicin combination in untreated sarcomas: two treatment schedules.

BACKGROUND: The Epirubicin (EPI) and ifosfamide (IFO) combination has been widely tested in soft tissue sarcomas, even though the optimal schedule of drug administration has still to be defined. In this article, we reviewed the activity and the toxicity of two EPI- and IFO-based schedules in newly diagnosed sarcomas. MATERIAL AND METHODS: 22 patients (group A) received a 'concurrent' schedule of short-infusion IFO at total dose of 7.5-9 g/m(2) over 5 days plus iv bolus EPI at 90-120 mg/m(2)/cycle, repeated every 3 weeks. The other 22 patients (group B) received a 'sequential' schedule of dose-intense, continuous infusion IFO at a total dose of 14-18 g/m(2) for 2 cycles followed by bimonthly EPI at 120-160 mg/m(2)/cycle. Application of growth factors was planned for each course of treatment. RESULTS: Since 1994, 44 consecutive patients have been treated. The overall response rate was 35% with no significant differences between the two treatment groups in terms of response rate (group A: 33%, group B: 37%), time to progression (group A: 7 months, group B: 8 months), and overall survival (group A: 12 months, group B: 15 months). General tolerance to treatment was better in group A. Gastrointestinal symptoms occurred significantly more often with the sequential regimen. Severe hematologic toxicity was common but no toxic deaths were observed. CONCLUSIONS: Based on this limited experience, a concurrent schedule of EPI and IFO seems to be an appropriate management strategy in the front-line therapy of advanced sarcomas. Nevertheless, a randomized trial is warranted to define the optimal dosages to be used for further clinical trials.

A phase II study of dose-intense ifosfamide plus epirubicin with hematopoietic growth factors for the treatment of patients with advanced soft tissue sarcomas; a novel sequential schedule.

PURPOSE: The efficacy and feasibility of a novel sequential schedule of high-dose ifosfamide (HD-IFO) and full-dose epirubicin (EPI) with granulocyte colony-stimulating factor (G-CSF) was evaluated in adult patients with soft tissue sarcomas (STS). METHODS: Since November 1995, 22 chemotherapy-naive patients have been treated. HD-IFO was given as a continuous infusion at a total dose of 14-18 g/m2 per cycle, with mesna, over 6 to 8 days, q 3 weeks, twice. EPI was administered subsequently as an i.v. bolus at a total dose of 120-160 mg/m2, on days 1-2, q 2 weeks, twice. G-CSF was planned for each course of treatment as a daily subcutaneous injection for 7 days, starting 24 h after the end of the treatment. After the first four cycles, patients were evaluated for surgery and patients with locally inoperable or metastatic disease received further chemotherapy up to a maximum of eight cycles. RESULTS: The response of 19 patients could be assessed. One complete response (CR) and six partial responses (PRs) were achieved for an overall response rate of 37% (95% confidence interval, 15-59%). Noteworthy is that two of the six leiomyosarcoma patients responded to the HD-IFO treatment. The median survival period was 15 months. Most common toxicities included myelosuppression, nausea and vomiting, and stomatitis. Six patients were hospitalized for complicated nadir fever. No severe renal and CNS toxicities were seen. Transient gross hematuria occurred in six patients and affected treatment in only one case. There were no treatment-related deaths. CONCLUSIONS: By the protraction of continuous infusion of HD-IFO over 6 to 8 days, ifosfamide-induced acute renal toxicity is avoided, while G-CSF support allows the delivery of the planned dose intensity in most of the patients. Although manageable in an oncology setting, the hematologic toxicity of such a regimen remains substantial. Moreover, in terms of efficacy and median survival, this regimen showed no benefits over a conventional-dose anthracycline-ifosfamide schema. Further evaluations of this novel ifosfamide-epirubicin schedule are not warranted, even if the HD-IFO regimen could be taken forward specifically for leiomyosarcomas in a phase II trial.

Capecitabine and oxaliplatin in advanced colorectal cancer: a dose-finding study.

PURPOSE: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer (ACRC). The aim of this dose-finding trial was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the activity of the combination in patients with advanced colorectal cancer. PATIENTS AND METHODS: Twenty-five chemotherapy-pretreated patients received the combination of capecitabine and oxaliplatin. Capecitabine was administered orally twice a day continuously for 14 days in doses ranging from 1,650 to 2,500 mg/m2/d, and oxaliplatin was administered as a two-hour infusion on day 1 using dose, ranges from 100 to 130 mg/m2 repeated every three weeks. RESULTS: Twenty-five patients were assessable for toxicity, and DLTs were diarrhea (grade > or = 3: 27%) and stomatitis (grade > or = 3: 9%) at dose level VI. Dose level V (capecitabine 2500 mg/m2 and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal, overall neurotoxicity (grade 1-4) was 27% with 1% grade 3-4. A global response rate was 17% (95% confidence interval (95% CI): 2%-32%) and the median overall survival was 12 months. CONCLUSION: The recommended dose for further phase II studies is capecitabine 2,500 mg/m2/d with intermittent schedule and oxaliplatin 120 mg/m2 every three weeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitis and vomiting. This combination should be studied in phase II trials in advanced colorectal.

Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview.

Dacarbazine (DTIC) is the only single-agent approved by the Food and Drug Administration for treating metastatic melanoma. With DTIC as single agent, an approximately 20% objective response rate can be achieved with median response duration of 5 to 6 months and complete response rates of 5%. Current status of DTIC single agent and DTIC-based combination chemotherapy has been extensively reviewed in this article. Moreover, future directions including new combination chemotherapies and/or new therapeutical approaches have been considered. The addition to DTIC of agents such as cisplatin, nitrosoureas and tubular toxins has been reported to yield high response rates, up to 40%, in single-institution phase II trials. Historically, promising combination regimens like BOLD (bleomycin, vincristine, lomustine and DTIC) and CVD (cisplatin, vinblastine and DTIC) have induced responses on metastatic lesions to the liver, bone and brain, commonly unresponsive to DTIC alone, even though have failed to produce impact on patient survival. Several other studies have suggested a significant enhancement of antitumor effect associated with the addition of tamoxifen to various cytotoxic regimens. The four-drug combination CBDT (cisplatin, carmustine, DTIC and tamoxifen) or "Dartmouth regimen" has yielded high response rates, up to 55%, with continuous, maintained, complete responses, up to 82 months, in a subset of patients, that is considerably longer than observed with other combinations. Some authors recommend CBDT as reference therapy, even though recently presented results of a randomized phase III trial of CBDT versus DTIC alone, show no statistical difference in survival between the two groups. While a survival benefit from DTIC-based chemotherapy or DTIC alone has never been shown in metastatic melanoma patients and, therefore, the survival has remained unchanged over the past 30 years, some long term survivors have been reported with the "Dartmouth regimen" and/or with high dose interleukin-2 (IL-2) based regimens whose role is going to be defined in prospective randomized phase III trials. On the other hand, the better understanding of the mechanisms responsible for melanoma chemoresistance and the development of new therapeutical strategies could change the scenario in the next future.

Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for infiltrating transitional cell carcinoma of the bladder.

BACKGROUND: Based on the excellent results with combination chemotherapy such as M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in patients with advanced disease, neoadjuvant chemotherapy has been advocated to improve survival and in some cases to permit bladder conservation. METHODS: A Phase II study of neoadjuvant M-VAC chemotherapy was performed in patients with T2-T4N0M0 bladder tumors. After clinical staging, three cycles of M-VAC were given. After patients underwent postchemotherapy clinical restaging, pathologic restaging (partial or radical cystectomy) was planned. RESULTS: Forty-six patients are evaluable. A clinical response was attained in 78%. Six patients (13%) had stable disease, and four (9%) had progression. After chemotherapy, 17 patients underwent radical cystectomy, none of whom were pTO. In this group, 10 of the 17 (59%) are alive at a median follow-up of 37+ months (range, 8-62+ months). Eleven patients had a partial cystectomy; 7 of the 11 (64%) are alive, 6 (55%) with a preserved bladder. Eighteen patients had clinical restaging only, and did not have pathologic staging. Median follow-up for this group is 36+ months (11-65+ months). Twenty-one of the 29 (72%) patients managed with conservative surgery or transurethral resection of the bladder alone are alive with a functional bladder. Median survival for all patients has not yet been reached. Two-year survival is 82%, and 3-year survival is 70%. CONCLUSIONS: The current study is of interest in terms of bladder conservation. Assessment of the true success of any bladder-preserving treatment will require longer follow-up.

Carboplatin and 5-fluorouracil in poor performance status patients with advanced urothelial cancer.

BACKGROUND: In view of the difficulties in administering aggressive treatment to elderly patients, frequently with concomitant medical problems, a treatment program with the combination of carboplatin and 5-FU for advanced urothelial tumors was designed. The aim was to maintain an efficacious therapeutic schedule while minimizing toxicity. PATIENTS AND METHODS: Twenty-three patients with advanced bidimensionally measurable urothelial carcinoma were given carboplatin 100 mg/m2 and 5-fluorouracil 500 mg/m2 days 1-3 which was escalated to carboplatin 125 mg/m2 and 5-fluorouracil 625 mg/m2. 5 patients were > 70 years, the ECOG performance status was 2-3 in 10 patients (43%), and the creatinine was > 2.0 mg/dl in 3 patients (13%). Five patients (22%) had pre-existing cardiac disease, and 1 had hepatopathy. Nine patients (39%) had prior cisplatin. RESULTS: Ten patients remained at level 1, and 12 others had the dosage escalated to level 2. Twenty-one patients are evaluable for response. Response was observed in 5 of 21 (24%) evaluable patients (95% confidence limits 15%-33%), only at dose level 2. There was 1 CR (5%) and 4 PR (19%). There were no responses in patients who had prior DDP versus 5 of 13 (38%) responses in patients who had not had prior DDP. The median time to response was 2 months. The median duration of response was 8 months. At level 2 myelotoxicity was significant, and led to a return to level 1 in 2 patients. Nine of 12 patients (75%) treated at level 2 had grade 3 leukopenia, and 1 patient had nadir sepsis. 4 patients (33%) had grade 4 thrombocytopenia. CONCLUSIONS: Moderate activity was shown with this regimen in untreated patients at level 2. This regimen presents a feasible outpatient alternative for patients who are unable to undergo more aggressive chemotherapy.

The lymphatic route. VIII. Distribution and plasma clearance of recombinant human interleukin-2 after SC administration with albumin in patients.

It has been postulated that favouring the absorption of interleukin-2 via lymphatics rather than venous capillaries after subcutaneous administration may improve its therapeutic index. We have now evaluated in 12 cancer patients the plasma pharmacokinetic of interleukin-2 either dissolved in water or in 20% albumin solution with an internal cross-over after at least three days. Our data show that when albumin is present, the plasma concentrations of interleukin-2 versus time is increased and swelling at the injection sites is reduced. It remains to be seen whether efficacy improves during a prolonged treatment.

Recombinant tumor necrosis factor for superficial bladder tumors.

Twenty patients with histologically documented superficial bladder cancer (Ta, T1, Tis) were treated with intravesical administration of TNF 400-1800 micrograms. Of 18 patients with a marker lesion, 2 obtained a complete response for 8+ and 18 months. Two had a partial response and were given other intravesical therapies after 5 and 7 months. No or minimal systemic absorption of TNF was observed and documented in 4 of 20 patients by pharmacokinetic studies, and no patients developed antibodies to intravesically administered TNF. TNF was well tolerated in doses up to 1800 micrograms. No systemic or local side effects were observed. Modest activity was attained with intravesical TNF, even in pretreated patients.

Cytotoxic effect of the association of BCNU with rhein or lonidamine on a human glioma cell line.

The effect of association of 1,3-bis-(2-chloroethyl)-l-nitrosourea (BCNU)- Rhein (RH) and BCNU-Lonidamine (LND) on the clonogenic activity of human glioma cells was evaluated. Both RH and LND modulate the lethal effect of BCNU regardless of the schedule of treatment. The analysis of the interactions, performed with the isbolar method according to Berembaum, demonstrates an additivity of the effects. The possible mechanisms as well as the implications for the design of brain tumor schedule treatment are discussed.

Growth inhibition by rhein and lonidamine of human glioma cells in vitro.

The effect of Rhein (RH) and Lonidamine (LND) on the clonogenic activity of cultured human glioma cells has been evaluated. Both these drugs decrease the survival fraction, but their effect is strictly related to the duration of exposure. A brief exposure, i.e. 4 hours, even at the highest drug concentrations does not induce any significant decrease in the survival which, on the contrary, is strongly affected by 24 and 48 hours of exposure. The reason for this behaviour lies in the mechanism of action of these drugs which do not interfere with replicative processes, but selectively affect the energy metabolism of the neoplastic cell. The validity of currently employed screening tests to evaluate the antitumoral activity of non anti-mitotic drugs is also discussed.

Inhibition of protein synthesis in neoplastic cells by rhein.

The action of rhein, 4,5-dihydroxyanthraquinone-2-carboxylic acid, on protein synthesis of neoplastic cells has been investigated. Rhein decreases amino acid incorporation in all cells tested. The inhibition of incorporation of labeled precursors into acid-insoluble material cannot be ascribed to an impairment of amino acid uptake, which is unaffected by the drug. Tests on cell-free system showed that rhein does not inhibit the TMV-mRNA directed in vitro protein synthesis, thus indicating that the protein machinery per se is not affected. The inhibition of protein brought about by the drug must be ascribed to an effect on the energy-yielding processes with a remarkable decrease in ATP content. The mechanism is similar to that of other metabolic inhibitors, but rhein, for its capability to inhibit both respiration and glycolysis, is effective at much lower concentrations.