Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Cisplatin-gemcitabine as palliative chemotherapy in advanced squamous vulvar carcinoma: report of two cases.

Vulvar cancer (VC) is a rare disease, usually diagnosed in a stage still amenable to potentially curative treatments, including surgery and/or radiation therapy with or without chemotherapy. Several patients however present at diagnosis with metastatic disease and another 30-50% will relapse. Prognosis of metastatic or recurrent disease not amenable to salvage surgery or radiotherapy is very poor. Evidence about the efficacy of chemotherapy in this setting is limited and its role still remains unclear. At present there is no standard treatment for advanced VC and patients are usually treated with schedules adopted for chemoradiation or extrapolated from cervical cancer. We report our experience using a cisplatin-gemcitabine regimen in two cases of metastatic squamous cell VC. No response was obtained with this schedule. No other data are available in the literature about the choice of a cisplatin-gemcitabine regimen in this patient subset. The paucity of evidence about the role of palliative chemotherapy in metastatic VC justifies any effort to implement knowledge. For this reason we think it is notable to also report a negative experience. It is not possible for us to conclude that this chemotherapy would be unable to provide any benefit in a larger sample of patients; nonetheless we think that new agents, rather than combinations of older drugs, could hopefully provide more benefit.

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.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of 4'-epidoxorubicin (EPI) in combination with full dose of ifosfamide (IFO) when granulocyte-macrophage colony-stimulating factor (GM-CSF) was used, to estimate its clinical efficacy, and to evaluate the mobilization of hematopoietic progenitors. PATIENTS AND METHODS: Previously untreated advanced patients were treated with fixed doses of IFO at 1.8 g/m2/d for 5 days and escalating doses of EPI. The starting dose level of EPI was 50 mg/m2 bolus on days 1 and 2; subsequent levels were 60 mg/m2 and 70 mg/ m2 given on days 1 and 2. GM-CSF (5 micrograms/kg/d) was administered from days +6 to +19. Clinical evaluation of response was performed after three consecutive cycles. Mobilization of hematopoietic progenitors was evaluated as day 14 CFU-GM after the first cycle only. RESULTS: Overall, six, 18, and 13 assessable patients were entered onto each EPI dose level, respectively. The first and the second EPI level were considered feasible. Conversely, at the third level, only six of 13 patients [46%] tolerated full EPI doses at the scheduled time. Therefore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1%, respectively. Overall, 20 of 37 patients (54%) obtained an objective response. The response rates for the three EPI dose levels were significantly different [17%, 33%, and 100%, respectively; test for trend, P < .001]. Considering only lung metastases, the overall response rate was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI level, when both GM-CSF and IL-3 were used as in vitro-stimulating factors. CONCLUSION: The third EPI level (70 mg/m2 on days 1 and 2) is the MTD of this program, since it was administered, without dose reduction or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting with regard to response rate (13 of 13 objective responses) and in mobilization of the hematopoietic progenitors.

Etoposide (VP-16-213) in malignant brain tumors: a phase II study.

Twenty-two consecutive patients with recurrent malignant brain tumors after radiation therapy and systemic combination chemotherapy with BCNU and vincristine, four of whom were not evaluable due to early death, were treated with etoposide (VP-16-213) (50-100 mg/m2 for five days every three weeks). Response, defined as improvement in both clinical examination and computed tomography scan in absence of glucocorticoids dosage increase, was observed in three (17%) of 18 evaluable patients, lasting greater than 21, seven, and two months, respectively. Six additional patients had stable disease for greater than 10, seven, four, four, three, and two months: all of them had improvement of clinical symptoms but no variation in their scans. Overall median survival from the start of VP-16-213 was 4.5 months (range, 1-23 + months), whereas patients with response or stable disease had a median survival of eight months. Overall, treatment was well tolerated. In 10 patients concomitant plasma and cerebrospinal fluid samples were evaluated with a high-performance liquid chromatographic method for drug assay. The concentration of VP-16-213 in cerebrospinal fluid was less than 1% that found in plasma, even in the two patients with response. The activity of etoposide in patients with malignant, lomustine-vincristine-resistant brain tumors suggests an interesting potential use for this drug.

High-dose versus low-dose cisplatin in advanced head and neck squamous carcinoma: a randomized study.

From November 1981 to February 1983, 64 patients with advanced head and neck squamous carcinoma were randomly treated with either high-dose (120 mg/m2) or low-dose (60 mg/m2) cisplatin. Of the 62 eligible patients, 59 were evaluable: the response rate observed in patients receiving high-dose and low-dose cisplatin was 16.1% and 17.8%, respectively. Survival was superimposable in the two treatment arms. No evidence of dose dependency of cisplatin activity in advanced head and neck squamous carcinoma was noted in this randomized trial.

Surgical second look in ovarian cancer: a randomized study in patients with laparoscopic complete remission--a Northeastern Oncology Cooperative Group-Ovarian Cancer Cooperative Group Study.

PURPOSE: The usefulness of extensive and repetitive surgery for patients with ovarian cancer still remains unproven (at least for some conditions). We planned an accurate prospective test of the hypothesis that patients with advanced-stage disease, after they had reached a clinical complete remission (CR), may benefit from surgical second look (SSL). PATIENTS AND METHODS: One hundred two patients in CR (as assessed by clinical findings, markers, and visualization by computed tomographic [CT] scan and laparoscopy), after initial debulking and first-line chemotherapy, were randomized to two arms, which were well balanced for predictive criteria such as age, stage at presentation, histology, grading, date of randomization, and residua after first surgery. Forty-eight patients were randomly assigned to receive follow-up evaluation only, while 54 were assigned to receive second surgery (eight of them refused). Of 46 surgical patients, 35 had negative and 11 positive surgical findings (24% clinically false-negative). RESULTS: Despite the microscopic residua found at open surgery, and the fact that the patients were then treated with second-line chemotherapy, SSL did not increase the probability of survival in this setting. In an analysis of the results according to the intention-to-treat criteria, after a 60-month follow-up period, the overall survival rates in the two groups of patients (SSL v no SSL) were 65% and 78%, respectively (P = .14). Multivariate analysis according to predictive criteria confirmed there was no significant difference between the two groups (P = .39). CONCLUSION: Our study shows the following: (1) our second-line treatment is scarcely effective; (2) SSL accurately defines complete responders to first-line chemotherapy; (3) SSL per se does not prolong survival; and (4) if confirmed, a less invasive procedure could replace SSL as a valuable method in new first-line regimens in ovarian cancer patients with clinical CR confirmed by laparoscopy.

Phase I-II intraperitoneal mitoxantrone in advanced pretreated ovarian cancer.

36 previously treated patients (25 with anthracyclines) with advanced epithelial ovarian cancer have been treated with intraperitoneal (i.p.) mitoxantrone (M) at increasing doses. The response was evaluated through repeated laparoscopy with multiple biopsies and serial measurement of Ovarian Cancer Antigen 125 (CA 125); 11/36 patients had a complete (6 patients) or partial (5 patients) response. Toxicity (both local and general) was observed starting from 25 mg/m2 of M per cycle. The amount of drug reaching systemic circulation was monitored by measuring M plasma value after i.p. treatment. This study showed wide variations in serum levels obtained after i.p. doses ranging from 23 to 36 mg/m2. The area under the curve (AUC) of mitoxantrone plasma samples, did not correlate with the i.p. administered dose. Conversely, a correlation seems to exist between the plasma AUC and the responder status. Patients who showed clinical responses to i.p. treatment with mitoxantrone had AUCs and plasma peak levels of the drug that were significantly higher than those in non-responders (P = 0.03, Fisher's exact test).

Phase II trial of flutamide in advanced ovarian cancer: an EORTC Gynaecological Cancer Cooperative Group study.

New active non-toxic therapeutic regimens are warranted in ovarian cancer relapsing after platinum-based chemotherapy. Some investigators have determined that androgen receptors predominated over oestrogen and progesterone receptors in untreated common epithelial ovarian cancer tissue cytosols. In an effort to test its antitumoural activity, 68 pretreated patients with epithelial ovarian cancer were given flutamide 750 mg/day orally for at least 2 months. Of 32 patients who received a minimum of 2 months of therapy, pretreated with at least one platinum-based chemotherapy, and a median of two chemotherapy regimens, two (6.3%) objective responses (one complete and one partial) and nine (28%) disease stabilisations were observed; these lasted 44 and 72 weeks, respectively (for the complete and partial response), and for a median of 24 weeks for stabilisations (range 12-48+). Nausea and vomiting were the most frequent side-effects. These occurred in 19/55 (34.5%) patients evaluable for toxicity. Flutamide has to be considered ineffective in patients extensively pretreated with chemotherapy, and it is not devoid of side-effects.

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group.

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.

Combined radiotherapy and chemotherapy with cyclophosphamide, adriamycin, methotrexate, procarbazine (CAMP) in 64 consecutive patients with epidermoid bronchogenic carcinoma, limited disease: a prospective study.

Sixty-four consecutive patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were treated with radiotherapy to the primary and nodal areas and combination chemotherapy with cyclophosphamide, adriamycin, methotrexate and procarbazine. The overall response rate (CR + PR) to combined treatment was 62%. The median survival time was 12.7 months. The toxicity was acceptable and no treatment-related death occurred.

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.

In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.

Randomized crossover antiemetic study in cisplatin-treated patients. Comparison between high-dose i.v. metoclopramide and high-dose i.v. dexamethasone.

This prospective, randomized, nonblind study comparing the antiemetic effectiveness of high-dose IV metoclopramide and high-dose IV dexamethasone was performed in 78 advanced cancer patients. Chemotherapeutic treatment consisted in cisplatin at a high-dose (120 mg/m2) (HD-CDDP) and at a low-dose (LD-CDDP), either alone (60 mg/m2) or in combination with other chemotherapeutic agents (50 mg/m2). The evaluation of the effectiveness of antiemetic therapy was based on three parameters: prevention of vomiting ("major protection"), number of emetic episodes, and subjective preference. Out of 78 study patients, 67 were evaluable. Overall, metoclopramide proved to be statistically superior to dexamethasone in preventing vomiting (P less than 0.005), in reducing the median/mean number of emetic episodes (P less than 0.001/0.001), and in subjective preference (P less than 0.01). The results divided between HD-CDDP and LD-CDDP groups were also in favor of metoclopramide for reduction of the median/mean number of emetic episodes (P less than 0.001/0.001 for the HD-CDDP group and P less than 0.001/0.005 for the LD-CDDP group) and in subjective preference (P less than 0.001 and P less than 0.001 for the HD- and LD-CDDP groups, respectively). No statistical differences were noted when LD-CDDP was used in monochemotherapy, whereas when LD-CDDP was used in combination chemotherapy, statistical differences in favor of metoclopramide were noted again for the median/mean number of emetic episodes (P less than 0.01/0.05) and for subjective preference (P less than 0.01), even though the effectiveness of both antiemetic agents was greatly reduced. The evaluation of previously untreated patients reflected the overall results: for the HD-CDDP group all three parameters demonstrated statistical significance in favor of metoclopramide; for the LD-CDDP group, of all three parameters, prevention of vomiting (major protection) was the only one for which there was no significant difference. Mild sedation was the only side effect of metoclopramide. No extrapyramidal reactions were noted during this trial, but concomitant orphenadrine treatment was given. Dexamethasone was always well tolerated. In conclusion, high-dose IV metoclopramide demonstrated its superiority over high-dose IV dexamethasone in all subsets of our population except the LD-CDDP monochemotherapy group, in which the two antiemetics were found to be equivalent in effect.

cis-platinum and etoposide combination chemotherapy of advanced non-oat cell bronchogenic carcinoma.

From December 1981 to November 1982, a consecutive series of 37 patients with advanced non-oat cell bronchogenic carcinoma were treated with cis-platinum and etoposide in doses of 20 mg/m2 and 75 mg/m2, respectively, for 5 consecutive days every 3 weeks. Among the 33 evaluable patients, one complete response, 11 partial responses, five minor responses, seven unchanged states, and nine cases of progression were noted. Median duration of response was 30+ weeks. Toxicity was significant, but no treatment-related deaths were encountered. Combined cis-platinum and etoposide can provide significant palliation in approximately one-third of patients with the doses and schedule used.

VM26 in malignant hematological diseases. A phase II study.

From August 1979 to April 1981, 33 consecutive patients with malignant hematological diseases, entered this phase II study. Sixteen patients had NHL, eight CLL, four Myeloma, three HD, one ALL, and one Polycythaemia vera. Two patients were unevaluable because of early death. The median age was 67 years. Eight patients were not pretreated with drugs. Two CR (5+, 20+ weeks) were obtained among NHL patients, whereas five PR were observed among two NHL, one CLL, one Myeloma, and one HD patients, respectively. Toxicity was almost exclusively hematologic and occurred in ten patients, in one of them causing severe myelosuppression. Moreover, severe asthenia, attributable to VM26, was encountered in three patients, in one requiring the suspension of the treatment.

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma.

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n = 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17-95%)] and clearance [CL, 1.1 (0.7-2.3)l h(-1) m(-2)] resulting in a normal degree of systemic exposure (AUC(oral) 27 microg h ml(-1)). Normal protein binding [PB 93.2% (84.4-98.1%)] contributed to a normal level of exposure to free drug (AUC(f, oral) 1.9 microg h ml(-1)). The distribution volume [V(SS) 8.4 (6.1-13.2) l/m2] and the effective half-life [t1/2eff, 5.1 (3.0-9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of > 1.2 mg/dl as compared with the ten patients with total bilirubin levels of < or = 1.2 mg/dl (1.3 versus 1.01 h(-1) m(-2) and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring.

A phase II study of AMSA in head and neck cancer.

AMSA was given to 22 evaluable patients with advanced head and neck cancer with measurable lesions. The starting dose was 90-120 mg/m2 by i.v. infusion over 45 min every 3 weeks. The dose of AMSA was escalated by 30 mg/m2 in absence of bone marrow toxicity. At least two cycles were given prior to the evaluation of response. Only one patient with oropharyngeal cancer achieved a partial response, lasting for 20 weeks. Toxicity was mild and mainly hematological. We conclude that AMSA given at this dose and schedule has little activity in head and neck cancer.

Phase II study of five-day continuous infusion of vinblastine in patients with metastatic renal-cell carcinoma.

Vinblastine 5-day continuous infusion in metastatic renal-cell carcinoma was evaluated in a Phase II trial. The dosage varied from 1.4 to 1.6 mg/m2/day every 3 weeks according to previous treatment and performance status (PS). From September 1983 to January 1986, 25 consecutive patients entered the study; 21 were evaluable for response and 23 were evaluable for toxicity. The median number of cycles administered was three (range, one to six). One complete response (liver) lasting 5 months, one partial response (lung) lasting 3 months, 12 cases of stable disease, and seven progressions were noted. Toxicity (WHO criteria) was relevant and mainly hematological: one treatment-related death occurred. Vinblastine continuous infusion did not demonstrate significant antineoplastic activity against metastatic renal-cell carcinoma.