Birgit Schüll

Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx

PURPOSE We assessed the influence of hemoglobin level and r-HuEPO administration on response to chemoradiotherapy, locoregional tumor control, and overall survival in patients treated with neoadjuvant chemoradiotherapy and surgery for a squamous cell carcinoma of the oral cavity or oropharynx. METHODS AND MATERIALS The 191 study patients were treated with mitomycin C (15 mg/m(2) day 1), 5-fluorouracil (750 mg/m(2)/day, days 1-5), and radiotherapy (50 Gy in 25 fractions weeks 1-5), followed by resection of the primary tumor bed and neck dissection at the General Hospital Vienna, Austria, between November 1989 and October 1998 for a T2-4, N0-3, M0 SCC of the oral cavity or oropharynx. Starting in May 1996, patients with a low hemoglobin (Hgb) before or during chemoradiotherapy received r-HuEPO 10,000 IU/kg s.c. 3-6 times/week until the week of surgery. RESULTS On multivariate analysis, Hgb level and use of r-HuEPO were independent prognostic factors for response to chemoradiotherapy and locoregional tumor control (p < 0.01). Pathologic response to neoadjuvant therapy was also predictive of locoregional control (p < 0.001). Patients with a pretreatment Hgb > or = 14.5 g/dL had significantly higher complete response, locoregional control, and survival rates than the patients with a pretreatment Hgb < 14.5 g/dL who did not receive r-HuEPO (p < 0.05). The response, control, and survival rates in patients with a pretreatment Hgb < 14.5 g/dL given r-HuEPO were significantly higher than in low Hgb patients not given r-HuEPO (p < or = 0.001) and equivalent to patients with a pretreatment Hgb > 14.5 g/dL (p > or = 0.3). CONCLUSION Low pretreatment Hgb is a negative prognostic factor for oral cavity and oropharyngeal SCCA patients, but was completely abrogated by r-HuEpo administration during neoadjuvant chemoradiotherapy. Randomized trials of radiation and/or chemotherapy with or without r-HuEPO for patients whose Hgb level is either low at the start of therapy or is anticipated to become low during therapy are indicated.

Randomized Multicenter Phase II Trial of Two Different Schedules of Capecitabine Plus Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

PURPOSE Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. PATIENTS AND METHODS Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. RESULTS Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). CONCLUSION Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg m−2 on day 1 (arm A) or irinotecan 200 mg m−2 on day 1 plus raltitrexed 3 mg m−2 on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3–40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.

Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer

PURPOSE Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

Treatment of Advanced Hepatocellular Carcinoma with Biweekly High-Dose Gemcitabine

Introduction: Until today, an optimal palliative treatment regimen has not been defined for patients with advanced hepatocellular carcinoma. Since the novel cytidine analog gemcitabine has shown strong antitumor effects in vitro in a human hepatoma cell line and its therapeutic potential seems well established in several different tumors including gastrointestinal adenocarcinomas, the present phase II trial using a dose-intensified biweekly administration schedule was initiated. Patients and Methods: 17 patients with histologically confirmed unresectable advanced or metastatic hepatoma were treated with gemcitabine 2,200 mg/m2 given as a 30-min intravenous infusion on days 1 and 15. Treatment courses were repeated every 4 weeks. Results: All patients were evaluable for response and toxicity assessment. No objective response was achieved, stable disease occurred in 8 patients (47%), and 9 progressed while on chemotherapy. The median time to progression was 4 months (range 1.5–14 months), and the median survival time was 8.5 months (range 2.5–16.0+ months). Treatment was well tolerated with mild or moderate leukopenia, thrombocytopenia and anemia representing the most common side effects. Gastrointestinal and other subjective toxicities were infrequent and also generally mild. Conclusions: In view of the disappointing treatment results, gemcitabine using this particular dose regimen should not be considered for further investigation in patients with advanced hepatocellular carcinoma.

Second-Line Treatment of Advanced Gastric Cancer with Oxaliplatin plus Raltitrexed

Background: Treatment with oxaliplatin plus raltitrexed has demonstrated an encouraging therapeutic index in patients with advanced colorectal cancer and malignant pleural mesothelioma. The aim of this multi-institutional study was to determine the antitumor potential of this combination in patients with metastatic gastric cancer failing prior palliative first-line chemotherapy, and to reconfirm its favorable toxicity profile. Patients and Methods: 21 patients with metastatic gastric cancer, who progressed while on or within 6 months after discontinuing palliative first-line chemotherapy, participated in this study. They received raltitrexed 3,0 mg/m² and oxaliplatin 130 mg/m² both given intravenously on day 1 every 3 weeks. Results: One patient achieved a partial response, 6 had stable disease, and 14 patients progressed. Median progression-free and overall survival from the onset of salvage chemotherapy was 2.0 and 4.5 months, respectively. Hematologic adverse reactions, specifically neutropenia and anemia were common, though generally mild to moderate with only 3 patients experiencing grade 3/4 toxicity. The most frequent non-hematologic adverse events included nausea/emesis, asthenia, and transient elevation of liver functional parameters, again with grade 3 symptoms occurring only in a minority of patients. Conclusion: Despite reproducibility of a favorable toxicity profile of oxaliplatin + raltitrexed, our data suggest that this combination regimen has no substantial antitumor activity in patients with progressive, chemotherapeutically pretreated metastatic gastric cancer.

Oxaliplatin-Induced Fever and Release of IL-6

Background: Oxaliplatin is a novel cytotoxic agent with documented activity in colorectal cancer. Side effects are generally moderate, and include peripheral neuropathy along with mild bone marrow suppression and gastrointestinal side effects. To our knowledge, induction of febrile episodes by this agents has not been described in the literature. Case Report: We present the case of a 74-year-old male patient admitted to our institution for palliative treatment of metastatic colorectal carcinoma. Due to progression during treatment with 5-fluorouracil and leucovorin, chemotherapy consisting of oxaliplatin 85 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 repeated every 28 days was initiated. The first cycle of this combination was tolerated without side effects, but the patient experienced fever up to 39°C starting 2 h after oxaliplatin administration on day 15 of the second cycle, which persisted for 3 days. Fever again recurred at the same interval following administration of oxaliplatin on day 1 of the next cycle. Blood samples taken at regular intervals disclosed an increase in IL-6 serum levels parallel to the body temperature curve, with the peak corresponding to the highest temperature, while C-reactive protein values remained unchanged. In spite of intensive premedication with steroids, antipyretics and clarithromycin, fever promptly recurred during the third cycle of treatment. Conclusion: Our data suggest a clear- cut correlation between fever, the release of IL-6 and oxaliplatin administration. Whether IL-6 release is directly triggered by the application of oxaliplatin or is a bystander phenomenon, however, remains unclear at the moment.

Effective combination chemotherapy with bimonthly docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer.

Purpose: A phase II trial was performed to determine the antitumor efficacy and tolerance of combined docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Patients and Methods: Thirty-seven patients with histologically confirmed metastatic gastroesophageal cancer were entered in this trial. Treatment consisted of 4-weekly courses of docetaxel 50 mg/m2 and cisplatin 50 mg/m2 both given on day 1 and 15. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1,000–2,000/µl), a 5-day course of human granulocyte colony-stimulating factor (G-CSF) 5 µg/kg/day was given subcutaneously; in addition, if hemoglobin was <12.0 mg/dl, erythropoietin 10,000 IU was administered subcutaneously 3 times per week. Results: The confirmed overall response rate (intent-to-treat) was 46%, including 4 complete responses (11%) and 13 partial responses (35%). Eleven patients (30%) had stable disease and 9 (24%) progressed while on treatment. The median time to response was 3 months, the median time to progression was 7 months and the median overall survival time was 11.5 months with 16 (43%) patients currently alive. Hematologic toxicity was common, though WHO grade 4 neutropenia occurred only in 3 patients. Nonhematologic adverse reaction were usually mild to moderate; grade 3 toxicities included alopecia in 5 patients (14%), infection in 1 (3%), neutrotoxicity in 2 (5%) and anaphylaxis in 1 patient. Conclusion: Our data suggest that the combination of docetaxel and cisplatin with or without G-CSF and/or erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal cancer.

Capecitabine as salvage therapy for a breast cancer patient with extensive liver metastases and associated impairment of liver function.

Background: Breast cancer metastasizing to the liver with presence of a parenchymatous icterus presents a therapeutic dilemma. Treatment-related toxicity can be unpredictable due to altered drug clearance, and bilirubin exceeding 5,0 mg/dl is generally considered an absolute contraindication for the administration of cytotoxic agents. The pharmacokinetics of capecitabine – an active oral 5-fluorouracil prodrug for the treatment of advanced breast cancer – are not affected in patients with mild to moderate hepatic dysfunction, but there are no data available for patients with severe hyperbilirubinemia. Patient and Methods: We herein report the case of a female patient with advanced breast cancer with predominant liver metastases and severe hyperbilirubinemia (12 mg/dl). The patient received oral capecitabine at a dose of 2,500 mg/m2/day in 2 divided doses for 2 weeks, followed by 1 week rest. Results: Several assessments of liver function parameters including serum bilirubin showed a decrease to normal values within 2,5 months. After 7 courses of treatment, a partial remission was confirmed by CT scan. Treatment with capecitabine was well tolerated with grade 2 hand-and-foot syndrome and mild nausea being the only side effects. Conclusion: This case report suggests that capecitabine can be safely administered without dose adjustment in patients with extensive liver metastases and hepatic dysfunction.

Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies.

A phase II study was performed to assess the safety and efficacy of mitoxantrone and cisplatin in locally recurrent and/or metastatic carcinomas of the salivary glands. Between May 1997 and March 2001, a total of 14 patients were entered on this trial. All of them had previously undergone radical resection and 10 were subsequently treated with adjuvant radiation therapy with (n =3) or without (n =7) concomitant chemotherapy. Therapy according to the study protocol consisted of mitoxantrone given as i.v. bolus on day 1 at a dose of 12 mg/m2 and cisplatin given as 90-min infusion at a dose of 30 mg/m2 on days 1–3. We observed two partial responses (14.3%) and stabilization of disease in nine patients (64.3%); progression during therapy was noted in only three cases (21.4%). The median time to progression was 15 months (range 2–36) and the median survival time was 27 months (range 4–54). Myelosuppression was commonly observed. Leukocytopenia occurred in all patients, and was grade 3 or 4 in three (21%) and four (29%) patients. WHO grade 3 thrombocytopenia and anemia was seen in three (21%) and four (29%) patients, respectively. Non-hematologic toxicity was in general mild to moderate except for two cases (14%) of grade 3 nausea and vomiting; overall incidence rates were nausea and vomiting (n =14), stomatitis (n =6), diarrhea (n =3), alopecia (n =11), infection (n =7), increase of serum creatinine (n =3), and peripheral neuropathy (n =3). The combination of mitoxantrone and cisplatin seems to be an active and fairly well-tolerated regimen for the treatment of advanced salivary gland cancers. According to the observed high rate of abrogating progressive disease for a long duration, and the resulting promising progression-free and overall survival time, further investigation seems warranted.