Phase II study of induction chemotherapy followed by concomitant chemoradiotherapy in advanced head and neck cancer: clinical outcome, toxicity and organ/function preservation.

The purpose of the study was to assess response rate, clinical outcome, organ/function preservation and toxicity in head and neck cancer patients treated with induction chemotherapy followed by concomitant chemoradiotherapy and, when necessary, limited surgery. The study design was a phase II non-randomized trial in hospitalized patients setting. The treatment plan consisted of 3 cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin and interferon alpha2b (PFL-IFN) followed by 7 cycles of 5-FU, hydroxyurea and concomitant radiation for 5 days (FHX) for a total radiation dose of 70 Gy. Surgical resection was performed, when necessary, with the intent to spare organ/function. Seventeen patients were treated at one institution. Three patients had stage III and 14 patients stage IV disease. Twelve patients were analyzed for response to PFL-IFN: 2/12 (16.7%) patients achieved a CR and 10/12 (83.3%) achieved a PR for an ORR of 100%. FHX was administered on protocol to 10 patients: 4 patients (40%) had CR, 3 (30%) had PR >/=70% for an ORR of 70%, 1 patient (10%) had SD and 2 patients (20%) had PD. As for local therapy, of the 8 eligible patients who completed chemoradiotherapy, the 3 patients with CR were submitted to random biopsies, results of which were histologically negative, 3 patients with PR >/=70% underwent conservative organ-preserving surgery, and 1 patient with PR >70% refused surgery, whereas the patient with SD underwent salvage surgery, preserving voice. Thus, organ preservation was achieved in all 8 patients at the completion of all therapy: 4 patients had no surgical procedure and 4 patients only conservative surgery. Overall, after completion of all therapy, 5/8 (62.5%) patients were rendered disease-free. The median overall survival time was 23 months, the median duration of response was 6 months and the median time to progression was 9 months. Both induction chemotherapy and concomitant chemoradiotherapy resulted in significant toxicity, which consisted mainly of mucositis and thrombocytopenia. In conclusion, PFL-IFN was very active, producing high ORRs and, followed by FHX, resulted in high overall survival rates permitting an optimal organ preservation, at the cost of a severe toxicity.

Results of a dose-intense phase 1 study of a combination chemotherapy regimen with cisplatin and epidoxorubicin including medroxyprogesterone acetate and recombinant interleukin-2 in patients with inoperable primary lung cancer.

Based on the role of cytokines in the pathogenesis of cancer-related anorexia-cachexia and the ability of progestins, such as medroxyprogesterone acetate, to reduce cytokine production and relieve cancer-related anorexia-cachexia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), including recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate for patients with stage IIIB to IV inoperable primary lung cancer. The end points were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia-cachexia symptoms; the assessment of patient serum levels of IL-1beta, IL-6, tumor-necrosing factor-alpha (TNF-alpha), and soluble IL-2 receptor (sIL-2R). From March to October 1997, 16 patients (M:F ratio, 14:2; mean age, 60.5 years; age range, 41 to 74 years) were enrolled. All patients were evaluable for toxicity and 14 of them for response. The patients were assigned to increasing dose levels of drugs according to a dose-escalation schedule. The weekly schedule consisted of a combination of CDDP given intravenously on day 1, EPI given intravenously on day 1, 1 g/day medroxyprogesterone acetate given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered subcutaneously on days 2 to 7 plus 300 microg granulocyte-colony stimulating factor support given subcutaneously on days 2 to 5. Administration of medroxyprogesterone acetate began 1 week before the first cycle. Dose escalation of the drugs was as follows: 30 mg x m2 x week(-1) CDDP and 25 mg x m2 x week(-1) EPI (first level, two patients); 30 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (second level, 2 patients); 40 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (third level, 6 patients); and 40 mg x m2 x week(-1) CDDP and 40 mg x m2 x week(-1) EPI (fourth level, 6 patients). Six cycles were planned for each patient. The actual dose intensity delivered was more than 80% of the projected dose intensity of all drugs. After six cycles, clinical response (according to World Health Organization criteria), toxicity (according to World Health Organization criteria), Eastern Cooperative Oncology Group (ECOG) performance status, body weight, appetite, and serum levels of cytokines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partial response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had progressive disease, and the objective response rate was 64.3%. ECOG performance status and body weight did not change significantly after treatment, whereas appetite showed an increase that was of borderline statistical significance. Toxicity was acceptable and only hematologic. Dose-limiting toxicity was established at the fourth dose level; consequently, maximal tolerable dose was assessed at the third dose level. Before treatment, the serum levels of IL-1beta, IL-6, and TNF-alpha were significantly greater in the patients than in healthy persons. The comparison between pretreatment and posttreatment serum values of IL-1beta, IL-6, TNF-alpha, and sIL-2R did not reveal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or non-responders (stable or progressive disease) to therapy. Only IL-6 serum levels were increased (p = 0.014) after treatment.

Phase II study of induction chemotherapy followed by concomitant chemoradiotherapy in advanced head and neck cancer: clinical response and organ/function preservation.

We planned to conduct a trial of induction chemotherapy followed by concomitant chemoradiotherapy with the goal of organ-function preservation in advanced head and neck cancer patients with the response rate and local control of disease as primary endpoints and the assessment of toxicity as secondary endpoint. The overall treatment plan consisted of 3 cycles, each q. 28 days, of induction chemotherapy with cisplatin, 5-FU, leucovorin and interferon alpha2b (PFL-IFN), followed by response evaluation and local therapy with concomitant chemoradiotherapy with 5-FU, hydroxyurea and concomitant radiotherapy (FHX). The evaluation of clinical response was performed during the 2nd week after the 3rd cycle of induction chemotherapy and FHX was initiated 28 days after the 3rd cycle of induction chemotherapy. Hydroxyurea was administered orally at doses of 1 g every 12 h x 11, 5-FU was administered on days 1 through 5 at 800 mg/m2/d for 5 days. Daily fraction of radiotherapy were administered at 2.0 Gy on days 1 through 5. FHX cycles were repeated every 14 days until completion of radiotherapy. Total radiotherapy doses consisted of 70 Gy. Seventeen patients (mean age 56.53 years, range 40-73, male/female 15/2, site: oral cavity 6, 35.29%; oropharynx 3, 17.6%; hypopharynx 3, 17.65%; larynx 2, 11.76%; paranasal sinuses 2, 11.76%; salivary glands 1, 5.88%; ECOG PS 0/1: 10/7, stage: III/IV 3/14) were enrolled from January 1998 to August 1998. All 17 patients initiated induction chemotherapy on this protocol. Twelve patients were analyzed for response (5 patients were not evaluable): 2/12 (16.7%) patients achieved a CR and 10/12 (83.3%) achieved a PR for an ORR of 100%. Concomitant chemoradiotherapy was administered on protocol to 10 patients: 4 patients (40%) had CR, 3 patients (30%) had PR >/=70% for an ORR of 70%, 1 patient (10%) had SD and 2 patients (20%) had PD. As for local therapy, according to treatment plan, of the 8 eligible patients who completed chemoradiotherapy, the 4 patients with CR were submitted to random biopsies, which resulted histologically negative, the 3 patients with PR >/=70% underwent conservative organ-preserving surgery, the patient with SD underwent salvage surgery, preserving voice. Thus, organ-preservation was achieved in all 8 patients at the completion of all therapy: 4 patients had no surgical procedure and 3 patients only conservative surgery. Overall, after completion of all therapy, 6/8 (75%) patients were rendered disease-free. Both induction chemotherapy and concomitant chemoradiotherapy resulted in significant toxicity, which consisted mainly of mucositis and thrombocytopenia. In conclusion, in the present study we have achieved a good clinical response and an optimal organ preservation, at the cost of a severe toxicity.

Assessment of the efficacy of two dosages and schedules of human recombinant erythropoietin in the prevention and correction of cisplatin-induced anemia in cancer patients.

Despite the numerous studies demonstrating the effectiveness of epoetin á (human recombinant erythropoietin) versus placebo in cisplatin-induced anemia of cancer patients, data are lacking on the most effective doses and schedules of administration of epoetin á in this setting. The aim of the present study was to assess the best dose and schedule of administration of epoetin á in cancer patients with cisplatin-induced anemia. This was an open, randomized, single-institution phase II study comparing the ability of two doses and schedules of epoetin á of preventing and/or correcting anemia, measured as the increase in hemoglobin level and decrease in transfusion requirements, in 20 chemotherapy-naive patients with advanced stage head and neck, esophageal, and lung cancer, treated with cisplatin at doses 80 mg/m2. The secondary endpoint of the study was to assess the serum levels of certain cytokines involved in cancer anorexia/cachexia syndrome. The eligible patients were randomly assigned to treatment with either: a) subcutaneous epoetin á 150 U/kg three times a week for up to 12 consecutive weeks (Group A); b) subcutaneous epoetin á 50 U/kg daily for up to 12 consecutive weeks (Group B). The following laboratory parameters were assessed before the study entry and during the study: hemoglobin (weekly); serum iron, transferrin and ferritin (before entry). The following immunological parameters were assessed before and after study end: Interleukin (IL)-1á, IL-1 , IL-6 and Tumor Necrosis Factor (TNF) á. Twenty patients were enrolled, data were available for 17. Nine patients were assigned to Group A and 8 to Group B. No statistically significant difference of hemoglobin level was found between the 2 groups at baseline, at month 1, 2 and 3, neither in the comparison of the change from baseline between the two groups. In Group A fewer transfusions were administered per patient per month after the first month of epoetin á therapy, compared to Group B. No significant difference was found as for transfusion requirements at month 1, 2 and 3 between Group A and B. The epoetin á dose administered was slightly higher than that projected. Epoetin á was well-tolerated. There was no statistically significant correlation between change in hemoglobin level and tumor response for either group, neither between change in hemoglobin level and change in ECOG score from baseline to final was observed. The changes from baseline of IL-1á and IL-1 , IL-6 and TNFá were not remarkable nor univocal in either group, there was not correlation between hemoglobin change and serum cytokine changes from baseline, except for IL-6 in Group A.

Prevention of nausea and vomiting (N&V) in cancer patients receiving high-dose cisplatin. Assessment of the potential antiemetic activity of transdermal fentanyl (TTS-F) compared to standard antiemetic treatment in acute and delayed N&V: first clinical report.

UNLABELLED: A single-institution, prospective, open crossover study was performed to compare the effectiveness and tolerability of transdermal fentanyl (TTS-F) vs intravenous (i.v.) ondansetron (OND), both combined with i.v. DEX, in the prevention of acute nausea and vomiting (N&V), and TTS-F vs metoclopramide (M), both combined with intramuscular (i.m.) DEX, in the prevention of delayed N&V in patients with advanced stage head and neck squamous cell carcinoma receiving high-dose (> or = 100 mg/m2) cisplatin. This is the first report on the clinical use of TTS-F in this setting. PATIENTS AND METHODS: All patients were adequately informed of the study characteristics and gave their written informed consent before study entry. The antiemetic treatment for acute N&V consisted of A) OND 8 mg plus DEX 20 mg (i.v.) or B) TTS-F 75 micrograms/h plus DEX 20 mg i.v. For prevention of delayed N&V, patients receiving TTS-F for acute N&V were given TTS-F at the same dosage (75 micrograms/h) on days 2-5, whereas patients receiving OND for acute N&V were treated with M 20 mg orally every 6 h on days 2-5, starting 24 h after CDDP. All patients received DEX 8 mg i.m. every 12 h on days 2 and 3, 4 mg i.m. every 12 h on days 4 and 5, starting 24 h after CDDP. From November 1997 to April 1998, 15 consecutive patients entered the study and were assigned to one of the two alternative treatments for acute N&V. All of them were evaluable. Twelve patients were evaluable for delayed N&V. Seven patients were assigned to Group 1 starting with treatment A (OND + DEX) and 8 patients were assigned to Group 2 starting with treatment B (TTS-F + DEX). In the prevention of acute N&V, the overall efficacy of OND + DEX was statistically significantly higher than that of TTS-F + DEX in achieving Complete Response (CR) and Major Efficacy (ME = CR + Major Response, MaR). As for delayed N&V, the overall efficacy of M + DEX, both in achieving CR and ME, although higher, was statistically not significantly different from that of TTS-F + DEX. Unfortunately, due to the small number of patients included in the study, the sophisticated criteria for evaluating response in antiemetic research, such as the persistence of efficacy, the response after crossing-over, did not make it possible for us to draw additional conclusions, although the trend was in favor of "standard" treatments, particularly in acute N&V. The 'response to treatment A (OND + DEX) in the prevention of acute N&V was in the same range as the response to treatment A (M + DEX) for delayed N&V. The response to treatment B (TTS-F) for acute N&V was lower than the response to the same treatment for delayed N&V. The TTS-F treatment was well-tolerated with no significant side-effects including the well-known opioid-related symptoms. Our study confirms that the currently available standard antiemetic treatments both for acute and delayed N&V must be considered by far the most effective ones for clinical use.

Clinical evaluation of two dosages and schedules of ifosfamide in combination with cisplatin in neo-adjuvant chemotherapy of patients with advanced (stage III-IV) head and neck squamous cell carcinoma: a phase II randomized study.

The aims of the present open, randomized, single-blind (patient), single institution, phase II study were: i) to compare the therapeutic effectiveness and toxicity of two dosages and schedules of ifosfamide (IFO) in combination with cisplatin (CDDP) mainly in the neo-adjuvant setting of patients (pts) with locally advanced (stage III-IV) head and neck squamous cell cancer (HNSCC) (primary endpoint); ii) to assess the quality of life (QL) of pts included in the study before and after treatment (secondary endpoint). From July 1996 to June 1997, 28 pts, all males (mean age 56.79 years, range 37-72), hospitalized in the Department of Medical Oncology, University of Cagliari, were enrolled in the study. Twenty pts (M/F 20/0, mean age 53.6, range 37-71 years; stage III 1 pt, stage IV 19 pts) were evaluable for response and all 28 pts enrolled were evaluable for toxicity. Arm A: IFO 2.2 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 2 cycles. Fifteen pts (11 of whom were evaluable) were enrolled in this Arm. Arm B: IFO 1.5 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 3 cycles. Thirteen pts (9 of whom were evaluable) were enrolled in this Arm. The two Arms were well-balanced for sex, age, site of primary, ECOG PS and clinical stage. After completion of 2 (Arm A) or 3 (Arm B) cycles of chemotherapy, the pts were assessed for response. All evaluable pts received treatment as planned. Six pts (54.5%) of Arm A and 4 pts (44.5%) of Arm B had partial response (PR) with an overall response rate (ORR) of 54.5% and 44.5%, respectively: it is worth noting that all (100%) pts who had PR in Arm B achieved a high-grade PR, i.e. >/=70%, whereas only one pt (16.7%) who had PR in Arm A achieved a high-grade PR. Three pts (27.3%) in Arm A and 2 pts (22.2%) in Arm B had stable disease (SD); 2 pts (18.2%) in Arm A and 3 pts (33.3%) in Arm B had progressive disease (PD). The actual dose intensity was over 80% of the projected dose intensity for both drugs and for both Arms. Over a total of 59 cycles administered, the total number of episodes of toxicity was 24 for Arm A and 17 for Arm B. Three pts out of 28 evaluable for toxicity (10.8%) died for Grade 5 hematological toxicity: all pts were included in Arm A. In Arm A, 2 pts (13.3%) experienced hematological Grade 3 toxicity and 2 pts (13.3%) hematological Grade 4 toxicity. In Arm B no pt experienced Grade 3-4 hematological toxicity. No Grade 3-4 toxicity of any other type was found in either Arm. The QL evaluation, using the Cella's FACT-G scale supplemented with disease-specific scale (FACT-H&N scale), did not show significant beneficial effect of neo-adjuvant chemotherapy treatment.