Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study.

PURPOSE: Amifostine (WR-2721) is an important cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy. PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction. RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P <.04). The delays in radiotherapy because of grade 3 mucositis were significantly longer in the group of patients treated with radiotherapy alone (P <.04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P <.0006). CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy's early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.

Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer.

PURPOSE: Stealth (ALZA Corporation, Palo Alto, CA) liposomal drug formulation allows a higher intratumoral accumulation and a prolonged plasma half-life of the encapsulated drugs. In the study presented here, we evaluated the feasibility of Stealth liposomal doxorubicin (Caelyx; ALZA Corporation) administered concurrently with conventionally fractionated radiotherapy in the treatment of non-small-cell lung cancer (NSCLC) and head and neck cancer (HNC). PATIENTS AND METHODS: Fifteen patients with NSCLC and 15 with squamous-cell HNC were recruited in two phase I dose-escalation trials. The starting dose of Caelyx was 10 mg/m(2) every 2 weeks (for three cycles during radiotherapy) and was increased by 5 mg/m(2) dose increments for every three patients. RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m(2) for HNC and 25 mg/m(2) in NSCLC patients. Oral/pharyngeal mucositis was the dose-limiting toxicity for HNC patients. "In field" radiation skin toxicity was slightly increased. Hematologic toxicity was minimal. Single photon emission computed tomographic evaluation of Caelyx distribution, using technetium-99m-diethylenetriamine pentaacetic acid labeling, revealed a high intratumoral accumulation of the drug. The tumor to thoracic vessel area count ratio in the NSCLC cases ranged from 0.6 to 1.6 (mean +/- SD, 1.01 +/- 0.29), whereas this ratio was higher (0.8 to 1.85; mean +/- SD, 1.35 +/- 0.39) in HNC cases (P =.049). The complete response rate was 21% in the NSCLC cases and 75% in the HNC cases. NSCLC cases with higher Caelyx tumor accumulation responded better to the regimen. The tumor microvessel density assessed with the anti-CD31 monoclonal antibody directly correlated with the degree of the Caelyx accumulation (P =.007; r =. 92). CONCLUSION: We conclude that combination of radiotherapy with Stealth liposomal doxorubicin is feasible. The potential role of such a regimen in the treatment of highly angiogenic tumors requires further investigation.

Oral administration of recombinant human granulocyte macrophage colony-stimulating factor in the management of radiotherapy-induced esophagitis.

Radiation-induced esophagitis often results in treatment interruption, which may severely affect the probability of control of the local disease in patients undergoing chest radiotherapy (RT). No effective regimen that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of oral mucosal healing using topical recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) has been reported, the mechanism of such an interaction remains obscure. Effective topical application of rhGM-CSF for the treatment of radiation-induced esophagitis has never been reported in the past. In pharmacological studies, we observed that glycerol exerts a remarkable stabilizing effect on rhGM-CSF immunoreactivity. After studying the kinetics of esophageal emptying with nuclear imaging, we proposed a rhGM-CSF regimen that could be applied for topical treatment of esophagitis during RT. The regimen was applied for 5 consecutive days in a cohort of 36 patients undergoing chest RT, immediately after the documentation of grade 3 esophagitis. RT was not interrupted. Mucosal biopsies were performed endoscopically and examined immunohistochemically. Regression of dysphagia to grade 0/1 was observed in 19 of 36 (52%) patients, whereas grade 2 dysphagia persisted in 12 of 36 (33%) patients. Progression of dysphagia was seen in 5 of 36 (14%) patients. Recurrence of severe esophagitis within 5-8 days after rhGM-CSF therapy was observed in 7 of 31 (22%) patients with initial response to rhGM-CSF. Four of these patients presented significant improvement of symptomatology after additional rhGM-CSF medication. In immunohistochemical studies, active intraepithelial neovascularization and thymidine phosphorylase and vascular endothelial growth factor overexpression were observed in the damaged epithelium, which was not accompanied by macrophage or neutrophil infiltration. We conclude that rhGM-CSF topical therapy (p.o. administration) exerts a significant therapeutic effect against RT-induced esophagitis. The rhGM-CSF mucosa healing effect is probably due to its direct angiogenic activity and/or to the potentiation of the activity of other angiogenic factors released by the damaged epithelium.

Combined treatment with low-dose interferon plus vinblastine is associated with less toxicity than conventional interferon monotherapy in patients with metastatic renal cell carcinoma.

The outcome of treatment of advanced renal cell carcinoma is disappointing. In interferon (IFN)-treated patients, the high incidence of adverse effects causes many patients to withdraw from treatment. This 12-week randomized study compared the incidence of toxicity associated with high-dose IFN monotherapy (15 x 10(6) U thrice weekly) and treatment with the combination of low-dose IFN (5 x 10(6) U thrice weekly) and 6 mg/m2 vinblastine (VBL) every 14 days in 100 consecutive patients. There was no significant difference in response rate between treatment arms (42% IFN vs. 34% IFN + VBL) or between subgroups (by tumor location). Combined treatment was associated with a significantly lower incidence of fever, fatigue, and weight loss but with a higher incidence of leukopenia. There was no significant difference in the incidence of other events. More patients treated with IFN monotherapy required bed rest, and overall treatment costs were 60% higher than for combined treatment. It is concluded that combined treatment with low-dose IFN and VBL, without loss of short-term efficacy, is better tolerated and less expensive than high-dose IFN monotherapy.

Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer.

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m2 every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m2, while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m2) was administered i.v. before carboplatin and GM-CSF (480 microg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50 mg/m2 of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2-4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4-12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60 mg/m2 and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m2) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.

Ultrastructural study of the noninvolved urothelium of tumor-bearing patients after two years of intravesical interferon therapy.

OBJECTIVE: Seventeen patients with transitional cell carcinoma of the urinary bladder were studied. Twelve patients did not have a recurrence 2 years after a transurethral resection (TUR) followed by interferon (IFN)-alpha 2b treatment. This observation led us to study the ultrastructural morphology of the noninvolved urothelium in 8 of the above 12 patients. METHODS: All patients had a primary solitary grade I or II tumor. Topical therapy was started after TUR. Each patient received a total of 22 instillations of 50 MU IFN-alpha 2b in 12 months according to the standard procedure. After the first year, a repetitive dose of 50 MU IFN-alpha 2b was administered every 2 months for a period of 1 more year. RESULTS: At the end of therapy, certain ultrastructural modifications were observed indicating a partial restoration of the urothelium: the existence of asymmetric unit membrane, a well-developed Golgi apparatus and an increase of the filaments. The cells were joined to each other with well-developed tight junctions. Tubuloreticular inclusions were also observed. CONCLUSIONS: Prevention of recurrence by restoring the morphology of the noninvolved urothelium in response to IFN treatment deserves further examination.

Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection.

The substantial augmentation of the radiation sequelae during chemo-radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo-radiotherapy scheme with Stealth liposomal doxorubicin (Caelyx and Docetaxel (Taxotere in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere was 20 mg m(-2) week and of Caelyx was 15 mg m(-2) every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere/Caelyx was, thereafter, increased to 20/25 (five patients) and 30/25 mg m(-2) (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.

Comparative efficacy of a high or low dose of interferon alpha 2b in chronic hepatitis C: a randomized controlled trial.

OBJECTIVES: Our objective was to determine the relative efficacy of 6 months of treatment with 10 MU versus 3 MU of interferon-alpha 2b (IFN-alpha), three times weekly, in chronic hepatitis C (HCV) in a randomized trial. METHODS: Ten megaunits of IFN-alpha were given to 28 patients (group A), and 3 MU were given to 30 patients (group B). After treatment ended, follow-up was continued for 26 wk. RESULTS: Overall, the sustained response rate was higher in group A than in group B (16/26 or 61.5% vs. 12/28 or 42.9%, p = 0.17), but the difference did not reach statistical significance. However, it was higher in group A than in group B among patients with minimal or mild chronic hepatitis (15/20 or 75% vs. 9/24 or 37.5%, p = 0.013) and among those with mild or moderate fibrosis (15/17 or 88.2% vs. 11/19 or 57.9%, p = 0.042). IFN-alpha treatment significantly reduced histological activity index (HAI) scoring and all its parameters, except fibrosis, but the decrease was similar in the two groups. Sex, age, stage, and HCV genotype were statistically significant predictors of sustained response in univariate analysis. However, multiple logistic regression analysis revealed that advanced histological stage (severe fibrosis and cirrhosis) was the only significant prognostic factor of poor sustained response (RR = 31.0, 95% CI 2-460, p = 0.01), whereas the presence of genotype 1 had marginal statistical significance (RR = 5.0, 95% CI 0.9-28, p = 0.07). CONCLUSIONS: 1) A larger dose of IFN-alpha does not improve the sustained response rate; however, it may be of benefit in early stages of chronic hepatitis C. 2) Pretreatment, histological stage, and possibly HCV genotype appear to be the main prognostic factors of sustained response.

Interferon-a2b reduces neo-microvascular density in the 'normal' urothelium adjacent to the tumor after transurethral resection of superficial bladder carcinoma.

BACKGROUND: As angiogenesis represents one of the hallmarks of cancer we investigated whether intravesically administered interferon-a (IFN-a2b) reduces neo-angiogenesis in the 'normal' urothelium adjacent to the tumor in patients with superficial bladder carcinoma after complete transurethral resection (TUR) of the tumor. PATIENTS AND METHODS: In the present study 47 patients after TUR of the tumor were examined. 10 patients (group A) received no further treatment (control group); 37 patients (group B) received intravesical treatment with IFN-a2b. The instillations started within 7 days after TUR, were performed weekly for 2 months, twice a month for the next 4 months, and thereafter monthly for 6 more months. Cold cup biopsies were taken before TUR of the transitional cell carcinoma (TCC): from the tumor (T), near tumor (NT) and from normal epithelium (N). Cold cup biopsies 'near tumor', were also taken during follow-up cystoscopy (C1, C2, and C3) 2, 6, and 12 months after TUR, respectively. Angiogenesis was estimated by counting the microvessels detected with CD31 immunostaining. RESULTS: Significant differences of microvascular density (MVD) between patients of group A and B appear after TUR (p < 0.005, Kruskal-Wallis and Wilcoxon test). The MVD difference was maximal 6 months after TUR (C2(A)-C2(B), second cystoscopy) and measured at 12.17 microvessels/ mm(2) (26.2%). CONCLUSION: Our results show that the intravesical administration of IFN-a2b after TUR significantly decreases the angiogenic potential of the 'healthy' urothelium adjacent to the tumor in patients with TCC. This observation could possibly explain, to a certain extent, the mechanism by which IFN-a2b reduces the recurrence rate of primary TCC.

Surgical adjuvant therapy of rectal carcinoma: a controlled evaluation of leucovorin, 5-fluorouracil and radiation therapy with or without interferon-alpha2b.

BACKGROUND: The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV) and radiation therapy (RT) could be improved by the addition of interferon-alpha2b (IFN-alpha) in patients who have had a 'curative' resection, for rectal adenocarcinoma (Dukes' B2/C; T3 N0, T4 N0, N1-3). PATIENTS AND METHODS: A total of 207 eligible patients with a performance status of 0 or 1 were randomized postoperatively between days 21 and 70 to one of the two treatment groups: group A, LV 20 mg/m2 i.v. bolus and 5-FU 425 mg/m2 i.v. days 1-5 and 29-33, LV 20 mg/m2 and 5-FU 400 mg/m2 days 57-60 and 85-88, LV 20 mg/m2 and 5-FU 380 mg/m2 days 1-5 and 29-33 with the second day 1 occurring 28 days after the completion of RT (45 Gy); group B, LV, 5-FU and RT as in group A, and IFN-alpha 5 x 10(6) IU s.c. three times during each week chemotherapy is given. RESULTS: 104 patients were randomized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups. Toxicity was also the same, except for the flu-like syndrome associated with the IFN-alpha administration. CONCLUSIONS: There was no difference in efficacy between the two combinations. Toxicity was greater with the LV + 5-FU + IFN-alpha regimen because of the flu-like syndrome.