Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients.

BACKGROUND: A phase III multicenter randomized trial has been designed in order to address whether amifostine (WR-2721, Ethyol), an organic thiophosphate cytoprotector, can protect ovarian cancer patients from toxicity induced by carboplatin-paclitaxel chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin [area under the curve (AUC) 5 mg.min/ml] and paclitaxel (175 mg/m(2)) with (arm A) or without (arm B) amifostine (910 mg/m(2)) every 21 days for six cycles. RESULTS: One-hundred and eighty-seven patients were accrued: 93 patients in arm A and 94 patients in arm B. There was no difference in terms of erythrocytopenia between the two arms; grade 3-4 thrombocytopenia was higher in arm A (3.3% versus 0.6%; P = 0.0010). There was no significant reduction of grade 3-4 leukopenia in arm A (11.8% versus 13.8%). The incidence of grade 3-4 neutropenia was lower in arm A (31.3% versus 37.9%; P = 0.03), as was the incidence of severe mucositis (4.7% versus 15.4% in arm A versus arm B, respectively; P <0.0001). Finally, amifostine appears to be protective against neurotoxicity (grade 3-4 neurotoxicity 3.7% versus 7.2%; P = 0.02). With a median follow-up of 24 months (range 2-41), time to progression was similar between the two groups. CONCLUSIONS: We showed that amifostine can exert some protection from the cumulative toxicity associated with this regimen. The results need to be confirmed in other randomized trials with this combination.     

A randomized trial of adjuvant chemotherapy in head and neck cancer

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.     

Economic analysis of amifostine as adjunctive support for patients with advanced head and neck cancer: preliminary results from a randomized phase II clinical trial from Germany

In a randomized phase II trial in Germany, we investigated the clinical and economic impact of amifostine protection against the hematological and oral toxicities of carboplatin administered concurrently with standard fractions of radiotherapy. 28 patients with squamous cell carcinomas of the head and neck received adjunctive or primary radiotherapy (5 days per week with daily fractions of 2 Gy, up to a total dose of 60 Gy) in conjunction with carboplatin (70 mg/m2) on days 1-5 and days 21-26. All patients received radiation encompassing at least 75% of the major salivary glands. Patients were randomized to receive radiation and carboplatin (RCT) alone or RCT preceded by rapid infusion of amifostine (500 mg) on days carboplatin was administered. The 14 patients who received amifostine, in comparison to 14 patients in the control arm, had significantly fewer episodes of grade 3 or 4 thrombocytopenia (p = 0.001), mucositis (p = 0.001), and xerostomia (p = 0.001). The patients receiving amifostine accrued significantly lower supportive care costs for resources related to infection ($241 vs. $1,275, p < 0.01), red blood cell and platelet support ($286 vs. $1,276 p = 0.06) alimentation ($343 vs. $894, p = .01), and hospitalization ($286 vs. $2,429, p < 0.01). Overall, including the costs of amifostine, mean per patient supportive care costs were $4,401 for the amifostine group and $5,873 (p = .02) for the control group. Our results from a randomized phase II trial indicate that selective cytoprotection with amifostine potentially offers clinical and economic benefits in patients with advanced head and neck cancer receiving radiochemotherapy. Additional economic studies alongside randomized phase III trials and from other countries are needed.     

Phase II trial of ifosfamide in recurrent and metastatic head and neck cancer

Thirty-six patients with recurrent carcinoma of the head and neck and no prior exposure to chemotherapy were treated with Ifosfamide. This drug was administered, concomitantly with Mesna, as a 24-hr infusion at a dose of 5-6.25 g/m2 every 3 weeks. Objective activity in 32 evaluable patients was 28% (9/32, 95% C.I. 17%-39%); 40% of patients had leukocyte values less than 2000 mm3 and 6% platelets less than 50,000 mm3. Nonhematologic toxicity consisted mainly of nausea/vomiting (66% greater than or equal to grade 2) and alopecia (80% greater than or equal to grade 2). The activity encountered warrants further studies with this drug in head and neck cancer.     

Phase II trial of mitoxantrone in head and neck carcinoma.

Nineteen patients with measurable and incurable head and neck carcinoma (17 squamous cell and two adenoid cystic) received intravenous bolus doses of 14 mg/m2 mitoxantrone in the first course. The doses were escalated or de-escalated by 2 mg/m2 in subsequent courses, based on leukocyte nadir, to achieve mild (3,000-3,999/mm3) or moderate (2,000-2,999/mm3) toxicity and response. The courses were repeated every 3 weeks. All 60 courses were evaluated for toxicity. Leukopenia was mild, moderate, severe (1,000-1,999/mm3), and life-threatening (less than 1,000/mm3) in 17%, 23%, 42%, and 2% of courses, respectively. Mild thrombocytopenia (100,000-129,999/mm3) occurred in two courses. The median interval to nadir leukopenia was 14 days (range 7-36) with a median of 13 days (range 3-50) to recover to normal. After the first course, leukopenia was mild in 16%, moderate in 32%, severe in 26%, and life-threatening in 5%. One patient died of pulmonary embolism 8 days after the first course and had concomitant leukocyte count of 700/mm3. Eighteen patients had at least one course resulting in leukopenia. Three of six patients receiving greater than or equal to 4 courses (cumulative dose 56-102 mg/m2) had an asymptomatic decrement of 14%, 17%, and 29%, respectively, in radionuclide left ventricular ejection fraction. The other toxicities were mild. In the 16 patients with squamous cell carcinoma that could be evaluated for response, one had a partial response lasting 8 months, and six had stable disease. One of the two patients with parotid adenoid cystic carcinoma had a minor response lasting 16 months. Mitoxantrone on a bolus schedule has minimal activity and is not indicated in head and neck squamous cell carcinoma.     

Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients

There has been concern that long-term supplementation with high-dose antioxidant vitamins, especially vitamin E (alpha-tocopherol), may increase all-cause mortality. We conducted a randomized controlled trial with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) supplements among 540 head and neck cancer patients treated by radiation therapy. Supplementation with beta-carotene was discontinued during the trial. The supplements were given during radiation therapy and for 3 additional years. During the follow-up (median 6.5 years), 179 deaths were recorded. All death certificates were obtained. All-cause and cause-specific mortality rates were compared between the 2 arms of the trial by Cox regression. All-cause mortality was significantly increased in the supplement arm: hazard ratio: 1.38, 95% confidence interval 1.03-1.85. Cause-specific mortality rates tended to be higher in the supplement arm than in the placebo arm. Our results concur with previous reports to suggest that high-dose vitamin E could be harmful.     

Has the outlook improved for amifostine as a clinical radioprotector?

Amifostine has recently been approved for clinical radiotherapy as a protector against irradiation-induced xerostomia. It is our aim to review the outlook for using amifostine as a general clinical radioprotector.Protection against X-rays is mainly obtained by the scavenging of free radicals. The degree of protection is therefore highly dependent on oxygen tension, with protection factors ranging from 1 to 3. Maximal protection is observed at physiological levels of oxygenation. A great variability in protection has also been observed between different normal tissues. Some tissue, like brain, is not protected while salivary glands and bone marrow may exhibit a three-fold increase in radiation tolerance. Amifostine is dephosphorylized to its active metabolite by a process involving alkaline phosphatase. Due to lower levels of alkaline phosphatase in tumor vessels, amifostine is marketed as a selective protector of normal tissue and not tumors. However, the preclinical investigations concerning the selectivity of amifostine are controversial and the clinical studies are sparse and do not have the power to evaluate the influence of amifostine on the therapeutic index. Conclusion: based on the present knowledge amifostine should only be used in experimental protocols and not in routine practice.     

A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer

BackgroundConcurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT.Patients and methodsPatients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m² on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF).ResultsIn the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6–20.4), 14.3 (95% CI, 11.8–19.3) and 13.8 months (95% CI, 11.0–17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9–11.8), 7.9 (95% CI, 6.5–11.8) and 8.2 months (95% CI, 6.7–12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable.ConclusionOverall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN (ClinicalTrials.gov number, NCT00261703).     

Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer

Background: Amifostine has reduced toxicities associated with radiationtherapy and platinum-based chemotherapy. In a phase II randomized trial, weinvestigated the ability of amifostine to reduce the toxicity of carboplatinplus radiotherapy (RCT) in patients with head and neck cancer.Patients and methods: Thirty-nine patients with stage III or IV squamouscell carcinomas of the head and neck received RCT (following surgery or asprimary treatment). Radiotherapy was given five days per week with dailyfractions of 2 Gy, up to a total dose of 60 Gy in conjunction withcarboplatin 70 mg/m² on days 1 through 5 and days 21 through26. Eligible patients were randomised to receive RCT alone or preceded by arapid infusion of amifostine (500 mg) on the days when carboplatin wasadministered.Results: Patients receiving amifostine + RCT (n = 25) had significantlyreduced mucositis (P = 0.0001) and xerostomia (P = 0.0001) in comparisonwith patients receiving RCT alone (n = 14). Additionally, patients receivingamifostine + RCT had significantly less thrombocytopenia (P = 0.001) andleukopenia (P = 0.001). At 12 months following therapy, 79% ofpatients receiving amifostine + RCT had no evidence of disease compared with64% of those receiving RCT alone.Conclusions: Amifostine reduces the RCT-induced toxicities in patients withhead and neck cancer and has no negative impact on antitumour efficacy.     

Phase 2 trial of oxaliplatin and pemetrexed as an induction regimen in locally advanced head and neck cancer

BACKGROUND:

This phase 2 trial evaluated the tolerability and clinical efficacy of the combination of oxaliplatin and pemetrexed as an induction chemotherapy regimen in locally advanced head and neck squamous cell carcinoma (HNSCC).

METHODS:

Forty‐two patients were enrolled in the study. Patients received pemetrexed 300 mg/m² intravenously (IV) and oxaliplatin 85 mg/m² IV every 14 days for a total of 4 cycles. A subset of patients consented to correlative studies including tumor tissue for human papillomavirus (HPV) detection and expression of DNA repair genes that may be predictive of response or resistance to oxaliplatin or pemetrexed.

RESULTS:

Response data were available for 40 patients. Eighteen had a partial response, and 1 had a complete response, for a response rate of 47.5%. Patients with HPV⁺ disease demonstrated superior response rates, progression‐free survival, and overall survival. The regimen was well tolerated, with predominantly grade 1 or 2 alanine aminotransferase/aspartate aminotransferase elevation. One patient had grade 5 toxicity with neutropenia and sepsis. The authors did not identify genes predictive of response or toxicity, although HPV⁺ tumors demonstrated a unique gene expression signature.

CONCLUSIONS:

Although the response rate of oxaliplatin and pemetrexed proved less than anticipated, the combination remains an active induction regimen in HNSCC. This regimen should be evaluated further in combination with targeted agents, such as cetuximab, especially in the HPV⁺ patient population. Cancer 2012;. © 2011 American Cancer Society.     

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.     

氨磷汀减轻头颈部恶性肿瘤放疗损伤的临床观察

目的探讨氨磷汀联合三维适形放疗对头颈部恶性肿瘤放疗损伤的影响。方法 216例头颈部恶性肿瘤患者随机分为治疗组和对照组。每组108例,行三维适形放疗治疗,总剂量50～72Gy分28～40次5.6～8周完成。治疗组放射治疗前静脉点滴氨磷汀注射剂。结果治疗组有效率为75.0%,对照组有效率为58.3%,两组差异无统计学意义(P>0.05)。治疗组患者的生活质量评分提高率明显高于对照组,两组差异有统计学意义(P<0.05)。治疗组黏膜炎、口干、吞咽困难、血液系统毒性、神经系统毒性发生率均明显低于对照组,两组差异有统计学意义(P<0.05)。结论氨磷汀可减轻头颈部恶性肿瘤放疗损伤,提高患者生存质量,并不影响临床疗效。     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.

PURPOSE: Therapy of recurrent/metastatic squamous cell carcinoma of the head and neck results in median progression-free survival (PFS) of 2 months. These cancers are rich in epidermal growth factor receptor (EGFR). We wished to determine whether the addition of cetuximab, which inhibits activation of EGFR, would improve PFS. PATIENTS AND METHODS: Patients with recurrent/metastatic squamous cell carcinoma of the head and neck were randomly assigned to receive cisplatin every 4 weeks, with weekly cetuximab (arm A) or placebo (arm B). Tumor tissue was assayed for EGFR expression by immunohistochemistry. The primary end point was PFS. Secondary end points of interest were response rate, toxicity, overall survival, and correlation of EGFR with clinical end points. RESULTS: There were 117 analyzable patients enrolled. Median PFS was 2.7 months for arm B and 4.2 months for arm A. The hazard ratio for progression of arm A to arm B was 0.78 (95% CI, 0.54 to 1.12). Median overall survival was 8.0 months for arm B and 9.2 months for arm A (P = .21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26% [corrected] for arm A and 10% [corrected] for arm B (P = .03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells. CONCLUSION: Addition of cetuximab to cisplatin significantly improves response rate. There was a survival advantage for the development of rash. Progression-free and overall survival were not significantly improved by the addition of cetuximab in this study.     

Oral candidiasis in head and neck cancer patients receiving radiotherapy with amifostine cytoprotection

This controlled study assessed the incidence of oral candidiasis, a xerostomia-related complication, in head and neck cancer patients receiving radiotherapy, with amifostine cytoprotection. Thirty-eight patients received 500 mg amifostine i.v., prior to each radiotherapy fraction, while 16 patients received radiotherapy alone. Oral candidiasis was diagnosed according to the criteria described before. Subjective xerostomia scales were completed by all patients. Mucositis was evaluated using the RTOG criteria. Oral candidiasis was diagnosed in 11/38 amifostine patients and in 9/16 controls (P = 0.07). Severe xerostomia was reported by 4/38 amifostine patients and by 7/16 controls. Oral candidiasis was reduced with amifostine cytoprotection. Oral candidiasis is suggested as an objective, early, though indirect, endpoint for amifostine's radioprotective effect on salivary glands.     

A randomized trial of amifostine as a cytoprotective agent in patients receiving chemotherapy for small cell lung cancer

A randomized trial was conducted to determine whether administration of Amifostine with chemotherapy for small cell lung cancer could decrease the toxicity. 84 patients with small cell lung cancer of favourable prognosis (limited disease, performance status 0-1; limited disease with performance status 2 but normal sodium and alkaline phosphatase, or extensive disease with performance status 0-1, normal sodium and alkaline phosphatase) received treatment with Ifosfamide 3 g/m(2)intravenously, Carboplatin (Glomerular filtration rate + 25) x6 mg intravenously, Etoposide 50 mg orally, twice daily, for 7 days, every 3 weeks. Patients were randomized to receive amifostine 740 mg/m(2)immediately prior to the intravenous drugs (n = 42) or to receive chemotherapy alone (n = 42). The two groups were similar with respect to baseline prognostic factors. There was no significant difference in the occurrence of grade III or IV neutropenia or thrombocytopenia between the two groups, nor in the response rate or overall survival, for which the median was 11 months in the chemotherapy only group and 14 months in the group treated with amifostine. This study has not shown a protective effect from the use of amifostine with this regimen and there does not appear to be any effect upon the efficacy of treatment.     

Evaluation of a neutron boost in head and neck cancer. Results of the randomized RTOG trial 78-08

Patients with untreated squamous cell cancer of the head and neck region were randomized to receive either a boost of 25-30 Gy using photon-beam irradiation (photons) or an equivalent boost using neutron-beam irradiation (neutrons). All patients received an initial 45-50 Gy of wide-field photon irradiation. A total of 57 patients was evaluable on the neutron arm and 58 were evaluable on the photon arm. The proportion of patients with complete responses was 60 and 64% on the neutron and photon arms, respectively. The locally disease-free proportion at 2 years was estimated to be 20 and 31%, and the 2-year survival was estimated to be 32 and 41%, respectively. These differences are not statistically significant. There was a higher rate of severe complications on the neutron arm, 16 versus 7%. Thus, there was no evidence that a neutron boost produces better initial tumor clearance, local tumor control, or survival than a photon boost, and it may produce more complications.