Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors.

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.

BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

Doxorubicin, paclitaxel, and cisplatin based chemotherapy for the treatment of angiosarcoma: Two case reports.

INTRODUCTION: Angiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations. CASE DESCRIPTIONS: Here we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second. DISCUSSION: These cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases. CONCLUSION: The role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.

Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the Radiation Therapy Oncology Group (RTOG 99-03).

PURPOSE: To determine whether the addition of recombinant human erythropoietin (Epo) could improve the outcomes of anemic patients receiving definitive radiotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Eligible patients had SCCHN, with a plan for continuous-course definitive radiotherapy (66-72 Gy) with or without chemotherapy. Patients with Stage III or IV SCCHN were required to undergo concurrent chemoradiotherapy and/or accelerated fractionation radiotherapy. Preradiotherapy hemoglobin was required to be between 9.0 g/dL and 13.5 g/dL (12.5 g/dL for women). Patients randomized to Epo received 40,000 U once weekly, starting 7-10 days before start of radiotherapy. RESULTS: A total of 148 patients were enrolled; 141 were evaluable. Median pretreatment hemoglobin was 12.1 g/dL. Hemoglobin levels at 4 weeks rose by an average of 1.66 g/dL in the Epo arm, compared with an average 0.24 g/dL decrease in the control arm (p = 0.0001). Median follow-up was 2.5 years (3.1 years for surviving patients). There was no statistically significant difference in the primary endpoint of local-regional failure (LRF) rate between the treatment arms. The 3-year LRF rate was 36% for control and 44% for Epo (p = 0.56). There were also no significant differences in local-regional progression-free survival (LRPFS), patterns of failure, overall survival, or toxicity. The 3-year LRPFS rate was 52% for control and 47% for Epo. The overall survival rate was 57% and 56%, respectively. CONCLUSIONS: The addition of Epo to definitive radiotherapy for SCCHN did not improve outcomes. The study was not specifically designed to detect a potential negative association between Epo and tumor progression/survival.

Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: a University of Pennsylvania Phase II Trial.

PURPOSE: To determine the efficacy, feasibility, and toxicity of a new regimen for locally advanced oropharyngeal carcinoma. PATIENTS AND METHODS: Patients had technically resectable stage III/IV squamous cell carcinoma of the oropharynx, exclusive of T1-2N1. Induction chemotherapy consisted of carboplatin (area under the curve formula equal to 6) and paclitaxel 200 mg/m(2) for two cycles, followed by re-evaluation. Patients with major response continued to definitive radiotherapy (70 Gy over 7 weeks) plus concurrent once-weekly paclitaxel (30 mg/m(2)/wk). Patients with advanced neck disease also underwent post-radiation therapy neck dissection and two more chemotherapy cycles. RESULTS: Fifty-three patients were enrolled. Median follow-up was 31 months (minimum follow-up for survivors was 18 months). The major response rate to induction chemotherapy was 89%; 90% of patients had a complete response after concurrent chemoradiation. Actuarial survival at 3 years was 70%, and 3-year event-free survival was 59%. The 3-year actuarial locoregional control was 82% and the 3-year actuarial rate of distant metastases was 19%. Organ preservation was achieved in 77% of all patients. One patient (2%) died during therapy. Late grade 3 toxicity occurred in 24% of patients, consisting mainly of chronic dysphagia/aspiration and/or radiation soft tissue ulceration. The treatment-related mortality rate was 4% (two patients died from respiratory failure). CONCLUSION: Response to induction chemotherapy as studied in this trial was not useful as a predictive marker for ultimate outcome or organ conservation. Overall, however, this regimen offers good disease control and survival for patients with locally advanced oropharyngeal carcinoma, comparable with other concurrent chemoradiation programs. Further study of similar protocols is indicated.

Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck.

PURPOSE: This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa). METHODS AND MATERIALS: The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm. RESULTS: A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms. CONCLUSIONS: This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.

Pilot study of postoperative reirradiation, chemotherapy, and amifostine after surgical salvage for recurrent head-and-neck cancer.

PURPOSE: Salvage surgery alone after radiotherapy (RT) failure for locally advanced head-and-neck cancer is frequently unsuccessful because of subsequent recurrence. We designed a prospective protocol to determine the feasibility, toxicity, and preliminary efficacy of a regimen of postoperative reirradiation, chemotherapy and the radioprotector amifostine after salvage head-and-neck surgery. METHODS AND MATERIALS: Eligible patients had biopsy-proven locally advanced, but resectable, recurrence without distant metastases >6 months after previous RT. After adequate healing from surgery, patients underwent RT to 54-66 Gy within 5-5.5 weeks to the resection bed (lifetime RT dose, 100-130 Gy). The fractionation was 1.5 Gy b.i.d. within 2 weeks, followed by a 1-week break, followed by 1.5 Gy b.i.d. to a total of 54-66 Gy. Chemotherapy consisted of cisplatin 25 mg/m(2)/d three times and 5-fluorouracil 500 mg/m(2)/d continuous infusion for 4 days, for two cycles (Weeks 1 and 5). Amifostine (500 mg i.v.) was administered daily, 30 min before either the morning or the afternoon RT. RESULTS: Between 1998 and 2001, 16 patients were enrolled and studied. Two patients had gross residual disease after surgery; all other patients underwent complete surgical resection but had high-risk features (rT3-T4 and/or N+ disease). Three patients (19%) had serious acute toxicity events (nonneutropenic infections) that were reversible. The median follow-up was 35 months. The actuarial locoregional control rate was 81% at 3 years. Three patients developed isolated distant metastases and one developed a fatal second primary cancer (hepatoma). The 2- and 3-year actuarial event-free survival rate was 81% and 50%, respectively. The 2- and 3-year actuarial overall survival rate was 81% and 63%, respectively. Both patients who had gross residual disease after surgery had early recurrence; if these patients were excluded from analysis, the 3-year actuarial survival and event-free survival rate was 67% and 59%, respectively. Of the 16 patients, 6 (38%) developed Grade 3+ late toxicity, including one fatal stroke and two life-threatening major vessel necrosis and/or bleeding events. CONCLUSION: This regimen of postoperative reirradiation/chemotherapy plus amifostine is feasible and was well tolerated acutely, with encouraging oncologic efficacy. However, the incidence and severity of late effects was significant and suggests that modifications are necessary for future studies in this patient population.

A phase 1 study of fixed dose rate gemcitabine and irinotecan in patients with advanced pancreatic and biliary cancer.

BACKGROUND: The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination. METHODS: There were 32 patients with metastatic pancreatic and advanced unresectable/metastatic biliary adenocarcinoma who were entered into this open-label, phase 1 dose escalation trial. Gemcitabine was administered at an FDR of 10 mg/m(2)/minute intravenously (iv). Irinotecan was administered iv over 60 minutes after gemcitabine. Both gemcitabine and irinotecan were given on Days 1 and 8 of a 21-day cycle. RESULTS: The MTD of the combination was gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The DLTs were neutropenia and neutropenic fever. Other DLTs included diarrhea, dehydration, and fatigue. Two patients developed deep venous thrombosis during the treatment. The efficacy of the combination was encouraging, even at the lower dose levels. Of 30 assessable patients, there was 1 complete response, 6 partial responses, and 16 patients with stable disease, with a response rate of 23%, a disease control rate of 76%, a median progression-free survival of 4.7 months, and a median overall survival of 7.0 months. The average number of treatment cycles received was 11. CONCLUSIONS: The recommended doses of the combination for future study are gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The efficacy of the combination is encouraging. Further assessment of the combination with or without biologic agents is suggested.

Preliminary investigation of symptom distress in the head and neck patient population: validation of a measurement instrument.

OBJECTIVE: Observations indicate that the acute toxicity of chemoradiation for squamous cell carcinoma (SCC) of the head and neck is not the same as that which occurs with radiation therapy alone. Thus, the specific aim of this pilot study was to estimate the reliability and validity of a modified version of a symptom distress scale used to assess the qualitative difference in symptom distress between the 2 populations. METHODS: Over a period of 4 months a consecutive sample of 56 patients with head and neck cancer were recruited from the Department of Radiation Oncology to take part in our pilot study. The Cancer Disease and Treatment Concern Scale (CDTCS) was modified by adding 15 additional items and called the Head and Neck Distress Scale (HNDS). All dimensions were interrogated with at least four questions and a domain score was generated. In addition, the Head and Neck Radiotherapy Questionnaire (HNRQ), an established 22-item multidimensional questionnaire was also administered by interview after completion of the HNDS. RESULTS: Fifty-six patients, 32 chemoradiation patients (mean age 64 years) completed the HNDS, taking 8 to 10 minutes to complete. The HNDS scores correlated well with the HNRQ scores (r = 0.835), demonstrating an acceptable level of content and concurrent validity. There was a significant difference in the overall HNDS scores between the chemoradiation group and the radiation therapy group (ANOVA, P = 0.001). CONCLUSION: The HNDS is a valid measure of acute symptom distress and appears able to discriminate between the chemoradiation and radiation alone patients. There is considerable variation in symptoms that cause these patients distress.

Merkel cell carcinoma.

Merkel cell carcinoma is a rare cutaneous neoplasm most commonly affecting the head and neck of elderly white patients. Even with treatment, Merkel cell carcinoma has a strong propensity toward local recurrence, lymphatic spread, and distant metastasis. Because of its rarity and the subsequent lack of well-controlled clinical trials, no single standard of care exists for the treatment of this aggressive tumor. In our institution, primary lesions are excised with wide margins or by Mohs' micrographic surgery. After local removal, the excision site is treated locally with external radiation therapy. Sentinel lymph node mapping and biopsy are performed. Patients with tumor within a sentinel lymph node undergo lymph node dissection and radiation to the lymphatic basin. Adjuvant chemotherapy is offered to high-risk patients with local disease and to patients with metastases. Patients with distant metastases are treated with a combination of salvage chemotherapy and radiation therapy.

Final report of a pilot trial of accelerated radiotherapy plus concurrent 96-hour infusional paclitaxel for locally advanced head and neck cancer.

Recent data show that accelerated radiotherapy (XRT) improves local-regional control (LRC) over standard-fractionation XRT. Concurrent chemoradiotherapy improves LRC and survival over XRT alone. This study assesses the feasibility, toxicity, and preliminary efficacy of concurrent 96-hour paclitaxel infusion with accelerated XRT. Eligible patients had stage IV squamous cell carcinoma of the head and neck, exclusive of nasopharynx cancer. Tumor had to be considered technically unresectable after evaluation by our multidisciplinary head/neck tumor board. XRT was given continuous course using an accelerated regimen with twice a day fractionation for the cone down (70-72 Gy/6 weeks). Chemotherapy consisted of 2 cycles of paclitaxel via 96-hour infusion during weeks 1 and 5 of XRT. The first 10 patients received doses of 40-120 mg/m2/cycle, and the subsequent 13 patients received 100 mg/m2/cycle. Twenty-three patients were studied. Median follow-up was 20.4 months (44.4 months for the 10 long-term survivors). Most (19/23) patients had reversible grade 3 acute mucositis. Median treatment time was 44 days, and all but 1 patient received both cycles of paclitaxel at their planned dose. The 3- and 4-year actuarial survival was 37%. Three- and 4-year LRC was 50%. Four patients (18%) developed distant metastases. Two patients (9%) developed severe esophageal strictures requiring permanent gastrostomy/tracheostomy, and 2 patients developed other late grade 3+ toxicities. Accelerated XRT plus concurrent 96-hour infusional paclitaxel as given in this study has intense but acceptable toxicity and is feasible. LRC and survival compare favorably with other aggressive regimens for this poor-prognosis population. Further study of accelerated XRT with concurrent chemotherapy is indicated.

A phase I study of SPI-077 (Stealth liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer.

BACKGROUND: Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design. RESULTS: Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m2 in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade I (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response. CONCLUSIONS: Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.