Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy.

BACKGROUND: The optimal management of oropharyngeal squamous cell carcinoma (OPSCC) is controversial. Modern radiotherapy typically employs intensity-modulated radiation therapy (IMRT), and herein, we report the Dana-Farber Cancer Institute (DFCI) experience with IMRT-based treatment of OPSCC. DESIGN: Retrospective study of all patients treated at DFCI for OPSCC with definitive or adjuvant IMRT between 8/04 and 8/09. The primary end point was overall survival (OS); secondary end points were locoregional control (LRC) and freedom from distant metastases (FFDM). Propensity score matching was used to create concurrent chemoradiotherapy (CCRT) and sequential therapy (ST) cohorts equally balanced for patient and disease characteristics. RESULTS: One hundred and sixty-three patients were included with 75% presenting with stage IV disease. Fifty-six patients (34%) were treated with ST. The three-year actuarial OS, LRC, and FFDM rates for the entire cohort/ST subset were 86%/89%, 86%/87%, and 88%/93%, respectively. There were no differences in OS, LRC, or FFDM between CCRT and ST in the propensity-matched cohort. CONCLUSIONS: IMRT was associated with excellent OS, LRC, and FFDM. Although the results following ST were superb, there was no obvious benefit to ST after adjustment for selection bias. We recommend that ST be reserved for medically fit patients with a high risk of distant metastases.

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation.

BACKGROUND: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. PATIENTS AND METHODS: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. RESULTS: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31-not reached] versus 24 months (95% CI: 13-42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41-0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12-59) versus 11 months (95% CI: 8-14) for PF (HR: 0.66; 95% CI: 0.45-0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37-0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). CONCLUSIONS: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.

A phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%). CONCLUSIONS: UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

A phase II trial of palliative docetaxel plus 5-fluorouracil for squamous-cell cancer of the head and neck.

PURPOSE: A phase II study to determine the response rate and toxicity of docetaxel and 5-fluorouracil (5-FU) every four weeks ('TF'), in patients with incurable SCCHN. PATIENTS AND METHODS: Patients with metastatic or recurrent SCCHN with an ECOG PS < 3 were enrolled in an institutional review board approved trial. Prior induction or adjuvant chemotherapy was permitted provided six months had elapsed. The regimen was docetaxel 70 mg/m2 i.v., day 1 and 5-FU 800 mg/m2/d x 5 days, days 1-5, as a continuous intravenous infusion, repeated every 28 days. Planned intra-patient dose modifications were based on hematological, cutaneous, and gastrointestinal toxicities. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: Seventeen patients were enrolled. Fourty-six cycles of TF were administered. Reasons for discontinuance of TF included: progressive disease, 12 patients; toxicity, 3 patients; concomitant illness, 1 patient; death, 1 patient. The most common toxicities were neutropenia, mucositis, anemia, fatigue, alopecia, pain, diarrhea and nausea. Evaluation of responses to TF showed that there were four patients of seventeen (24%, 95% exact CI: 6.8-49.9) who achieved a PR or CR. Accrual was terminated after interim analysis of the response rate of the first 17 patients failed to exceed 4 of 17. CONCLUSIONS: The response rate to TF in patients with SCCHN was lower than expected. Trials of other regimens should take precedence over further exploration of the TF regimen.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Selective chemoembolization in the management of hepatic metastases in refractory colorectal carcinoma: a phase II trial.

PURPOSE: Metastatic involvement of the liver frequently determines the evolution of the clinical picture in colorectal cancer patients. We examined the efficacy and toxicity of chemoembolization in this setting, identifying prognostic factors to define patients most likely to benefit from the procedure. METHODS: Forty patients underwent chemoembolization of metastatic liver lesions from colorectal carcinoma. Selective angiography of the hepatic artery was performed to identify the feeding vessels of the metastatic lesions. The injected chemoemulsion consisted of 1,000 mg of 5-fluorouracil, 10 mg of mitomycin C, and 10 ml of ethiodized oil in a total volume of 30 ml. Gelfoam embolization then followed, until stagnation of blood flow was achieved. Patients were evaluated for response, overall survival, and toxicities. RESULTS: Overall median survival from date of first chemoembolization was ten months. Factors that predicted a longer median survival included favorable performance status (24 months), serum alkaline phosphatase and lactate dehydrogenase levels less than three times normal (24 and 12 months, respectively), and metastatic disease confined to the liver (14 months). Most patients tolerated the procedure well. The most common side effects were transient fevers, abdominal pain, and fatigue. Three patients died within one month from the procedure. CONCLUSION: This study suggests that chemoembolization of hepatic metastases in colorectal cancer should be further evaluated; it may be beneficial in patients who have failed systemic chemotherapy, have a good performance status, and have metastatic disease confined to the liver.

Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer.

STUDY OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of high-dose intravenous zidovudine (ZDV). DESIGN: Phase 1, dose-escalating, unblinded study in patients with cancer. SETTING: A university-affiliated cancer treatment center. PATIENTS: Fourteen patients (6 women) with solid tumors that were unresponsive to standard therapy received 31 courses of therapy. INTERVENTIONS: Intravenous ZDV was administered in doses of 2, 3, 4, 5.5, 7, 8.5, 10, 12, 15, or 20 g/m2/day as a continuous infusion over 48 hours. Patients also received fluorouracil plus leucovorin for 24 hours before the start of and during the ZDV infusion. If no dose-limiting toxicities were encountered, subsequent doses were escalated. Blood samples were collected at 24 and 48 hours after the start of the infusion, and hourly for 4 hours after stopping the infusion. Urine was collected in five patients during the infusion and for 24 hours after stopping it. Blood for measuring peripheral white blood cells was collected before and at the end of the infusion in seven patients to measure DNA chain breaks due to incorporation of ZDV. MEASUREMENTS AND MAIN RESULTS: Zidovudine was measured in plasma by high-performance liquid chromatography and in urine fluorescence polarization immunoassay. Its incorporation into DNA was measured by determining DNA strand breakage in peripheral white blood cells using fluorescence analysis. Pharmacokinetic models were fit to plasma ZDV concentrations using extended least squares regression. Short-term high-dose ZDV was generally well tolerated, with adverse effects related to large amounts of free water administered during the infusion. The mean (SD) ZDV pharmacokinetic values were total clearance 1.44 (1.09) L/hr/kg, volume of distribution 2.72 (2.97) L/kg, and half-life 1.2 (0.6) hours. There was considerable interpatient variability in total drug clearance. Although ZDV exposure increased proportionately with increasing dose, two of three patients receiving the highest dose (20 g/m2/day) had markedly low total drug clearances. The relation between the percentage of abnormal DNA in peripheral white blood cells and zidovudine area under the plasma ZDV versus time curve was described by the Emax pharmacodynamic model. CONCLUSIONS: The pharmacokinetics of high-dose ZDV administered by continuous infusion to patients with cancer are similar to those reported with lower doses in patients with infection due to the human immunodeficiency virus. Further study of potential nonlinear pharmacokinetic behavior at doses above 20 g/m2/day is necessary. The high between-patient variability in ZDV clearance results in variable levels of exposure in vivo, and indicates the need for concentration- or effect-controlled study designs in the further evaluation of the agent's antineoplastic effects.

High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.

BACKGROUND: The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity. METHODS: A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed. RESULTS: Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. CONCLUSIONS: Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.

An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck.

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.