Head and neck cancer presents most commonly as a locoregionally advanced malignant process [1]. Distant metastases are clinically rare, but may be present more frequently at the microscopic level. Patterns of failure following standard surgery and/or radiotherapy indicate the inability of that therapy to successfully eradicate locoregional disease in the majority of patients. Investigational therapy, therefore, must focus on increasing the efficacy of locoregional therapy as its primary goal. Eradication of systemic microscopic disease remains a secondary goal that may gain greater importance in patients whose locoregional disease can be controlled [2]. Finally, the prevention of second malignancies represents an important long-term goal that can help to maintain the cancer-free status in patients cured of their primary disease [3].
Thirty patients with chemotherapy-induced anemia were treated with recombinant human erythropoietin for 4 weeks. In this dose-escalation study, cohorts of five to eight patients were treated per dose level. The doses of erythropoietin were 25, 50, 100, 200, or 300 IU/kg/d given intravenously for 5 days each week. Of 30 patients, 15 (50%) had a greater than 10% increase of their hemoglobin (Hb) values and were considered responders. At the two highest dose levels, 11 of 13 patients (85%) responded. In the 15 responding patients, the mean Hb level increased by 1.7 g/dL from baseline compared with an average decrease of 1.5 g/dL in the previous cycles of chemotherapy without erythropoietin administration. Recombinant human erythropoietin is effective in ameliorating chemotherapy-induced anemia when administered in adequate doses.
Background : The majority of patients with head and neck cancer die of locoregional rescurrence of disease following surgery and/or radiotherapy. Purpose : Our purpose was to administer induction chemotherapy, perform surgery, and administer concomitant chemoradiotherapy in rapid sequence and to evaluate their impact on locoregional and distant tumor control. Methods : Sixty-four patients with previously untreated, Locoregionally advanced head and neck cancer received two cycles of cisplatin, Bleomycin, and methotrexate (PBM) (33 patients) or cisplatin, fluorouracil (5-FU), and leucovorin (PEL) (31patients). PFL was given to patients who were unable to receive bleomycin. Local therapy consisted of surgery and/or concomitant chemoradiotherapy with 5-FU, hydroxyurea, leucovorin, and radiotherapy (FHX-L), all administered every other week. Results : Complete and overall induction response rates were 21% and 79%, respectively, for PBM and 29% and 81%, respectively, for PFL. At completion of local therapy, 81% of the patients were disease-free. With a median follow-up of 35 months, the mddian survival and time to progression are 22 and 17 months, respectively, for PBM and have not been reached for PFL. Locoregional recurrence of disease is 30% for PBM and 26% for PFL. Distant disease progression is 24% for PBM and only 3% for PFL. Conclusions : The sequencing of induction chemotheraphy and concomitant chemoradiotherapy is feasible and results in a high local control rate and in an encouraging survival rate with PFL. The high distant failure (i.e, outside the head and neck area) rate of PBM suggests insufficient systemic activity for that regimen. Implications : Concomitant FHX-L chemoradiotherapy may improve regional control arates of advanced head and neck cancer. Effective systemic therapy may be needed to control systemic micrometastases. PFL, but not PBM, appears to be suitable to accomplish that goal. [J Natl Cancer Inst 84:877–882, 1992]
The combination of Cisplatin and Infusional fluorouracil has been widely used for the treatment of locally advanced squamous head and neck cancer, at diagnosis and recurrence [1–4]. When applied in the Neo-Adjuvant setting, it has resulted in high response rates and probably a reduced incidence of distant metastases. Overall survival, however, has not been proven to be increased and therefore use of this drug combination remains investigational in primary management [5, 6).
PURPOSE To increase the activity of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) through further biochemical modulation and study the pharmacologic interaction of 5-FU and interferon alfa-2b (IFN). PATIENTS AND METHODS Escalating doses of IFN (0.5 to 4.0 x 10(6) U/m2/d x 6) were added to cisplatin 100 mg/m2, continuous infusion 5-FU 800 or 640 mg/m2/d x 5, and leucovorin 100 mg orally every 4 hours. Forty-eight previously untreated patients with locoregionally advanced head and neck cancer received up to three cycles of PFL-IFN. RESULTS Twenty-one patients were treated during a phase I cohort study. Dose-limiting mucositis was seen with 800 mg/m2/d of 5-FU and 0.5 x 10(6) U/m2/d of IFN. After decreasing the 5-FU dose to 640 mg/m2/d, the maximally tolerated dose (MTD) of IFN was 2.0 x 10(6) U/m2/d. Mucositis and myelosuppression were dose-limiting. Of 34 patients treated at this MTD, 56% (95% confidence interval, 39% to 73%) had a complete remission. There was no correlation between 5-FU clearance and IFN dose. Pharmacodynamic analyses at the MTD showed that older age, female sex, and higher 5-FU area under the time versus concentration curve (AUC) were associated with lower nadir counts and/or increased mucositis. Seven patients with diabetes mellitus had significantly increased myelosuppression, serum creatinine, hypocalcemia, higher 5-FU concentrations, and lower 5-FU clearance compared with nondiabetics. CONCLUSION The recommended doses for PFL-IFN are 640 mg/m2/d for 5-FU and 2.0 x 10(6) U/m2/d for IFN. Sex, age, 5-FU AUC, and diabetes mellitus may have an impact on the pharmacodynamics of this regimen.
