William R. Panje

Prosthetic Vocal Rehabilitation following Laryngectomy The Voice Button

The Voice Button is a simple biflanged silicone device placed in the tracheoesophageal wall which has been found to enable speech without aspiration in approximately 80% of unselected laryngectomy patients. A simple surgical outpatient procedure provides the necessary tracheoesophageal fistula for insertion of the Voice Button. Indications, results, advantages, disadvantages and complications are discussed.

Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.

Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease.

PURPOSE To determine survival rates and the pattern of failure in head and neck cancer patients treated with induction chemotherapy, limited surgery and concomitant chemoradiotherapy. PATIENTS AND METHODS Three cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin, and interferon alfa-2b (PFL-IFN) were followed by optional surgery, and seven or eight cycles of 5-FU, hydroxyurea, and concurrent radiation for 5 days (FHX) for a total radiation dose of 65 to 75 Gy. Surgical resection was performed with the intent to spare organ function. RESULTS Seventy-one patients were treated at three institutions. Sixty-five patients (91%) had stage IV disease with N2/3 in 46. Thirty-three patients (51%; 95% confidence interval, 39% to 63%) achieved a clinical complete response (CR) to PFL-IFN. Local therapy consisted of surgery in 37 and/or FHX in 55 patients. With a median follow-up duration of 37 months, there have been 20 recurrences (15 local, four distant, and one both local and distant), and 29 deaths, 15 in patients with disease progression and 14 not directly related to the primary tumor. Four patients have developed second malignancies. At 3 years, 69% (+/- 6%) are progression-free and the overall survival rate is 60% (+/- 6%). Toxicity of PFL-IFN included severe or life-threatening mucositis (54%) and myelosuppression (60%). Five patients died of toxicity. During FHX, 70% of patients had grade 3 or 4 mucositis. CONCLUSION PFL-IFN is highly active, producing clinical CRs in 51% of patients, and, when followed by FHX, resulting in high local and distant control and overall survival rates. Second malignancies and intercurrent medical disease emerge as major risks to long-term survival. In view of the high toxicity and long treatment duration, further modifications of this approach are required.

The influence of embryology of the mid‐face on the spread of epithelial malignancies

A review of 150 cases of mid‐face skin cancers treated by the fresh tissue technique of microscopic controlled excision has revealed local epithelial cancer spread to be markedly influenced by embryological fusion planes. Knowledge of facial embryology which is reviewed in this article should allow the surgeon to better predict and treat mid‐facial skin cancer.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis.

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.

Electroporation Therapy of Head and Neck Cancer

The purpose of this paper is to introduce the concept of electroporation therapy and present our results from using this new technique combined with intralesional bleomycin in head and neck cancer patients. Electroporation therapy is a technique wherein high-voltage electric impulses delivered into a neoplasm transiently increase cell membrane permeability to large molecules, including cytotoxic agents. In this phase I/II study, extremely low-dose bleomycin sulfate was electroporated into head and neck malignant neoplasms in 10 patients. Tumor responses included 2 nonresponders, 3 partial responders, and 5 complete responders, with a mean follow-up of 40 weeks. We conclude that this technique offers promising possibilities in the local treatment of head and neck cancer.

Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer.

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.

Prognostic factors in advanced head and neck cancer patients undergoing multimodality therapy.

A retrospective analysis was performed to investigate potential prognostic factors for complete remission to neoadjuvant chemotherapy and overall survival in patients with previously untreated stage III and stage IV head and neck cancer. Eighty consecutive patients were treated in one of two studies investigating three or four courses of neoadjuvant chemotherapy. Before local therapy with surgery and/or radiotheapy, 29% attained a complete remission. No strong significant and independent predictor of complete remission was identified. Only nodal stage (N) was found moderately associated with complete remission (p = 0.06). Node-negative patients had higher remission rates. Less important predictors were tumor stage (T) and site of disease; nasopharyngeal patients had superior remission rates (56%). With a median followup of 45 months and estimated 3-year survival rate of 38% (median 23.7 months), individual factors predictive of survival included pretherapy weight loss, performance status, alcohol use, pretherapy serum albumin level, site of disease, and N stage. In multivariate testing weight loss was identified as the strongest independent predictor of survival (p < 0.0001) and surpassed other health status measures, such as performance status and serum albumin level. In addition, N stage (p = 0.019) and alcohol use (p = 0.017) were found to be predictive. A cross-classification by N stage and weight loss revealed risk groups with distinctly different prognoses, which may be useful for design and analysis in future trials.

Cisplatin, fluorouracil, and leucovorin augmented by interferon alfa-2b in head and neck cancer: a clinical and pharmacologic analysis.

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.

Radiobiological characterization of head and neck and sarcoma cells derived from patients prior to radiotherapy

The radiobiological parameters of 33 tumor cell lines were studied in biopsy samples obtained from patients prior to radiotherapy. Epithelial tumor cells derived from head and neck cancer patients were more radioresistant than tumor cell lines derived from patients with sarcoma regardless of method of analysis. The presence of radioresistant tumor cell lines was associated with local failure in some patients. However, the presence of radiosensitive tumor cells did not necessarily predict local control. Our data suggest radiocurability is complex and inherent radiobiological parameters of tumor cells may be only one factor in radiotherapy outcome.