John R. Clark

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

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.

Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies.

The addition of local hyperthermia to radiation therapy has significantly improved the ability of oncologists to control superficial malignancies. Large tumours, tumours which cannot be heated adequately, and those situated in areas where surrounding normal tissues have decreased radiation tolerance, however, are difficult to eradicate even with this combination treatment. We believe that properly selected and scheduled anticancer drugs will add substantially to the efficacy of local hyperthermia and radiation. A review of the literature concerning the cytotoxic interactions of various anticancer agents with hyperthermia, with radiation and with relevant physiological parameters is presented. From this review, anticancer drugs which are good candidates for trimodality therapy are identified and a general approach to trimodality scheduling is suggested.

Human papillomavirus 16 and head and neck squamous cell carcinoma

Evidence suggests that human papillomavirus (HPV)16 seropositivity reflects past HPV16 exposure and is associated with risk for head and neck squamous cell carcinoma (HNSCC). Our objectives were to test the hypothesis that HPV16 seropositivity is associated with risk for HNSCC, to correlate HPV16 seropositivity with HPV16 tumor DNA, and to correlate HPV16 seropositivity and HPV16 DNA with sexual history and patient survival. In a case–control study of approximately 1,000 individuals, we assessed serology to the HPV16 L1 protein and in cases only, assayed tumors for HPV16 DNA. HPV16 seropositivity was associated with 1.5‐ and 6‐fold risks for tumors of the oral cavity and pharynx, respectively. There was a dose response trend for HPV16 titer and increasing risk of HNSCC (p < 0.0001) and HPV16 tumor DNA (p < 0.0001). In cases, HPV16 DNA and seropositivity were significantly associated with sexual activity; odds ratios (ORs) of 12.8 and 3.7 were observed for more than 10 oral sexual partners and ORs of 4.5 and 3.2 were associated with a high number of lifetime sexual partners, respectively. Finally, HPV16 seropositivity and HPV16 tumor DNA were associated with hazard ratios of 0.4 and 0.5, respectively, indicating better survival for HPV positive individuals. HPV16 seropositivity was associated with risk for HNSCC, with greatest risk for pharyngeal cancer. We observed dose response relationships between serology titer and both risk for HNSCC and HPV16 tumor DNA. In cases, HPV16 tumor DNA and positive serology were associated with sexual history and improved disease free survival.

Continuous Infusion High-Dose Leucovorin with 5-Fluorouracil and Cisplatin for Untreated Stage IV Carcinoma of the Head and Neck

STUDY OBJECTIVE To study the activity of continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin (PFL) as induction chemotherapy in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. DESIGN Nonrandomized, prospective trial. SETTING A comprehensive cancer center. PATIENTS Thirty-five patients (4 patients [11%], stage III; 31 patients [89%], stage IV [MO]), all evaluable for response and toxicity. INTERVENTIONS Two to three cycles of PFL before definitive, local-regional therapy (surgery and radiation therapy or radiation therapy alone). Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2 body surface area daily, days 1 through 5); 5-fluorouracil (800 mg/m2 body surface area daily, days 2 through 6); and leucovorin (500 mg/m2 body surface area daily, days 1 through 6) administered once every 28 days. Pathologic response was evaluated by surgical resection or biopsy. Serum-reduced folates were measured before and 18 hours after the initiation of chemotherapy. RESULTS A clinical response to PFL was achieved in 28 of 35 (80%) patients: 23 (66%) patients had a complete response (90% CI, 50% to 79%) and 5 (14%) patients, a partial response. A complete response was confirmed pathologically in 14 of 19 (74%) patients. The most common toxicity was mucositis (grade 2 to 3; 94% of patients). Dose reduction for toxicity was necessary in 11 (31%) patients. There were no treatment-related deaths. Serum levels of leucovorin and (6S)5-methyltetrahydrofolate were measured in 7 patients. After 18 hours, the mean leucovorin level (+/- SD) was 34.3 +/- 1.5 mumol/L, of which only 8.0 +/- 0.5% was the active 6S isomer. The mean serum (6S)5-methyltetrahydrofolate was 9.2 +/- 0.6 mumol/L. CONCLUSIONS Continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin is a new and highly active chemotherapy regimen that can achieve clinical and pathologically confirmed complete responses in a substantial proportion of patients with advanced, local-regional squamous cell carcinoma of the head and neck. Further studies are needed to confirm the activity of PFL and to determine its potential impact on local tumor control and disease-free and overall survival.

Response of Some Head and Neck Cancers to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors May Be Linked to Mutation of ERBB2 rather than EGFR

Purpose: Small-molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have shown modest yet reproducible response rates in patients with squamous cell carcinoma of the head and neck (SCCHN). Somatic mutations in EGFR have recently been shown to be predictive of a clinical response in patients with non–small cell lung cancer (NSCLC) treated with these inhibitors. The objective of this study was to determine if such mutations, or recently reported mutations in ERBB2, also underlie EGFR-TKI responsiveness in SCCHN patients. Experimental Design: We sequenced the kinase domain of EGFR and exon 20 of ERBB2 in tumor specimens from eight responsive patients. In addition, mutational analysis was done on tumor specimens from nine gefitinib nonresponders and 65 unselected cases of SCCHN. Results: None of eight TKI-responsive specimens had mutations within the kinase domain of EGFR. EGFR amplification was also not associated with drug responsiveness. However, a single responsive case had a somatic missense mutation within exon 20 of ERBB2. Conclusion: Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.

HPV-16 infection predicts treatment outcome in oropharyngeal squamous cell carcinoma:

Objective: To determine if patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) treated with chemoradiation have improved outcomes. Study Design: A retrospective search was used to identify patients with OPSCC treated with concurrent chemoradiation. Pretreatment biopsy specimens were tested for HPV-16 infection and p16 expression. Methods: Forty-four patients with OPSCC treated with concurrent chemotherapy and intensity-modulated radiation therapy were identified. Eligibility criteria included a minimum two years of follow-up, or biopsy-proven recurrence. In situ hybridization was applied to archival tumor specimens, with HPV-16-positive status defined as positive staining of tumor cell nuclei. p16 expression was assessed by immunohistochemistry. Results: Twenty-seven tumors (61%) were positive for HPV-16 and 29 tumors (66%) expressed p16. HPV-16 infection was highly correlated with p16 expression (P < 10−7). Three-year disease-free and overall survival for all patients was 66 percent and 79 percent respectively. Patients with tumors infected with HPV-16 had improved overall (OS) and disease-free survival (DFS) after chemoradiation (OS: hazard ratio [HR] = 0.21, P = 0.01; DFS: HR = 0.30, P = 0.02). Conclusion: Patients with OPSCC tumors that are infected with HPV-16 have improved survival after treatment with concurrent chemoradiation.

Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin

Thirteen patients with carcinomas of major and minor salivary gland origin (nine adenoid cystic carcinomas and four adenocarcinomas) were treated with cyclophosphamide (500 mg/m2), doxorubicin (50 mg/m2), and cisplatin (50 mg/m2) (CAP) by intravenous injections on the first day of a 28‐day regimen. Sixty‐one cycles of CAP were administered (mean, 4.7 cycles per patient). Eleven patients were treated for palliation of recurrent disease (locoregional, ten; lung, ten; liver, three; and bone, three). Two patients untreated previously, one with extensive local disease involving the base of the skull and one with a solitary lung metastasis (resected with a positive margin) and an initially unappreciated base of tongue primary, received two cycles of CAP followed by local treatment and adjuvant CAP. Previous therapy for the 11 patients with recurrent disease included surgery (ten), radiotherapy [RT(11)], chemotherapy (three), or hormonal therapy (two). Three complete and three partial responses to chemotherapy were noted for an overall response rate of 46%. The median duration of response in palliative patients was 5 months (range, 2 to 9). Of the two patients receiving induction CAP, one relapsed with distant disease 26 months after treatment, and the other remains disease‐free after 60 months of follow‐up examination. Chemotherapy was well tolerated generally, and no chemotherapy‐related deaths occurred. One hypertensive patient suffered a stroke after 3 cycles of therapy. CAP is an active regimen against salivary gland carcinomas and deserves further study. Also, it may be of value as induction or adjuvant treatment for patients with advanced disease untreated previously.

Pretherapy dental status of patients with malignant conditions of the head and neck

Maxillofacial problems after radiotherapy to this region are common and have at least a temporal relationship to preexisting odontogenic disease. This study was undertaken to determine the dental status of patients before multimodality therapy for head and neck cancer. One hundred thirty-one patients were examined during their initial visit to a head and neck tumor clinic. The majority of dentulous patients were noncompliant with routine dental care (76%) and oral hygiene (65%). There was a high incidence of alveolar bone loss (66%), clinical caries (71%), and failing restorations (91%). Overall, 73 (97%) of the dentulous patients needed dental care before radiotherapy; however, follow-up visits revealed that 59 (81%) of these patients did not seek the indicated treatment. These data suggest that thorough oral examinations should be performed on all patients before radiotherapy that involves the oral cavity.

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.