C. M. Norris

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.

Dose to Larynx Predicts for Swallowing Complications After Intensity-Modulated Radiotherapy

PURPOSE To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. METHODS AND MATERIALS Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Womens Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. RESULTS A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose-volume metrics, including the volume of the larynx receiving >or=50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving >or=50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. CONCLUSION Aspiration and stricture are common side effects after intensity-modulated radiotherapy for head-and-neck squamous cell carcinoma. The dose given to the larynx and inferior constrictors correlated with these side effects.

Phase II Trial of Docetaxel, Cisplatin, Fluorouracil, and Leucovorin as Induction for Squamous Cell Carcinoma of the Head and Neck

PURPOSE To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

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.

Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN).

The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m2 in combination with 100 mg/m2 cisplatin intravenous bolus, and 2,800 mg/m2 5-FU continuous infusion and 2,000 mg/m2 leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m2. Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m2 docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule.

Phase I study of gefitinib plus celecoxib in patients with metastatic and/or locally recurrent squamous cell carcinoma of the head and neck (SCCHN)

5540 Background: Treatment options for incurable metastatic and/or locally recurrent SCCHN are limited. Platinum-based therapy yields response rates of approximately 30%, and median survival of 6-7 months. Epidermal growth factor receptor (EGFR) and Cyclooxygenase-2 (COX-2) are both overexpressed and thought to contribute to the malignant phenotype in SCCHN. The EGFR inhibitor, gefitinib, has a single-agent response rate of 11% in this population. Preclinical and pharmacodynamic data suggest that the addition of a COX-2 inhibitor may enhance the antitumor effect of gefitinib. METHODS A phase I trial was designed to determine the maximum tolerated doses (MTD) of gefitinib and celecoxib (GC) in patients with incurable SCCHN. Secondary objectives were to describe toxicities of this combination and to study biomarkers of activity, including Ki-67, CD31, activation of EGFR, ERK1/2, and Akt, and serum IL-8 and EGFR. Response will also be determined. MTD was defined as one dose level below which dose-limiting toxicities (DLTs) occurred in 2 or more of 6 patients, or the highest dose level tested. Eligible patients had measurable metastatic and/or locally recurrent SCCHN, at least 1 prior chemotherapy, performance status 2 or better, and adequate end-organ function. RESULTS Thus far, 12 patients have enrolled. Dose escalation and toxicities are outlined in Table 1. The most common toxicities were rash (predominately acneiform), diarrhea and hand-foot syndrome (HFS). To date, no DLTs have occurred. Three of nine evaluable patients achieved a partial response. Additional transient responses were observed. Biomarker analysis is pending. CONCLUSIONS Overall, GC is very well-tolerated in patients with incurable SCCHN. Preliminary data suggest that celecoxib enhances gefitinib activity. A phase II study is warranted. [Figure: see text] No significant financial relationships to disclose.

Neo-adjuvant infusion Cisplatin, 5-FU and high-dose leucovorin for squamous cell carcinoma of the head and neck (SCCHN): high rates of complete response (CR) and definitive radiotherapy as primary site management

The role of Neo-Adjuvant chemotherapy for patients with advanced SCCHN remains controversial. While results from randomized trials of Neo-Adjuvant therapy have confirmed an association between response and treatment outcome, an improvement in survival has not been reported. Critical review of latter studies however, reveals flaws which limit the value of their findings [1]. An improvement in the survival of patients who receive Neo-Adjuvant therapy for SCCHN may not be confirmed until the rate of CR is consistently over 50 % and local-regional treatment is optimal [1].

Acupuncture for dysphagia after chemoradiation therapy in head and neck cancer: An ongoing pilot, randomized, sham-controlled trial.

TPS270 Background: Dysphagia is a common side effect following chemoradiation therapy (CRT) in patients with head and neck cancer (HNC). Dysphagia and other treatment-related conditions such as asp...

Organ preservation for patients treated with induction chemotherapy (IC) followed by radiation therapy (RT) or chemoradiation (CRT) for advanced stage squamous cell carcinoma of the larynx (SCCL)

5600 Background: We reviewed the charts of patients with laryngeal cancer treated with IC and definitive RT or CRT to determine the rates of overall organ preservation and function. METHODS Between September 1995 and December 2001, 29 patients with stage III (45%) and IV (55%) SCCL, were treated with IC and definitive RT or CRT on one of seven consecutive trials. The median age at diagnosis was 54 years (range 38-74). 55% had clinically node-positive disease. 55% and 45% had T3 and T4 tumors, respectively. All received 3 cycles of IC with a platinum-based regimen. QD RT was given to 48%, BID RT to 45%, and concomitant boost (CB) RT to 7%. CRT was given with carboplatin (28%) or docetaxel (28%). Those treated with BID RT did not receive CRT. RESULTS Median follow-up is 52 months (range 17-85). Overall survival is 66%. Relapse occurred in12 (41%) patients, and 6 underwent salvage laryngectomy (5 Stage III, 1 Stage IV). Of the entire cohort, 59% (17/29) are alive at last follow-up with an anatomically intact larynx, and 48% (14/29) are alive with a functional larynx. Detailed information on g-tube placement/removal was available for 23 patients. Median time with G-tube was 12 months (range, 1-50 months), and 15/23 (65%) had g-tube for 6 months or longer. 23 of all 29 patients (79%) retained an anatomically intact larynx, but 30% (7/23) did not resume their pre-treatment swallowing mechanics and airway protection. Overall rate of functional organ preservation, regardless of survival was, 55% (16/29). The 7/29 patients (26%) who retained a non-functional larynx required permanent g-tube or were unable to return to pretreatment oral intake capability. Nine of 13 with T4 SCCL (69%) compared to 7 of 16 (44%) T3 SCCL retained a functional larynx. CONCLUSIONS The rate of larynx preservation is high, but toxicity remains significant with combined modality therapy. Advanced stage was not an indicator of poor outcome. Half of all patients were alive, able to retain their larynx, and return to pretreatment function. [Table: see text].

Regional control after induction chemotherapy for adbanced squamous cell carcinoma of the head and neck: A retrospective analysis of 303 patients

Induction chemotherapy for squamous cell carcinomas of the head and neck has been the subject of a number of clinical trials with ambiguous results. Response data from phase II studies suggest a 20–40% complete response rate which has lead to an association between chemotherapy and survival and an improvement in survival when compared to historical controls. Eight separate prospective randomized trials have been published to date. Although these have yet to show an improvement in survival, there are critical flaws in each, which limit their interpretation and leave the role of induction chemotherapy an open question [1].