Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

Background: The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens. Design: We nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017. Results: TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further. Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT. PATIENTS AND METHODS: Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF). RESULTS: In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable. CONCLUSION: Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. PATIENTS AND METHODS: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m(2)/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). RESULTS: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. CONCLUSION: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.

Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck.

BACKGROUND: The efficacy and safety of a novel combination of weekly paclitaxel and the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab for the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck were investigated. PATIENTS AND METHODS: Patients received paclitaxel (80 mg/m(2)) and cetuximab (400/250 mg/m(2)), weekly, until disease progression or unacceptable toxicity. The primary end point was response rate. RESULTS: Among 46 patients enrolled, the overall response rate was 54% [95% confidence interval (CI) 39% to 69%], with 10 (22%) complete responses and a disease control rate of 80%. Median progression-free and overall survival times were 4.2 (95% CI 2.9-5.5 months) and 8.1 months (95% CI 6.6-9.6 months), respectively. Common grade 3/4 adverse events were acne-like rash (24%), asthenia (17%) and neutropenia (13%). Prior chemotherapy and the development of acne-like rash were associated with tumor response but not survival. No association between tumor EGFR expression or EGFR gene copy number and response or survival was found. CONCLUSION: The combination of cetuximab and weekly paclitaxel was active and well tolerated by these poor prognosis patients and may be an option for the treatment of medically unfit patients, particularly those for whom platinum is contraindicated.

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity. RESULTS: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. CONCLUSION: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study.

BACKGROUND: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. PATIENTS AND METHODS: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. RESULTS: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. CONCLUSION: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

BACKGROUND: Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. MATERIALS AND METHODS: Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. RESULTS: In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4 months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. CONCLUSION: After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment.

BACKGROUND: Platinum-based therapy (PBT) is the standard therapy for recurrent and/or metastatic head and neck cancer (HNC), but the incidence of recurrence remains high. This study evaluates the efficacy and tolerability of capecitabine as palliative monotherapy for recurrent HNC previously treated with PBT. METHODS: Patients aged 18-75 years, with Eastern Cooperative Oncology Group performance status 0-2, squamous HNC with locoregional and/or metastatic recurrence previously treated with PBT and adequate organ functions, were included. Capecitabine (1.250 mg m(-2) BID) was administered on days 1-14 every 21 days for at least two cycles. RESULTS: A total of 40 male patients with a median age of 58 years were analysed. All patients received a median number of four cycles of capecitabine (range: 1-9) and the median relative dose intensity was 91%. Seven patients were not evaluable for response. Overall response rate was 24.2%. Median time to progression and overall survival were 4.8 and 7.3 months, respectively. Haematological adverse events (AEs) grade 3/4 were reported in six patients. Most common grade 3/4 non-haematological AEs were asthenia (12.5%), palmar-plantar eritrodisestesia (10%), mucositis (10%), dysphagia (10%) and diarrhoea (7.5%). CONCLUSIONS: Capecitabine seems to be an active, feasible and well-tolerated mode of palliative treatment for advanced HNC patients who have previously received PBT schedules.

Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: A phase III trial demonstrated that cetuximab is the first agent in 30 years to improve survival when added to platinum-based chemotherapy (platinum-fluorouracil) first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). This analysis of the trial assessed the impact of treatment on quality of life (QoL). PATIENTS AND METHODS: The European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30 (QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35) module were used to assess QoL. RESULTS: Of 442 patients randomly assigned, 291 (QLQ-C30) and 289 (QLQ-H&N35) patients completed at least one evaluable questionnaire. For QLQ-C30, cycle 3 and month 6 mean scores for platinum-fluorouracil plus cetuximab were not significantly worse than those for platinum-fluorouracil. Pattern-mixture analysis demonstrated a significant improvement in the global health status/QoL score in the cetuximab arm (P = 0.0415) but no treatment differences in the social functioning scale. For QLQ-H&N35, the mean score for the cetuximab arm was not significantly worse than that for the chemotherapy arm for all symptom scales at all post-baseline visits. At cycle 3, some symptom scores significantly favored the cetuximab arm (pain, swallowing, speech problems, and social eating). CONCLUSION: Adding cetuximab to platinum-fluorouracil does not adversely affect the QoL of patients with recurrent and/or metastatic SCCHN.

Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors.

BACKGROUND: Several randomized trials have tested the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in relieving chemotherapy-induced bone marrow suppression. However, the use of CSFs in the treatment of neutropenic fever remains virtually unexplored. PURPOSE: This study evaluated the benefits of adding CSF therapy to the standard antibiotic treatments given to cancer patients for chemotherapy-induced neutropenic fever. The usefulness of CSFs was quantified in terms of reducing the following: (a) the duration of neutropenia, (b) the length of hospitalization, and (c) the overall cost of the treatment. METHODS: A randomized trial was conducted to test whether the administration of either G-CSF or GM-CSF improved the outcome of standard antibiotic therapy (ceftazidime plus amikacin) in nonleukemic cancer patients with fever (> 38 degrees C) and grade IV neutropenia (absolute neutrophil count [ANC] < 500/mm3) induced by standard-dose chemotherapy. Of 121 patients who entered the trial, 39 received G-CSF (5 micrograms/kg body weight per day), 39 received GM-CSF (5 micrograms/kg body weight per day), and 43 received a placebo beginning just after the first dose of antibiotics. Treatments were continued for at least 5 days (7 days with clinically or microbiologically documented infections) or until 2 days after fever subsided and ANCs rose above 1000/mm3. RESULTS: The median duration of grade IV neutropenia (ANC of < 500/mm3) was 2 days in both CSF arms and 3 days in the placebo arm (P < .001). The median duration of neutropenia with an ANC of less than 1000/mm3 was also significantly shorter in patients receiving G-CSF or GM-CSF (P < .001). The median duration of fever was similar in the three arms. The median hospital stay was 5 days (range, 5-14 days) in the G-CSF arm, 5 days (range, 5-10 days) in the GM-CSF arm, and 7 days (range, 5-34 days) in the placebo arm (P < .001). The median time on CSF was 4 days in both treatment arms. The mean cost of overall treatment was reduced by $1300-$1400 in the CSF arms compared with the placebo arm (P = .11 for G-CSF versus placebo; P = .06 for GM-CSF versus placebo; P = .7 for G-CSF versus GM-CSF). CONCLUSIONS: Adding G-CSF or GM-CSF therapy to antibiotic treatment shortens the duration of neutropenia and the duration of hospitalization in patients with neutropenic fever. A statistically nonsignificant trend toward lower cost was observed in the CSF arms as compared with the placebo arm. IMPLICATIONS: The benefits of CSFs to cancer patients with chemotherapy-induced neutropenic fever merit further evaluation in large randomized trials.

Patient selection in high-dose chemotherapy trials: relevance in high-risk breast cancer.

PURPOSE: To evaluate the impact of the selection criteria that are used in current high-dose consolidation chemotherapy (HDCT) trials on the outcome of high-risk breast cancer patients treated with conventional adjuvant chemotherapy. PATIENTS AND METHODS: From 1975 to 1995, 265 breast cancer patients at our institution showed involvement of ten or more positive axillary lymph nodes. Of these, 171 received standard adjuvant combination chemotherapy, but not HDCT consolidation, and were the subjects of our study. One hundred twenty-eight patients met the standard selection criteria for HDCT with hematological support (< 60 years, no significant concomitant disease, and no progression during adjuvant treatment), whereas 43 did not. Clinical outcome was analyzed by using disease-free survival (DFS) and overall survival (OS) as endpoints. To provide an assessment of the short-term efficacy of HDCT, we also evaluated the outcome in a cohort of 39 patients from the last 4 years who met the criteria for, and were actually treated with, HDCT after adjuvant chemotherapy. RESULTS: With a median follow-up of 4.4 years (range, 0.7 to 17.2 years), 112 of the 171 patients have had a relapse, and 87 have died. The estimated 5-year DFS was 32.3%, and OS was 49.4%. DFS was significantly higher for patients who met the HDCT criteria (36.6% at 5 years) than for those who did not (15.8% at 5 years; P < .05). OS was also significantly more favorable in patients meeting HDCT criteria (55.4% at 5 years) than in patients not meeting HDCT criteria (22.7% at 5 years; P < .01). We performed a multivariate analysis to adjust for other potential prognostic factors and found that meeting the HDCT criteria and having undergone locoregional radiotherapy were the only significant independent predictors for DFS and OS. Finally, we compared the outcome of the 128 patients who met the HDCT criteria and were treated with conventional adjuvant chemotherapy only with that of the 39 patients who met the criteria and who actually underwent HDCT, and we did not observe significant differences in the DFS or OS between these groups. CONCLUSIONS: Meeting HDCT inclusion criteria is an independent indicator of favorable prognosis in high-risk breast cancer patients. The selection of patients by these criteria may explain, at least in part, the promising short-term results of nonrandomized adjuvant HDCT trials in high-risk breast cancer.

Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS: Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.

beta-Catenin, Nf-kappaB and FAS protein expression are independent events in head and neck cancer: study of their association with clinical parameters.

In spite of much effort, no good markers have yet been found for predicting prognosis or response to therapy in advanced head and neck squamous cell carcinoma (HNSCCs) patients. beta-catenin, a protein involved in the cytoskeleton, cell-cell adhesion and gene transcription, is a factor associated with tumour progression. Recently, an interaction has been reported between beta-catenin, and NF-kappaB coupled with an inverse association of beta-catenin, and FAS (CD95/APO-1) protein expression in breast and colorectal tumours. To confirm these observations and to test their clinical impact in HNSCCs we have evaluated the expression of beta-catenin, NF-kappaB and FAS proteins. We used tissue microarrays to simultaneously analyse the levels of these proteins immunohistochemically in 118 HNSCCs. Among the 113 tumours evaluable for beta-catenin, increased and decreased levels were detected in 41 (36%) and 62 (55%) of the tumours, respectively. beta-catenin, protein staining was mainly membranous but 10 tumours (9%) showed the clear presence of protein in the cytoplasm, and none in the nucleus. Moreover, 81% of the tumours had decreased FAS protein expression, indicating that loss of FAS protein is a common feature of HNSCCs. Abnormal or nuclear NF-kappaB staining was observed in 24% of the tumours. No association was detected between the expression levels of the proteins evaluated. Regarding clinical associations, tumours from the hypopharynx had significantly lower levels of beta-catenin expression than those from other locations (P<0.05). Moreover, our data revealed that patients whose tumours had low levels of beta-catenin protein expression had decreased survival probability (24.8 months vs. NR, P=0.03) and reduced response to therapy (15.4 vs. 43 months; P=0.01) compared with patients whose tumours had high levels of beta-catenin. Taken together, our observations indicate that beta-catenin, NF-kappaB and FAS expression are independent events during HNSCC development and that levels of beta-catenin protein may identify subsets of advanced HNSCCs patients with different prognosis and response to therapy capabilities.

A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy.

AIMS: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) develops in around 72,000 people in Europe every year. Treatment options are limited, mainly consisting of platinum-based palliative chemotherapy, with median overall survival times of only 6-8 months. No standard second-line treatment after progression on platinum-based chemotherapy is available. Few data have reported the efficacy of these treatments and the outcome of the patients. In an effort to generate such data, this retrospective study analysed clinical records from 151 patients with SCCHN refractory to platinum-based chemotherapy treated between 1990 and 2000 at seven different centres around Europe. MATERIALS AND METHODS: Most patients (45%) received only best supportive care (BSC), and had a median survival of 56 days. A total of 28.5% of the patients received second-line chemotherapies: 16.6% radiotherapy and 9.9% chemoradiotherapy. RESULTS: No objective response was observed with the various second-line chemotherapies. The overall median survival was 103 days (95% confidence interval [CI]: 77-126 days) for the whole cohort. The overall objective response rate (ORR) to second-line treatment in this population was calculated to be 2.6%. CONCLUSION: These results highlight the need for additional treatment options for this disease. Similar, if not superior, response rates have already been observed in initial clinical studies of novel, targeted anti-cancer agents.

Study of escalating doses of paclitaxel plus cisplatin in patients with inoperable head and neck cancer.

This phase I/II study sought to determine the response rate and toxicity profile of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered with fixed doses of cisplatin with granulocyte colony-stimulating factor support in 28 patients with head or neck cancer. The study was designed as a modified dose-finding trial and contained five dose-escalation levels of paclitaxel. Dose level 1 contained seven patients, and doses ranged from 175 to 220 mg/m2; dose level 2, 230 to 250 mg/m2 (five patients); dose level 3, 250 mg/m2 only (four patients); dose level 4, 260 to 280 mg/m2 (six patients); and dose level 5, 280 to 300 mg/m2 (six patients). Dose levels greater than 200 mg/m2 were supported with concomitant granulocyte colony-stimulating support. Paclitaxel was given on day 1 by 3-hour infusion; cisplatin 75 mg/m2 was given on day 2. Courses were given every 3 weeks. All patients were evaluable for toxicity and 27 were evaluable for response. The overall response rate was 77% (10 complete responses, 11 partial responses, four no change, and two disease progression). Over a median follow-up of 15 months (range, 7 to 22 months), 16 patients showed no evidence of disease and three are alive with disease. A dose-effect relationship was found between paclitaxel and peripheral neuropathy. Twenty-seven of 28 patients experienced alopecia, peripheral neuropathy, myalgias, and arthralgias. Most toxicities were grade 1 or 2; the mean duration of symptoms was 7 days. No dose-limiting hematologic toxicity was observed, nor was any significant neutropenia seen in those patients receiving filgrastim. The paclitaxel/cisplatin combination was found to be an effective first-line regimen for patients with head or neck cancer. Although the number of patients in this study was small, no relationship was noted between patient response and disease site.

A phase I/II study of paclitaxel plus cisplatin as first-line therapy for head and neck cancers: preliminary results.

Improved outcomes among patients with head and neck carcinomas require investigations of new drugs for induction therapy. Preliminary results of an Eastern Cooperative Oncology Group study of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) reported a 37% response rate in patients with head and neck cancer, and the paclitaxel/cisplatin combination has been used successfully and has significantly improved median response duration in ovarian cancer patients. We initiated a phase I/II trial to determine the response and toxicity of escalating paclitaxel doses combined with fixed-dose cisplatin with granulocyte colony-stimulating factor support in patients with untreated locally advanced inoperable head and neck carcinoma. To date, 23 men with a median age of 50 years and good performance status have entered the trial. Primary tumor sites were oropharynx, 10 patients; hypopharynx, four; larynx, two; oral cavity, three; unknown primary, two; and nasal cavity and parotid gland, one each. Of 20 patients evaluable for toxicity, four had stage III and 16 had stage IV disease. Treatment, given every 21 days for a maximum of three cycles, consisted of paclitaxel by 3-hour infusion followed the next day by a fixed dose of cisplatin (75 mg/m2). The dose levels incorporate escalating paclitaxel doses, and intrapatient escalations within a given dose level are permitted if toxicity permits. At the time of this writing, dose level 4 (260, 270, and 280 mg/m2) is being evaluated; three patients from this level are evaluable. With paclitaxel doses of 200 mg/m2 and higher, granulocyte colony-stimulating factor 5 micrograms/kg/d is given (days 4 through 12). Of 18 patients evaluable for response, seven (39%) achieved a complete response and six (33%) achieved a partial response. Three patients had no change and disease progressed in two. The overall response rate is 72%. Eleven responding patients had subsequent surgery/radiotherapy or radical radiotherapy. Two pathologic complete responses were observed in patients who had achieved clinical complete responses. Alopecia, paresthesias, and arthralgias/myalgias have occurred frequently, but with one exception (a grade 3 myalgia) they have been grade 1 or 2. No dose-limiting hematologic toxicity has been seen. Paclitaxel/cisplatin is an effective first-line regimen for locoregionally advanced head and neck cancer and continued study is warranted. Results thus far suggest no dose-response effect for paclitaxel doses above 200 mg/m2.

Phase I/II study of paclitaxel/cisplatin as first-line therapy for locally advanced head and neck cancer.

A phase I/II study was conducted to determine the response rate and the toxicity of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus cisplatin with granulocyte colony-stimulating factor support in patients with untreated advanced head and neck carcinoma. Twenty-eight patients with locally advanced inoperable squamous cell head and neck carcinoma were included. Median age was 51 years. Karnofsky performance status was > or =90% in all patients. Primary tumor sites were oropharynx, hypopharynx, larynx, oral cavity, parotid gland, nasal cavity, and unknown primary. We observed 13 complete responses, eight partial responses, four patients with stable disease, and two patients with progressive disease for an overall response rate of 78%. Toxicity was paresthesia grade 1/2 in 27 patients, and myalgias were grade 1/2 in 23 patients and grade 3 in four patients. One patient died 5 days after the first cycle due to acute renal failure, respiratory distress, and pancytopenia. No dose-limiting hematologic toxicity has been observed, and intrapatient escalations were performed in all patients when planned. Calculated dose intensity for the two drugs was 100% in all evaluable patients. The combination of escalating doses of paclitaxel 175 to 300 mg/m2 and cisplatin 75 mg/m2 was active in untreated head and neck carcinoma, with an overall response rate of 78%. No dose-limiting toxicity has been encountered at paclitaxel doses up to 300 mg/m2 given with granulocyte colony-stimulating factor.

p53 expression in locally advanced pharyngeal squamous cell carcinoma.

BACKGROUND: Prognosis for advanced head and neck squamous cell carcinoma remains poor despite advances in treatment, although a small number of patients may benefit from induction therapy leading to increased local control. Mutations of the p53 gene, which are present in a considerable percentage of head and neck squamous cell carcinomas, have been associated with poor response to chemotherapy. The role of p53 protein overexpression (which is associated with p53 gene mutations) in predicting the response to chemotherapeutic agents and survival rates is not clear. OBJECTIVE: To determine the association of p53 expression with chemotherapy response rates and disease-free survival rates in 62 patients with locally advanced pharyngeal cancer treated with induction cisplatin-5-fluorouracil chemotherapy between 1983 and 1995. DESIGN: Historical cohort. Archival tissue from biopsies done before chemotherapy was immunohistochemically stained for the p53 tumor suppressor gene (clone D0-7; DAKO Corp, Glostrup, Denmark). RESULTS: Positive staining for p53 occurred in 45 (73%) of 62 cases, with the percentage of reactive cells ranging from 35% to 98%. Chemotherapy response rates were higher in the p53-negative group (15/17 [88%]) compared with the p53-positive group (27/45 [60%]) (P =.07). The risk of recurrence was lower in the p53-negative group compared with the p53-positive group at 2, 3, and 5 years after treatment (P = .03, P = .01, and P = .007, respectively). The median relapse-free survival rates of patients in the p53-negative group was 16 months, whereas those with p53 protein expression demonstrated a median relapse-free survival time of 9 months (P = .07). In multivariate analyses, the only independent factor of relapse-free survival rates was age older than 70 years. CONCLUSION: The present study shows a trend favoring p53 overexpression as a predictive and prognostic factor in locally advanced pharyngeal cancer treated with induction chemotherapy.

Designing salvage antiretroviral regimens. Some basic guidelines and use of resistance testing.

Treatment of HIV infection is rapidly changing from a hit-or-miss hodgepodge of unknowns, in which nearly anything beneficial was acceptable, to a true science based on reproducible principles. With this growth in complexity, HIV therapy has become a valid field of medicine. The potency of available agents, their success in suppressing the destructive nature of HIV infection, and the increasingly rapid pace of technology development in this area require that HIV-seropositive patients be treated by physicians specializing in the field. The growing but finite number of antiretroviral therapeutic agents demands that a thoughtful, strategic, long-term approach be formulated. The evolving science of antiretroviral resistance testing offers great promise for better shaping this approach, which is still less than straightforward. Potential interactions, some good and some bad, between mutations within HIV genes will profoundly affect therapy and are still to be defined. Declaring that a regimen has failed and choosing a new one to replace it is a complex task, particularly when all the factors involved are considered (e.g., rising viral load, declining CD4 count, patient adherence, patient preferences, drug interactions, adverse effects). Care of HIV-positive patients has always been an art, and now at last it is becoming a science.

Hitt or miss: the President's council goes to bat over needle exchange & names reporting. Interview by Donna Rochon.

AIDS: The first annual Houston Treatment Advocacy Forum focused on the mechanisms and institutions that provide access to care for persons living with HIV/AIDS, as well as issues of needle exchange programs and mandatory name reporting. Dr. R. Scott Hitt, Chairman of the Presidential Advisory Council on HIV/AIDS, is interviewed about these issues. Dr. Scott responds to questions concerning what the Council has told the President about funding needle exchange programs and the Council's position on mandatory reporting. While the President recognizes and supports the efficacy of needle exchange programs, no Federal funding has been approved. There appears to be a lack of political will on this issue giving the appearance of an administration uninterested in HIV prevention efforts. Dr. Hitt views the mood of the country as endorsing local control over both needle exchange programs and mandatory name reporting, a viewpoint which he shares. There appears to be a national trend toward names-based HIV/AIDS surveillance systems despite concerns over confidentiality. Currently, the Texas State Health Department is evaluating a names-based HIV/AIDS surveillance system against one that uses unique identifiers.^ieng