Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

Gemcitabine and paclitaxel in metastatic or recurrent squamous cell carcinoma of the head and neck: a phase I-II study

The purpose of this study was to determine the maximum tolerated dose, toxicity profile and anti-tumor activity of paclitaxel in combination with gemcitabine when administered to patients with unresectable locally recurrent or metastatic squamous cell carcinoma of the head and the neck (SCCHN). Twenty-seven patients were treated in a phase I-II study with gemcitabine at a dose of 800 mg/m on days 1 and 8, escalating to a dose of 1,000 mg/m, plus escalating doses of paclitaxel (100, 135 and 175 mg/m) on day 2. Treatment consisted of 6 cycles repeated every 3 weeks. The main toxicity was myelosuppression. Other toxicities were mild and manageable. Due to grade 4 neutropenia at higher doses the recommended dose level of the gemcitabine/paclitaxel combination was 1,000/135 mg/m. Four patients achieved a partial response and no patient had a complete remission, giving an overall response rate of 14.8%. The median time of survival was 24 weeks. We conclude that the combination of paclitaxel and gemcitabine is tolerated, but shows insufficient clinical activity in patients with recurrent and/or metastatic SCCHN to warrant further testing.     

A Clinical Screening Cooperative Group phase II evaluation of lobaplatin (ASTA D-19466) in advanced head and neck cancer

Summary We evaluated the efficacy and tolerability of lobaplatin, a new platinum compound, given at the dose of 50 mg/m² by i.v. bolus every 4 weeks, in 49 patients with advanced and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). One complete and 2 partial responses were observed in 43 eligible patients for an overall response rate of 7% (95% confidence interval: 1–19%). The duration of responses was 11, 16 and 32 weeks. Toxicities of WHO grade 3 were hematologic: thrombocytopenia in 26%, granulocytopenia in 12% and anemia in 12% of patients. There was no therapy-related death. Nausea/vomiting, diarrhoea and paresthesia were mild and rare. In conclusion, lobaplatin was well tolerated, but its efficacy in advanced SCCHN at the presented dose and schedule, was marginal.     

Phase II Trial of Aminocamptothecin (9-AC/DMA) in Patients with Advanced Squamous Cell Head and Neck Cancer

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M²/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions wererepeated at 21 day intervals until progression or prohibitive toxicity occurred.A median of 3 cycles (range 1–7) was given. No objective responses wereobserved. Median survival of the group was 6 months. Toxicity was hematologicwhich was modest and promptly reversible. 9-AC/DMA is inactive against this tumortype at the dose and schedule employed in this study.     

Induction chemotherapy with docetaxel, cisplatin, fluorouracil and l-leucovorin for locally advanced head and neck cancers: a modified regimen for Japanese patients

Combination chemotherapy with docetaxel (T), cisplatin (P), fluorouracil (5-FU) and leucovorin has been reported to have major activity against squamous cell carcinoma of the head and neck (SCCHN) administered as a 4-day (TPFL4) or 5-day (TPFL5) regimen. The purpose of this study was to evaluate the efficacy and toxicity of a modified TPFL regimen (m-TPFL) for locally advanced SCCHN, consisting of a modified dosage with docetaxel, cisplatin, 5-FU and l-leucovorin (l-LV) designed for Japanese patients. Organ preservation of the primary tumor site was also assessed. Thirty-four Japanese patients with locally advanced SCCHN were eligible. Docetaxel was administered as a 1-h i.v. infusion at 48 mg/m2 on day 1; cisplatin, 24 mg/m2/day; 5-FU, 560 mg/m2/day and l-LV, 125 mg/body/day were delivered on days 1-4 by continuous i.v. infusion. This regimen was administered every 28 days. Patients who achieved a complete response (CR) after induction chemotherapy underwent radiation therapy alone. Ninety-one cycles were administered. The main hematological toxicity was neutropenia, classified as grade III or IV in 18.7% of cycles. The most common non-hematologic toxicities included anorexia, stomatitis and alopecia. The clinical overall response rate to m-TPFL was 88.2%, with 58.8% CRs and 29.4% partial responses. After definitive locoregional therapy, 25 of 34 patients were disease-free with preserved primary tumor site anatomy. Overall and progression-free survival rates at the 2-year follow-up are 92.8 and 75.3%, respectively. Our m-TPFL regimen designed for Japanese patients yielded excellent response rates with an acceptable toxicity profile in good-performance-status patients.     

Afatinib in squamous cell carcinoma of the head and neck

Introduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.

Areas covered: We searched the literature for published and ongoing studies with afatinib in HNSCC.

Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.

Expert opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.     

Southwest Oncology Group study of Mitoxantrone for treatment of patients with advanced squamous cell carcinoma of the head and neck

Summary Twenty-two patients are evaluable for response in a Phase II trial of Mitoxantrone for advanced squamous cell carcinoma of the head and neck. One patient had a partial response, one an improvement and twenty had progressive disease. The major toxicities were leukopenia and thrombocytopenia. There was no significant antitumor activity of Mitoxantrone in this group of patients with head and neck cancer, most of whom were previously treated with radiation and chemotherapy.     

Phase II study of a combination of low-dose cisplatin with 13-cis-retinoic acid and interferon-alpha in patients with advanced head and neck squamous cell carcinoma.

Preclinical and clinical data have suggested antitumor efficacy in squamous cell carcinoma (SCC) of interferon (IFN)-alpha and 13-cis-retinoic acid (13-c-RA) as single agent with greater activity in combination. Cisplatin was added to potentiate activity. Twenty-three patients with pretreated advanced or metastatic head and neck squamous cell carcinoma were given a combination of IFN-alpha (6 x 10(6) U/day, 84 days s.c.), 13-c-RA (1 mg/kg/day, 84 days) and cisplatin (40 mg/kg/day, day 1, 28 and 56). Seventeen patients had discontinuation of treatment and three patients received overall treatment without dose reduction. Hematological toxicity was more frequent; only three patients experiencing grade 3 or higher extra-hematological toxicity. Four out of 14 evaluable patients were in response, with one in complete pathological response. Median duration of response was 6 months with a 9 month median survival. Association of IFN-alpha, 13-c-RA and cisplatin induces modest but definite antitumor activity with moderate and manageable toxicity. Further studies of different combination modality therapy with chemotherapy and differentiating agents need to be performed in less pretreated patients.     

An ECOG Phase II Study of Amonafide in Unresectable or Recurrent Carcinoma of the Head and Neck (PB390)

The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m², over two hours each day for five consecutive days every 21 days. There was one partial response [39] which lasted four months. The dose limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m² for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.     

Phase II study of intravenous melphalan (NSC-8806) in the treatment of patients with advanced squamous carcinoma of the head and neck

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m² every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/l 36%), and thrombocytopenia (< 50,000/l 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.     

Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: a phase II randomized trial

Summary Retinoids, the analogs of vitamin A, are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans. These data led us to design a prospective, multi-institutional, randomized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma. We randomly assigned 40 patients to receive isotretinoin or methotrexate, the best-studied and most active single agent for this disease. Overall, the study patients had extremely poor prognoses, i.e., low performance statuses and recurring disease after surgery and/or irradiation. Three objective responses (16%), including one complete response, occurred in the 19 evaluable isotretinoin-treated patients. Only one minor response (5%) occurred in the methotrexate-treated group. Toxicity occurred with both drugs, but was manageable and never life threatening in the retinoid group. These results and the established activity of retinoids in oral leukoplakia (a precursor of head and neck cancer) indicate the need for further study of this class of drugs in head and neck cancer.     

Polymorphisms of vitamin D receptor gene protect against the risk of head and neck cancer

Vitamin D has potent anti-tumour properties. Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including human squamous cells of the head and neck. Several polymorphisms of the vitamin D receptor (VDR) gene have been described, including a FokI restriction fragment-length polymorphism (RFLP) in exon 2 and an adjacent TaqI RFLP in exon 9. We hypothesized that the VDR FokI and TaqI polymorphisms are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). We conducted a hospital-based, case-control study of 719 SCCHN cases and 821 cancer-free controls (all non-Hispanic Whites) to assess the association between VDR polymorphisms and SCCHN risk. The cases and controls were frequency-matched on age, sex and ethnicity. Polymorphisms at the TaqI and FokI restriction sites were determined from genomic DNA by polymerase chain reaction-RFLP methods. Both homozygous variant genotypes (ff and tt) were associated with a decreased risk of SCCHN [odds ratio (OR)=0.72, 95% confidence interval (CI)=0.53-0.98 and OR=0.64, 95% CI=0.47-0.87, respectively] compared to the common FF and TT genotypes. The VDR variant genotypes were associated with a decreasing risk of SCCHN in a variant allele dose-dependent manner, and the decreasing trend in OR was statistically significant, particularly for the combined genotypes (Ptrend<0.001). These data suggest that the VDR f and t alleles and their genotypes may protect against SCCHN. However, further studies are warranted to confirm these findings.     

Phase II study of mitoxantrone in advanced squamous cell carcinoma of the head and neck

Summary A phase II study of mitoxantrone in squamous cell carcinoma of head and neck origin was conducted. Fifty-three evaluable patients were treated with this agent at a dosage of 5 mg/M²/week. The majority of patients were of high performance status. Twenty-seven patients had received previous chemotherapy plus surgery and/or radiotherapy. Twenty-six had not been treated with chemotherapy previously although thirteen of these patients had prior radiotherapy and surgery, eight radiotherapy only, one surgery only, and four no previous treatment. There was only one objective response. Toxicity was relatively mild, although 45% of the patients at some time experienced at least moderate leukopenia. Further studies of this agent in this disease are not warranted.     

Population pharmacokinetics of cetuximab in patients with squamous cell carcinoma of the head and neck

Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor and is indicated in the treatment of squamous cell carcinoma of the head and neck. The population pharmacokinetics of cetuximab were characterized by nonlinear mixed effects modeling (NONMEM V) using a total of 912 concentrations from 143 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck enrolled in 2 phase I/II studies. Cetuximab pharmacokinetics were best described by a 2-compartment model with Michaelis-Menten-type saturable elimination. Population estimates (between-subject variability, percent coefficient of variation) of the pharmacokinetic parameters were V(max) 4.38 mg/h (15.4%), K(m) 74 mug/mL, central compartment volume V(1) 2.83 L (18.6%), peripheral compartment volume 2.43 L (56.4%), and intercompartmental clearance 0.103 L/h (97.2%). Ideal body weight and white blood cell count were identified as predictors of V(max) and total body weight as a predictor of V(1). Clinical dose adjustments beyond the approved body surface area-based dosing of cetuximab may be warranted in patients with extreme deviations of their actual body weight from ideal body weight. Agreement between simulated and measured concentrations monitored for up to 43 weeks of therapy indicates that cetuximab pharmacokinetic parameters remained constant during prolonged therapy.     

Evaluation of topotecan in patients with recurrent for metastatic squamous cell carcinoma of the head and neck

Summary Twenty-nine patients with persistent, recurrent and/or metastatic squamous cell carcinoma of the head and neck were treated daily for five days at three-week intervals with topotecan 1.5 mg/m². Four patients received prior chemotherapy, 23 prior surgery and 29 prior radiation therapy. Of the 29 eligible patients, 8 patients were not evaluable for response and were assumed to be non-responders. Of the remaining 21 évaluable patients, there were zero responses (0%, 95% confidence interval [0,.12]). The most common toxicities were myelosuppression, dyspnea and malaise/fatigue/lethargy. Topotecan has limited activity in advanced head and neck cancer with this dose and schedule.     

头颈部鳞状细胞癌靶向治疗的研究进展

靶向治疗是目前治疗头颈部鳞状细胞癌的研究热点。许多新型的药物制剂治疗方案都在进行临床试验的评估。治疗头颈部鳞状细胞癌的靶向治疗制剂主要有涉及EGFR信号通路的单克隆抗体,如西妥昔单抗;EGFR-TKI,VEGF抑制剂、NF-kB信号通路的阻断剂、IGFR抑制剂和p53信号通路的载体。     

Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck

Summary Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0–2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m² for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3–4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/ recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.     

Ifosfamide and mitoxantrone in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck

A phase II study was performed to assess the safety and efficacy of ifosfamide and mitoxantrone in recurrent and/or metastatic squamous cell carcinomas of the head and neck. Treatment consisted of ifosfamide 1500 mg/m2 in 1000 ml saline, infused over 60 min and mesna 20% of the total dose of ifosfamide in three doses for 3 days combined with mitoxantrone 12 mg/m2 given as a short infusion on day 1. Treatment courses were repeated every 4 weeks until a total of six cycles. Twenty-two patients entered this trial, 13 of whom had received chemo- and radiation therapy, and nine patients who underwent radiation therapy with or without prior surgery. We observed no objective response, with the exception of two patients who experienced minor response (reduction of tumor size of 25%). The dose-limiting toxicity was myelosuppression with grade 3/4 leukocytopenia in seven patients (32%) and grade 3/4 neutropenia in 15 (68%). Severe organ toxicity except alopecia (91%) was not observed. Ifosfamide combined with mitoxantrone does not improve the therapeutic armentarium in recurrent squamous cell carcinoma of the head and neck.     

Effects of tamoxifen on human squamous cell carcinoma lines of the head and neck

Tamoxifen (TAM) is a well-tolerated compound in the treatment of breast cancer and is primarily considered to act by competition with estrogen receptors (ER). Here we investigated the in vitro efficacy and potentially underlying mechanisms of TAM in established cell lines of squamous cell carcinomas of the head and neck (SCCHN). Using proliferation and apoptosis assays the antitumor activity of TAM in five SCCHN and the breast carcinoma line MCF-7 (positive control) was determined. MCF-7 was more sensitive to low-dose TAM (below 1 microM), whereas SCCHN showed significant growth inhibition at higher TAM concentrations (5-10 microM). Growth curve analysis and apoptosis assays were indicative for a cytostatic effect of low-dose TAM and high-dose TAM led to cell loss by apoptosis in sensitive SCCHN. In order to further characterize the observed antitumor effects we determined the amount of steroid hormone receptors with the dextran-coated charcoal method and immunocytochemistry. In addition, production of transforming growth factor (TGF-)-alpha, -beta1 and -beta2 was measured by ELISA, and protein kinase C (PKC) activity was assessed with a radioligand assay. Except MCF-7, none of the SCCHN lines was positive for ER. TAM caused decreased TGF-alpha and increased TGF-beta levels in MCF-7, but not in SCCHN supernatants. Furthermore, the antiestrogen reduced PKC activity in MCF-7, but not in SCCHN. In the present in vitro system, the observed antitumor activity of high-dose TAM in SCCHN cannot be explained by estrogen antagonism, alterations of TGF-alpha/beta levels or decreased PKC activity.     

吗替麦考酚酯对自身免疫性疾病患者白细胞计数和感染的影响

目的：考察吗替麦考酚酯（MMF）对自身免疫性疾病患者白细胞计数和感染的影响。方法：采用自身前后对照法进行回顾性研究,纳入使用吗替麦考酚酯治疗的免疫病患者共计51人,考察治疗前后患者血液常规检查结果以及感染发生情况。结果：使用吗替麦考酚酯后患者白细胞计数显著降低（6.01 vs. 4.93,P=0.007）。此外,吗替麦考酚酯的使用与细菌感染（P=0.001）和病毒感染（P=0.041）显著相关,但与真菌感染无关（P=0.050）。结论：吗替麦考酚酯治疗自身免疫性疾病可能导致白细胞减少并增加细菌感染和病毒感染发生的风险。因此,在使用吗替麦考酚酯治疗期间,建议定期复查血常规并嘱托患者注意避免劳累、受凉和感染。