Antitumor activity of BOF-A2, a new 5-fluorouracil derivative

A compound containing both CNDP (3-cyano-2,6-dihydroxypyridine), an inhibitor of 5-fluorouracil (5-FU) degradation, and EM-FU (1-ethoxymethyl-5-fluorouracil), a masked form of 5-FU, was synthesized and named BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxy methyl-5- fluorouracil). The antitumor activity of BOF-A2 was investigated in sarcoma-180-bearing mice and Yoshida sarcoma-bearing rats. The ED50 (the dose for 50% inhibition) values of BOF-A2 were 25 mg/kg against sarcoma-180 and 15 mg/kg against Yoshida sarcoma. In vitro studies showed that BOF-A2 was rapidly degraded to EM-FU and CNDP in homogenates of the liver and small intestine of mice and rats, and in sera of mice, rats and human, and the conversion of EM-FU to 5-FU occurred only in the microsomal fraction of rat liver in the presence of NADPH. After oral administration of BOF-A2 at 15 mg/kg to Yoshida sarcoma-bearing rats, BOF-A2 was hydrolyzed to EM-FU, CNDP and 5-FU, and their maximum concentrations in the blood were 2000 ng/ml, 300 ng/ml and 40 ng/ml, respectively. Moreover when BOF-A2 was given at the same dose to tumor-bearing mice and rats, the 5-FU levels in the tumor tissue increased much more than those in the blood and persisted for more than 8 h, whereas those in the blood decreased more rapidly. This accumulation and maintenance of a high level of 5-FU in the tumor tissue are concluded to be related to the high antitumor activity of BOF-A2.     

Metabolic characteristics and antitumor activity of BOF-A2, a new 5-fluorouracil derivative

A new 5-fluorouracil (5-FU) derivative, BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1- ethoxymethyl- 5-fluorouracil), is consisted of EM-FU (1-ethoxymethyl-5-fluorouracil) which is specifically and gradually converted to 5-FU by the drug-metabolizing enzyme of liver microsomes and CNDP (3-cyano-2,6-dihydroxypyridine), a potent inhibitor of 5-FU degradation in the liver. When BOF-A2 was given orally, blood levels of the main metabolites, EM-FU and CNDP, were maintained for a longer time in the tumor-bearing rats, and eventually the blood 5-FU levels were maintained over 12 hours. Moreover, 5-FU levels in the tumor tissue tended to be maintained higher and longer time over 24 hrs. than those in the blood of rats. Antitumor activity of such characterized BOF-A2 was investigated with transplantable tumors in rodents and DMBA-induced breast carcinomas in rats. The ED 50 (the dose for 50% inhibition of tumor growth) value was about 15 to 25 mg/kg against the tumors tested. These result may suggest that BOF-A2 has potent antitumor activity in accordance to the long persistence of 5-FU level in the tumor tissue.     

Antitumor activity and metabolism of BOF-A2, a new 5-fluorouracil derivative, with human cancers xenografted in nude mice

Antitumor activity of BOF-A2, a new 5-fluorouracil (5-FU) derivative, was evaluated with human gastric (H-111 and H-81), colorectal (H-143), pancreatic (H-48) and breast (H-31) cancers xenografted in nude mice. Twenty-five consecutive oral administration of BOF-A2 at 17.5 to 30 mg/kg over 4 weeks caused marked inhibition or regression (over 92% of inhibition rate) to the growth of H-81, H-143 and H-31 cancers. Moreover, BOF-A2 effected to both H-111 and H-48 which have low sensitivity to 5-FU and its known derivatives. Throughout the experiments, the mice seemed to tolerate the consecutive administration of BOF-A2 without severe toxicity. When BOF-A2 was given orally, 5-FU levels in the blood of mice was notably durative for a long time as compared to 5-FU and UFT. Furthermore, 5-FU levels in the tumor tissue tended to increase and persist much more than those in the blood. This maintenance and persistence of objective level of 5-FU in the blood would be concluded to produce a high antitumor effect of BOF-A2 against human cancers xenografted in nude mice.     

BOF-A1 and BOF-A2, new 5-FU degradation-inhibitory agents

2, 6-Dihydroxy-3-cyano pyridine (CNDP) was found from the study of inhibitory effects of pyrimidine and pyridine derivatives on 5-FU degradation catalyzed by dihydrouracil dehydrogenase. CNDP, a new inhibitor on 5-FU degradation was 300 times more effective than uracil. Co-administration of an equi-molar CNDP with some fluorinated pyrimidine preparations potentiated their antitumor activity. Tegafur (FT-207) and EM-FU in combination with CNDP were found most effective. This potentiation was exhibited not only to 5-FU derivatives but also to FdUrd and its derivatives. BOF-A1 and BOF-A2, new compounds combined with CNDP were markedly active against mouse sarcoma 180 and rat Yoshida sarcoma.     

Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin.

The authors treated 14 patients with advanced squamous cell carcinoma (SCC) of the skin or lip with one to four cycles of combination chemotherapy consisting of cisplatin by bolus injection, and 5-fluorouracil (5-FU) and bleomycin by continuous 5-day infusion. Objective responses were seen in 11 of the 13 evaluable patients (84%). Four patients had a complete remission (30%) and seven patients, a partial remission (54%). Local control after definitive complementary radiation and/or surgical treatment was achieved in seven patients. Toxic side effects was acceptable; they consisted of nausea and vomiting in all patients, transient skin changes, hematologic (Grade 3/4) abnormalities in four patients, and pulmonary fibrosis in one elderly patient. These results show that this chemotherapy combination could play a role in reducing the tumor mass and in facilitating definitive treatment to obtain better functional and cosmetic results in advanced SCC of the skin.     

Celecoxib与5-FU联用对人肝癌细胞系HepG2细胞增殖的影响

目的体外观察氟尿嘧啶（5-FU）与Celecoxib联用对人肝癌细胞系HepG2细胞增殖的相互作用。方法采用MTT法观察不同浓度Celecoxib、5-FU单独或联合应用对HepG2细胞生长的抑制作用,并利用中效原理判定两药合用的效果。结果两种药物单独应用时,对HepG2细胞的抑制作用呈明显的剂量效应依赖关系;Celecoxib的中效浓度（IC50）为93.55μmol/L,5-FU的中效浓度为734.32μmol/L。这两种药物联用时存在“加速抑制作用”。应用中效原理分析显示,两种药物联用在很宽的效应范围内存在协同效应,增大Celecoxib的用量可在更宽的效应范围内获得两种药物的协同效应,而与药物应用的先后顺序无关。结论Celecoxib与5-FU在联合应用时的相互作用为协同效应,研究结果对肝癌的治疗具有一定的临床意义。     

Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged

Multiple or recurrent squamous cell skin carcinoma is a rare tumor in the aged. These patients are currently treated with 5-fluorouracil (5-FU) cream as a local chemotherapy; in cases in which the disease progresses, few treatments are available. Two reports deal with the treatment of progressive squamous cell skin carcinoma with systemic 5-FU, but in only eight patients age less than 70 years. We prospectively investigated oral 5-FU therapy in 14 consecutive patients (average age 76 1/2 years) with histologically proven squamous cell skin carcinoma. The disease was aggressive, multiple, or recurrent and had not been eradicated by surgery, radiation therapy, topical 5-FU cream, and non-5-FU chemotherapy. Oral 5-FU was administered as mannitol-coated 5-FU tablets at the daily dose of 175 mg/m2 for 3 weeks every 5 weeks. Toxicity, effectiveness, quality of life, and compliance to therapy were evaluated. Total cycles amounted to 55 (range: 2-6, mean: 4 for each patient) at an average dose intensity of 740 mg/m2/week for from 12 to 36 weeks. Only gastrointestinal toxicity World Health grade I occurred. Quality of life and compliance to therapy were 90%. Therapy induced measurable improvement in nine patients (64.3%): two partial remissions (14.3%), three minimal remissions (21.4%), and four arrests of disease (28.6%) with a median duration of 30+ months. The study ended because of a lack of patients. We can conclude that, if elderly patients require chemotherapy because of progressive multiple or advanced squamous cell skin carcinoma, appreciable results may be obtained with oral 5-FU as a single agent.     

Sequential methotrexate-5-fluorouracil treatment of squamous cell carcinoma of the head and neck

Thirty-six patients with squamous cell carcinoma of the head and neck were treated with sequential methotrexate-5-fluorouracil followed by leucovorin rescue. The frequency of objective tumor regression obtained was 64% (complete response + partial response) with 19% complete regression. In 20 not previously treated patients, the objective response rate was 70%. Approximately the same result was obtained for tumors of different anatomical sites of the head and neck. The degree of differentiation of the squamous cell carcinoma did not seem to be of prognostic importance for the initial tumor response. Toxicity was very mild and usually disappeared when the interval between the chemotherapy courses was prolonged from 1 to 2 weeks. Radiotherapy could be added sequentially to the treatment without measurable escalated toxicity.     

Concomitant 5-fluorouracil infusion, mitomycin C and radical radiation therapy in esophageal squamous cell carcinoma

This is a retrospective comparison of patients with unresected esophageal squamous cell carcinoma treated by radiation therapy and chemotherapy (21 patients) versus radiation therapy alone (34 patients). Pretreatment characteristics were comparable in both groups. In the combined modality group, treatment was given in split courses with concomitant radiation therapy (20 to 25 Gy in 10 fractions on days 1-12 and days 42-54) and chemotherapy (bolus Mitomycin C on day 1; 96 hr. of continuous 5 Fluorouracil infusion on days 1-4 and days 42-46). There was improvement in local disease control with the combined modality approach. Initial complete response was achieved in 86% of the radiation and chemotherapy group, versus 57% of the radiation alone group. The one-year local relapse-free rate was 67% versus 35%, and 2 year rate was 41% versus 28%. (p less than 0.05). The 1-year and 2-year survival was 64% and 32% respectively, for the radiation and chemotherapy group, versus 28% and 10% respectively for the radiation alone group (p less than 0.05). The majority of patients had disease relapsed, 81% of the combined modality group and 97% of the radiation alone group. However, the pattern of failure was different in the two groups. In the radiation and chemotherapy group, 29% had local failure alone, 53% had distant failure alone, and 18% had both local and distant failure. In the radiation alone group, 33% had local failure alone, 24% had distant failure alone, and 43% had both local and distant failure. Concomitant radiation therapy, 5 Fluorouracil infusion and bolus Mitomycin C is effective treatment for local control in esophageal squamous cell carcinoma, but not for distant hematogenous metastases. This combined modality treatment was well tolerated, with little additional hematological toxicity, esophagitis and stomatitis over radiation therapy alone.     

Antitumor Activity of BOF-A2, a New 5-Fluorouracil Derivative

A compound containing both CNDP (3-cyano-2,6-dihydroxypyridine), an inhibitor of 5-fluorouracil (5-FU) degradation, and EM-FU (1-ethoxymethyl-5-fluorouracil), a masked form of 5-FU, was synthesized and named BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil). The antitumor activity of BOF-A2 was investigated in sarcoma-180-bearing mice and Yoshida sarcoma-bearing rats. The ED₅₀ (the dose for 50% inhibition) values of BOF-A2 were 25 mg/kg against sarcoma-180 and 15 mg/kg against Yoshida sarcoma. In vitro studies showed that BOF-A2 was rapidly degraded to EM-FU and CNDP in homogenates of the liver and small intestine of mice and rats, and in sera of mice, rats and human, and the conversion of EM-FU to 5-FU occurred only in the microsomal fraction of rat liver in the presence of NADPH. After oral administration of BOF-A2 at 15 mg/kg to Yoshida sarcoma-bearing rats, BOF-A2 was hydrolyzed to EM-FU, CNDP and 5-FU, and their maximum concentrations in the blood were 2000 ng/ml, 300 ng/ml and 40 ng/ml, respectively. Moreover when BOF-A2 was given at the same dose to tumor-bearing mice and rats, the 5-FU levels in the tumor tissue increased much more than those in the blood and persisted for more than 8 h, whereas those in the blood decreased more rapidly. This accumulation and maintenance of a high level of 5-FU in the tumor tissue are concluded to be related to the high antitumor activity of BOF-A2.     

Long-term follow-up of neoadjuvant cisplatin and 5-fluorouracil chemotherapy in bulky squamous cell carcinoma of the cervix.

Fifteen patients with bulky (designated as > 3 cm largest diameter) FIGO stage Ib or IIa squamous cervical cancer were treated with cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 continuously on days 1-5) administered intravenously at 21-day intervals for a total of two or three courses before planned radical hysterectomy. A complete clinical response was noted in four patients and a partial response in ten patients, which represents a 93% overall response rate. One patient had stable disease (two courses of chemotherapy), and none had progressive disease. Median tumor volume was 78.5 cm3 and 2.5 cm3 at diagnosis and after neoadjuvant chemotherapy, respectively (p < 0.001). This indicates that chemotherapy resulted in a 97% median reduction of tumor volume. Median overall and disease-free survival was not reached, and the actuarial five-year survival rate was 73% and 67%, respectively. There was no grade 4 toxicity. Myelosuppression was acceptable; however, two patients experienced significant ototoxicity, and in two patients serum creatinine increased. All patients with major toxicity received two cycles of chemotherapy only. The improved local control and survival in our series are in accordance with other results reported, but need to be confirmed in a randomized prospective trial.     

Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil

Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC-4, were treated with CDDP and/or 5-FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase-3 and -8 activities was then observed by the addition of agonistic anti-Fas antibody, CH-11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH-11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5-FU resulted in an increasing susceptibility to apoptosis. Caspase-3 and -8 inhibitors, but not caspase-9 inhibitor, reduced Fas-mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD-like interleukin 1-converting enzyme-inhibitory protein (c-FLIP) levels, whereas neither the Fas-associated death domain-containing protein (FADD) nor procaspase-8 changed the expression. Moreover, antisense oligonucleotide to c-FLIP confirmed that down-regulation of c-FLIP induced sensitization to Fas-mediated apoptosis. These results suggest that CDDP and 5-FU may enhance the susceptibility to Fas-mediated apoptosis through down-regulation of c-FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs.     

Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin

Seven patients with advanced locoregional or metastatic squamous cell carcinoma of the skin were treated with cis-daimminedichloroplatin (cisplatin) and 5-fluorouracil (5-FU). Responses were seen in six of seven patients (three partial responses [PR] and three complete responses [CR]). One patient is alive and disease-free at 2 years. These results indicate that cisplatin and 5-FU is an effective combination regimen that should be used in future clinical trials in squamous cell carcinoma of the skin.     

AEG-1在5-氟尿嘧啶诱导的人口腔鳞状细胞癌细胞耐药中的作用

目的:探讨星形胶质细胞升高基因-1（astrocyte elevated gene-1,AEG-1）对5-氟尿嘧啶（5-FU）诱导的口腔鳞状细胞癌（oral squamous cell carcinoma,OSCC）细胞系耐药性的影响。方法:验证高（SCC15）、中（转染空质粒的对照组SCC15、CAL27）、低（CAL27）四组不同AEG-1表达量细胞模型AEG-1基因转染效果。MTT实验观察四组细胞对5-FU耐受性的变化;蛋白质印迹法和细胞划痕实验观察四组细胞在5-FU作用下caspase-3、MMP-2、MMP-9蛋白表达水平变化及细胞迁移能力的变化。结果:AEG-1基因在细胞中转染成功。MTT实验显示不同浓度5-FU作用四组细胞后,过表达组细胞的半数抑制浓度（IC50）为423.7 μg/ml,其对照组为213.5 μg/ml（P<0.05）;沉默细胞组IC50值为291.6 μg/ml,其对照组为463.1 μg/ml（P<0.05）。Western blot显示过表达组及其对照组中5-FU的浓度分别为400 μg/ml和200 μg/ml时,MMP-2、MMP-9及caspase-3的表达水平开始升高（P<0.05）;沉默组及其对照组中5-FU的浓度分别为240 μg/ml和480 μg/ml时,MMP-2、MMP-9及caspase-3的表达水平开始升高（P<0.05）。划痕实验显示加入相同浓度5-FU后过表达组细胞迁移率明显高于其对照组（P<0.05）;而沉默组细胞迁移率明显低于其对照组（P<0.05）。结论:上调/下调AEG-1表达能增加/降低OSCC细胞对5-FU的耐药性,提示OSCC细胞的耐药性可能与AEG-1表达量相关,OSCC细胞系中AEG-1的表达情况可能能间接干扰临床药物化疗的效果。     

Effects of plasma concentrations of 5-fluorouracil on long-term survival after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

Background

A substantial body of literature has accumulated during the past 20 years showing the plasma concentrations of 5-fluorouracil (5-FU) to correlate with clinical response and/or toxicity in colorectal cancer, and head and neck cancer, but little information is available concerning effects on long-term survival. Here, Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-FU/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the association between prognosis and the plasma concentration of 5-FU was evaluated.

Methods

Forty-nine patients with ESCC, who were treated with a definitive 5-FU/CDDP-based CRT, were enrolled. A course consisted of the continuous infusion of 5-FU at 400 mg/m²/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m²/day on days 1 and 8, and the radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5:00 PM on days 3, 10, 38 and 45, and at 5:00 AM on days 4, 11, 39 and 46.

Results

The overall 5-year survival rate was 42.9%. Age (P = 0.020), body weight (P = 0.019), and disease stage (P = 0.048) affected the survival, and the survival depended on the clinical response assessed at 1 month after the treatment (P = 0.001). Higher plasma concentrations of 5-FU resulted in a better clinical response (P = 0.043), and trended to prolong survival (P = 0.321).

Conclusions

The long-term survival after treatment with a definitive 5-FU/CDDP-based CRT possibly depends on the plasma concentrations of 5-FU, and further clinical studies with a larger number of cases are needed to clarify the relationship between them.     

Growth inhibitory effects of pegylated IFN-alpha2b and 5-fluorouracil in combination on renal cell carcinoma cell lines in vitro and in vivo

We investigated the effects of pegylated IFN-alpha2b (PEG-IFN-alpha2b) alone and PEG-IFN-alpha2b plus 5-fluorouracil (5-FU) in vitro on the proliferation of renal cell carcinoma (RCC) cell lines. After the transplantation of RCC cells into nude mice, we administered IFN (PEG-IFN-alpha2b or IFN-alpha2b) alone, 5-FU alone, or IFN (PEG-IFN-alpha2b or IFN-alpha2b) plus 5-FU; and investigated tumor volume, tumor weight, the numbers of apoptotic cells and artery-like blood vessels, relative mRNA expression levels of enzymes which relate to 5-FU metabolism, angiogenesis factor, and type I interferon receptor. RCC cells in vitro were generally and relatively resistant to the anti-proliferative effects of PEG-IFN-alpha2b, but the addition of 5-FU augmented IFN-induced anti-proliferative effects with the induction of apoptosis. PEG-IFN-alpha2b in vivo presented stronger anti-tumor effects than IFN-alpha2b, and its combination with 5-FU augmented the effects. The significant anti-tumor effect of the combination treatment was the increase in apoptotic cell number, but there were no significant differences in the suppression of angiogenesis, expression of IFN receptor, and the actions of metabolic enzymes of 5-FU. In conclusion, PEG-IFN-alpha2b presents stronger anti-tumor effects than non-pegylated IFN, and the effects are augmented in the combination with 5-FU. Our findings suggest the clinical usefulness of PEG-IFN-alpha2b in the treatment of RCC.     

Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck

One hundred and eight patients with squamous cell carcinoma of the upper aerodigestive tract (UADT) (T3, T4, NO-N3; 17% stage II, 54% stage III, 27% stage IV) were given three courses of chemotherapy before any local treatment. The regimen consisted of cis-platinum 100 mg m-2 on day 1 and 5-fluorouracil 1000 mg m-2 on days 2-6; drugs were administered by continuous infusion. The toxicity of this protocol was acceptable, as 82% of the patients were able to receive the initially scheduled drug dose. The overall response rate of 86.5% included a 35% rate of complete lesion regression. The effect of this regimen on primary tumours was especially remarkable--87.5% responses, including 47.5% complete responses. Results for lymph node metastases were not as good--66% responses, including 33% complete responses. The best results were obtained for tumours of the oropharynx and hypopharynx; oral cavity lesions were the most refractory. For those patients who were subsequently operated on, histological examination of the surgical specimen either confirmed sterilization or demonstrated the persistence of small disease foci. After local treatment, which consisted of radiotherapy alone for 69% of patients, the lesion control rate was 80%. At 18 months follow-up, the survival rate for patients who achieved a complete response with chemotherapy was significantly better than that for patients with a response of less than 50%.     

Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma

Epigenetic alterations such as histone acetylation and DNA methylation play an important role in the regulation of gene expression for cell cycles and apoptosis that may affect the chemosensitivity of cancers. Previously, we have reported that the combination of suberoylanilide hydroxamic acid (SAHA), a newly developed histone deacetylase inhibitor, with cisplatin (CDDP) possessed synergistic cytotoxicity against human oral squamous cell carcinoma (OSCC) cell line HSC-3. In this study, we used a novel DNA methyltransferase inhibitor, zebularine (Zeb), to investigate the epigenetic influence on the sensitivity of carcinoma cell lines to 5-fluorouracil (5-FU) or CDDP by evaluating apoptotic inducibility. Treatment with CDDP or 5-FU either alone or in combination with Zeb or SAHA continued for 48 or 72 h. In HSC-3 cells, Zeb had chemosensitive efficacy with CDDP, but not 5-FU, whereas SAHA showed efficacy with both CDDP and 5-FU. We showed that Zeb has strong anti-proliferative activity against HSC-3 cells, shown by decreased cellular growth and G2/M cell cycle phase accumulation. Furthermore, DNA methylation could be a regulatory mechanism for dihydropyrimidine dehydrogenase (DPD), known to be a principal factor in 5-FU resistance. CDHP (5-chloro-2,4-dihydroxypyridine), an inhibitor of DPD, had an enhancing effect on the apoptotic ability of 5-FU alone or 5-FU/Zeb combination. In conclusion, the present study suggests that low-dose (IC20) Zeb may sensitize cancer cells to CDDP, which may be an important characteristic for solid cancer treatment, and that DPD and other agents activated by Zeb in cancer cells could be an inhibitory factor in the response to apoptosis induced by 5-FU.     

DCF (docetaxel,cisplatin and 5-fluorouracil) chemotherapy is a promising treatment for recurrent advanced squamous cell anal carcinoma

BackgroundSquamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed at early stage. After concurrent chemoradiation (CRT) with mitomycin C and 5-fluorouracil (5FU), local or metastatic recurrences occur in >20% of the patients. After treatment failure, cisplatin (CDDP)-based chemotherapy is the standard option, but complete response (CR) is a rare event and the prognosis remains poor.Patients and methodsEight consecutive patients with advanced recurrent SCCA after CRT were treated with DCF regimen (docetaxel 75 mg/m² day 1, CDDP 75 mg/m² day 1 and 5FU at 750 mg/m²/day for 5 days every 3 weeks). Tumour samples were analysed for human papillomavirus (HPV) genotyping, as well as p16 and p53 expression.ResultsAfter a median follow-up of 41 months, the overall survival rate at 12 months was 62.5% (95% CI 22.9–86.1 months). Four patients achieved a complete remission and remain relapse-free at the time of analysis with a progression-free survival of 19, 33, 43 and 88 months. Three of these patients underwent surgery for all involved metastatic sites. For all of them, pathological CR was confirmed. DCF regimen appeared feasible in these patients previously exposed to pelvic CRT, and no grade IV toxicity occurred. All patients in complete remission had HPV-16-positive SCCA, while HPV could only be detected among 50% of the non-responding patients. Of interest, immunohistochemical study revealed a p16⁺/p53^- phenotype in these patients, while none of non-responders expressed p16.ConclusionThe high level of complete and long-lasting remission among SCCA patients treated with DCF regimen supports the assessment of this strategy in prospective cohorts.