Combination therapy with molecular targeting drugs for head and neck cancer

Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for advanced head and neck cancer (HNC). Intensive combination chemotherapy has been re-considered for neo-adjuvant chemotherapy in functional preservation protocol. Molecular targeting drugs (MTG) have proved effective for HNC not only in basic study but in many clinical phase II trials. Cetuximab, an anti-EGFR monoclonal antibody, is a key drug for regimens including MTG. Phase III trials with CDDP/carboplatin+5-FU vs CDDP/carboplatin+5-FU+cetuximab proved the combination with cetuximab was statistically effective for survival of patients with recurrent/metastatic HNC. Combination with cetuximab prolonged survival from 7.4 months to 10.1 months in this report. A good response rate and survival rate are reported in phase II study for chemoradiotherapy with CDDP and cetuximab. The three-year overall survival and local control rate were 76% and 71%, respectively. The combination with MTG will be important in CCRT for advanced HNC. It may well be considered the standard treatment for recurrent/metastatic HNC patients in future.     

Concurrent chemoradiotherapy (CRT) with S-1 and cisplatin (CDDP) in patients (pts) with locally advanced head and neck cancer (HNC)

The standard care for unresectable locally advanced head and neck cancer (HNC) is concurrent chemoradiotherapy (CRT). Although there is no standard regimen of CRT, a platinum-based regimen has shown a better survival benefit than other regimens. The control arm in a randomized trial for unresectable locally advanced HNC is radiotherapy concurrent with CDDP (100 mg/m2, every 3 weeks), which has been considered to be too toxic for clinical practice in Western countries and has required frequent dose modifications. Because the Japanese also have been considered unable to tolerate this regimen, no prospective study of it has been conducted in Japan. Most Japanese patients with locally advanced head and neck cancer have received concurrent chemoradiotherapy with 5-FU and CDDP (70-80 mg/m2). S-1 has shown high activity in HNC with a response rate of 34%. Furthermore, a combination of cisplatin and S-1 therapy for HNC has been reported to have good efficacy. With this rationale in mind, we conducted a phase I study of CRT with S-1 and CDDP for unresectable locally advanced squamous cell carcinoma of the head and neck. The CR rate was very promising, though preliminary, and warrants further investigation. The Japan Clinical Oncology Group (JCOG) is planning a multicenter phase II study of concurrent chemoradiotherapy with S-1 and CDDP for locally advanced unresectable HNC.     

S-1 plus cisplatin: another option in the treatment of advanced head and neck cancer?

Evaluation of: Fujii M, Tomita K, Nishijima W et al. Phase I/II study of S-1 plus cisplatin combination chemotherapy in patients with advanced/recurrent head and neck cancer. Jpn. J. Clin. Oncol. 40(3), 214–221 (2010).

A combination of 5-fluorouracil (5-FU) and cisplatin is the most commonly used chemotherapy regimen in patients with advanced head and neck cancer (HNC). Japanese investigators replaced 5-FU with the oral fluoropyrimidine S-1 (40 mg/m² twice daily on days 1–14 every 4 weeks) to treat patients with locally advanced, recurrent, or metastatic HNC; and determined that the dose of cisplatin on day 8 should be 70 mg/m². The authors also studied the efficacy and safety of this regimen in a continuing Phase II trial. Treatment with S-1 plus cisplatin resulted in a confirmed response rate of 44.1% and a median overall survival duration of 16.7 months. The most common grade 3 or 4 adverse events included anorexia (26.5%), nausea (14.7%), and neutropenia/thrombocytopenia (11.8%). Despite inclusion of patients heterogeneous in disease status and incomplete response evaluation, this study demonstrated that S-1 in combination with cisplatin is feasible for treatment of advanced/recurrent HNC.     

Combination therapy with S-1 and CDDP for head and neck cancer

The combination with cisplatin (CDDP) and 5-FU is considered the first choice chemotherapy for squamous cell carcinoma of the head and neck (HNSCC). S-1, a modulation of tegafur developed in Japan, is an active agent for HNSCC. Some clinical phase I/II studies about the combination with CDDP and S-1 have been reported. The combination showed a good response rate of 67.6% for advanced and recurrent HNSCC in our clinical phase I/II study. The regimens of S-1 combined with carboplatin or nedaplatin have also been reported. Regimens containing S-1 appear to have been effective for HNSCC. Multi-institutional phase II studies with a large sample size are needed in the future. The compliance for patients is better than a 5-FU injection because S-1 is orally administrated. The adverse effect, especially for bone mallow toxicity, is equal or upgraded compared with a 5-FU injection. The efficacy and adverse effects of CDDP plus S-1 should be studied in carefully designed phase II/III trials. S-1 will be one of the key drugs for HNSCC in the future.     

Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study.

PURPOSE: The Southwest Oncology Group (SWOG) conducted a randomized comparison of cisplatin plus fluorouracil (5-FU) and carboplatin plus 5-FU versus single-agent methotrexate (MTX) in patients with recurrent and metastatic squamous-cell carcinoma (SCC) of the head and neck. The primary objective was to compare separately the response rates of each combination regimen to standard weekly MTX. PATIENTS AND METHODS: Two hundred seventy-seven patients diagnosed with SCC of the head and neck were randomized to one of three treatments: (1) cisplatin 100 mg/m2 intravenously (IV) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days; (2) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days; and (3) MTX 40 mg/m2 IV given weekly. RESULTS: All three treatment regimens were well tolerated. However, both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX (P = .001). Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens. The complete and partial response rates were 32% for cisplatin plus 5-FU, 21% for carboplatin plus 5-FU, and 10% for MTX. The comparison of cisplatin plus 5-FU to MTX was statistically significant (P less than .001), and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance (P = .05). Median response durations and median survival times were similar for all three treatment groups. Logistic regression models showed that only treatment assigned was associated significantly with response (P = .001). Cox proportional hazards models indicated that only performance status was associated significantly with survival (P less than .01). CONCLUSIONS: We conclude that combination chemotherapy resulted in improved response rates but was associated with an increased toxicity and no improvement in overall survival. Therefore, new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified.     

Low-dose CDDP and 5-FU for head and neck cancer patients]

Combination chemotherapy with CDDP and 5-FU is one of the most effective regimens for head and neck cancer. Recent studies have focused on biochemical modulation in the combination of CDDP and 5-FU. We studied the difference in effectiveness and adverse effects between two CDDP administration schedules for CDDP-5-FU combination chemotherapy. For regimen A, CDDP was administered on 5 consecutive days from day 1 to day 5, with a daily dose of 16 mg/m2. For regimen B, CDDP was administered at 80 mg/m2 on day 1. 5-FU was administered at 600 mg/m2/day in a continuous drip infusion for 120 hours from day 1 to day 5 for regimens A and B. Twenty-seven patients with head and neck squamous cell carcinoma were included in this study, and received either regimen A or B. Thirteen patients were given regimen A and 14 regimen B. With regimen A, 3 patients showed CR and the response rate was 76.9%. With regimen B, 3 patients showed CR and the response rate was 64.3%. The rates of efficacy were not different between regimen A and B. In contrast, a difference was seen with organ toxicity. Regimen B was more toxic for renal function than regimen A, while regimen A showed greater toxicity to bone marrow function. Acute nausea and vomiting were observed more frequently with regimen B. The difference in organs and symptoms of adverse effects, according to the schedule of CDDP administration would seem to be important in the treatment of head and neck cancer patients. The schedule of CDDP administration should be adjusted depending on the renal and bone marrow functions of the patients. Because multiple infusion of CDDP proved to be efficacious, low-dose CDDP and 5-FU will have a role for patients with head and neck squamous cell carcinoma. We also introduce other reports on the efficacy of low-dose CDDP and 5-FU.     

Phase II study of carboplatin and continuous infusion bleomycin followed by cisplatin and 5-fluorouracil in recurrent head and neck cancer

BACKGROUND: Recurrent squamous cell carcinoma of the head and neck is poorlyresponsive to most chemotherapy regimens. Carboplatin and bleomycinare effective single agents with non-overlapping toxicity; therefore,we sought to explore the efficacy of this regimen in a phaseII study. In the second stage of the study, patients who didnot respond to carboplatin and bleomycin were given treatmentwith cisplatin and 5-fluorouracil (5-FU). PATIENTS AND METHODS: Patients with recurrent squamous cell carcinoma of the headand neck were treated with carboplatin 400 mg/m² followed bybleomycin 15 units intravenously as a continuous infusion for4 days. Patients with no tumor response after 3 cycles of carboplatinand bleomycin were crossed-over to receive cisplatin 100 mg/m²and 5-FU 1000 mg/m²/day continuous infusion for 5 days. RESULTS: Among the 20 carboplatin-bleomycin patients evaluable for toxicity,no cases of grade 4 granulocytopenia were reported and grade3 or 4 thrombocytopenia developed in only three patients. Threepartial responses occurred among the 19 patients (16%) [95%Cl. 0% to 32% evaluable for response to carboplatin-bleomycin.None of the 11 patients crossed-over to cisplatin and 5-FU hada major response. CONCLUSION: The combination of carboplatin and bleomycin is well toleratedin patients with recurrent head and neck cancer, but the activitydoes not appear to be superior to the activity of either agentalone. Patients who did not respond to carboplatin and bleomycinwere also resistant to the cisplatin and 5-FU regimen. head and neck cancer, chemotherapy     

Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III–IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.     

A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck

We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.     

Treatment of recurrent and/or metastatic squamous cell head and neck carcinoma with a combination of vinorelbine, cisplatin, and 5-fluorouracil: A multicenter phase II trial

PURPOSE:: Vinorelbine has been demonstrated to be active against squamouscell carcinomas of the headneck (SCHNC) and lung. This multicenterphase II trial was carried out to evaluate the activity andtolerability of the combination of vinorelbine, cisplatin, and5-fluorouracil given on an outpatient schedule in a series of80 patients with recurrent SCHNC. PATIENTS AND METHODS:: Eighty patients with recurrent and/ or metastatic SCHNC weretreated with a combination of CDDP 80 mg/m2 on day 1, 5-FU 600mg/m2 as a 4-hour infusion on days 2-5, and vinorelbine 25 mg/m2on days 2 + 8. This cycle was repeated every 28 days. Most patientshad oral cavity, larynx, or oropharynx carcinoma (88%). Forty-sevenhad previously received surgery alone, two radiotherapy alone,and 31 surgery plus radiotherapy. Seventy-two patients had locoregionalrecurrency, and eight had distant metastases. RESULTS:: According to an intent-to-treat analysis, complete response(CR) of a mean duration of 12.7 months was achieved in 13% ofcases (95% CI 5%-21%), and partial response of 8.3+ months in45% of patients (95% CI 33%-56%), for an overall response rateof 55% (95% CI 43%-65%). Nine patients (11%) showed no change,and 22 (28%) progressed. Five patients were not evaluable forresponse and toxicity. CR were seen more frequently in patientspre-treated with only surgery than in those who had also receivedradiotherapy (15% vs. 9%; p = 0.7). No statistically significantdifferences in response rate according to site of primary tumorwere found (p = 0.8, NS). The received dose intensities of 5-FU,CDDP, and VNR were 90%, 92%, and 82%, respectively. The overallsurvival of the series as a whole was 9.7+ months (range 4-27).Toxicity was generally acceptable. Grades 3 and 4 leukopniawere recorded in 11% and 5% of patients, respectively. Noteworthywas the occurrence of pain at the tumor site after vinoreleadministration in 5 patients. CONCLUSION:: The combination regimen of CDDP, 5-FU and vinorelbine is quiteactive in the treatment of metastatic and/or recurrent SCHNC.This regimen should be tested as initial treatment in previouslyuntreated patients and compared to a standard regimen in recurrentSCHNC. head/neck cancer, vinorelbine, cisplatin, 5-fluorouracil, chemotherapy     

多西紫杉醇联合卡铂与氟尿嘧啶联合卡铂治疗局部晚期鼻咽癌近期疗效的比较

背景与目的:以铂类为基础联合氟尿嘧啶(5-fluorouracil,5-FU)方案是鼻咽癌患者最常用方案,但患者的疗效一直维持在50%～60%。多西紫杉醇是治疗头颈部恶性肿瘤有效的单药,其给药方式简单、给药时间短。本研究通过比较多西紫杉醇联合卡铂(TC)方案与5-FU联合卡铂(FC)方案对局部晚期鼻咽癌患者的近期疗效和不良反应,探讨局部晚期鼻咽癌诱导化疗的新方案。方法:2005年11月1日至2008年12月1日,58例局部晚期鼻咽癌患者按照相同的临床分期和性别,随机抽签进入试验组和对照组。试验组29例患者采用多西紫杉醇联合卡铂诱导化疗2个疗程后,行2疗程卡铂单药同期放化疗;对照组29例患者采用5-FU代替多西紫杉醇诱导化疗,余治疗方案同试验组。χ2检验比较两组患者诱导化疗及同期放化疗的近期疗效和不良反应。结果:试验组的平均化疗周期数比对照组多(3.31vs.2.83,P=0.043)。两组近期疗效及1年总生存率差异均无统计学意义(P>0.05)。试验组和对照组Ⅲ度及Ⅲ度以上中性粒细胞减少的发生率分别为72.4%和37.9%,差异有统计学意义(P=0.05)。试验组血小板减少和呕吐发生率均较对照组少,差异有统计...     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck

Background: Paclitaxel has been demonstrated to have significant activityin recurrent or metastatic head and neck cancer (HNC). In addition, thecombination of paclitaxel and cisplatin is active in untreated patients withinoperable HNC. Substitution of carboplatin for cisplatin allows the treatmentto be delivered on an outpatient basis.Purpose of the study: To evaluate the activity and toxicity of thecombination of paclitaxel by three-hour infusion and carboplatin as first-linechemotherapy in patients with recurrent or metastatic HNC.Patients and methods: From March 1994 until August 1996, 49 patients withrecurrent or metastatic HNC were treated with paclitaxel (200mg/m², by three-hour infusion) followed by carboplatin at anAUC of 7 mg·min/ml, every four weeks. G-CSF was administeredprophylactically on days 2 to 12 of each cycle. There were 41 men and 8 womenwith a median age of 57 years (range 23–73). The majority of thepatients were symptomatic and they had recurrent disease locoregionally.Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cellcancers of other areas of the head and neck region (non-NPC).Results: At the completion of treatment, two patients with NPC demonstratedcomplete and six partial responses for an overall response rate of 57%(95% CI 29%–82%). Among patients with non-NPC, theresponse rate was 23% (95% CI 9%–37%). Aftera median follow up period of 15 months, the median time to progression was 4.3months in the non-NPC group and 16.5 months in the NPC group. At the time ofthe analysis, median survival had not been reached in NPC while it was 7.3months in non-NPC patients. Grade 3–4 toxicities included anemia(2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting anddiarrhea (4% each).Conclusions: The combination of paclitaxel and carboplatin appears to bewell tolerated but only moderately active in patients with advanced non-NPCof the head and neck region. However, its activity appears promising in NPCand deserves further investigation.     

Progress in chemotherapy for colorectal cancer

Among colorectal cancer patients with recurrent or metastatic sites, survival was significantly prolonged for a group undergoing LV/5-FU therapy based on biochemical modulation compared with a group receiving no chemotherapy (best supportive care). LV/5-FU combination therapy is recognized as the standard therapy for colorectal cancer, but recently LV/5-FU plus oxaliplatin and LV/5-FU plus CPT-11 have appeared to be more effective than LV/5-FU in some randomized studies. Capecitabine, UFT/LV and S-1 are new oral drugs that are at least comparable to LV/5-FU in antitumor activity, but superior in tolerability, which benefits the patients' quality of life, especially elderly patients with colorectal cancer. Clinical combination studies using CDDP or CPT-11 with these oral drugs are now being performed. Much is expected of these drugs.     

Combination therapy with TS-1

The combination with cisplatin (CDDP) and 5-FU is considered the chemotherapy of choice for squamous cell carcinoma of the head and neck (HNSCC). TS-1, a modulation of tegafur developed in Japan, is an orally administered active agent for HNSCC. Some clinical phase I/II studies on the combination of CDDP and TS-1 have been reported. The combination showed a good response rate, 67.6% for both advanced and recurrent HNSCC, in our clinical phase II study. Regimens of TS-1 combined with carboplatin or nedaplatin are also reported.TS-1 containing regimens appear to be effective for HNSCC, and multi-institutional phase II studies with large sample size are needed in future.The combination TS-1 and radiotherapy, its dose and schedule,are being studied in phase I trials for advanced HNSCC. Patient compliance is better than with 5-FU injection because TS-1 is orally administered.The adverse effect, especially in terms of bone marrow toxicity, is equal or better than with 5-FU injection. The TS-1 combination with radiotherapy is a useful regimen for outpatients. The efficacy and adverse effects should be studied in carefully designed phase I/II trials. TS-1 will be one of the key drugs for HNSCC in future.     

A phase II trial of cisplatin, methotrexate, levofolinic acid, and 5-fluorouracil in the treatment of patients with locally advanced, metastatic squamous cell carcinoma of the head and neck

BACKGROUND: Induction chemotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) might improve survival with respect to radiation therapy alone. Furthermore, chemotherapy represents the only therapeutic option in metastatic head and neck carcinoma. METHODS: To improve further the results that could be obtained with an induction regimen of cisplatin (CDDP) plus 5-fluorouracil (5-FU), the authors treated 50 patients with locally advanced or metastatic SCCHN with a combination of CDDP 65 mg/m2 on Day 1, methotrexate 500 mg/m2 on Day 1, levofolinic acid 250 mg/m2 on Day 2, and 5-FU 800 mg/m2 on Day 2. Cycles were repeated every 2 weeks. The authors' aim was to increase the activity of CDDP plus 5-FU (PF) using a regimen that combined the three most active drugs in SCCHN and provided an adequate biochemical modulation of 5-FU, which was administered as an intravenous bolus infusion. RESULTS: Forty objective responses were observed among 50 evaluable patients (80%; 95% confidence interval [C.I.], 66-90%), including 7 complete responses (14%; 95% C.I., 5-27%), and 33 partial responses (66%; 95% C.I., 51-79%). Locoregional treatment, consisting of radiotherapy or surgery, was given at the end of chemotherapy. On completion of induction chemotherapy and locoregional treatment, 42 of 46 patients (91%) were rendered disease free. After a median follow-up of 20 months, the median duration of response was 10 months, the median failure free survival was 10 months, and the median overall survival was 21 months. The treatment was generally well tolerated. Grade 3-4 neutropenia occurred in 25 patients (50%), but it was febrile in only 3 patients. Nausea and vomiting were well managed with serotonin-3 blocking agents. Severe mucositis was seldom observed and easily manageable, and it never required hospitalization. CONCLUSIONS: The high level of activity, the manageable toxicity, and the noteworthy survival data of this regimen compare favorably with most of the drug combinations used worldwide to treat similar patient populations, with the additional advantage of significantly lower cost.     

Chemo-radiotherapy for head and neck cancer

Many randomized trials have investigated the effect on survival of induction chemotherapy; none however, has demonstrated improved survival. A study of the Department of Veterans Affairs Laryngeal Cancer Study Group demonstrated the feasibility of induction CDDP/5-FU plus surgical salvage as an alternative to initial laryngectomy, but it did not include a radiation-alone treatment arm. Thus, a three-arm trial (R 91-11) was needed to compare the regimen of induction chemotherapy plus surgical salvage treatment with radiation alone and with concurrent chemo-radiation, to determine whether the addition of chemotherapy led to better results than conventional radiation alone. R 91-11 data revealed that concurrent chemo-radiation significantly increased the time to laryngectomy and chemotherapy suppressed distant metastasis, but there was no difference in overall survival. Single-agent docetaxel is known to induce a response in 22-45% of patients with recurrent squamous cell cancer of the head and neck. When used in combination with CDDP, response rates of between 40 and 54% have been reported. Increased expression the epidermal growth factor receptor (EGFR) is reported in head and neck cancer. Anti-EGFR monoclonal antibody is associated with decreased cell proliferation, inhibition of metastasis and angiogenesis, and it has a synergistic effect with chemotherapy or radiotherapy. It is hoped that further advances will lead to greater realization of the therapeutic potential of these compounds as anticancer agents.     

Chemotherapy for metastatic gastric cancer in Japan

Until the 1990s, there were no chemotherapy regimens with old-generation anticancer agents showing a survival benefit over 5-fluorouracil (FU) alone, and standard chemotherapy for metastatic gastric cancer had not been established. In the late 1990s, several new active agents were developed and some phase III trials with these agents were conducted; the new agent S-1 showed noninferiority to 5-FU in these trials. S-1 plus cisplatin is the first doublet chemotherapy to have shown a survival benefit over monotherapy with S-1. It has been demonstrated that capecitabine and oxaliplatin (OHP) can replace 5-FU and cisplatin (CDDP), offering more convenient treatment options. Thus, combination chemotherapy with an oral fluoropyrimidine (S-1 or capecitabine) and platinum (CDDP or OHP) has been recognized as standard chemotherapy for metastatic gastric cancer all over the world. However, it can be said that none of these new combination chemotherapies have shown remarkable progress from 5-FU plus cisplatin regimens. It is expected that triplet chemotherapy with a taxane; the use of molecular targeting agents; and the establishment of treatment strategies including second line chemotherapy, will lead to remarkable progress in personalized medicine in the near future.     

Clinical development of S-1 (TS-1) for advanced gastric cancer

The 5-FU plus cisplatin containing regimen like FP, ECF and DCF, is considered to be the most effective treatment for advanced gastric cancer in the United States, Europe, and Korea. In Japan, oral fluoropyrimidine S-1 (TS-1) is currently considered to be the first candidate as the standard drug for advanced gastric cancer. S-1 based combination therapies with other promising drugs like cisplatin, irinotecan and taxanes, are expected to yield good results. Above all, S-1+CDDP therapy showed a high efficacy and expected to be a standard therapy for advanced gastric cancer. Two large phase III studies, JCOG 9912 5-FU vs S-1 vs CPT-11 +CDDP and S-1 vs S-1+CDDP, are now on going to establish an acceptable frontline standard for patients with AGC. We therefore need to develop new agents and combination chemotherapy regimens to achieve a greater survival benefit in AGC.     

Continuous infusion 5-fluorouracil with escalating doses of intermittent cisplatin and etoposide. A phase I study

Continuous infusion 5-fluorouracil (CI 5-FU) and the combination of cisplatin (CDDP) plus etoposide (VP-16) have emerged as salvage regimens for metastatic breast carcinoma (MBC). In this study, 18 patients (15 with MBC) were entered into a Phase I study to determine the maximum intermittent doses of CDDP and VP-16 that could be added to 200 mg/m2/d CI 5-FU. The maximum tolerated dose of the combination was 40 mg/m2 of CDDP and 60 mg/m2 of VP-16 weekly for the first 8 weeks and every other week thereafter. The dose-limiting toxicities of the regimen were myelosuppression and thrombocytopenia. Two complete responses (both patients had received no previous chemotherapy) and one partial response were noticed. This regimen at the doses described here is appropriate for Phase II trials as an alternative to doxorubicin-based regimens for MBC.