白蛋白结合型紫杉醇在局部晚期/晚期头颈部肿瘤治疗中的研究进展及展望

化疗在局部晚期/晚期头颈部肿瘤的治疗中发挥重要作用,对提高肿瘤局部控制率、延缓肿瘤进展、减少远处转移及延长患者生存时间有重要的意义。TP（紫杉醇类加铂类）和TPF（紫杉醇类、顺铂及5-氟尿嘧啶）方案是头颈部肿瘤的经典有效化疗方案,故紫杉醇类（如紫杉醇和多西他赛）是头颈部肿瘤常用的化疗药物。白蛋白结合型紫杉醇作为一种新型紫杉醇类药物,以其独特剂型优势,已在多个临床试验中显示出良好的疗效及安全性。本文总结了以白蛋白结合型紫杉醇为基础分别联合其他不同化疗药物方案治疗局部晚期/晚期头颈部肿瘤的安全性及有效性,对白蛋白结合型紫杉醇在局部晚期/晚期头颈部肿瘤中应用的最新临床研究作一综述,并对未来该药治疗局部晚期/晚期头颈部肿瘤进行展望。      

Paclitaxel, cisplatin, 5-fluorouracil and radiotherapy in the management of advanced squamous cell carcinoma of the head and neck: a phase II trial.

Aim of the present study was to test, activity and toxicity of a rapidly alternating chemoradiation (paclitaxel based) in 31 patients with unresectable, locally advanced or recurrent after surgery, head and neck cancer. Three-year overall survival and progression-free survival were 61.4 and 73.7%, respectively. Main side effects remain a major problem.     

Paclitaxel, carboplatin, and concomitant radiotherapy for resected patients with high risk head and neck cancer

Many resected patients with locally advanced head and neck cancer are found on pathological assessment to have high-risk features for recurrence. We thus performed a feasibility trial of post-operative radiotherapy with paclitaxel and carboplatin in high-risk carcinoma of the head and neck. All patients were planned for 6 cycles of weekly paclitaxel (40 mg/m2) and carboplatin (AUC=1) and concomitant radiotherapy, 60 Gy in 6 weeks. The most common side effect was grade 3 and 4 mucositis in 5/6 patients and g-tube placement in 4/6 patients. Five out of 6 patients remain alive without evidence of disease at a mean time of 19 months since completion of therapy. Our pilot study treated 6 postoperative patients. Since 4 of 6 enrolled patients were unable to complete the treatment as prescribed, we conclude that this regimen is not feasible. With an 83% grade 3 or 4 mucositis rate and 67% of patients enrolled requiring feeding tube placement, this regimen is not tolerable.     

Paclitaxel,Carboplatin, and Concomitant Radiotherapy for Resected Patients with High Risk Head and Neck Cancer

Abstract

Many resected patients with locally advanced head and neck cancer are found on pathological assessment to have high-risk features for recurrence. We thus performed a feasibility trial of post-operative radiotherapy with paclitaxel and carboplatin in high-risk carcinoma of the head and neck. All patients were planned for 6 cycles of weekly paclitaxel (40 mg/m²) and carboplatin (AUC=1) and concomitant radiotherapy, 60 Gy in 6 weeks. The most common side effect was grade 3 and 4 mucositis in 5/6 patients and g-tube placement in 4/6 patients. Five out of 6 patients remain alive without evidence of disease at a mean time of 19 months since completion of therapy. Our pilot study treated 6 postoperative patients. Since 4 of 6 enrolled patients were unable to complete the treatment as prescribed, we conclude that this regimen is not feasible. With an 83% grade 3 or 4 mucositis rate and 67% of patients enrolled requiring feeding tube placement, this regimen is not tolerable.     

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.     

Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer.

BACKGROUND: Our goal was to evaluate long-term efficacy outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel (Taxol) and radiotherapy. PATIENTS AND METHODS: We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m(2) and paclitaxel 40 mg/m(2) were administered i.v. once a week during external beam radiation therapy (180 cGy per fraction) for 6-7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. RESULTS: Fifty-five patients were enrolled. Fifty-two patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. Twenty-one patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment that was related to complications of gastrostomy tube placement. Forty of 50 assessable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months for surviving patients, the 5-year progression-free survival was 36% and the 5-year overall survival was 35%. Two of the 18 long-term survivors of >50 months were gastrostomy tube feeding dependent. Patients undergoing brachytherapy boost (n = 21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. CONCLUSION: Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN.     

Paradigm shift in the treatment of head and neck cancer: the role of neoadjuvant chemotherapy

Chemotherapy is an integral component of the management of patients with locally advanced head and neck cancer, though the optimal use of chemotherapy remains to be defined. The combination of a platinum agent and 5-fluorouracil has been used as the standard neoadjuvant treatment and has been shown to permit organ preservation in operable patients and improve long-term survival outcomes in operable and inoperable patients. Recently, the addition of a taxane, docetaxel or paclitaxel, to standard platinum plus 5-fluorouracil induction chemotherapy has been shown to further improve response rates and survival outcomes. Phase III data are emerging to support combinations of docetaxel or paclitaxel with a platinum plus 5-fluorouracil as a new, more effective and less toxic standard for neoadjuvant chemotherapy. Sequential treatment regimens, incorporating a combination of induction chemotherapy and chemoradiation, are also under study in efforts to further improve long-term survival outcomes. Induction regimens incorporating docetaxel or paclitaxel with a platinum plus 5-fluorouracil are under evaluation in this setting. Randomized trials comparing a sequential treatment approach with standard therapies are also being undertaken and will likely define a new treatment paradigm for patients with locally advanced head and neck cancer.     

Sequential and synchronous chemo-radiotherapy in the management of locally advanced carcinoma of the head and neck

Thirty-nine consecutive patients with stage III-IV squamous cell carcinoma of the head and neck entered a pilot study of sequential and synchronous chemo-radiotherapy. The study was planned as follows: two cycles of induction chemotherapy (MTX, BLM, DDP) followed by radical radiotherapy (66 Gy) with synchronous weekly administration of DDP (20 mg/m2) as a radiosensitizer. Out of the 39 patients evaluable for induction chemotherapy 25 (64%) achieved partial or complete response. Two patients underwent radical surgery after induction chemotherapy and 3 patients died of treatment. Out of the remaining 34 patients, 25 were untreated and 9 presented recurrence after primary surgery. Grade 4 mucositis was the major side effect of concurrent chemo-radiotherapy. Local control after synchronous therapy was obtained in 11 (44%) previously untreated patients and only in 1 (11%) patient of the surgically pre-treated group. At the time of the analysis 11 patients were alive, 8 of them free from disease (4 after salvage surgery). Actuarial 2-year survival for previously untreated patients was 33% and 24% for all the patients. This survival is not significantly different (log rank test) from that of a similar group of 24 patients treated at the same institution with radiotherapy alone. The important toxicity of the induction chemotherapy regimen and the poor 2-year survival do not show any benefit from such a combined approach in locally advanced head and neck carcinoma. Nevertheless, despite our disappointing results many data in the literature suggest a role for chemotherapy-based treatments of locally advanced head and neck cancer. Further controlled randomized studies are required to better define the place of chemotherapy in the multi-modality management of stage III-IV head and neck cancer.     

紫杉醇为主联合化疗方案治疗晚期头颈部肿瘤

目的：回顾性分析１９９９～２００７年间含紫杉醇（ＰＴＸ）为主联合化疗方案治疗４２例晚期头颈部肿瘤的临床资料,探讨含ＰＴＸ为主方案治疗晚期头颈部肿瘤的临床疗效和相关不良反应。方法：含ＰＴＸ的联合化疗方案治疗诊断明确的晚期头颈部肿瘤４２例,初治１７例,复治２５例;其中ＰＴＸ联合顺铂（ＤＤＰ）治疗２３例,ＰＴＸ联合卡铂（ＣＢＰ）４例,ＰＴＸ联合ＤＤＰ及氟尿嘧啶（５-ＦＵ）１１例,ＰＴＸ联合异环磷酰胺（ＩＦＯ）及平阳霉素（ＰＹＭ）４例。严格按照ＷＨＯ（２０００）实体肿瘤客观疗效评价标准进行疗效评价,并观察治疗后生存时间。结果：随访截止２００７年１２月底,共计完成化疗１２７周期,平均每例３.１个周期,可评价疗效病例３８例,有４例因故未完成１个周期化疗或资料欠缺无法评价。总有效率（ＲＲ）为３４.２％,其中初治ＲＲ为５０.０％,复治ＲＲ为２２.７％;疾病进展时间（ＴＴＰ）为３.８个月,其中初治和复治ＴＴＰ分别为５.７个月和２.１个月;１年生存率５５.２％,其中初治和复治分别为５８.９％和３６.０％。主要不良反应为消化道反应和骨髓抑制,３度以上反应分别达１１.７％和２２.６％,经相应治疗后均可控制;无ＰＴＸ过敏反应发生,无化疗相关死亡病例。结论：含ＰＴＸ联合化疗方案治疗晚期头颈部肿瘤的临床疗效确切,其中对二线复治的病例仍有较高的有效率,不良反应可以耐受。     

Taxanes in the treatment of head and neck cancer

PURPOSE OF REVIEW: This review presents new data on the role of paclitaxel and docetaxel in the management of squamous cell carcinoma of the head and neck. Recently both agents have been tested in squamous cell carcinoma of the head and neck in combination with other chemotherapeutic agents, targeted drugs, and radiotherapy in in-vitro experiments and in the clinic as first-line treatment of patients with metastatic/recurrent and locally advanced squamous cell carcinoma of the head and neck. RECENT FINDINGS: The combination of taxanes with standard or accelerated radiotherapy is feasible and induction chemotherapy followed by chemoradiation is active and feasible without excessive toxicity in patients with locally advanced squamous cell carcinoma of the head and neck. The use of low-dose fractionated radiotherapy shows promising in-vitro and clinical results and is further explored. SUMMARY: Both docetaxel and paclitaxel can be combined with chemotherapeutic agents and radiotherapy, but phase III studies are needed to prove the superiority of these approaches compared to standard treatment. The final results of the combination study of cisplatin and 5-fluorouracil with or without docetaxel may change the standard chemotherapeutic regimen for induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.     

Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): analysis of chemoradiation treatment approaches in the United States

BACKGROUND:

A study was undertaken to examine the patterns of systemic therapy use in conjunction with radiation therapy for patients with locally advanced head and neck squamous cell cancer.

METHODS:

Between December 1, 2005 and May 11, 2009, 2874 patients with newly diagnosed head and neck squamous cell cancer who were scheduled to receive radiotherapy and/or drug therapy were registered in a prospective national database. The database was specifically analyzed to examine patients who received chemotherapy in conjunction with definitive radiotherapy.

RESULTS:

A total of 1144 patients received systemic therapy in conjunction with radiotherapy; 645 (56%) patients received agents concurrent with radiation therapy, 49 (4%) patients received chemotherapy before radiotherapy (induction), 224 (20%) patients received chemotherapy before and during radiotherapy (sequential), and 226 (20%) patients received chemoradiation after surgery. Single‐agent cisplatin, single‐agent cetuximab, and carboplatin plus paclitaxel were, in order, the 3 most commonly prescribed concurrent regimens. Concurrent cisplatin was more frequently used in the academic setting compared with the community setting (P = .0015). Postoperative chemoradiation, rather than radiation alone, was more commonly used in academic centers compared with community practice centers (P = <.0001).

CONCLUSIONS:

The LORHAN (Longitudinal Oncology Registry of Head and Neck Carcinoma) database is a useful barometer of current US practice patterns and can be applied to analyze future trends in the combined modality management of head and neck cancer. Sequential chemotherapy is used frequently, but cisplatin‐based concurrent chemoradiation remains the most commonly used regimen for locally advanced head and neck cancer. Cancer 2011. © 2010 American Cancer Society.     

混合核苷片联合同步放化疗治疗局部晚期头颈部恶性肿瘤的疗效和安全性

目的:观察混合核苷片联合同步放化疗治疗局部晚期头颈部恶性肿瘤的疗效及安全性。方法:50例明确诊断的局部晚期头颈部恶性肿瘤患者随机分成观察组以及对照组,每组各25例。两组患者均行同步放化疗,同时观察组联合应用混合核苷片。放疗后评价全部患者的疗效、相关毒副反应。结果:50 例患者均完成治疗,观察组和对照组的近期有效率（RR）分别为92.0%和84.0%,差异无统计学意义(P＞0.05);毒副反应方面,观察组骨髓抑制及感染发生率明显好于对照组,有统计学差异(P＜0.05)。结论:在局部晚期头颈部恶性肿瘤同步放化疗过程中联合应用混合核苷片,可减轻放化疗毒副反应,不影响治疗效果。     

Treatment of squamous cell carcinoma of the head and neck with multi-drug chemotherapy and radiotherapy

Multi-drug chemotherapy containing cisplatin has been reported to be one of the most active chemotherapy regimens in advanced or recurrent head and neck squamous cell carcinoma. In this study, the current status of clinical investigation of combination chemotherapies is reviewed. And our data are presented in head and neck cancer with multi-drug chemotherapy containing cisplatin. Thirty-five patients of stage 3-4 and 70 patients with recurrent and/or metastatic head and neck squamous cell carcinoma were treated by multi-drug chemotherapy containing cisplatin, and radiotherapy and/or operation. The overall response rate was 71.4%, with 17.1% complete remission in previously untreated, locally advanced patients and 31.4% in recurrent or metastatic patients. Problems of chemotherapy combined with radiotherapy and future direction of clinical study in locally advanced or recurrent head and neck cancer are discussed.     

Ifosfamide in the treatment of head and neck cancer

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24-26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III-IV is probably more active than IFO alone (ORR = 60-72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.     

Standard, and novel cytotoxic and molecular-targeted, therapies for HNSCC: an evidence-based review

(1) Head and neck squamous cell carcinoma is the sixth most frequently occurring cancer worldwide.(2) Chemotherapy has shown some success as part of multimodal treatment schedules for locally advanced, nonmetastatic head and neck squamous cell carcinoma, and too a much lesser extent for metastatic head and neck squamous cell carcinoma.(3) A recent meta-analysis of 32 studies involving >10,000 patients concluded that chemotherapy added to radiotherapy produces a large survival advantage relative to radiotherapy alone.(4) Concurrent or alternate chemoradiotherapy, with a schedule based on cisplatin, has an established place in the management of locally advanced nonmetastatic head and neck squamous cell carcinoma.     

紫杉醇联合顺铂方案同步放疗治疗局部进展期宫颈癌的疗效分析

目的 分析紫杉醇联合顺铂方案同步放疗对局部进展期宫颈癌患者的疗效及不良反应.方法 选取局部进展期宫颈癌患者68例,FIGOⅢ~Ⅳa期,接受根治性放疗,累积剂量为80 Gy,同时每周给予顺铂30 mg/m2+紫杉醇50 mg/m2.观察记录患者的疗效及不良反应.结果 68例患者的不良反应包括胃肠道损害、贫血及脑梗死等,2年累积远期不良反应发生率为25%.中位随访时间27个月,2年PFS为83.8%(75.1%~92.6%),2年OS为92.7%(86.4%~98.9%),2年DM为13.2%(5.2%~21.3%).结论 紫杉醇联合顺铂同步放疗治疗局部进展期宫颈癌的疗效显著,且方案安全可行.     

Concomitant cisplatin and radical radiation in locally advanced head & neck carcinoma

Effective treatment modalities for locally advanced squamous cell carcinoma of the head and neck are limited and seldom result in long term survival. The improved results with cisplatin chemotherapy are encouraging and represent an additional therapeutic modality for head and neck cancer. To estimate the effectiveness, safety and tolerance of simultaneous cisplatin and radiotherapy in advanced carcinoma of the head and neck this phase II study was undertaken. 40 eligible patients with advanced squamous cell carcinoma of the head and neck were entered into the study. Group I (20 patients) received conventional radical radiation 64 Gy/32 F/6.5 weeks and Group II (20 patients) received in addition to above radiotherapy, concomitant cisplantin 100 mg/m² every 3 weeks for three doses with forced diuresis and antiemetic schedule, on day 1, 22 and 43rd of rediation treatment. The complete response with RT alone was 40% and with combined treatment 70%. The treatment tolerance was approximately equal in both groups and all patients completed treatment in scheduled time.     

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.     

Sequential administration of methotrexate, cisplatin, and 5-fluorouracil in multimodal therapy for locally advanced head and neck cancer

Thirty-eight previously untreated patients with locally advanced head and neck cancer received three cycles of induction chemotherapy with methotrexate (120 mg/m2) followed by cisplatin (100 mg/m2) and a 5-day continuous infusion of 5-fluorouracil (1,000 mg/m2 per day). The response rate in 34 evaluable patients was 94%, with a complete response rate of 26%. Thirty-one patients underwent local therapy following induction chemotherapy, and 25 (81%) were rendered free of disease: 14 of 15 treated with surgery and radiotherapy and 11 of 16 treated with radiotherapy alone. At a median follow-up of 11 months, 8 patients have relapsed while the remaining 17 patients continue free of disease. The dose-limiting toxicity of chemotherapy was mucositis resulting in reduction of the 5-fluorouracil dose in 28 patients. This regimen is highly effective in inducing responses in patients with locally advanced head and neck cancer; 81% of the patients who complete local therapy are rendered free of disease with this multimodal approach. Due to short follow-up, the relapse rate, overall survival, and disease-free survival cannot yet be determined.     

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.