Familial Nasopharyngeal Carcinoma 6

Drug Therapy for Nasopharyngeal Carcinoma: Cytotoxic and Targeted Therapy 153et al. 2008; Li et al. 2008), methotrexate (Molinari1978) ), alkylating agents (e.g., cyclophosphamide(Molinari 1978), ifosfamide (Stein et al. 1996),microtubule inhibitors (e.g., paclitaxel (Tan et al.1999; Yeo et al. 1998; Au et al. 1998; Airoldi et al.2002), docetaxel (Hui et al. 2009; Johnson et al.2004) ), anthracyclines (e.g., epirubicin (Azli et al.1995), doxorubicin (Molinari 1978), mitoxantrone(Dugan et al. 1993) ), vinca alkal oids (vinorelbine(Wang et al. 2006) ), irinotecan (Poon et al. 2005),bleomycin (Boussen et al. 1991; Molinari 1978),and mitomycin C (Hong et al. 1999) (Table 11.1).Some of these agents, such as gemcitabine (Foo et al.2002), capecitabine (Chua et al. 2008), and irinotecan(Poon et al. 2005) are active in the second- or thirdlinetreatment of patients who have progressed afterplatinum-based chemotherapy.11.3.3Factors Affecting Response to Drug Therapy11.3.3.1Multi-Drug Regimen vs. DoubletsTo date, there is no randomized data supporting atherapeutic advantage of multi-drug regimens withthree or more agents, over platinum-based doublets.As shown in Table 11.1, although the reported overallresponse rates of multi-drug regimens (three or moredrugs combination: up to 80% [Siu et al. 1998; Leonget al. 2005]) appear to be slightly higher than platinum-baseddoublets (up to 73% [Ngan et al. 2002])in phase II studies, the survival rates reported for thefirst-line palliative setting are comparable, while theincidence of serious toxicities were higher for themulti-drug regimens. For instance, the respectivemedian progression-free and overall survival rates ofa cisplatin–gemcitabine combination were 10.6 and15 months (Ngan et al. 2002), while the correspondingrates reported in another study where paclitaxel(70 mg/m 2 , days 1 and 8) was added to a carboplatin–gemcitabine backbone were 8.1 and 18.6 months(Leong et al. 2005). Without growth factor support,the respective incidence rates of grade 3–4 neutropeniaand thrombocytopenia were 78% and 41% withthe three-drug regimen (Leong et al. 2005), and only37% and 16% in the two-drug regimen (Ngan et al.2002). Combinations with four or more older agentssuch as mitomycin and bleomycin were associatedwith a higher incidence of toxic deaths in some phaseII studies (Siu et al. 1998; Taamma et al. 1999;Hasbini et al. 1999).11.3.3.2Dose Intensity and Drug MaintenanceAiroldi and De Crescenzo (2001) was the onlygroup that reported their preliminary experiencewith autologous peripheral blood stem cell transplantationin the treatment of six patients withpredominantly locore gional relapse following radiotherapy.Cisplatin and epirubicin were used for stemcell mobilization, followed by high-dose ifosfamide,etoposide, and carboplatin with stem cell rescue. At30 months follow-up, two patients remained alivewithout disease, one was alive with bone metastases,and the rest had died (Airoldi and De Crescenzo2001). There is a paucity of evidence supporting therole of dose intensification in the treatment of NPC,and the available evidence seems to suggest thatsuch strategy only increased toxicity without therapeuticgain. For instance, two groups have independentlypublished their phase II experience withcarboplatin and paclitaxel in metastatic NPC. Bothstudies used carboplatin at AUC of six withoutgrowth factor support, but the study by Tan et al.(1999) used paclitaxel at a modestly higher dose of175 mg/m 2 , while Yeo et al. (1998) used a lower doseat 135 mg/m 2 . Although the response rates reportedby Tan et al. was higher than Yeo et al. (78% vs. 59%),the neutropenic sepsis rate was much higher (28%vs. 3%), and the median overall survival was only 12months when compared with 13.9 months asreported by Yeo et al. (1998).The use of “maintenance” chemotherapy – thecontinuation of chemotherapy once best response isachieved after neoadjuvant chemotherapy – in thetreatment of recurrent and metastatic NPC has notbeen formally evaluated in randomized studies. Theonly published report is a phase II study, whereresponders to four cycles of cisplatin, doxorubicin,and mitomycin C received weekly 5-fluorouraciland leucovorin until disease progression for amedian duration of 38 weeks (Hong et al. 1999).The weekly treatment was well tolerated, and therespective median time to progression and overallsurvival were 11.6 and 18 months, respectively.These data are comparable with those reportedwith phase II studies of platinum-based doubletsdiscussed in Sect. 11.2.1, and further studies arewarranted.