Ifosfamide and Doxorubicin Combination Chemotherapy for Recurrent Nasopharyngeal Carcinoma Patients

As opposed to other head and neck cancers, NPC is highly prone to show locoregional and distant metastasis. It is well known that, metastasis develops within 3 years after the initiation therapy and following conventional definitive radiotherapy (RT), local recurrence or distant metastasis develops in about 20-30 % of patients. This ratio is reported as high as 38-87 % in autopsy series (Perez et al., 1992; Fong et al., 1996; Brady et al., 2010). In recurrent or metastatic disease where surgery and re-irradiation are not applicable, the main method of treatment is CT. To date, no randomized controlled trial, comparing different CT regimens in metastatic NPC is reported. However platinum containing combination regimens are accepted as first line due to high response rates. Different trials report response rates ranging from 29% to 56% with different chemotherapeutics in cases unresponsive to platinium based CT regimens. But there is no single regimen accepted generally as second line (Yeo et al., 1998; Chua et al., 2000; Huang et al., 2002;


Introduction
As opposed to other head and neck cancers, NPC is highly prone to show locoregional and distant metastasis. It is well known that, metastasis develops within 3 years after the initiation therapy and following conventional definitive radiotherapy (RT), local recurrence or distant metastasis develops in about 20-30 % of patients. This ratio is reported as high as 38-87 % in autopsy series (Perez et al., 1992;Fong et al., 1996;Brady et al., 2010). In recurrent or metastatic disease where surgery and re-irradiation are not applicable, the main method of treatment is CT. To date, no randomized controlled trial, comparing different CT regimens in metastatic NPC is reported. However platinum containing combination regimens are accepted as first line due to high response rates. Different trials report response rates ranging from 29% to 56% with different chemotherapeutics in cases unresponsive to platinium based CT regimens. But there is no single regimen accepted generally as second line (Yeo et al., 1998;Chua et al., 2000;Huang et al., 2002; RESEARCH COMMUNICATION
Ifosfomide; which is an analogue of cyclophosphamide; is a chemotherapeutic shown to be effective in testis cancer, lung cancer, sarcomas, pediatric tumors and nasopharyngeal cancer (Chua et al., 2000;Huang et al, 2002;Altundag et al., 2004). Anthracycline containing regimen has also been studied and proven to be effective in treatment of the NPC (Azli et al., 1995;Siu et al.,1998;Hasbini et al., 1999;Taamma et al., 1999;Huang et al., 2002;Onat H et al., 2002;Altundag et al., 2004). The aim of this study is investigating the efficacy of ifosfamide and doxorubicin combination as second line treatment in patients with recurrent and metastatic NPC.

Materials and Methods
From January 1999 to December 2010, the patients with recurrent and/or metastatic nasopharyngeal cancer previously treated with cisplatin containing regimen were analyzed retrospectively. A total of 30 patients were included in the study. The combination of ifosfamide 2500mg/m 2 days 1-3, mesna 2500mg/m 2 days 1-3, doxorubicin 60mg/m 2 day 1 (IMA), was repeated every 3 weeks. Depending on response, a total of two to six cycles were given. Patients who achieved at least disease stability after two cycles of this chemotherapy, were given additional two cycles. For responsive patients, a maximum of six cycles of treatment were given irrespective of the response rate. Treatment was stopped when response assessment after two cycles showed progressive disease, when there was evidence of progressive disease at any time or after six cycles of CT.
The statistical software SPSS for Windows (version 18) was used for statistical analysis.

Results
Thirty patients were included in the study. Patients' characteristics are shown in Table 1. Median age was 47 (min-max; 17-60). Twenty six (86.7%) patients were male. Twenty seven (90%) patients were classified as WHO Type 2 undifferentiated carcinoma, and 3 (10%) patients were classified as WHO Type 1 keratinizing squamous cell carcinoma. Median period of time from diagnosis to start of IMA regimen was 18 months (min-max; 5-108). Median time from last CT regimen to start of IMA regimen was 11 months (min-max; 1-89).
Eleven patients received only one cycle of treatment; 6 patients were lost to follow up after first cycle; 2 patients developed ifosfamide encephalopathy on the third day of the first cycle. After switching ifosfamide to cyclophoshamide, one patient had a partial response at the end of sixth cycle and the other patient refused receiving further treatment. One patient who had liver and bone metastases developed tumor lysis syndrome on the second day of the treatment and died on seventh day of IMA regimen; one patient who had liver metastasis developed severe hepatotoxicity, hepatic coma and the treatment was stopped; one patient was admitted to intensive care unit because of severe pneumonia on the eight day of the IMA treatment and CT was stopped. One (3.3%) patient underwent radical neck dissection and 4 (13,3%) patients received palliative RT after CT.
None of the patients achieved complete response. Nine patients (30.0%) had a partial response, 5 (16,7%) patients had stable disease. Disease progression was observed in 6 (20.0 %) patients (Table 2). We were unable to evaluate response to treatment in 10 (33.3%) patients. The median time to progression for eligible 20 patients was 4 mo (minmax; 1-48).
Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 2227 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.5.2225 Ifosfamide and Doxorubicin Combination Chemotherapy for Recurrent NPC No significant difference in response rates was found between those who had previously received CF regimen as induction treatment or recurrent disease (p=0,973). There was one treatment related death due to tumor lysis. Two patients developed ifosfamide encephalopathy on the first cycle of IMA regimen. Six (20%) patients had a neutropenic fever episode after chemotherapy. One patient required RBC transfusion and 3 (10%) patients required platelet transfusion. G-CSF support was given to 6 (20%) patients. One patient experienced gross hematuria during IMA CT that resolved after increasing the dose of mesna. Dose modification became necessary in 7 (23,3%) patients because of the toxicities mentioned above. No acute and chronic cardiotoxicity was seen during or after IMA regimen (Table 3).

Discussion
Despite the similar ratios reported in studies about incidences of NPC, course of the disease was changed through new treatment modalities . Due to the tecniquel development of RT and incorporation of chemoradiation, high local control rates was achieved in the treatment and distant metastasis became more common presentation of recurrence in NPC (Razak et al., 2010).
To date, there is no randomized trial comparing the efficacy of any type of CT with supportive treatment in the management of metastatic NPC (Ma et al., 2008). Early trials investigating the most efficacious therapy in metastatic disease are all phase II, nonrandomized trials in which a platin based regimen is usually used. It is difficult to compare these studies since they show extreme heterogeneity in aspects such as number of patients, involvement criteria, stage of disease and previous CT and RT regimens. Despite the 5-30% of complete response rates reported in these phase II trials, it is well known that the disease recurs in 5-10 months and survival is not more than 12-18 months in metastatic NPC (Boussen et al., 1991;Auet al., 1994;Siu et al.,1998;Yeo et al.,1998;Taamma et al., 1999;Ngan et al., 2002;;Chua et al., 2005;Leong et al., 2005;Chan et al., 2007). Studies in which newer chemotherapeutic agents combined with cisplatin, report a 25-75% of total response rate and a median survival of 9, 5 to 15 months (Ma et al., 2002;McCarthy et al., 2002;Ngan et al., 2002;Chua et al., 2003;Chua et al., 2005;Wang et al., 2008).
There is no standard regimen suggested for cases who received a platin based regimen beforehand and who have resistant disease. Ifosfamide and doxorubicin are agents which have been studied in such patients who received a platin based regimen beforehand and who have resistant disease (Chua et al., 2000;Huang et al., 2002). It is not possible to make a head to head comparison of our study with other studies on this subject, since the involvement criteria are variable and we have a small study population. However, when compared to studies with platin based regimens mentioned above, our study showed a lower total response rate (46,7%) and a shorter (4 months) median time to progression. Six patients developed neutropenic fever during treatment, G-CSF is given to all and none of them progressed to sepsis. We think that this result is related to strict application of evidence based therapy guidelines and proper dose modification of the drugs.
To date, there is no study to report any survival benefit or contribution to quality of life with any CT regimen in metastatic NPC. Randomized studies comparing standard platin containing regimens with the regimens like IMA which is given mainly for palliation will be useful. Additionally, quality of life and palliation of symptoms in metastatic NPC are the other important subjects waiting for proper assessment in randomized studies.
In summary, ifosfamide doxorubicin combination is an alternative for salvage therapy in patients with resistant NPC, if the toxicities are well controlled. However one should bear in mind that response duration provided by this regimen is not long and that it has a limited effect on survival.