Concurrent radiation therapy with high dose cisplatin represents the definitive treatment for locally advanced head and neck squamous cell carcinoma
Concurrent radiation therapy with high dose cisplatin represents the definitive treatment for locally advanced head and neck squamous cell carcinoma (Adelstein, Li et al. 2003);(Bernier, Cooper et al. 2005) who are unresectable unfit or refuse surgery with an associated complete response rate of 40% and median OS of 19.1 months. The results from the two large phase III adjuvant studies confirm that the addition of cisplatin improves loco-regional control and disease-free survival In comparison to radiation alone with mixed results on overall survival.(Bernier, Cooper et al. 2005). However, a separate study by the European Organization of Research and Treatment of Cancer (EORTC) that included 167 patients with LAHNC confirmed that both 5 year PFS (47% vs 36%) and OS (53% vs 40%; HR = 0.70(95% CI 0.52–0.95) favored concurrent CRT over RT alone. (Bernier, Domenge et al. 2004)
In addition to CDDP, cetuximab (Cmab), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is used in combination with RT in patients with LASCCHN. Bonner et al.(Bonner, Harari et al. 2006) demonstrated that Cmab plus RT significantly improved loco-regional control, PFS, and OS compared with radiation therapy alone. However, Cmab plus RT couldn’t be established to be the standard therapy for LASCCHN, as Cmab plus RT has never been compared with triweekly cisplatin plus RT in a prospectively randomized Phase III study. Furthermore, no prospective trials of Cmab plus RT have been conducted in patients who are not eligible for treatment with CDDP. The study by Bonner et al. included patients with normal organ function, younger age, and high KPS. Regarding toxicity, concurrent Cmab and RT led to a higher number of Grade 3 or 4 skin toxicity than those receiving RT alone (35.1 versus 21.2%, P ; 0.05), although there were few cases of nausea, vomiting, renal impairment and neuro- and ototoxicity (Bonner, Harari et al. 2010). Other studies have also observed Grade 3 or 4 radiation dermatitis in over 30% of patients treated with Cmab plus RT (Giro, Berger et al. 2009, Studer, Brown et al. 2011) . Severe skin reactions could reduce the patient’s quality of life and may sometimes lead to treatment interruption and dose reduction. Taken together, the currently available data do not support the use of Cmab plus RT as an alternative to RT alone in patients who cannot tolerate cisplatin.
The mechanism of action of both carboplatin and cisplatin is similar. Carboplatin induces the same platinum-DNA adducts as those induced by cisplatin; however, Hongo et al. (Hongo, Seki et al. 1994) have demonstrated that carboplatin required 7.5 times longer incubation time and 10 times higher drug concentration than cisplatin to induce an equal degree of conformational change on plasmid DNA. Myelosuppression is known to be higher with carboplatin than cisplatin , however, carboplatin causes less nephrotoxicity, neurotoxicity, and nausea with hyperemesis.(Zakotnik, S?mid et al. 1998)
Cisplatin has a more powerful antitumor effect than carboplatin.(Marcial and Pajak 1985) It is not clear whether carboplatin has the same radio-sensitizing effect as cisplatin or not.
In theory, carboplatin could replace cisplatin in some patients who have contraindications to cisplatin, especially in patients with inadequate renal function, baseline hearing impairment, and borderline performance status, or those who may have difficulty tolerating hydration with high fluid volume associated with high-dose cisplatin such as patients with congestive heart failure or severe emphysema.
In a prospective randomized clinical trial in patients with locally advanced nasopharyngeal carcinoma (NPC), concurrent carboplatin (100 mg/m2 on days 1, 8, 15, 22, 29 and 36) plus RT demonstrated comparable efficacy and better tolerability when compared with concurrent cisplatin (100 mg/m2 on days 1, 22 and 43) plus RT (Chitapanarux, Lorvidhaya et al. 2007). There was no significant difference in the 3-year disease-free (61 vs 63% for the carboplatin and cisplatin regimens, respectively) or overall survival (79 vs 78%, respectively) between both regimens.
For non-nasopharyngeal LASCCHN, a prospective randomized three-arm Phase III trial was conducted to compare the 3-year survival rate with radiation therapy alone (total dose, 70 Gy), concurrent cisplatin (100 mg/m2 on days 2, 22 and 42) plus RT, and concurrent carboplatin (AUC, 7 on days 2, 22 and 42) plus RT (Fountzilas, Ciuleanu et al. 2004).This study showed that platinum-based CRT significantly prolonged 3-year survival when compared with radiation therapy alone (42, 52 and 17.5% for carboplatin, cisplatin, and RT alone, respectively).
There is no specific consensus of ineligibility for the use of cisplatin. Therefore, in our study, we considered the patient ineligible for high dose cisplatin based on the known toxicity of cisplatin and on the inclusion or exclusion criteria used in the clinical trials using cisplatin for head and neck cancer. As a result, we listed five factors in the materials and methods section.
Carboplatin has less nausea and vomiting, renal toxicity, neurotoxicity, and no requirement for much hydration, compared with cisplatin. So, we would think carboplatin is safer than cisplatin for those who meet our criteria.
In our study, although all patients were considered to be ineligible for cisplatin treatment, mainly due to advanced age or renal impairment, they were able to receive a total dose of 70 Gy of irradiation.
Furthermore, about 40% of these patients were able to achieve complete response (CR), despite the high proportion of stage IV (71%) and unresectable cases (38%). These results suggest that concurrent carboplatin and radiation therapy achieved very good treatment outcomes compared with RT alone.
Regarding toxicity of CBDCA; in a study by Jodrell et al. (Jodrell, Egorin et al. 1992) , there was a significant relationship between administered AUC dose of carboplatin and the likelihood of development of thrombocytopenia and leukopenia. Therefore, we should be careful to prevent myelotoxicity caused by high doses of carboplatin that cay cause infection. Low dose weekly carboplatin plus RT may be less myelotoxic .
In terms of safety, there was no Grade 3 or 4 neurotoxicity, nephrotoxicity, nausea or vomiting. However, discontinuation or dose reduction of carboplatin was necessary due to myelotoxicity in our patients. Three patients developed an infection, including two with pneumonia, and one with febrile neutropenia.
Tri-weekly CBDCA plus RT was not compared in clinical trials with weekly CBDCA plus RT. In the aforementioned randomized study for locally advanced nasopharyngeal carcinoma, weekly carboplatin plus RT was as effective as tri-weekly cisplatin plus RT and caused Grade 3 or 4 leukopenia in 10% and Grade 3 or 4 thrombocytopenia in 8% of patients (Chitapanarux, Lorvidhaya et al. 2007). For non-nasopharyngeal LAHNSCC, Tri-weekly CBDCA plus RT caused Grade 3 or 4 leukopenia in 18% and Grade 3 or 4 thrombocytopenia in 27% of patients (Fountzilas, Ciuleanu et al. 2004)
These results suggest that the myelotoxicity of weekly CBDCA plus RT is lesser than that produced by tri-weekly CBDCA plus RT and may be an alternative treatment to tri-weekly CBDCA plus RT for LASCCHN.
In our study, most patients (71%) have received tri-weekly CBDCA plus RT. However, tri-weekly CBDCA caused severe myelotoxicity which subsequently leads to infection and neutropenic fever which may be explained by the older age of our patients. Therefore, the use of weekly CBDCA plus RT is increasing recently in our hospital due to its mild myelotoxicity.
In conclusion, concurrent carboplatin plus RT is feasible and may be an option for treatment of LASCCHN patients who are not eligible for cisplatin treatment. As this study has limitations, such as a small number of patients and performance at a single oncology center, our observations should be confirmed with more prospective multi-institutional studies with a large number of patients.