|Year : 2017 | Volume
| Issue : 2 | Page : 453-457
Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy
V Noronha1, V Sharma2, A Joshi1, VM Patil1, SG Laskar3, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Dr E Borges Marg, Parel, Mumbai, Maharashtra, India
2 Department of Hematology, Bone Marrow Transplantation Unit, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Radiation Oncology, Tata Memorial Hospital, Dr E Borges Marg, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||21-Feb-2018|
Dr. K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Dr E Borges Marg, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
BACKGROUND: Cisplatin-based chemoradiation (CTRT) is the standard of care in locally advanced head and neck cancers. Limited treatment options are available in patients unfit for cisplatin. AIMS: This audit was carried out to study the toxicities, tolerance, and outcomes of carboplatin-based CTRT in patients who are not eligible for cisplatin. MATERIALS AND METHODS: A total of 63 locally advanced head and neck cancer patients treated between January 2011 and October 2015 were administered carboplatin-based CTRT. The dose of carboplatin was equivalent to area under the curve equivalent to 2 administered once a week for a maximum of 7 cycles. Toxicity was coded as per the CTCAE version 4.03. SPSS software version 16 was used for statistical analysis. STATISTICAL ANALYSIS: Descriptive statistics was performed. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier survival analysis. Cox proportional hazard model was used for identifying factors affecting PFS and OS. RESULTS: The reasons for patients being unfit for cisplatin were low serum creatinine clearance in 41 (65.07%), sensorineural hearing loss in 18 (28.57%), uncontrolled medical comorbidities in 3 (4.76%), and old age in 1 patient (1.6%). 53 patients (84.1%) completed planned radiotherapy. The median number of chemotherapy cycles administered was 6. Grade 3–4 toxicities were seen in 32 patients (50.8%). The median OS and PFS were 28 months (95% confidence interval [CI]: 20.9–34.6 months) and 17 months (95% CI: 08.2–25.7 months), respectively. Age was the only factor significantly affecting OS and PFS. CONCLUSION: Carboplatin-based CTRT is well tolerated in patients unfit for cisplatin and seems to have superior outcomes than those reported in radical radiotherapy studies.
Keywords: Carboplatin, chemoradiation, cisplatin, head and neck cancers, unfit
|How to cite this article:|
Noronha V, Sharma V, Joshi A, Patil V M, Laskar S G, Prabhash K. Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. Indian J Cancer 2017;54:453-7
|How to cite this URL:|
Noronha V, Sharma V, Joshi A, Patil V M, Laskar S G, Prabhash K. Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. Indian J Cancer [serial online] 2017 [cited 2019 Sep 21];54:453-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/2/453/225807
| » Introduction|| |
Concurrent chemoradiation (CTRT) has significantly improved survival in locally advanced head and neck cancers, compared to conventional radiotherapy alone. Various chemotherapeutic agents have been used with radiotherapy in head and neck cancers. These include methotrexate, hydroxyurea, cisplatin, carboplatin, bleomycin, gemcitabine, mitomycin-c, 5-fluorouracil, vincristine, taxanes, and cyclophosphamide. Meta-analysis of chemotherapy in head and neck cancer suggests that platinum-based chemotherapy is a better option than nonplatinum-based chemotherapy (hazard ratio: 0.74 vs 0.89, respectively; P = 0.006).
Cisplatin-based CTRT protocol may have the best outcome in this setting. Cisplatin has been administered in various schedules: weekly, 3 weekly, 4 weekly, daily, days 1–5, but 3 weekly protocol has the maximum data for efficacy. There is a significant proportion of head and neck cancer patients who are not fit for cisplatin-based CTRT protocol. Derks et al. showed that, in 45–60 years' age group, 89% of patients of head and neck malignancies received standard treatment whereas in the age group of >70 years, only 62% patients received standard treatment.
Carboplatin has radiosensitizing properties and has lesser renal and gastrointestinal toxicities than cisplatin and is considered an effective option in the National Comprehensive Cancer Network (NCCN) guidelines for patients unfit for cisplatin. Phase II studies of carboplatin-based concurrent chemoradiotherapy (CTRT) showed complete response (CR) rates of 65%–70%, similar to those seen with cisplatin  Carboplatin has been used in a weekly dose of 100 mg/m 2, area under the curve (AUC) 1.5 or AUC 2. There is very limited data for carboplatin-based CTRT protocol in head and neck cancers other than carcinoma nasopharynx. We carried out a retrospective analysis to evaluate the safety and efficacy of carboplatin-based CTRT therapy in patients not fit for cisplatin.
| » Materials and Methods|| |
This is a retrospective analysis of a prospectively maintained database of patients of locally advanced head and neck cancers in medical oncology division of head and neck disease management group of a tertiary care cancer center in India. Tumor extent was evaluated by physical examination, examination under anesthesia when necessary, and appropriate imaging. Disease was staged as per the American Joint Committee on Cancer 7th edition. Patients in the database, treated from January 2011 to October 2015, were included in this study. The treatment plan of each patient was formulated after discussion in a multidisciplinary joint clinic. The patients included in this study received chemotherapy with carboplatin dosed at AUC 2 at weekly intervals given concurrently with radiotherapy, a maximum of seven cycles. Data were collected regarding the following parameters: demography, tumor characteristics and baseline blood parameters, and reason for being unfit for cisplatin-based chemotherapy. Patients were planned to receive 60 Gray radiotherapy in adjuvant CTRT arm and 66–70 Gray in radical CTRT arm along with weekly chemotherapy.
The data were also collected for completion rate of planned CTRT, treatment-related acute-grade 3–4 toxicities (graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events, [NCI-CTCAE] toxicity criteria version 4.03), percentage of patients having weight loss >10% of baseline body weight, delays in treatment, causes of treatment delay, and reasons for discontinuation of carboplatin. Completion of chemotherapy was defined as receiving at least 5 cycles of concurrent weekly carboplatin. Completion of radiotherapy was defined as receiving at least the planned dose of radiotherapy. Delay in chemotherapy was defined as any delay beyond the anticipated date of chemotherapy cycle. After treatment completion, patients were first evaluated at 8–12 weeks for response and toxicity assessment. Thereafter, they were followed up every 3–4 months in the first and second year and every 6 months thereafter. Evaluation was done by clinical examination, radiological examination, and supplemented by endoscopies and biopsies when pertinent. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Local failure was defined as persistence of disease or reappearance of disease at or in close vicinity to the primary site. Loco-regional failure was defined as persistence of disease or reappearance of disease either at the primary site and/or draining regional lymph nodes. Recurrence was defined as re-appearance of disease at the primary, regional, or distant site.
Patient characteristics were summarized using descriptive statistics such as mean, median, and percentages as required. The overall survival (OS) was calculated in months from the time of diagnosis to death from any cause. Progression-free survival (PFS) was calculated in months from the time of start of treatment to clinical or radiological progression or death. The disease status of patients who had completed the planned course of therapy, but not actively following up, was updated by telephonic contact. Nonresponding patients were considered lost to follow-up and censored for statistical consideration. The PFS and OS were calculated using the product-limit method of Kaplan–Meier. Cox proportional hazard method was used for identifying factors affecting PFS and OS. All analyses were done using SPSS software version 16 (SPSS Inc., Chicago, IL, USA).
| » Results|| |
Sixty-three patients were included in the analysis. Median age of the patients was 62 years (range: 36–81 years). Male:female ratio was 3.84. All patients had adequate bone marrow function (hemoglobin >8.0 g%, platelet count >100,000/μl, total leukocyte count >3000/μl, and absolute neutrophil count >1000/μl) and adequate hepatic function. [Table 1] summarizes the demographic characteristics of the patients included in this study.
[Table 2] summarizes the tumor characteristics of the patients included in this study.
All patients received either radical CTRT or surgery followed by adjuvant CTRT. Out of 63 patients, 43 received radical CTRT (68.2%) and 20 received adjuvant CTRT (31.7%). The indications for adjuvant CTRT were perinodal extension in 18 patients (28.6%) and close cut margins in two patients (3.1%). The indications for radical CTRT were as follows: unfavorable location for surgery (nasopharynx, hypopharynx, and oropharynx) in 30 patients (47.6%), larynx preservation in seven patients (11%), and extensive inoperable disease in six patients (9.5%) (ca maxilla extending to ptrygopalatine fossa and orbit apex: 2; ca maxilla with base of skull and infratemporal fossa involvement: 1; ca maxilla with pterygoid plate involvement: 1; ca oral cavity with tumor encasing carotid vessels: 1; and ca oral cavity with high infratemporal fossa involvement: 1).
All patients included in this study were unfit for cisplatin-based CTRT. Reasons for not using cisplatin were as follows: low calculated creatinine clearance in 41 patients (65.07%), sensorineural hearing loss in 18 patients (28.57%), uncontrolled comorbidities in 3 patients (04.76%), and old age in one patient (01.6%). In our practice, creatinine clearance 50 ml/min (as calculated by Cockcroft-Gault formula) and below is considered as low creatinine clearance. Median calculated creatinine clearance was 39 ml/min (range: 28–49 ml/min).
Compliance to treatment
The details of treatment compliance were available in sixty two patients. Fifty-three out of sixty three patients (84%) completed their planned course of radiotherapy (60 Gray in adjuvant CTRT and 66 Gray in radical CTRT arms) respectively [Table 3]. Out of the ten patients who did not complete planned course of radiotherapy, two were on adjuvant CTRT and eight on radical CTRT. Radiotherapy was delayed in six patients, ranging from 3 to 7 days.
Chemotherapy was given as a weekly schedule of carboplatin at a dose equivalent to AUC 2. The median number of chemotherapy cycles given was 6 (range: 1–7). Fifty-five out of 63 patients (87%) received adequate number of chemotherapy cycles (5). Eight patients received less than five cycles. Chemotherapy was delayed in 24 patients due to toxicities (38%) [Table 4]. In twelve patients, chemotherapy dose reduction was done. The reasons for chemotherapy dose reduction were decline in calculated creatinine clearance in nine patients and weight loss >10% baseline body weight in three patients.
Toxicities during therapy
In this study, all patients had some toxicity and thirty two patients (50.8%) had grade 3 or grade 4 toxicities. The most common grade 3/grade 4 toxicity was oral mucositis (22.2%). Two patients had to be hospitalized due to chemotherapy-related toxicities: one each due to febrile neutropenia and pneumonia. Six patients (9.5%) had grade 3 or grade 4 myelosuppression. [Table 5] summarizes the toxicities noted during therapy. Other toxicities noted during therapy were nonneutropenic fever in six patients, febrile neutropenia in two patients, oral candidiasis in ten patients, transaminitis in three patients, and weight loss >10% from baseline body weight in eleven patients (17.5%). There was no mortality due to chemotherapy-related toxicity.
Complete response was attained in thirty eight patients (60%). At the time of analysis, thirty seven patients had progressed, ten having local progression, eleven having locoregional progression, two developing distant metastases, and six had both distant and local site progression. Details of the site of progression were not available in eight patients. At the time of analysis, twenty four patients had died.
Median OS was 28 months (range: 3 months–40 months; 95% confidence interval (CI): 20.9–34.6 months) [Figure 1].
Median PFS was 17 months (range: 0–37 months; 95% CI: 8.2–25.7 months) [Figure 2].
On multivariate analysis, the only factor that significantly influenced PFS was age (hazard ratio [HR]: 1.07, 95% CI: 1.001–1.137, P = 0.046) while the same factor influenced OS also (HR: 1.15, 95% CI: 1.044–1.268, P = 005).
| » Discussion|| |
In locally advanced head and neck cancers, 3 weekly cisplatin at 100 mg/m 2 concurrent with radiotherapy is routinely used in the western world ,,, and weekly cisplatin at 30–40 mg/m 2 in Asia.,,,, There is a significant proportion of patients who cannot receive cisplatin due to contraindications.
Many patients of locally advanced head and neck cancer are not fit for cisplatin-based concurrent CTRT due to old age, compromised performance status, or medical comorbidities. According to Ahn et al., the absolute contraindications to cisplatin include the Eastern Cooperative Oncology Group performance status 3 or more, creatinine clearance <50 ml/min, grade 2 or higher organ dysfunction based on the National Cancer Institute Common Toxicity Criteria version 4.0, such as hearing loss, tinnitus, or neurologic disorder, platinum hypersensitivity, pregnancy, lactation, and HIV/AIDS patients with CD4 count <200/μl. In our study, the reasons for patients being unfit for cisplatin included low calculated creatinine clearance in 63.5%, sensorineural hearing loss in 27%, uncontrolled comorbidities in 4.8%, and old age in 1.6% of patients. There are limited treatment options for locally advanced head and neck cancer patients who are unfit for cisplatin. Patients may receive targeted therapy or noncisplatin-based chemotherapy concurrent with radiotherapy. In developing countries, access to targeted therapy is limited due to cost constraints. There have been some studies exploring the role of carboplatin with radiotherapy in head and neck cancer. It will be important to have evidence for the role of carboplatin in patients not fit for cisplatin.
Branislav et al, in a three arm study, compared concurrent CTRT with daily low-dose cisplatin 6 mg/m2, CTRT with daily carboplatin 25 mg/m2 and radical radiotherapy alone in advanced head and neck cancers (Stage III/IV). They showed similar overall response rates in both cisplatin and carboplatin arms, both arms doing better than radical radiotherapy alone. Patients in both CTRT arms had significantly longer median survival time (MST) and higher 5-year survival rates than those in radical radiotherapy alone group (MST 32 months and 30 months vs. 16 months respectively, P = 0.011; 5-year survival rates 32% and 29% vs. 15% respectively, P = 0.019), with no significant difference between the two CTRT arms. Median time to local recurrence (MTLR) and 5-year local recurrence-free survival (LRFS) were significantly higher for both CTRT arms compared to radical radiotherapy alone (MTLR not yet attained and 30 months vs. 10 months respectively, P = 0.018; 5-year LRFS 51% and 48% vs. 27% respectively, P = 0.040) with no significant difference between the two CTRT arms.
Chitapanarux et al. showed that in nasopharyngeal cancer, treatment completion rates were 59% versus 73%, respectively, in cisplatin versus carboplatin arm of concurrent CTRT. The treatment efficacy of both cisplatin and carboplatin was similar. Dutta et al. compared carboplatin AUC 6 every 3 weekly and cisplatin 100 mg/m 2 every 3 weekly, both given concurrently with radiotherapy, in locally advanced unresectable head and neck cancers excluding nasopharyx and oral cavity cancers. They reported response rates (CR plus partial response) of 76.9% and 63.6% in carboplatin and cisplatin arms, respectively. They reported significantly higher rates of nausea, vomiting, dermatological toxicity, and mucositis in cisplatin than in carboplatin arm. Hematological toxicities were higher in carboplatin than in cisplatin arm. No significant difference between disease-free survival was noted in these two treatment arms.
Branislav et al., in a three-arm study on advanced head and neck cancers, compared radical radiotherapy, concurrent CTRT with cisplatin, and concurrent CTRT with carboplatin. They found similar nonhematological toxicities in the three groups. Hematological toxicities were similar in the two CTRT arms but higher than the radical radiotherapy arm. Treatment interruptions were similar in the two CTRT arms but higher than the radical radiotherapy arm (Branislav et al., 1997). Chitapanarux et al., in a study on concurrent CTRT in nasopharyngeal carcinoma, showed that carboplatin was better tolerated than cisplatin. In our study, 50.8% patients had grade 3 or grade 4 toxicities. The most common grade 3/grade 4 toxicity was oral mucositis (22.2%). Grade 3 or grade 4 myelosuppression was seen in 9.5% patients. Weight loss >10% from baseline body weight was seen in 17.5% patients.
These previously mentioned studies with carboplatin have included patients who were fit to receive cisplatin.
Hamauchi et al. have published results of carboplatin based concurrent CTRT in 25 patients who were unfit for cisplatin. In this study, the main reasons for choosing carboplatin were age (40%), renal impairment (36%) and cardiac dysfunction (20%). All patients received planned radiotherapy with dose of 70 Gray. CR was observed in 70% patients. Median PFS duration was 42.7 months. The main grade 3/grade 4 toxicities were oral mucositis (56%), thrombocytopenia (34%), neutropenia (28%) and infection (24%). In our study, the reasons for not using cisplatin were renal impairment in 63.5%, sensorineural hearing loss in 27%, uncontrolled comorbidities in 4.8% and old age in 1.6% patients. 84% of our patients completed planned radiotherapy and 87% received adequate chemotherapy. Median number of chemotherapy cycles given in our study is six. CR was seen in 60% patients. Median OS in the present study was 28 months and median PFS was 17 months. In our study, age was the only factor significantly affecting OS and PFS.
| » Conclusion|| |
This analysis suggests that carboplatin-based concurrent CTRT is well tolerated for patients who are unfit for cisplatin. Outcome of patients receiving carboplatin based chemotherapy is encouraging. Toxicity of carboplatin is manageable and it can be used in patients who are not fit for cisplatin-based chemotherapy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]