|Year : 2021 | Volume
| Issue : 2 | Page : 61-67
Weekly vs. daily low dose cisplatin in chemoradiation of locally advanced head and neck cancers: Comparison of compliance and clinical outcomes
Ayush Garg, Piyush Kumar, Pavan Kumar, Arvind K Chauhan
Department of Radiation Oncology, Shri Ram Murti Smarak Institute of Medical Sciences, Bhojipura, Bareilly, Uttar Pradesh, India
|Date of Submission||12-Jun-2021|
|Date of Acceptance||26-Aug-2021|
|Date of Web Publication||23-Feb-2022|
Dr. Piyush Kumar
Department of Radiation Oncology, Shri Ram Murti Smarak Institute of Medical Sciences, Bhojipura, Bareilly, Uttar Pradesh 243202
Source of Support: None, Conflict of Interest: None
Aim: Concurrent cisplatin with radiotherapy improves outcomes in locally advanced squamous cell carcinomas of the head and neck cancers. Cisplatin has been used in different doses in various schedules. The present study is designed to evaluate the compliance, clinical outcomes, and long-term side effects in two different dose schedules of cisplatin used as concurrent therapy with radiotherapy. Materials and Methods: A total of 50 patients were included in the study from November 2015 to March 2017 with 25 patients in each group. The total radiotherapy dose planned was 70 Gy/35 fractions in 7 weeks, along with either cisplatin 35 mg/m2 weekly (Group I) or 6 mg/m2 daily (Group II). Assessment of toxicity was done by the RTOG scoring criteria. The WHO Response criterion was used to assess clinical response. Results: The compliance for radiotherapy treatment (80% vs. 84%) and chemotherapy cycles (52% vs. 60%) was almost similar in both the groups with no statistical difference seen. At the end of 3 months, Group II (60%) had better complete response than Group I (40%), although the difference was not statistically significant (P = 0.08). During treatment, no Grade III/IV hemoglobin toxicity was observed in either of the groups. Grade III/IV mucositis was predominant in Group II with 40% vs. 24%; P-value was not statistically significant. No Grade III/IV xerostomia was seen in either of the groups. The median follow-up of patients is 15 months. The median overall survival (11 vs. 6 months) and disease-free survival (4 vs. 2 months) are less in patients who received daily cisplatin infusion as concurrent therapy, although the difference is not statistically significant. Conclusion: Low dose cisplatin with radiotherapy appears feasible and is a logistically suitable “outpatient” option without increasing long-term toxicity.
Keywords: Compliance, head and neck cancer, low dose cisplatin, outcomes
|How to cite this article:|
Garg A, Kumar P, Kumar P, Chauhan AK. Weekly vs. daily low dose cisplatin in chemoradiation of locally advanced head and neck cancers: Comparison of compliance and clinical outcomes. J Curr Oncol 2021;4:61-7
| Introduction|| |
Head and neck cancer (HNC) is the 17th most common cancer in the world and 2nd most common cancer in India. There are approximately 380,000 new cases of HNC diagnosed and 180,000 deaths each year worldwide. Incidence rates are more than twice as high in men than in women.
Concurrent chemoradiotherapy (CCRT) is the standard of care in HNCs after the publication of various meta-analyses.,,,, Meta-analysis of chemotherapy in HNC reported 8% survival benefit with the addition of concurrent chemotherapy.,, CCRT can be used in primary or adjuvant settings.
The most common schedules for cisplatin monotherapy in squamous cell carcinoma of head and neck include 100 mg/m2 every 21 days for two or three cycles or weekly, at doses ranging from 30 to 80 mg/m2/week.,,, Cisplatin can also be given daily at 6 or at 100 mg/m2 spread over several days.,,, Weekly cisplatin seems to be preferred because of its outpatient administration feasibility and lower cost.
A relative infrequently used regimen in chemoradiotherapy for HNCs is the use of daily low dose cisplatin, which includes the administration of cisplatin 6 mg/m2 on each radiotherapy day.
Toxicities of cisplatin include ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions; the main dose-limiting side effect of cisplatin is nephrotoxicity.,,,,
Furthermore, cisplatin-induced renal and hematologic toxicities can be overcome by daily low-dose infusion of the drug and the use of antiemetics and hydration to reduce nephrotoxicity. Inevitable side effects, e.g., stomatitis and xerostomia, disappear after the completion of treatment.,, Acute toxicity increases with CCRT when compared with radiation alone. Grade III/IV toxicity may be as high as 50% in terms of mucositis, dysphagia, and dermatitis. Toxicities track with both cumulative radiation dose and daily fraction size. Acute direct toxicities such as dry mouth and mucositis are often triggered by cumulative radiation doses of 10–20 Gy.
So far, there are only few reports on efficacy and toxicity of low dose cisplatin in chemoradiotherapy for advanced head and neck squamous cell carcinoma., Therefore, the purpose of this study was to compare compliance and clinical outcomes among patients treated with weekly or daily low dose cisplatin in chemoradiation of locally advanced HNCs.
| Materials and Methods|| |
For the present study, patients who presented in the outpatient department from November 2015 to May 2017 were selected.
This includes previously untreated patients of histologically proven locally advanced malignancies of the head and neck region, age ≥18 years, Karnofsky performance status >70, normal hemogram, renal function tests and liver function tests, and normal ECHO.
This includes patients with prior or synchronous malignancy, patients who underwent prior surgery, distant metastasis, and previously treated patients with radiotherapy.
Radiotherapy planning and technique
All patients were immobilized with 5-point orfit cast. Patients were conventionally planned by three fields [two opposing lateral fields and lower anterior neck field (LAN)].
The mastoid area was shielded in opposing lateral field by placing a multileaf collimator using electronic portal image. Similarly, central shielding of around 1 × 1 cm was done on the LAN field at the junction with lateral fields. Spinal cord was shielded after 44 Gy in 22 fractions in opposing lateral fields.
The total dose prescribed was 70 Gy in 35 fractions over 7 weeks.
Patients were then randomized alternatively into two groups as follows:
Group I was given concurrent cisplatin 35 mg/m2 i.v. infusion every week; therefore, the number of planned chemotherapy cycles was 7.
Group II was given concurrent cisplatin 6 mg/m2 i.v. infusion daily (on the day of radiation); therefore, the number of planned chemotherapy cycles was 35.
Group I patients received cisplatin 35 mg/m2 weekly
They were adequately hydrated with 2–2.5 L of i.v. fluids and supplemented with Inj. KCl and Inj. MgSO4.
Radiotherapy was delivered within half an hour of administration of cisplatin.
Proper antiemetic therapy with 5-HT3 antagonist, dexamethasone, and ranitidine was given prior to chemotherapy administration.
Group II patients received cisplatin 6 mg/m2 daily
Chemotherapy was given on an outpatient basis, and hydration with 500 mL NS was done.
Radiotherapy was delivered within half an hour of administration of cisplatin.
Antiemetic therapy with i.v. 5-HT3, dexamethasone, and ranitidine antagonist was given prior to chemotherapy administration.
Assessment of compliance
The compliance was seen in terms of overall treatment time of radiotherapy, no. of chemotherapy cycles received, and cumulative dose of cisplatin received. Patients were considered to comply with radiation treatment if they completed 66–70 Gy within 51 days. Further, chemotherapy compliance was considered if the patients received a minimum of five chemotherapy cycles. In Group II, five cycles of daily infusion was considered equivalent to one weekly cycle.
Assessment of toxicity
Hematological toxicities were assessed by Common Toxicity Criteria and Adverse Events Version 4.03. Radiation toxicity (skin, mucosal, and salivary gland) was assessed by RTOG (Radiation Therapy Oncology Group) acute and late morbidity scoring criteria. Acute RTOG morbidity criteria were applicable from day of commencement of radiotherapy up to 3 months of follow-up. Patients were assessed weekly during chemoradiation to evaluate acute radiation reactions; after completion of radiotherapy, they were assessed monthly. Late radiation reactions were assessed using RTOG late morbidity criteria that were from 3 months to last follow-up date.
Clinical response assessment was done for objective tumor response according to the WHO Response Criteria at the end of 3 months.
The overall survival (OS) was evaluated from the date of registration. The cases lost to follow-up were considered as events and thus the survival was computed as the worst-case scenario. The disease-free survival (DFS) was evaluated from the date of complete response (on completion of treatment) to the re-appearance of disease.
Descriptive statistical analysis has been carried out in the present study using SPSS software version 20.0. Significance is assessed at the 5% level of significance. The χ2 test has been used to find the significance of study parameters on categorical scale between two or more groups. Student’s t-test (two-tailed, dependent) has been used to find the significance of study parameters such as correlation among various clinical, treatment, and toxicity parameters on continuous scale within each group.
| Results|| |
Fifty patients of locally advanced HNC were included from November 2015 to May 2017. All the patients received radiation treatment and concurrent chemotherapy at Department of Radiation Oncology, R.R. Cancer Institute and Research Centre. The median follow-up of patients is 15 months.
Almost three-fourths of the population was less than 60 years of age [Table 1]. In Group I, mean age was 54.1 years and in Group II it was 54 years, whereas median age was 55 years in both the groups. Majority of the patients came with chief complaints of swelling over neck and difficulty along with pain while swallowing. All the patients in both the groups had a history of smoking and there were around 28–32% of the patients who had a history of combined intake of alcohol and tobacco. Overall 40% of the patients were associated with comorbid conditions of which the most common was diabetes mellitus. Stage IVA was the most common stage of presentation in both the groups and was with nodal presentation with more than three-fourths of the patients.
The compliance for radiotherapy treatment (80% vs. 84%) and chemotherapy cycles (52% vs. 60%) was almost similar in both the groups with no statistical difference seen [Table 2]. Median OTT in Group I was 51 days, whereas in Group II it was 52 days. The mean cumulative chemotherapy dose was 187.2 and 201.9 mg in Groups I and II, respectively, which was not statistically significant.
Clinical response at the end of 3 months
At the end of 3 months, Group II (60%) had better complete response than Group I (40%), although the difference was not statistically significant (P = 0.08). Similarly, females had better complete response in Group II (75% vs. 67%) although not statistically significant. Patients less than 60 years of age had better response in Group II when compared with Group I (63% vs. 33%), which was not statistically significant (P-0.07). Comorbid conditions had no significant impact on response to the treatment.
When complete response was compared with T Stage and N Stage, no statistically significant difference was seen. On the contrary, when compared with group staging, Stage IV had a statistically significant poor response (P = 0.05). Overall response when compared with individual sites of head and neck had no significant difference.
During treatment, no Grade III/IV hemoglobin toxicity was observed in either groups. No significant neutropenia was observed in any of the grade in both the groups. Thrombocytopenia was not statistically significant in either of the groups. Grade I/II nephrotoxicity was observed in both the groups and the P-value was not significant. No Grade III/IV toxicity was seen in any of the groups.
On follow-up, Grade I and II skin reactions were more in Group I when compared with Group II, and P-value was not significant. Grade III/IV mucositis was predominant in Group II with 40% vs. 24%, and P-value was not statistically significant. No Grade III/IV xerostomia was seen in either of the groups. Grade I/II toxicities were manageable. No Grade III/IV reactions were present in the 4–6th month of follow-up.
Clinical response at 3 years
The complete response in the last follow-up was slightly more in patients of Group I (44% vs. 32%), which was not statistically significant (P = 0.56). The clinical response in [Table 3] also reveals no statistically significant difference when correlated with various treatment characteristics.
|Table 3: Correlation of treatment characteristics with assessment of overall clinical response (WHO Criteria) at 3 years|
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In the assessment done at the end of 3 years, all the patients of Group I were dead or lost to follow-up. On the contrary, 24% of Group II patients were alive and rest were either dead or lost to follow-up. The median follow-up of alive patients in Group II is 50 months.
More than half of the patients (56%) were lost to follow-up. Among these, 10% of the patients did not turn up after treatment and another 20% of patients did not come after first follow-up within 3 months. For evaluating OS and DFS, the patients lost to follow-up were considered dead.
The median OS (11 vs. 6 months) and DFS (4 vs. 2 months) are less in patients who received daily cisplatin infusion as concurrent therapy, although the difference is not statistically significant [Table 4], [Figure 1]a and b.
|Figure 1: a) Kaplan Meier graph showing OS for both the study arms b) Kaplan Meier graph showing DFS for both the study arms|
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| Discussion|| |
In the present study, the chemoradiation protocol of daily low dose cisplatin given along with radiotherapy to head and neck patients was found to be feasible and equally effective as that of weekly cisplatin. The advantage of low dose cisplatin is that it can be given on outpatient basis and does not need admission. Further, patients did not need 2–2.5 L of hydration as needed in weekly regime of cisplatin. The low dose cisplatin will be useful for those patients who are unfit for high dose cisplatin as low dose daily cisplatin may be stopped as soon as early signs of any toxicity appear.
There are controversial views of using prehydration in low dose cisplatin. The study of Hoebers et al. of 121 patients advised 1.5 L of oral fluid intake and 1 L of saline intravenous at each cisplatin infusion. It was done when the authors observed premature cessation of cisplatin due to its toxicity. In contrast, studies by Brizel et al. and Jeremic et al. did not incorporate prehydration. In the present study, low dose cisplatin was given with hydration of 500 mL normal saline. The chemotherapy was tolerated in both the groups, and there was no statistical difference in the compliance of patients receiving five concurrent cycles or more in both treatment groups. The response rates were slightly lower in the daily low dose cisplatin arm but it was not statistically significant. Late renal toxicity has been reported in a single patient by Hoebers et al., but none of the patients had late renal toxicity in the present study.
At the end of 3 years, only six patients are in follow-up without any evidence of disease and surprisingly all were treated with low dose daily cisplatin. Rest of the patients in both arms are either dead or lost to follow-up. The outcomes were found to be statistically significant. The median OS (11 vs. 6 months) and DFS (4 vs. 2 months) were less in the low dose daily cisplatin, although it was not statistically significant. OS at 3 years in the study by Hoebers et al. is 36%. The present study reveals very low survival of 12%, which may be attributed to our evaluation as worst-case scenario (dead and lost to follow-up considered as an event, 56% patients were lost to follow-up) and all patients were being treated by only conventional techniques.
In a study of 50 patients by Wolff et al., hematological toxicity of Grade III or more was seen in 14% and high-grade chronic toxicity of xerostomia was seen in 6% of the patients, which is contrary to findings in which none of the patients had Grade III or more hematological or chronic toxicity. It was restricted to Grade I/II only. In the same study, intended radiotherapy dose of 64 Gy was received by 94% of the patients, and 80% of the chemotherapy dose was received by 90% of the patients. On the contrary, the present study shows an intended radiotherapy dose of 66 Gy received by 84% of the patients, which can be explained by the higher intended radiotherapy dose also; chemotherapy compliance is lesser in the present study with 60% of the patients receiving five or more concurrent chemotherapy cycles. The probable reason may be that the present study population has 40% of the patients with comorbid conditions, diabetes being the commonest, although the study by Wolff et al. does not mention about comorbid conditions.
Gupta et al. compared the weekly and daily cisplatin schedule concurrent with accelerated radiotherapy (6 days per week, total duration 6 weeks). High incidence of Grade III/IV mucositis was seen which was more in the weekly arm (91% vs. 65%) and statistically significant. On the contrary, our study had overall lesser incidence of Grade III/IV mucositis and higher incidence in the daily cisplatin arm (40% vs. 24%). Overall higher incidence of severe mucositis in the study by Gupta et al. can be clearly explained due to the accelerated radiotherapy protocol in both arms. Further, the possible reason for increased mucositis in the daily cisplatin group rather in the weekly arm may be explained by radiobiology principles of radiotherapy, in which there is daily radiosensitization of tumor cells and normal cells by cisplatin, thereby causing more mucositis in this group of patients rather than weekly cisplatin group. The outcomes, compliance, and other toxicities (hematological toxicity and late toxicity) were almost comparable in both arms, as in our present study.
Carboplatin has been preferred in some patients when cisplatin is not found suitable. In a study of 119 patients by Homma et al., patients were treated either by weekly carboplatin (100 mg/m2) or daily cisplatin (4 mg/m2) for the initial 4 weeks of radiotherapy and were completed to a total dose of 65 Gy if good tumor response was seen at 40 Gy. Surgical resection was optionally used for the remaining patients. Forty-nine (81.7%) of 60 patients treated with carboplatin and 41 (69.5%) of 59 patients treated with cisplatin received the full dose of radiotherapy. The local control rate at 5 years was significantly higher in 56.2% for the carboplatin-treated arm (56.2% vs. 35.5%, P = 0.034), although the 5-year OS difference was not statistically significant (71.4% vs. 66.0%). The total cisplatin dose is much lower than used in other studies, where cisplatin 6 mg/m2 is found to be effective and feasible. If higher cisplatin dose would have been used, maybe the local control rates would have been equivalent.
González Ferreira et al. concluded that a strong significant relationship between overall treatment time delay and LRC (86.2%) and/or OS (71.4%) exists, with most studies providing a multivariate analysis. Delays in RT may result in an average loss of LRC ranging from as low as 1.2% per day to as high as 12–14% per week. A daily dose extra of about 0.6–0.8 Gy/day would be required to compensate for the extra time occurring during the prolonged OTT. In the present study, OTT prolongation was associated with lower 3 years DFS and lower median OS in both the groups. Six patients survived, all of them completed their treatment within 51 days which clearly highlights the importance of OTT, as discussed in the study by González Ferreira et al.
Jeremic et al. compared the outcomes of their two previous studies., In the first study, patients had been treated by conventional RT (CF RT) or CF RT with concurrent low dose cisplatin 6 mg/m2 or concurrent carboplatin. In the second study, patients were treated with hyperfractionation RT (Hfx RT) or Hfx RT with low dose cisplatin 6 mg/m2. Comparing the outcomes of low dose cisplatin with CF RT and Hfx RT from two previous studies, they concluded that Grade III/IV acute toxicities were significantly higher in Hfx RT in terms of stomatitis (49% vs. 13%, P <0.001) and esophagitis (25% vs. 3%, P< 0.001). Further, OS was marginally superior in Hfx RT patients (46% vs. 31%, P = 0.051). In our study, 40% of the patients had Grade III/IV mucositis in the low dose cisplatin arm. The incidence of severe mucositis is almost comparable with the study of Jeremic et al., but it surely arises the thought for intensification of radiotherapy protocol, more so when there is some hope for increase in OS. The intensification of radiotherapy by hyperfractionation may be tried under institutional protocol in which optimum supportive management under close observation is possible in terms of adequate hydration, adequate nutrition, and control of comorbid conditions, especially diabetes mellitus, along with regular psychological counseling of the patients and attendants.
In another study done by Al-Mamgani et al., it was concluded that after a median follow-up of 31.6 months, the actuarial OS and DFS rates at 3 years for patients receiving cumulative dose of >200 mg/m2 were significantly better when compared with those who received <200 mg/m2 [74% vs. 51% for OS and 73% vs. 49% for DFS (P < 0.001)]. In the multivariate analysis, the cumulative cisplatin dose (>200 vs. <200 mg/m2) was significantly predictive for OS (hazard ratio 2.05; 95% confidence interval 1.35–3.13, P = 0.001). In our study, in median follow-up of 15 months, the OS is better in patients receiving more than 175 mg/m2 of weekly or daily cisplatin (12 vs. 9.5 months in the weekly arm and 14 vs. 4 months in the daily arm), but the difference was not statistically significant. The reason for not having results of significant difference may be the assessment being done at lower cumulative doses and a lesser patient population.
A study conducted by Hoebers et al. concluded that at 2 and 3 years, DFS was 36% and 33%, whereas OS was 41% and 36%, respectively. In our study, both the groups had lower DFS and OS at 2 and 3 years. DFS at 2 and 3 years is 8% and 4% for Group I and 16% and 12% for Group II, respectively. OS at 2 and 3 years is 16% and 8% for Group I and 16% and 12% for Group II, respectively. The OS and DFS are very low in comparison to Hoebers et al., the major reason being that more than half of the patients are lost to follow-up and are considered as an event (dead) for statistical analysis.
| Conclusion|| |
Low dose cisplatin with radiotherapy appears feasible and is a logistically suitable “outpatient” option without increasing long-term toxicity. Based on this experience, we recommend its usage in centers that are overburdened with patients and lack adequate resources, i.e., in door hospital beds. Still, we need a larger number of patients for the use of low dose cisplatin to be evaluated in future clinical trials.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]