Concurrent chemotherapy in advanced head and neck carcinoma – A prospective randomized trial

Purpose: The aim of this study is to compare two different concurrent chemoradiotherapy regimes – weekly cisplatin and three weekly cisplatin along with standard external beam radiotherapy in advanced head and neck cancer. Procedures: 90 untreated patients of advanced squamous cell carcinoma of head and neck were randomized into three arms: Arm A (n=30) patients received inj cisplatin 30mg/m2 weekly along with radiation; Arm B (n=30) patients received inj. cisplatin 100mg/m2 on a three weekly basis with radiation; Arm C (n=30) received only radiation. Radiotherapy was delivered to a dose of 66 Gy to 70 Gy in conventional fractionation in telecobalt machine. Findings: Complete response rate is significantly higher in arm B compared to that of arm A and arm C. Major toxicitities include neutropenia, anaemia and mucositis. Grade 3 neutropenia, anaemia and mucositis were found in arm A and arm B. No grade 3 toxicity was found in arm C. There was no grade 4 toxicity in any arm. Conclusion: We conclude that concurrent chemoradiation produce better response compared to that of radiation only. Toxicities were also increased in concurrent regimes. Out of two concurrent regimes, three weekly regimes showed better response with slightly increased but manageable hematological toxicities. Hence, this regime can be considered as standard of care for advanced head and neck cancer.


Introduction:
Head and neck malignancy is the commonest cancer seen in males of Indian subcontinent, constituting around 25% of the overall cancer burden. 1 Only one third of these patients present with localized disease.The vast majority of them present with loco-regionally advanced disease.When these advanced cases are treated with external beam radiation alone, achievement of cure is difficult.Local failure rate sometimes approaches as high as 50%. 2 To improve this outcome the addition of chemotherapy (CT) to radiotherapy (RT) has become one of the important developments for the management of loco-regionally advanced head and neck cancers.There are various researchers who investigated different combinations of CT and RT like concurrent chemoradiation (giving chemotherapy along with radiotherapy or CRT), neoadjuvant chemotherapy (the addition of chemotherapy prior to surgery and/or RT), adjuvant chemotherapy (giving chemotherapy after surgery or RT) and sequential therapy (induction chemotherapy followed by concurrent CRT).Initial trials of neoadjuvant and adjuvant chemotherapy in advanced head and neck cancer showed increased response rate, organ preservation and improved quality of life.But there is no survival benefit. 2 Concurrent radiotherapy was also evaluated by several trials.In the postoperative settings, randomized trials 3,4 have shown increased response and survival in favor of chemoradiation.In unresectable disease, a phase III trial showed significantly improved survival with addition of CT. 5 Meta analysis of CT-RT trials 6 showed the benefit of adding CT to loco-regional therapy for non-metastatic disease.These trials did not show any significant survival difference between the use of monotherapy and combination therapy.Cisplatin based regimens were established as the most effective regimens with single agent activity, synergistic interaction and nonoverlapping toxicity.
The dose and delivery schedules of cisplatin have ranged from intermittent higher dose [100 mg/m 2 ] every 3 weeks to low dose [6 mg/m 2 ] daily administration. 7In theory, high dose CT acts by eradicating occult micro-metastases where as low dose daily or weekly CT has pure radio sensitizing effect.At present there is insufficient data to suggest which CT schedule is superior in terms of better disease control.Benefit of adding CT to RT comes at the cost of markedly increased acute toxicity, but there is not enough data to compare toxicities of CT schedules.In this background, we have compared the two concurrent CT-RT schedules used for head and neck cancers at our institute along with radiotherapy alone in terms of response as well as toxicities

Methods:
Patient Selection: From Feb 2010 to Jan 2011, a randomized prospective study was performed with 90 patients who met the following inclusion criteria:

•
Age between 18 year and 70 year Treatment Protocol: The patients after pretreatment evaluation were randomized into three arms by sequential randomization according to their attendance in our OPD: • Arm A (n=30) patients received inj cisplatin 30mg/m 2 weekly on days 1, 8, 15, 22, 29, 36, 43 along with radiation.
Radiotherapy was delivered to a dose of 66 Gy to 70 Gy in conventional fractionation with spinal cord sparing after 44 Gy.Radiation was given by telecobalt machine with conventional planning.The portals were mostly lateral parallel opposed fields.
The primary endpoints of the study were disease response and toxicity profile.
Patients were monitored weekly during radiotherapy for toxicity and nutritional support.

Follow up:
After completion of therapy, follow up was done monthly to evaluate response and toxicities.Response was assessed by local examination, indirect laryngoscopy and direct laryngoscopy (where indicated) 4 weeks after completion of radiotherapy.

Results:
Demography: The characteristics of the three arms are summarized in Table I.All the baseline profiles in three arms were comparable.One patient of arm C and one in arm A refused to continue due to personal reasons; but they were included during statistical analysis.

Discussion:
The dominant pattern of failure for squamous cell carcinoma of head and neck remains loco-regional, although distant metastases are now being increasingly documented.
Radiotherapy and chemotherapy given concomitantly in advanced head and neck cancer is a dose-intensive approach that exploits the independent complementary activity of radiotherapy locally and chemotherapy distantly (spatial co-operation) and the enhanced local active (within the radiation field).Hence, radical radiotherapy with concurrent chemotherapy is contemporary standard of care in the management of this loco-regionally advanced cancer.
A variety of chemotherapeutic agents have been used concurrently with RT either as monotherapy or combination therapy in different schedules in the management of advanced head and neck cancer.The various combinations of chemotherapeutic drugs used are based on the response for metastatic and recurrent cancer.Single agent cisplatin; 8-11 fluorouracil; 12,13 methotrexate; 14 bleomycin 15 and mitomycin 16 have been used in combination with radiation therapy in several trials.These trials have shown improved response rates. 8-16Some of the trials have shown improvement in survival. 9,10,13,14everal groups have evaluated cisplatin and 5-FU in combination with radiation and shown improved control but at the cost of increased toxicity. 2MACH-NC, one of the largest metaanalyses, showed survival benefit of 8% from chemoradiation at five years. 4Although efficacious, this is associated with high acute morbidity necessitating intensive supportive care with attendant resource implications.The meta-analyses also showed that cisplatin is the most impressive of all agents and single agent CT based on platinum is the treatment of choice. 4e primary objective of this prospective study was to assess the efficacy and acute toxicity of two different schedules of cisplatin i.e. concurrent weekly cisplatin-based radical radiotherapy and concurrent three weekly cisplatin-based on radical radiotherapy.Hence, to find out their potential to be an optimal regimen in advanced head and neck cancers.In 3 weekly regime, 76% CR was very promising and it is 67% in weekly cisplatin arm, which is also higher compared to that of radiation only arm.To reveal whether there is any survival benefit, we need a longer follow up.
Acute reactions are markedly increased with chemo-radiation and patients need intensive supportive care for management of pain and maintenance of nutrition.At our institute, we have involved a team of pain and palliative care doctors along with radiation oncologists for the management of toxicity and pain.Dietary counseling is also done periodically.
We compared our two schedules with other studies reported in the literature.In our study, patients treated with 3 weekly regimen showed considerably less grade III toxicity of skin and mucous membrane compared to that of weekly regime.This could be attributed to delivery of CT in longer interval.Similar study also showed that with this approach the severity of systemic toxicity and mucositis was low without affecting the local control. 17hen we compared grade III hematological toxicity, it was 37% for anemia and 43% for nutropenia in our study in 3 weekly arm, 61 % in RTOG 3 and 13% in EORTC 4 study again reflecting the importance of CT delivery in fractionated doses.Eighty three percent of patients completed all 3 cycles of CT in our study in 3 weekly arm, which is comparable with the studies reported in the literature.Some studies 17,18 showed that a substantial fraction of patients could not receive the third planned dose of cisplatin and suggested that a cumulative dose of 200 mg/ m 2 might be adequate to yield same beneficial effect.
Very few studies with weekly CT have documented toxicity.Grade III mucositis was 40% in weekly regime and 33% in 3 weekly regimes in our study.Vokes EE et al. 19  When we compared weekly and 3 weekly schedules of CT, grade III skin, mucous membrane and hematological toxicity were higher in weekly CT.Although statistically not significant, the percentage of patients with significant weight loss was more in weekly CT group suggesting the need for feeding procedure for all patients.Also this group had more number of treatment interruptions.Quite a number of studies have shown those treatment interruptions during RT decreases local control and which is also true for altered fractionation schedule 20,21 but its effect with concurrent CT-RT is not clear.
This trial on head and neck squamous cell carcinoma patients confirms that the use of concurrent cisplatin is safe and concurrent chemoradiation is superior to radiation alone resulting in higher response.It can be recommended as standard of care.Among the two chemoradiation schedules, three weekly cisplatin is less toxic and thus with better compliance than weekly one.Weekly cisplatin can be made more acceptable by reducing the dose and using feeding tubes supplementing nutritional support.

Table - I
Demography

Table - V
Late toxicities DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al.