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|Year : 2006 | Volume
| Issue : 2 | Page : 56-64
The role of reirradiation versus chemotherapy in recurrent head and neck cancer
Jenifer Jeba, Reena George
Palliative Care Unit, Christian Medical College, Vellore - 632 004, India
Palliative Care Unit, Christian Medical College, Vellore - 632 004
Source of Support: None, Conflict of Interest: None
Head and neck cancer recurrences after definitive radiotherapy present a difficult therapeutic problem, as only a small proportion of patients have resectable disease. When surgery is not possible, reirradiation might be a feasible option for selected patients, particularly those with favourable prognostic factors such as second primaries, nasopharyngeal or laryngeal tumours or delayed recurrences. Current evidence indicates that in this group of patients reirradiation offers better control rates than palliative chemotherapy. The loco regional control rates of reirradiation without surgery is 20% at five years and 27% at two years. The overall survival rate with reirradiation ranges from 10% to 35% at two years and 0% to 14.6% at five years. The first randomized trial directly comparing chemotherapy with reirradiation is in progress. This article outlines the indications for and results of reirradiation and chemotherapy in post radiotherapy recurrences of head and neck cancer.
Keywords: Chemotherapy, head and neck cancer, larynx, nasopharynx, reirradiation, toxicity
|How to cite this article:|
Jeba J, George R. The role of reirradiation versus chemotherapy in recurrent head and neck cancer. Indian J Palliat Care 2006;12:56-64
| » Introduction|| |
More than 70% of patients with head and neck cancer present with advanced loco-regional disease (stage III and IV). Despite aggressive local therapy fewer than 30% remain disease free at three years. The local or regional failure rates of squamous cell carcinomas of the head and neck range between 20% and 57%.,,,, The cumulative estimated five year incidence of loco regional relapse is 29-31% in high risk patients after surgery and postoperative chemo radiotherapy.,, If left untreated the prognosis of patients with recurrent head and neck cancer is poor, with a median survival of five months. The incidence of second primary neoplasms is between 16-30%.,
The treatment options include surgery, palliative chemotherapy, supportive care or re-irradiation with or without concurrent chemotherapy. Surgery is the optimal therapy, when disease is amenable to complete resection; however, this is feasible only in a small subset of patients.
Currently, the most common treatment for patients with previously irradiated, unresectable disease remains single-agent or multi-agent chemotherapy with response rates between 10% and 40% and median survivals of six to eight months.,,
Administration of a second course of radiation to tissues within a previous radiation portal has been considered unsafe. Physicians are sometimes unaware that reirradiation is feasible in certain cases. Since radiation facilities are available in many parts of India, we wish to outline the role of reirradiation in recurrent head and neck cancer. The earliest clinical studies on re-irradiation, date back to 1959.
Patient selection and prognostic factors
From the limited available evidence patients most likely to benefit are: patients suitable for debulking surgery; patients with second primary cancers as opposed to local recurrences; primary tumours in the nasopharynx and larynx and longer disease free intervals.
[Table - 1],[Table - 2] summarize the results of some studies done on reirradiation alone and reirradiation with surgery respectively. Patients treated with resection and reirradiation [Table - 2] have better local control and survival as compared to those treated with reirradiation alone [Table - 1]. The loco regional control rate of reirradiation without surgery is reported as 20% at five years and 27% at two years, [Table - 1] as compared to 51-81% for reirradiation with surgery at three years [Table - 2]. The overall survival rate with reirradiation ranges between 10-35% at two years and 0-14.6% at five years. [Table - 1] The survival rates are higher in patients who have also had surgery and range from
22-63% at three years and as high as 34.5% at five years [Table - 2]. The high control rate and better overall survival is probably because the recurrence was small and amenable to surgery. Postoperative reirradiation has superior results to salvage surgery alone.
Second primary cancers
Second primary tumours, as opposed to true local regional recurrences, appear to have a better outcome. This may be because a true primary tumor recurrence arises from a group of radiation-resistant clonogens. In the radiation therapy oncology group (RTOG) 96-10 trial the one year survival rate for patients with a second primary was 54% compared with 38% in those with recurrence ( P = 0.083). Stevens et al reported a five-year survival of 37% for patients with new second primary cancers and 17% for patients with recurrent cancers. Loco-regional tumor control was also higher in the patients with new tumours when compared to those with recurrent tumours (60% vs 27%).
Primary site-nasopharynx and larynx
In patients who do have local recurrences, benefit with reirradiation is more likely to be seen when the primary is in the nasopharynx or larynx.,,,
Nasopharyngeal tumours are especially favourable, Wang et al reported five year survival rates of 50% (n=51), with T 1 and T 2 post RT recurrences. Seven patients were alive for more than ten years and three for more than 20 years.
In recurrent nasopharyngeal tumours, three dimensional conformal radiotherapy, intensity modulated radiation therapy and radio surgery boosts have been used with good results.,,,
Laryngeal recurrences also do well with high doses of re-irradiation with five-year local control and survival rates of 60% and 93%, respectively. Ohizumi et al identified nasopharynx, larynx and oropharynx as favourable sites and oral cavity, nasal cavity or hypopharynx as unfavorable sites.
Long disease free interval
In the RTOG 96-10 trial it was found that patients who received their primary radiation three years or more before the repeat radiation had a one-year survival rate of 48% as compared with 35% for patients treated within three years ( P = 0.017). The interval between prior radiation and re-irradiation was however, not a significant prognostic indicator of survival in RTOG 96-11.
| » Reirradiation|| |
There are many studies on Reirradiation and palliative chemotherapy [Table - 1],[Table - 2],[Table - 3] in patients with recurrent head and neck cancer, but there are no randomized trials comparing the two. The first randomized trial comparing re-irradiation and concurrent chemotherapy versus chemotherapy alone for inoperable, previously irradiated, locally recurrent or second primary squamous cell head and neck cancer is underway (RTOG 0421).
The Institut Gustave-Roussy reported one of the largest reirradiation experiences with 169 patients. The two-year survival in patients who received conventional radical radiotherapy with or without chemotherapy was 25%. Overall survival rates were higher in patients with smaller radiotherapy treatment volumes. In two multi institutional studies by the Radiation Therapy Oncology group the two-year survival rates were 16.9% and 24.9%.,
A retrospective study from India reported on 29 patients who received reirradiation along with chemotherapy. The overall response rate was 83% with complete response in 31%. All complete responders had received a cumulative radiotherapy dose of more than 100 Gy. The median survival was nine months and the one and two-year survival rates were 41% and 12%, respectively.
Post operative reirradiation [Table - 2]
Patients with locally recurrent, previously irradiated squamous cell carcinoma of the head and neck, who had poor prognostic findings post surgery (n=130), were randomized to either receive postoperative chemo radiotherapy (60 Gy) or observation. The results showed significant improvement in progression free survival in the postoperative chemo-re-irradiation group ( P= 0.01), but did not provide a statistically significant overall survival advantage.
Kasperts et al prospectively studied 39 patients who received postoperative reirradiation for poor prognostic factors. The three-year overall survival rate was 44% with a loco regional control rate of 74%.
Reirradiation has also been administered using local interstitial brachytherapy for primary and nodal recurrences. Reported local control rates have been 60% to 70% and 5-year overall survivals 60% to 70%.,,
Postoperative high dose rate brachytherapy was administered to 25 patients who underwent salvage surgery for cancers arising in a previously irradiated field. Although 88% of patients had either close or microscopically positive margins, the four-year local control rate and overall survival were 85.6% and 46.4%, respectively.
Radiation dose intensity
Adequate radiotherapy doses are needed for optimal outcomes in radical reirradiation. High doses of reirradiation are necessary in the radical treatment of recurrent tumor, because of the origin of recurrence from radiation resistant clonogens. Various studies have shown higher control rates with higher doses of radiation.,,,
Haraf et al reported a two year survival of 35% in patients who received over 58 Gy as compared to 8% in those who received less than 58 Gy. Langlois et al showed that local control was achieved in 55% of patients who received a dose greater than 60 Gy as compared to 8% for doses less than 60 Gy.
In a recent review, Wong et al have summarized the adverse effects of reirradiation.
The most serious reported toxicity is carotid rupture, which occurs in 1-5% of patients, in the setting of re-irradiation. Carotid rupture results in death in almost all instances, except in the study by Salama et al where one of six patients who had a carotid rupture survived.,, Vascular stenosis and thromboembolism have also been reported.,,,,,
The incidence of Grade 3 and 4 acute mucositis varies between 5-32% in different studies.,,,, De Crevoisier reported osteoradionecrosis in 16% and cervical fibrosis in 40%. Many studies have not comprehensively reported on late toxicity.
Aspects such as quality of life, difficulties with eating, nutrition, speech, pain, fatigue, which are important in weighing the benefit of re-irradiation, have not been addressed in most studies. Data from the University of Chicago show that intelligible speech was preserved in 85%, but only 25% of patients were able to swallow solids without dependence on enteral supplementation.
The frequency of significant hematologic toxicity varies and depends on the chemotherapy regimen used. The combination of hydroxyurea and 5 Fluorouracil (FU) has been found to have only mild to moderate myelosuppressive effects with fewer than 10% of patients developing grade 3 or 4 neutropenia, as compared to regimens such as docetaxel/cisplatin and paclitaxel/cisplatin where grade 3 or worse neutropenia occurs in approximately one third of patients.
| » Chemotherapy|| |
[Table - 3] lists studies on chemotherapy in recurrent head and neck cancer. Unlike in the studies on reirradiation, most studies have not reported two year or five-year survival rates or local control. Wong et al undertook a secondary analysis of two Eastern Cooperative Oncology Groups (ECOG) trials that studied cisplatin, paclitaxel or cisplatin with either 5FU or paclitaxel in patients with recurrent or metastatic cancer. The 2-year survival was 10.5%, which is less than results reported with reirradiation with or without chemotherapy. Most studies have reported response rates that range from 10-35% and median survival ranging from 5 -8.7 months [Table - 3].
Randomized trials on combination chemotherapy, with cisplatin and 5-FU or methotrexate have shown increased response rates but failed to show a survival benefit over single-agent therapy.,,
Two randomized controlled trials have studied the role of taxanes. The combination of cisplatin and paclitaxel was not more effective, in terms of response and survival, than cisplatin and 5-FU. Hematological toxicity was seen in upto 70% of patients despite the use of granulocyte-colony stimulating factor in those receiving high-dose paclitaxel and 78% in those who received low dose paclitaxel.
| » Targeted therapies|| |
Molecular targeted agents, which do not have overlapping toxicities with chemotherapy agents, are being studied for improving response to treatment. The epidermal growth factor receptor (EGFR) is expressed widely and at high levels in squamous cell carcinoma of the head and neck region and is associated with a poor prognosis.
EGFR inhibitors including monoclonal antibodies such as cetuximab and tyrosine kinase inhibitors, such as erlotinib and gefitinib have been used in small trials.,,
| » Conclusion|| |
Recurrent head and neck cancer, within the irradiated field is a difficult and common therapeutic problem. Though surgical resection is the best treatment, only a small subset of patients have resectable disease. In selected patients with borderline operability, the option of debulking followed by postoperative reirradiation can be considered.
When surgery is not possible, reirradiation is a feasible option for some patients. It is important to carefully select patients with favourable prognostic factors, such as second primary tumours, recurrence in the nasopharynx or larynx or delayed recurrences. From the evidence so far, it appears that in this select group of patients reirradiation offers better control rates than palliative chemotherapy. However the results of the RTOG 0421 will provide the first direct comparison between reirradiation and chemotherapy.
An optimal treatment schedule has not yet been defined. Radiation portals must be tight to avoid excessive irradiation of normal tissues. The reirradiation dose should be optimum, ranging from 60 to 70 Gy. Patients must be fully informed of the potential life-threatening toxicities and the impact on quality of life. Future trials should aim to identify those patients with the greatest chance of benefit while optimizing the chemotherapy and radiation schedules.
Attention to pain and symptoms; emotional and body image issues; and questions on nutrition and prognosis are important in these patients just as they are for the large proportion of patients with recurrent head and neck cancer who will either not be suitable for, or have access to salvage therapy.
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[Table - 1], [Table - 2], [Table - 3]