Prognostic factors in head-and-neck cancer patients treated with surgery followed by intensity-modulated radiotherapy (IMRT), 3D-conformal radiotherapy, or conventional radiotherapy

doi:10.1016/j.oraloncology.2006.05.006

Oral Oncology

Volume 43, Issue 6, July 2007, Pages 535-543

https://doi.org/10.1016/j.oraloncology.2006.05.006 Get rights and content

Summary

In 148 head-and-neck cancer patients treated with surgery plus radiotherapy (RT), IMRT, 3D-conformal RT, and conventional RT and 10 potential prognostic factors were evaluated for overall survival (OS), metastasis-free survival (MFS), and loco-regional control (LC). On univariate analysis, ECOG performance status, T-stage, AJCC-stage, extent of resection, and pre-RT hemoglobin level (⩾12 g/dl better than <12 g/dl) were significantly associated with treatment outcome, whereas RT technique had no significant impact. On multivariate analysis, performance status maintained significance for OS (P = 0.019), AJCC-stage for LC (P = 0.034), extent of resection for OS (P = 0.045) and MFS (P = 0.021), pre-RT hemoglobin for MFS (P < 0.001). IMRT was associated with less xerostomia than conformal RT and conventional RT (17% versus 63% and 73%, P = 0.037). Otherwise, acute and late toxicity was similar. Outcome was significantly associated with performance status, tumor stage, extent of resection, and pre-RT hemoglobin. The three radiation techniques provided similar disease control. IMRT was effective in significantly reducing xerostomia.

Introduction

Radiotherapy is a frequently applied modality for the treatment of head-and-neck cancer, as definitive or postoperative treatment. Several retrospective studies have suggested that postoperative radiotherapy improves loco-regional control in head-and-neck cancer patients.1, 2, 3 In 1998, Regine et al. demonstrated in a retrospective analysis postoperative radiotherapy during primary treatment to be associated with better loco-regional control and survival when compared to radiotherapy as salvage treatment for a recurrence after surgery.⁴ The data of a prospective randomized study, the RTOG 73-03 trial, demonstrated postoperative radiotherapy with 60 Gy provided better loco-regional control than preoperative radiotherapy with 50 Gy.5, 6

Surgery followed by radiotherapy is considered aggressive therapy. However, in the Intergroup Study 0034, this approach was associated with an actuarial survival rate of only 44% at 4 years in patients with completely resected locally advanced head-and-neck cancer.⁷ The question whether additional chemotherapy may improve the treatment outcome, was addressed in several studies. However, the potential benefit of postoperative chemo-radiotherapy when compared to postoperative radiotherapy alone is still controversial. The Intergroup study 0034 did not demonstrate a significant difference between radiotherapy plus three preceding courses of cisplatin/5-FU chemotherapy and radiotherapy alone with respect to loco-regional control (26% versus 29%) and overall survival (48% versus 44%) at 4 years.⁷ In the RTOG 95-01 study, concurrent chemo-radiotherapy with three courses of cisplatin was superior to radiotherapy alone for loco-regional control (82% versus 72% at 2 years, P = 0.01).⁸ However, 2-year overall survival was similar (63% versus 57%, P = 0.19). The EORTC Trial 22,931 suggested a benefit for chemo-radiotherapy with three courses of cisplatin when compared to radiotherapy alone for both estimated 5-year loco-regional control (82% versus 69%, P = 0.007) and survival (53% versus 40%, P = 0.04).⁹ However, the combined approach was associated with a substantial increase in acute toxicity. Grade 3 or higher adverse effects occurred in 77% versus 34% of patients (P < 0.001) in the RTOG 95-01 trial, and in 41% versus 21% of patients (P = 0.001) in the EORTC 22,951 trial.

Novel combinations of therapy are required to maintain the improved outcome associated with post-operative chemoradiotherapy but decrease the high levels of toxicity. Options which can be tried to improve the results of radiotherapy include altered fractionation or newer radiation techniques such as 3D-conformal radiotherapy and intensity-modulated radiotherapy (IMRT) instead of “standard” conventional radiotherapy. An improved dose distribution is achieved with 3D-conformal radiotherapy compared to conventional radiotherapy.10, 11 However, it is still uncertain whether the substantially greater time required to plan 3D-conformal radiotherapy is associated with better disease outcome or less toxicity than conventional radiotherapy. Thus, clinical studies comparing outcome and toxicity of these two radiation techniques are required.

Several one-arm studies have been published in recent years suggesting that IMRT results in low rates of radiation related xerostomia by sparing (at least) one parotid gland. Additionally, IMRT results in satisfactory loco-regional control and survival rates.12, 13, 14, 15, 16 However, little clinical data is available directly comparing IMRT with other radiation techniques for toxicity,¹⁷ and no study could be identified from the literature that compared IMRT with another radiation technique regarding disease control.

To our knowledge, the present study is the first study that compared the three major radiation techniques (IMRT, 3D-conformal radiotherapy, and conventional radiotherapy) in head-and-neck cancer patients treated with surgery followed by irradiation. The outcomes compared included overall survival (OS), metastasis-free survival (MFS), loco-regional control (LC), and toxicity. Furthermore, 10 additional potential prognostic factors were evaluated for relationships with treatment outcome.

Section snippets

Patient eligibility and patient characteristics

Between 05/1999 and 09/2005, 148 patients (47 females and 101 males) with squamous cell carcinoma of the head and neck were treated with surgery followed by radiotherapy at our institution. The following data were retrospectively evaluated: age, Eastern Cooperative Oncology Group (ECOG) performance status, tumor site, histologic grade, T-stage, N-stage, AJCC-stage, extent of resection, chemotherapy, radiation technique and dose, hemoglobin level prior to RT, overall survival (OS),

Results

The results of the univariate analysis with respect to OS, MFS, and LC are summarized in Table 2. The ECOG performance status (0–1 better than 2, P = 0.001), T-stage (T1–2 better than T3–4, P = 0.016), AJCC-stage (I–III better than IV, P = 0.037), extent of resection (R0 better than R1/2, P = 0.019), and pre-RT hemoglobin level (⩾12 g/dl better than <12 g/dl, P = 0.036) were significantly associated with OS. MFS was significantly influenced by pre-RT hemoglobin (P < 0.001), and the extent of resection

Discussion

The present study suggested that parotid-sparing IMRT is effective in substantially reducing the rate of radiation induced grade 2–3 xerostomia. Only three of 18 patients (17%) of the IMRT group experienced grade 2 xerostomia, and no patient grade 3 xerostomia. These results are similar to those observed by other authors who applied IMRT for postoperative radiotherapy of head and neck cancer patients. In the study reported by Muenter et al. also three of 18 patients (17%) treated with IMRT

Conflict of interest statement

All authors hereby confirm that there is no conflict of interest related to this study. The study was not funded.

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Older patients aged 65 years and above with non-metastatic NPC treated with curative intent IMRT between 2003 and 2013 were retrospectively analysed. Variables examined were gender, age, overall stage, chemotherapy use, Eastern Cooperative Oncology Group (ECOG) performance status and comorbidity. The comorbidity severity was determined by adult comorbidity evaluation (ACE-27). We considered hospitalization or placement of feeding tube during and up to one month post radiotherapy as surrogate endpoint for significant acute toxicities. Other endpoints examined were: OS (overall survival), DFS (disease free survival), DSS (disease specific survival).
A total of 185 patients were eligible for analysis. Median age was 70 (65–86 years). Most of the patients presented with Stage III and IVA/B (n = 127, 68.7%), of good performance status of ECOG 0–1 (n = 176, 95.1%) and had low comorbidities with ACE-27 score of 0–1 (n = 141, 76.2%). Chemotherapy was delivered to 84 patients (45.4%). OS, DFS, and DSS were 64.5%, 51.4%, and 72.8% respectively. High comorbidity burden but not chemotherapy had significant impact on OS and DFS in patients with advanced stage. Fifty patients (27%) required tube feeding or hospitalization during the course of RT. Males, chemotherapy use and ECOG score ≥2 were significant predictors of tube feeding or hospitalization during RT.
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Intensity-modulated Radiotherapy in the Treatment of Head and Neck Cancer
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After removing articles determined to be ineligible based on a title and abstract review, 13 eligible articles were ordered from the MEDLINE results, and two from the EMBASE results (15 articles in total were ordered for full-text review). Of the 15 fully published papers, two submitted papers and two abstracts that were ordered for full-text review, only 10 of the fully published papers were retained [3–12], together with both the author-submitted papers [13,14] and both the abstracts [15,16]. One of the abstract reports [15] was an update of a previously published paper [17], and this paper was also obtained for completeness.
Intensity-modulated radiotherapy (IMRT) is a newer method of radiotherapy that uses intensity-modulated beams that can provide multiple intensity levels for any single-beam direction and any single-source position, allowing concave dose distributions and dose gradients with narrower margins than those possible using conventional methods. IMRT is ideal for treating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting and provides increased tumour control through an escalated dose and reduces normal tissue complications through organ at risk sparing. Given the potential advantages of IMRT and the availability of IMRT-enabled treatment planning systems and linear accelerators, IMRT has been introduced in a number of disease sites, including head and neck cancer. This systematic review examined the evidence for IMRT compared with two-dimensional external beam radiotherapy (EBRT) in the treatment of head and neck cancer in order to quantify the potential benefits of this new technology and made recommendations for radiation treatment programmes considering adopting this technique. Findings were in favour of IMRT compared with two-dimensional EBRT where avoidance of the adverse outcomes xerostomia, osteoradionecrosis and blindness are the main outcomes of interest, based on a review of 15 papers including 1555 patients. There are insufficient data to recommend IMRT over two-dimensional EBRT if treatment-related outcomes are the main outcomes of interest. Future research should focus on additional normal tissue preservation, and the role of IMRT in the treatment of recurrent head and neck cancer, as well as its use in combination with surgery, chemotherapy and/or brachytherapy.
Radical radiotherapy for nasopharyngeal carcinoma in elderly patients: The importance of co-morbidity assessment
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Elderly patients represent a unique challenge for radical treatment in nasopharyngeal carcinoma (NPC) because of age and co-morbid conditions. We sought to evaluate the outcome of this particular group of patients and to identify key factors affecting treatment outcome. From 1998 to 2008, 990 consecutive NPC patients without distant metastasis were treated with radical radiotherapy with planned total dose >66 Gy. Among them, 103 (10.4%) patients were elderly aged >70 (group A). Their clinical characteristics and outcome were compared with those aged <70 (group B). Mortality at 90 days was used as a proxy of early deaths related to treatment. Co-morbidities were measured by the Adult Co-morbidity Evaluation 27 (ACE-27). Group A presented more commonly with poorer performance status. They showed higher rates of acute reaction, radiotherapy incompletion and mortality at 90 days (7.8% vs. 1.2%, p < 0.001). The 5-year overall survival rates were 43.9% and 78.1% for groups A and B, respectively (p < 0.001). No difference in failure free survival rates was noted. For group A, ACE-27 was the only predicting factor for mortality at 90 days [ACE-27 2–3 vs. 0–1: HR 15.86 (2.68–93.95), p = 0.002], and the most important prognostic factors for overall survival included age, presenting stage and ACE-27 (p < 0.05). Elderly NPC patients had poorer tolerance to radiotherapy. Early deaths related to treatment were not uncommon. A reasonable disease control can still be attained after radical radiotherapy for those who were able to survive through the peri-radiotherapy period. Patient selection and treatment approach with reference to ACE-27 should be considered.
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The head and neck region is a well-suited location for the treatment of cancer with IMRT because of the complex anatomic topography of this area and the potential severity of radiation-associated tissue defects in the proximity of vital organs (37). A characteristic benefit of IMRT is that clinical targets are treated at a therapeutically highly effective dosage while healthy neighboring structures receive the maximum protection attainable (38) although it requires considerably more time than 3D-RT for treatment planning and execution (16). Several studies suggested that patients treated with IMRT suffer from less radiation-induced xerostomia (16–18) by sparing at least 1 parotid gland (14, 15, 19–22) and thus provide patients with a major improvement in the quality of life (39).
Radiation therapy (RT) of malignant tumors in the head and neck area may have damaging effects on surrounding tissues. The aim of this investigation was to evaluate the effects of RT delivered by 3-dimensional conformal radiotherapy (3D-RT) or intensity-modulated radiotherapy (IMRT) on dental pulp sensitivity.
Twenty patients with oral or oropharyngeal cancer receiving RT with 3D-RT or IMRT underwent cold thermal pulp sensitivity testing (PST) of 2 teeth each at 4 time points: before RT (TP1), the beginning of RT with doses between 30 and 35 Gy (TP2), the end of RT with doses between 60 and 70 Gy (TP3), and 4 to 5 months after the start of RT (TP4).
All 40 teeth showed positive responses to PST at TP1 (100%) and 9 at TP2 (22.5%; 3/16 [18.8%] for 3D-RT and 6/24 [25.0%] for IMRT). No tooth responded to PST at TP3 and TP4 (0%). A statistically significant difference existed in the number of positive pulp responses between different time points (TP1 through TP4) for all patients receiving RT (P ≤ .05), IMRT (P ≤ .05), and 3D-RT (P ≤ .05). No statistically significant differences in positive sensitivity responses were found between 3D-RT and IMRT at any time point (TP1, TP3, TP4, P = 1.0; TP2, P = .74). A statistically significant correlation existed between the location of the tumor and PST at TP2 for IMRT (P ≤ .05) but not for 3D-RT (P = .14).
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Intensity-modulated radiotherapy versus conventional and 3D conformal radiotherapy in patients with head and neck cancer: Is there a worthwhile quality of life gain?
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Intensity-modulated radiotherapy (IMRT) is a technique that allows delivery of lower doses of radiation to normal tissue, while maintaining or increasing the tumour dose, compared with two-dimensional radiotherapy (2DRT) or three-dimensional conformal radiotherapy (3DCRT). This review of published data was undertaken to assess whether IMRT is associated with quality of life (QoL) benefits versus 2DRT and 3DCRT.
English-language literature published between January 2005 and August 2010 was searched for studies comparing IMRT versus 2DRT or 3DCRT in head and neck cancers that included QoL evaluation. Fourteen studies (five prospective and nine retrospective) were identified, two in abstract form only. Only one study was randomised. Studies included patients with nasopharyngeal cancer only, oropharyngeal cancer only and mixed populations.
The EORTC QLQ-C30 was the most widely used instrument, generally supplemented with the head and neck cancer module H&N35. IMRT was associated with statistically significant improvements in certain QoL domains versus 2DRT and 3DCRT, particularly those relating to xerostomia, including dry mouth, sticky saliva and eating-related domains. Improvements in global QoL were also observed in the IMRT groups in some studies.
Based on the studies reviewed, patients treated with IMRT experience statistically significant improvements in several important QoL domains versus 2DRT and 3DCRT. However, studies included heterogeneous populations, different timepoints for measurements and a variety of instruments for QoL assessment. Accepting the difficulties in execution, IMRT should be compared with 3DCRT in prospective randomised studies in homogeneous patient populations, using appropriate QoL assessments and clinical end points, to establish if IMRT provides enough value for the additional resources involved.

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