Reduced volume SIB-IMRT/IGRT to head and neck cancer in elderly and frail patients: outcome and toxicity

Around 48.000 new cases of oral cavity and pharyngeal cancer are diagnosed within the United States every year, causing about 9500 patients deaths annually [1]. For Germany the Robert-Koch-Institute counted 9.300 newly diagnosed cancers of the oral cavity and pharynx in men and 3.650 in women; for laryngeal cancer, 3.110 cases in men and 490 cases in women were expected for first diagnosis in 2012 [2]. Radical treatment, including multimodal approaches with surgery, radiotherapy (RT) and chemotherapy, or combinations of these, can offer significant advantage in local control as well as in overall survival compared with best supportive care. However, this beneficial results can be associated with side effects, which are related to the treated region, especially the large amount of mucosa included into the target volume [3‐5].

There is some controversy regarding the subgroup of elderly and frail patients; depending on the tumor stage, surgery and/or RT might be indicated, however, based on the reduced overall prognosis, the real value of radical local or palliative systemic treatment remains unclear [6, 7]. Taking the short survival of few weeks up to 4 months of patients with stage IV disease under best supportive care into consideration, it can be discussed that a reduction of treatment time is beneficial. However, this must outweigh any increase in short or mid-term side effects, which can be associated with higher local doses related to shortened treatment times [8]. Consequently, a RT regimen for elderly and frail patients should have a lower burden of side effects, and, taking the shorter overall survival times into account, should need a shorter total treatment time [9]. Several palliative regimens, most of them using 2D and 3D-techniques, have been evaluated in prospective clinical trials [10‐12]. However, use of modern techniques such as IMRT and IGRT might decrease side effects without decreasing the efficacy [13].

In the present manuscript we report on our experiences with a hypofractionated IMRT/IGRT SIB-regimen offered to patients in reduced overall performance status based on individual decision making in interdisciplinary discussion, with special focus on patient prognosis and treatment toxicity.

For local control of head-and-neck tumors in elderly patients with significant comorbidities and overall reduced performance status, RT can be an effective treatment. To reduce overall treatment time as well as to reduce the amount of healthy tissue effected by the treatment, a shortened-course regimen with SIB was evaluated on 27 patients; overall, the treatment was very well tolerated without any significant severe short or mid-term side effects. However, target volume concept was associated with reduced margins compared to standard radiotherapy, with the main focus of local tumor control. Thus, diligent patient selection not to risk under-treatment is necessary.

With this aim, several groups have focussed on this special patient population. Especially with the advent of modern high-precision radiotherapy techniques, safe and normal-tissue sparing concepts with local dose escalation have become feasible. For patients with head and neck cancer who are deemed to be unsuitable for aggressive loco-regional treatment, several regimens for palliative radiotherapy, with and without concomitant chemotherapy, have been published so far [10, 12, 16‐19]. Duration and intensity of RT-treatment regimens shows a huge variety, from 16 Gy in 16 fractions within 2 days to 60 Gy in 6 weeks [17, 20].

When deciding on such a regimen, which might be considered prospective palliation, exact staging, clinical workup and also clinical-oncological experience in patient assessment is required. Detailed patient history taking into account all other diseases, prior treatment or other important factors is essential. In most studies published previously, comorbidity was not reported. Moreover, it is a shortcoming of most guidelines for the treatment of head and neck cancer that there are no recommendations for treatment decision making taking into account comorbidities [21]. Nonetheless, concomitant diseases do have a strong effect on survival times, and cancer treatment itself might impact comorbidity outcome even when cancer specific survival is not affected [6, 22, 23].

A significant proportion of patients underwent limited volume radiotherapy for malignancies that did not yet cause distressing symptoms. In these patients, the treatment decision was made in order to avoid adverse symptoms that were deemed to result from further progressive local disease, termed “prospective palliation”. Temel et al. reported in 2010, that patients with end stage non-small-cell lung cancer had a better prognosis, when palliative treatment was started earlier [24]. In line with these results, patients undergoing aggressive early palliation in our cohort had a comparable better prognosis compared to patients that underwent treatment when distressing symptoms already developed (median survival 512 days vs. 121 days).

In our cohort, neither the CCI, nor age, nor KPS significantly affected treatment outcomes, possibly due to a high heterogeneity of comorbidities and relatively low number of cases. However, a decreased BMI and a decreased cholinesterase (ChE) activity were negative predictors for survival, markers that are related to cachexia and pre-cachexia [25]. It is known that tumor cachexia is a negative prognostic factor in various tumor types, predominantly head-and-neck or pancreatic cancer patients [26]. The analysis of a combination factor containing the number of comorbidities and the presence of cancer related risk factors was only descriptive, yet it significantly discriminated patients with very poor from patients with favourable outcome.

The palliative effect of a treatment is mainly related to the local response of the disease, and, vice versa, local tumor progression represents an important impact on the quality of life of patients with head and neck malignancies [13]. Tumor response at six weeks after radiotherapy could be assessed in 19 cases, with local response in 13 patients (68 %). As also UICC stage IVC patients were included, it is noteworthy to mention that two of these patients were in PD due to systemic or nodal disease while the irradiated tumors were in partial response, leading to a systemic response rate of 58 % (11/19 patients). Response rates have only been reported in patients with non-metastasized stages before onset of treatment. Hence, the local control-rate of 68 % should serve as a baseline to compare our results with others. Agarwal et al. reported about 73 % of patients in CR and PR after gross disease directed radiotherapy up to 40 Gy in 15 fractions. In difference to our study, also stage III patients were included into this cohort [19]. The same limitation should be considered when comparing the results from the “Hypo Trial”, where almost one third of patients where in stage I-III. The response rate was 80 %, however, the overall survival was 6.1 months, likely due to the high amount of patients with reasonable low performance status [10]. This is in line with the overall survival observed with 6 months observed in our study as well as with survival times after palliative intended radiotherapy reported in the literature, ranging between 5.7 and 7.2 months [11‐13, 19].

The palliation of symptoms is negatively affected by the amount of toxicity caused by the treatment. In our cohort, confluent mucositis as one of the most distressing symptoms occurred in about 33 % of cases and lasted less than 6 weeks. The degree of mucositis was significantly related to the irradiated volume, with larger tumors being related to more severe side effects during treatment (Table 5). However, not only the degree of toxicity, which is usually confined to the highest degree observed, but also the area involved by toxicities should be considered. Avoiding prophylactic nodal irradiation was one first step to reduce this area of lower-grade toxicity. A second step was to reduce the safety margins by implementing new techniques such as IGRT and IMRT, in the regimen presented here to 10 mm safety margin. In almost all reports 2D or 3D planning without daily image guidance was used, leading to safety margins used mostly ranging from 1.5 to 2.0 cm [10, 11]. Van Beek et al. retrospectively compared 2D, 3D and IMRT irradiated palliative patients. Grade 3-4 mucositis occurred more often in patients treated with older techniques than patients treated with IMRT (44 % vs. 26 %), concluding that IMRT should be considered also for palliative treatments [13].

This report has several limitations. Firstly, there is a significant heterogeneity within the study population, including patients with less symptoms but a high amount of concomitant diseases as well as patients with acute symptoms. Both groups had in common, due to the additive effects of oncologic and non-oncologic diseases, to be not able to undergo aggressive loco-regional treatment. The treatment decisions therefore were made on an individual basis. Of course, when clinically possible, conventionally accepted RT or RCHT is applied, and the presented short-course regimen is reserved for elderly and very comorbid patients. Moreover, no patient reported data of quality of life (QoL) is included into the present analysis. In the absence of patient reported quality of life data, the good tumor response as well as the acceptable toxicity profile can serve as surrogate parameters for the palliative efficacy of this regimen. Since patients are treated in several smaller centres or taken care of in palliative care centres or at home after treatment, it was difficult to assess all data in a standardized fashion since not all patients were present themselves for clinical follow-up. Long term tumor response and PFS could not be calculated, as most of the patients were in best supportive care after the end of RT and therefore no diagnostic attempts were undertaken in these cases. On the other hand, all patients were treated with modern IMRT/IGRT in a highly standardized fashion. In spite of these arguments, the present data can show that such a regimen is safe and effective. Moreover, the data show overall safety and very good tolerability. The low overall survival rates confirm the fact that death was not related to local progression and underline that such a regimen is justified in selected patients and should be kept in mind during RT planning and interdisciplinary decision making.

The presented SIB-regimen offers an effective local treatment with manageable toxicity. By reducing the total treatment time to 4 weeks, and limiting the treatment to gross disease, it should be considered for patients that are not able or not willing to undergo radical treatment. For patients with significant concomitant disease and tumor related risk factors such as G3 Grading, pre-cachexia or metastatic disease, even shorter treatments or best supportive care only might be taken into consideration.