Pain management during radiotherapy and radiochemotherapy in oropharyngeal cancer patients: single-institution experience

Abstract

Aim of the study: Radiotherapy (RT) is a radical therapeutic option for patients with oropharyngeal cancer (OPC). It induces an acute postradiation reaction that may cause significant pain. The aim of this study was to analyse pain occurrence and intensity, as well as type and effectiveness of analgesic treatment, in OPC patients undergoing RT or radiochemotherapy (RT-CT). Material and methods: Retrospective data were obtained for 42 OPC patients at clinical stages I–IVA, treated with adjuvant RT or RT-CT or definite RT or RT-CcT at the Comprehensive Cancer Center in Bialystok, Poland. Pain intensity and type of analgesic treatment during the therapy were analysed and compared with the intensity of the radiation-induced acute reaction, assessed weekly according to the Dische score. Results: Thirty-nine (92.9%) patients received analgesic treatment. Analgesic therapy was started in 27 (64.3%) patients with administration of non-steroidal anti-inflammatory drugs (NSAIDs) and/or paracetamol, in seven (16.7%) with mild opioids and in five (11.9%) with strong opioids. Strong opioids were used during therapy in 21 (50%) patients. Co-analgesics were administered to six patients. Breakthrough pain was observed in 10 (23.8%) patients. Conclusions: High incidence of pain during RT and RT-CT calls for increased awareness of the importance of pain monitoring and treatment during RT of OPC patients. The analgesic treatment had to be adjusted individually.

INTRODUCTION

In many countries, the incidence of oropharyngeal cancer (OPC) in men is 1 to 10 cases per 100,000¹. In Poland, OPC accounts for approximately 5% of all malignant cancers registered in 2008 year (about 7% in men and 1% in women). In the last five years, about 6000 new cases of OPC have been reported annually².

Currently, treatment approaches vary according to the disease stage3., 4.. Radiotherapy (RT) alone is used in early to advanced stages of OPC⁵. There are several treatment approaches for patients with OPC who present in intermediate or advanced stages of the disease: surgery followed by adjuvant RT or concurrent radiochemotherapy (RT-CT); definitive RT or RT-CT, followed by definitive RT-CT induction chemotherapy; and RT combined with a monoclonal antibody directed to epidermal growth factor receptor (EGFR) 4., 6., 7., 8.. RT alone, or RT combined with CT or monoclonal antibody therapy, is known to induce significant side effects9., 10., 11..

RT is usually delivered over a period of 6–7 weeks. Although RT per se is painless, it induces an acute postradiation reaction – a debilitating side effect, starting mainly as pronounced oral confluent mucositis and dermatitis, followed by decreased oral intake, weight loss and pain¹². The acute radiation reaction starts 2–3 weeks from the beginning of RT and gradually increases, with healing taking place through 4–6 weeks after RT cessation. Pathogenesis of the pain appears to be quite complex and not only related to direct mucosal damage by ionising radiation but also triggered by various cytotoxic reactions¹³. It has long been established that pain has a negative impact on quality of life (QoL), decreases tolerance of treatment and can also affect treatment compliance, resulting in undesirable pauses in the treatment process or even in the cessation of therapy¹⁴. The latter substantially influences the treatment results and the patients’ outcomes¹⁵. Therefore, appropriate pain management plays an important role in the overall outcome of therapy with regard to patient treatment tolerance and their QoL¹⁶.

The World Health Organization (WHO) recommends international guidelines for pain management, comprising a three-step analgesic ladder [the WHO analgesic ladder (WHOAL)], in which intensity of analgesic treatment is tailored to the individual needs of the patient¹⁷. A general principle is to start with the first (non-opioid) step of the ladder. As soon as the pain increases and non-opioid analgesics become insufficient, a mild opioid should be added (Step II of WHOAL). Severe pain could be relieved by strong opioids (Step III of WHOAL). This policy of pain treatment has been adopted in our hospital.

Cancer pain is broadly divided into two types – nociceptive pain and neuropathic pain, which results directly from cancer infiltration on peripheral nerves (i.e. cancer infiltration on peripheral nerves results in both nociceptive pain and neuropathic pain). This type of pain might also be alleviated by co-analgesics – adjuvant drugs that are known to increase the intensity of the analgesic effect. The patients may also experience breakthrough pain (BTP), which is severe, intermittent cancer pain that occurs despite well-tailored treatment with long-acting analgesic. It appears suddenly for short periods of time and ‘breaks through’ the medication. Short-acting drugs, such as non-steriodal anti-inflammatory drugs (NSAIDs) or strong opioids are recommended to treat BTP.

Currently, numerous analgesic treatment options are available, and many novel therapies are being introduced into clinical practise.

The aim of this study was to analyse pain occurrence and changes in its intensity, as well as the type and effectiveness of analgesic treatment, in OPC patients treated with RT or RT-CT.

MATERIAL AND METHODS

This study was based on retrospective analysis of medical data of 42 patients treated at the Comprehensive Cancer Center in Bialystok, Poland. Inclusion criteria were: a diagnosis of OPC with a treatment protocol including adjuvant RT or definitive RT, which was administered alone or in combination with CT (100 mg/m² of cisplatin, every 3 weeks) . Megavoltage external beam radiotherapy was delivered to the oropharyngeal tumor or tumor bed and neck lymph nodes as a daily fraction of 1.8–2 Gy (excluding weekends), for 6–7 weeks, to a total dose of 50–70 Gy.

The study group consisted of 42 OPC patients, 32–79 years of age, at clinical stages (CS) I–IV. The most common treatment strategy was definitive RT-CT (31%). Metastatic or relapsed disease, or previous anticancer treatment, were exclusion criteria. Patients’ characteristics are summarised in Table 1.

Table 1.

Patient and study group characteristics

Characteristic	n (%)
Sex
Male	36 (85.7)
Female	6 (14.3)
Stage of cancer
I	5 (12)
II	18 (43)
III	16 (38)
IVa	3 (7)
Methods of treatments
Definitive RT-CT	13 (31)
Definitive RT	7 (16.6)
Adjuvant RT	11 (26.2)
Adjuvant RT-CT	11 (26.2)

RT, radiotherapy; RT-CT, radiochemotherapy.

The Dische scale, a validated scoring system allowing assessment of both morphological and functional clinical symptoms appearing during RT of head and neck cancer patients¹⁸, was used at 1-week intervals during the 6–7 weeks of RT¹⁸ . The Dische score, ranging from 0 to 34 points, is calculated from assessments of the intensity of erythema, epitheliolysis, oedema, bleeding, radiation-induced ulcer, swallowing impairment and pain. Regarding the intensity of pain, the assessment included both pain duration (0 = absence; 1 = intermittent and short; 2 = constant; and 3 = alternately 1 and 2) and the method of its treatment (0 = no medications; 1 = analgesics ‘ad hoc’; 2 = analgesics given regularly; and 3 = strong opioids). Regarding pain, patients also described its intensity in a visual analogue scale (VAS) score (no pain; mild pain; moderate pain; severe pain or worst pain possible) and determined effectiveness of analgesic treatment (without need to increase analgesics or requiring drugs modification). The acute radiation reaction and pain intensity were rated regularly, once a week from the start of RT administration. Prescription of analgesic medication was also recorded systematically.

Statistical analysis was performed using the chi-square test.

The study was conducted in strict concordance with privacy protection policies and was independently reviewed and approved by the Ethics Committee of the Medical University in Bialystok, Poland. Research was conducted in full accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from all patients.

RESULTS

Of note, OPC patients who presented at the same stage of the disease were given various strengths of analgesics. For instance, among patients at CS III of the disease, four of 16 were treated with analgesic drugs from step I of WHOAL, another six required mild opioids (step II of WHOAL), whereas in the remaining cases either strong opioids (four patients; step III of WHOAL) or no analgesics (two patients) were used. Pain medication varied across OPC patients undergoing adjuvant or definite RT or RT-CT (Figure 1). Among patients receiving postoperative RT or RT-CT, strong opioids were used significantly more often than in those treated with RT alone or RT-CT (68% and 32%, respectively; P < 0.0001).

Figure 1.

Intensity of analgesic treatment depending on the methods of antineoplastic treatment of oropharyngeal cancer (OPC) patients. RT, radiotherapy; RT-CT, radiochemotherapy; WHOAL, World Health Organization analgesic ladder.

Most (97.6%) patients reported pain of different intensity (Figure 2). In one (2.4%) patient, neither data on pain nor on analgesic treatment was available. Analgesics were used in most (39; 92.9%) patients. Analgesic treatment was introduced most frequently from week 1of RT (17 patients; 40.5%), with the shortest analgesic treatment given from week 5 of RT.

Figure 2.

Pain intensity during the radiotherapy (RT) or radiochemotherapy (RT-CT) of oropharyngeal cancer (OPC) patients.

Among this group, nine patients were treated with definitive RT or RT-CT, whereas eight underwent adjuvant RT or RT-CT. Eleven (26.2%) patients required analgesic treatment from week 2 of RT and five (11.9%) required analgesic treatment from week 3 of RT. The analgesic treatment was started from week 5 in one (2.4%) patient only. Three (7.1%) patients did not receive any analgesic treatment.

Various medications were used to relieve the pain. Paracetamol, ketoprofen and ibuprofen from step I of WHOAL were the first-line analgesic treatment in 27 (64.3%) patients, whereas in seven (16.7%) patients the first-line pain treatment was tramadol or dihydrocodeine (step II of WHOAL) (Figure 3). Considering the entire 6–7 week duration of RT, strong opioids [step III of WHOAL; included oral morphine, buprenorphine in a transdermal therapeutic system (TTS), phentanyl in a TTS and oral oxycodone] were the ultimate method of pain relief in as many as 21 (50%) patients. The final analgesic treatment in nine (21.4%) patients was based on the medicaments from step II of WHOAL, whereas in another nine (21.4%), drugs from step I of WHOAL were sufficient to alleviate pain during the entire process of RT (Figure 3).

Figure 3.

Analgesic medications used at the beginning of radiotherapy (RT) or radio-chemotherapy (RT-CT) and the strongest analgesic used during the therapy. WHOAL, World Health Organization analgesic ladder.

The medications most frequently used were paracetamol and metamizole from step I of WHOAL, tramadol from step II of WHOAL, and morphine and phentanyl in a TTS from step III of WHOAL.

Among patients treated with strong opioids there was a tendency to use analgesic patches rather than tablets. Namely, in 11 (47.8%) patients, a TTS delivering buprenorphine or phentanyl was used. Oral oxycodone was used in four patients, whereas long-acting morphine, taken orally every 12 hours, was administered in six. A short-acting morphine mixture taken orally was used by four (17.4%) patients as basic pain treatment. These forms of therapy were used from week 2 of RT and were continued until the end of RT.

Strong opioids were most frequently needed in patients receiving adjuvant RT-CT (81.8% of patients) than in those undergoing definitive RT-CT (46.1%, P < 0.05). No strong opioids were required in patients treated with definitive RT alone. Nearly one-half (45.5%) of patients undergoing adjuvant RT received only NSAIDs/paracetamol during the entire course of RT. According to the Dische score, an increase in pain intensity during RT was mostly pronounced from week 2 to week 6 of RT or RT-CT (Figure 1). Moreover, there was a general trend that the longer the RT lasted, the higher was the Dische score, and at the end of the RT or RT/CT (week 7) the pain intensity described according to the Dische score tended to decrease. It was also noted that patients requiring analgesic treatment from step III of WHOAL scored, on average, 13 points in the Dische score at the point when strong opioids were introduced. However, the score ranged from 4 to 24 points.

Modification of analgesic treatment occurred throughout the 6- to 7-week period of RT administration. Strong opioids from step III of WHOAL were mostly introduced from week 2 to week 6, with a peak in week 3, during the whole period of RT-CT or RT in OPC patients. Whenever changes in analgesic medication were made, there was a trend to use more intensive analgesic treatment (i.e. to introduce drugs from a higher step of WHOAL). Changes were observed after each week; however, most occurred after weeks 3 and 4 of RT or RT-CT. Only one patient (undergoing adjuvant RT-CT) required strong opioids from week 1. A growing trend was observed in the use of drugs from step III of WHOAL from week 1 of RT or RT-CT to week 7. Of note, in as many as 31 (74.8%) patients the analgesic treatment had to be maintained after RT or RT-CT cessation. In nine (29%) patients, drugs from step I of WHOAL (mostly oral ketoprofen) were prescribed. Four patients continued analgesic treatment for the 2 weeks after RT or RT-CT, whereas in five it lasted for a month. Mild opioids (oral long-acting tramadol) were prescribed in another nine (29%) patients either for 1 (seven patients) or for 6 (two patients) months.

In 13 (42%) patients, analgesic treatment was continued with strong opioids (long-acting oral morphine or phentanyl in TTS) for 1 (five patients), 2 (four patients), 6 (two patients) or more than 6 (two patients) months after RT termination.

Occurrence of breakthrough pain was observed in 10 (23.8%) patients, usually in weeks 3–5 of RT or RT-CT, and was alleviated with metamizole, paracetamol or short-acting oral morphine.

Co-analgesics were administered to 10 (23.8%) patients with neuropathic pain. They included carbamazepine and hydroxyzine (in four and four patients, respectively). Topical lignocaine was used in four.

Opioid side-effects (constipation, dizziness and mild confusion) were noticed in seven (33.3%) patients; no symptomatic treatment was required.

DISCUSSION

Radiation-induced oral mucositis is a common toxic treatment effect of RT or RT-CT administered for head and neck cancer patients. At the beginning, oral mucositis appears as erythema of the oral mucosa, which frequently progresses to erosion, ulceration and confluent mucositis accompanied with pain of varying intensity19., 20.. Not only does the pain result from the mucositis, but it is also brought about by the growing cancer mass. In patients undergoing RT or RT-CT for OPC, pain is a common debilitating side effect. In this study, half of the patients reported severe pain starting from week 1 of RT and accordingly required analgesic treatment. In general, severe pain occurred from weeks 3 and 4 of RT. The method of therapy – adjuvant/definitive RT or RT-CT – did not influence the time when the analgesic treatment started (week 1 or another week of RT).

With continuation of RT, there was a general increase of pain intensity and there was growing number of patients who required analgesic treatment. Notwithstanding, for unknown reasons, three patients did not receive any analgesic medication: there was no information included in the medical documentation for one patient, the second patient did not experience pain and in the third patient the pain problem was underestimated by the doctors.

In patients receiving definitive RT there are several factors that induce oral mucositis, such as: presence of the tumour itself; infiltrating mucosae and nerves; or irritant food. However, patients receiving adjuvant treatment after surgical excision have scars and oedema, which not only cause pain but can also significantly aggravate existing oral mucositis.

Notwithstanding, combining chemotherapy with RT, especially schemes based on cisplatin, may lead to a higher acute postradiation reaction, expressed as mucositis and skin toxicity²¹. Powerful radiosensitising drugs, such as cisplatin, increase radiation sensitivity through dysregulation of the cellular S-phase²². Biological and cellular events occur predominantly in the submucosa, with the epithelium being the target tissue²⁰.

Secondary to the mucosal and epithelial injury induced by RT-CT and damage to the basal cells of the tissue, the remaining cells migrate to the outer layer where they are removed. As a result, the epithelium becomes thinner²³. In the course of these changes, morphological symptoms of mucosal healing are observed: spotted and confluent mucositis; erythema; and oedema. The most severe stage for patients is when ulcerated tissue is present, as they usually experience severe pain which compromises function, and the epithelium itself is vulnerable to colonisation with pathogens²⁴. This undesirable colonisation results in bacterial and fungal mucositis, which usually develops within 7–14 days after the conventional 7-week radiation protocol (a daily dose of 2 Gy, five times a week) of RT or RT-CT is initiated. The early radiation reaction is accompanied by clinical signs of mucositis with local discomfort as well as by difficulties in drinking, eating, swallowing and speech²⁵.

Patients with the same stage of cancer were treated with different strengths of analgesic, indicating that analgesic treatment had to be individualised for patients in the study group. That the response to antineoplastic therapy and the need for analgesic treatment following different therapeutic strategies varied among patients could be explained by either various intensities of adverse effects following those strategies or differences in pain sensitivity experienced by individual patients. This should be further explored in clinical studies.

A relationship was noticed between treatment modalities and the intensity of analgesic therapy. Strong opioids were used significantly more often during adjuvant RT or RT-CT than during definitive RT or RT-CT (P < 0.05), pointing to greater intensity of pain in patients who had previously undergone surgery. Of all treatment modalities, adjuvant RT-CT was related to the most frequent use of strong opioids. This could indicate the need for particular awareness, in terms of pain management, in this group of patients.

In almost two-thirds (64.3%) of patients who commenced analgesic treatment from step I of WHOAL these drugs were sufficient in pain relief to the end of anticancer therapy. This is consistent with the findings of a Cochrane review confirming the effectiveness of NSAIDs in cancer pain management²⁶.

Both nociceptive and neuropathic pain are proven to occur in head and neck cancer patients treated with RT¹³, indicating that the management of these two types of pain is strongly advisable. In the present study, co-analgesics, which were added to standard analgesic treatment to increase the effectiveness of neuropathic pain control, were given to nearly one-quarter (24.4%) of patients. However, in previous studies, neuropathic pain among head and neck cancer patients receiving RT was reported in as many as 56–73% of cases, which may suggest that the occurrence of this pain and the potential use of co-analgesics were underestimated in our study group13., 27.. Considering the high incidence of neuropathic pain among this group of patients, the proper assessment of this type of pain appears essential.

Several studies have reported that oxycodone is a potent neuropathic pain reliever through up-regulating expression of GABA B receptor in sensory neurons; in contrast, this type of pain is unaffected by the action of morphine²⁸.

According to recent findings of Ling and Larsson (2011) and Bar Ad et al. (2010), more attention should be paid to co-analgesics during analgesic treatment29., 30.. Taking into account that other prospects are lacking, it seems to be a good therapeutic aid. Moreover, inappropriate differentiation between the two abovementioned types of pain could result in excessive use of opioids, which are not only less effective in neuropathic pain management, but also pose a threat of side effects when used at high doses³¹.

This study revealed that the average pain score assessed according to the Dische score corresponded well to the average total score of this score, indicating intensity of the acute radiation reaction throughout RT (Table 1). It was noted that both the average score of pain alone and the overall Dische score tended to decrease from week 7 of RT. This can be explained by satisfactory pain control, as well as the healing of postradiation oral and skin inflammation. Nonetheless, despite the progressive reduction of pain intensity, it continued to be a significant clinical issue because analgesic treatment was maintained in nearly 75% of patients after completion of RT or RT-CT.

A tendency for the use of strong opioids was observed in patients in whom the acute radiation reaction scored ≥13 points in the Dische scale. However, other phenomena, in addition to RT-induced toxicity, are known to trigger or potentiate the pain: bacterial or fungal infection related to the oral ulceration; or a decrease of food and liquid intake and subsequent deterioration of the nutritional status32., 33.. Hence, there was an individual approach to analgesic treatment administration. For instance, one patient took strong opioids from the time when his radiation reaction scored 4 points in the Dische scale and a second patient did not take strong opioids until his radiation reaction scored 24 points.

An increase of analgesic treatment intensity (i.e. replacing mild opioids with strong opioids) occurred most often in weeks 3 and 4 of RT, probably because of the more pronounced inflammatory postradiation reaction. Similarly, the breakthrough pain, occurring predominately from weeks 3 to 5 of RT, was alleviated mainly with short-acting oral morphine, indicating its severity. As a result of irritation of the inflamed mucosa during the swallowing of tablets, the liquid morphine mixture was the medication of choice in BTP among patients with odynophagia.

TTS was found to be a slightly more popular way of administering strong opioids, probably because of the convenient method of application and the assurance of constant pain control. Of note, TTS was not available in the department in previous years; therefore, only tablets and the morphine mixture could be used in pain management during hospitalisations.

The limitations of our study include its retrospective nature, small number of patients as well as diversity in group characteristics, which suggests a need for further prospective assessment of the problem. However, the individualised approach to analgesic treatment in OPC patients undergoing RT is thought to be crucial for providing sufficient pain control and thus possibly assures the best quality of life³⁴.

CONCLUSIONS

High incidence of pain during RT and RT-CT of OPC patients makes it an important clinical problem. Given various levels of pain intensity during RT, the analgesic treatment had to be individualised. However, the significance of co-analgesics seems to be underestimated and could be explored in further studies. Increased awareness of the importance of the monitoring and treatment of pain during RT or RT-CT of OPC patients appears to be essential.

Acknowledgements

There are no acknowledgements.

Conflict of interest

The authors declare no conflict of interest.

Source of funding

There was no funding.