The first step of the ladder advices the initiation of paracetamol and non-steroidal anti-inflammatory drugs. The addition of a weak opioid, such as codeine, or tramadol, occurs at step 2 for moderate pain, with a strong opioid advised for severe pain at step 3. Adjuvant analgesics can be added at any step and are useful for the management of neuropathic pain.12 To ensure that the WHO ladder has maximum benefit, five recommendations support its implementation. First, oral forms of medication should be prescribed whenever possible. This grants patients more control and independence to manage their pain. Analgesia should be given at regular intervals, recognizing the pharmacokinetics of different medication. Slow or modified release mediations with appropriate quick acting medication for breakthrough pain are commonly prescribed in accordance to the patient’s pain intensity. While the WHO ladder provides a framework, no standard doses for the treatment of pain are advised. This is a recognition that adaption of pain medication is required for each patient. Finally, guidance highlights that pain management is an emotive and challenging topic. Careful education is beneficial to assist with successful application of analgesics.13

Although national guidelines advocate the continuation of regular paracetamol in conjunction with strong opioids for cancer pain, there is a lack of evidence for its efficacy.14 The Paracetamol vs Placebo in Conjunction With Strong Opioids for Cancer Pain trial is on-going to ascertain whether continuation of paracetamol provides symptomatic benefit.15 Codeine is often utilized first line as a weak opiate for moderate pain control. It is a prodrug, of which 5%–10% is converted to morphine by the liver. This metabolism varies between individuals with 30 mg of codeine approximately equivalent to 3 mg dose of morphine.16 Given this, debate exists to adapt and omit step 2 from the ladder due to equivocal effects of low dose strong opioids, such as morphine, and the potential for poor metabolizers of codeine. No study has yet clarified the efficiency and/or tolerability of using low dose strong opioids as an alternative in managing mild–moderate pain. Guidance is divided for the use of step 2 analgesia.17

A recent Cochrane review16 on opioids in cancer pain demonstrated that around 19 out of 20 people who experience moderate to severe pain, treated with opiates, and able to tolerate them, have a reduction in pain to mild or no pain within 14 days. This review highlighted that while opiates are commonly utilized as the mainstay of treatment for cancer pain, there is a paucity of quality evidence to support their use. Morphine is widely considered as the first choice opiate for severe pain as a result of its availability, familiarity, and low cost.18 Alternative opioids to morphine including oxycodone and hydromorphone are available. A Cochrane review demonstrated oral oxycodone provides similar pain relief and side effects as morphine and can be used as an alternative first-line oral opioid for cancer pain relief.19


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Morphine can be administered via multiple routes including orally or in a liquid form. Current guidance for opioids in palliative care recommends that oral sustained release morphine should be offered first line.20 For select patients, it is recognized that alternative routes of administration may be considered. For patients with stable analgesic requirement, transdermal patches can be utilized. Alternatively, subcutaneous administration of opioids is most frequently considered in patients with unstable analgesic requirements to ease titration to achieve adequate pain control.

MPM exhibits two of the most difficult to control pains; cancer induced bone pain and neuropathic pain. Pain experience by MPM patients has a strong neuropathic component due to local effects on the neurovascular bundle. Adjuvant drugs are utilized in addition to opioids to target specific neuropathic pain mechanisms. The most frequently used are tricyclic antidepressants and antiepileptics, such as gabapentin and pregabalin.12 A systematic review by Bennett21 suggested that the addition of adjuvants do not reduce pain intensity greater than one point on a 0–10 numerical rating scale. Important to clinical practice, this review highlighted that any benefits resulting from adjuvant therapy should be observed within 4–8 days and unlikely to improve beyond this time by increasing the dosage. In MPM, continual review of oral analgesia requirement will be the key to achieve adequate control due to its rapid disease progress.

RADIOTHERAPY

The safe delivery of tumoricidal doses of radiotherapy in MPM is challenging due to a combination of complex tumor shape, extensive disease burden, respiratory motion, and the close proximity of normal radiosensitive structures.22 The application of radiotherapy in MPM has therefore largely been limited to the palliation of symptoms, using modest doses which can be tolerated by normal tissue.

Seeding of malignant cells along instrument tracts at sites of diagnostic or therapeutic intervention affects ~40% of MPM patients and can be associated with painful subcutaneous tumor deposits.23 The use of post-procedure radiotherapy to decrease this risk is controversial and clinical practice varies widely, despite a number of negative studies.24,25 The recent publication of two, large, Phase III, randomized controlled multicentre studies has provided practice changing evidence in this field. The SMART study randomized 203 patients to either immediate (21 Gy in three fractions within 42 days of pleural intervention) or deferred radiotherapy (21 Gy in three fractions given within 35 days of procedure-tract metastases diagnosis). The Prophylactic Irradiation of Tracts trial recruited 375 patients who were randomized 1:1 to receive either 21 Gy in three fractions within 42 days of intervention or no prophylactic irradiation.26 Neither study found any significant difference in the incidence of tract site metastases between the cohorts and both concluded that there is no role for routine prophylactic radiotherapy in MPM.27

This recommendation now forms part of the current American Society of Clinical Oncology practice guidelines and it is therefore likely that prophylactic irradiation will fall out of practice.28 In contrast, radiotherapy has been widely used to palliate pain in this patient cohort for decades. Nevertheless, a systematic review published in 2014 highlighted the limited evidence supporting its role with no clear consensus on the optimal radiotherapy regime.29

In light of this paucity of evidence, the SYmptom Study of radioThErapy in MeSothelioma (SYSTEMS) study was conducted.30 This prospective, multicentre, single arm Phase II study was the first to use validated outcome measures to assess pain responses following radiotherapy in patients with MPM and remains the most robust source of evidence for the use of radiotherapy in this setting. A total of 40 patients were recruited from three centers over 18 months. Analgesia was optimized prior to embarking on a standard radiotherapy schedule of 20 Gy in five fractions, targeted at sites of pain. Treatment was delivered using parallel opposing pairs and while vulnerable organs could be shielded out, there was no “organ at risk” dosimetry data collected, reflecting the modest dose employed and the familiarity of clinicians with this palliative protocol. The results of SYSTEMS, published in 2015, demonstrated that, of the 30 patients assessable at week 5, 47% had experienced a clinically significant pain response with minimal toxicity. Consequently, the American Society of Clinical Oncology (ASCO) guidelines published in 2018 recommend that radiation therapy should be offered as an effective treatment modality for symptomatic disease.28 Importantly, the SYSTEMS study noted that there was no other palliative benefit of radiotherapy seen in this setting.30

The role of dose escalated, hypofractionated radiotherapy for pain control in MPM is now being investigated in the SYSTEMS-2 study.31 This multicentre, randomized Phase II study will compare the effect of standard dose radiotherapy (20 Gy in five fractions over 1 week) with a dose-escalated regime (36 Gy in six fractions over 2 weeks). The primary outcome is pain control at week 5 compared to baseline, assessed using the Brief Pain Inventory. Secondary endpoints include radiological response, toxicity, overall survival, and quality of life. The advance of increasingly sophisticated radiotherapy techniques underpins the solution to some of the logistical and practical challenges of radiotherapy dose escalation studies. Intensity-modulated radiotherapy (IMRT) in which multiple beams of radiotherapy of different shapes and intensity are delivered continuously as the gantry moves around the patient as detailed in Figure 2. This permits dose escalation to the tumor while keeping the dose received by nearby normal tissues at a safe level (Figure 3). All patients in SYSTEMS-2 will be planned using IMRT or 3-D conformal radiotherapy techniques. Organs at risk will be outlined according to the location of the target site to ensure that dose constraints to normal tissues are not exceeded. Any patient for whom a satisfactory plan cannot be achieved for the dose escalated arm will not be eligible for randomization. It is hypothesized that a higher dose of radiation will provide an improvement in analgesic effect and duration. The outcome of this study will provide much needed clarification of the role radiotherapy can play in pain control for MPM patients, in addition to providing an important insight into the potential for further dose escalation in this disease.


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