Assessing pain after cancer treatment

In the ICD-11 classification, chronic post-cancer treatment pain id divided into post-cancer surgery pain, post-radiotherapy pain, and post-cancer medicine pain, which include neuropathic pain due to chemotherapy-induced peripheral neuropathy (CIPN) and musculoskeletal pain due to trastuzumab, bisphosphonates and endocrine therapy [1]. The first step in assessing pain is to identify that the patient has pain. Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” [2]. This has to be differentiated from other sensory abnormalities. Many cancer treatments cause neuropathy and subsequent paresthesia (an abnormal sensation) or dysesthesia (an unpleasant abnormal sensation), which are not always painful. This is important to differentiate, particular in randomized clinical pain trials, which have often failed in CIPN. Most trials in CIPN have used neuropathy symptoms (including numbness, tingling and paresthesia) and not pain as inclusion criteria and outcome, which may explain why they have failed to show effect of drugs used for neuropathic pain [3]. Also in epidemiological studies, separating pain from non-painful sensory abnormalities is important and impact estimated prevalence of pain. We have previously found that patients more often report pain following breast cancer surgery in a questionnaire than in an interview, where they are also asked about unpleasant non-painful symptoms [4].

Chronic pain following cancer treatment is often a neuropathic or nociceptive pain. The grading system for neuropathic pain can be used to identify neuropathic pain [5]. It is sometimes straightforward e.g. to identify neuropathic pain in patients with phantom pain after amputation or pain in areas of sensory changes in the axilla and inner arm after lymph node excision or to identify nociceptive pain in the shoulder. At other times it is more challenging, e.g. to separate neuropathic pain in the feet due to chemotherapy from musculoskeletal pain due to endocrine treatment or skin toxicity due to other types of chemotherapy.

Chronic CIPN is common following several types of chemotherapy. Even though the symptoms and signs are similar to diabetic polyneuropathy, the scales used in assessing the polyneuropathy are different despite an overlap in the symptoms assessed, such as tingling, numbness, and burning pain [6]. Common scales include the EORTC CIPN20 (European Organization of Research and Treatment of Cancer), NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events), PNS (Peripheral Neuropathy Scale), and TNSc/TNSn (Total Neuropathy Score clinical and nurse version) [6]. Even though pain is an important symptom to identify given its impact and the availability of symptomatic treatments, many scales have no or limited assessment of pain [7] (Figure 1). The CIPN20 e.g. only captures pain if it has a shooting or burning character [8]. Others ask about localized pain predominantly in the extremities, others about joint, jaw and muscle pain. NCI-CTCAE, a widely used toxicity scale in the clinic, does not include pain in the toxicity assessment but solely paresthesia with no clear definition [9].

Figure 1:

Pain items in chemotherapy-induced peripheral neuropathy (CIPN) scales. Pain items comprising general toxicity tools, composite neurological tools and patient reported outcome tools. ECOG, Eastern Cooperative Oncology Group; 10 point VAS, 10 point Visual Analogue Scale; FACT/GOG NXT-12, Functional Assessment of Cancer Therapy/Gyneocologic Oncology Group Neurotoxicity 12 item version; PNQ, Patient Neurotoxicity Questionnaire; CIPN-self check, Chemotherapy Induced Peripheral Neuropathy – self check; TNS, Total Neuropathy Score; TNAS, Treatment-induced Neuropathy Assessment Scale; SCIN, Scale for Chemotherapy-Induced long-term Neuropathy; EORTC-CIPN20, European organization for research and treatment of cancer – Chemotherapy induced peripheral neuropathy; OANQ, Oxaliplatin-associated neurotoxicity questionnaire; CAS-CIPN, Comprehensive Assessment Scale for Chemotherapy Induced Peripheral Neuropathy; CIPNAT, Chemotherapy-Induced Peripheral Neuropathy Assessment Tool; ICPNQ, Indication for CTC Grading of Peripheral Neuropathy Questionnaire; FACT/GOG NXT-4, Functional Assessment of Cancer Therapy/Gyneocologic Oncology Group Neurotoxicity 4 item version; NSQ, Neuropathy Screening Questionnaire; DEB NTC, Neurotoxicity Criteria of Debiopharm; NCI-CTCAE, National Cancer institute Common Terminology Criteria for adverse Events; PRO-CTCAE, Patient Reported Outcome Common Terminology Criteria for adverse Events. References for above mentioned tools can be found in park et al. [7].

It is often relevant to assess the intensity (e.g. on a 0–10 numeric rating scale (NRS)) and impact of pain. Pain may have a major impact on mood, sleep, function, and quality of life. We have also seen that following cancer treatment, patients with persistent pain have less improvement in anxiety and depression symptoms compared to those without persistent pain [12]. For further assessment of pain qualities, specific pain scales such as the Douleur Neuropathique 4 Questions questionnaire (DN4q) [10] and the Neuropathic Pain Symptom Inventory (NPSI) [11] may be used.

Identifying underlying pain mechanisms is challenging. Quantitative sensory testing, nerve conduction studies, skin biopsy and laser-evoked potentials can be used to assess the functional and structural integrity of the pain pathways. Nerve excitability testing has shown that slowing in the gating of specific sodium and potassium channels may be involved in acute oxaliplatin-induced polyneuropathy but has found no changes in excitability of large fibers in chronic CIPN [13, 14]. Perception threshold tracking is a new method that can assess the excitability of distal cutaneous nerve fiber endings and has shown decreased large fiber sensitivity correlating to persistent CIPN [15]. Skin biopsy may be used to study molecular changes in the nerves and skin. Microneurography allows recording of single-fiber action potentials and can identify abnormal nociceptive C-fiber function and is an important method to identify the ectopic activity giving rise to pain and to study pain generating mechanisms [16].

Cancer treatments are generally getting more tailored and individualized. At the same time new targeted treatments are developed and used based on individual mutation status. As a result, the complexity of symptoms including pain after cancer treatment is increasing. The search for mechanisms and mechanism-based treatments in the future is highly relevant and important.