1. Introduction
1.1. Neuropathic Pain in Cancer Patients
One of the most extensively studied clinical complications that individuals diagnosed with cancer may face is neuropathic pain (NP). This type of pain often emerges at various stages during the progression of the disease and is primarily a consequence of injury to the somatosensory system. Such injuries can arise from different sources, including trauma or lesions caused by tumors. The physiological mechanisms underlying NP have been linked to inflammation in the area surrounding the tumor, which is typically associated with the compression or infiltration of nearby tissues by the growing tumor itself. This process can lead to significant damage to the surrounding healthy tissues, exacerbating the pain experienced by the patient. Moreover, NP is not solely a result of the cancer itself; it has also been associated with various treatment modalities. These include surgical interventions, radiotherapy, and chemotherapy. In particular, NP is frequently referred to as chemotherapy-induced peripheral neuropathy (CIPN), highlighting the neurotoxic effects of chemotherapy agents. These effects are believed to disrupt axonal transport, ultimately leading to lesions in sensory neurons located in both the central nervous system and the peripheral nervous system [ 1 , 2 ].
1.2. Characteristics and Impact of Neuropathic Pain
Neuropathic pain is typically characterized as chronic and can be of high intensity, manifesting through a range of symptoms. Patients may experience numbness, hyperalgesia (increased sensitivity to pain), anxiety, allodynia (pain from stimuli that do not normally provoke pain), paresthesia (tingling sensations), depression, and sleep disorders. The presence of these symptoms can significantly disrupt daily activities, strain social relationships, affect economic situations, and ultimately diminish the overall quality of life for those who suffer from it. Interestingly, NP is reported to occur more frequently as a side effect of surgical treatments, particularly in patients undergoing procedures for breast cancer. Many of these patients describe their pain as sharp, urgent, or resembling an electric shock, predominantly localized in the thoracic region following surgery [ 3 , 4 , 5 , 6 ].
1.3. Challenges in Diagnosis and Management
The challenge of diagnosing, characterizing, and effectively treating neuropathic pain represents a significant issue within the healthcare system. It is widely believed that early detection and monitoring of symptoms could play a crucial role in preventing the onset of NP. This belief underscores the urgent need for further investigation into the nuances of neuropathic pain, which could ultimately benefit patients who endure its debilitating effects. In conclusion, neuropathic pain is a complex and multifaceted condition that poses significant challenges for cancer patients. Understanding its mechanisms, symptoms, and impacts is essential for improving patient care and enhancing their quality of life [ 7 , 8 , 9 ] ( Figure 1 ).
The objective of this study is to describe the relationship between various types of cancer or different types of treatments and the presence of NP.
2. Methods
2.1. Protocol and Registration
This systematic review and meta-analysis were performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 10 ]. The registration number in the International Prospective Register of Systematic Reviews (PROSPERO) is CRD42022223061.
2.2. Eligibility Criteria
Studies that addressed the diagnosis of cancer and its association with the presence of neuropathic pain (NP) were included based on the following inclusion criteria: (1) Population: studies that reported patients diagnosed with cancer; (2) results: patients with various types and stages of cancer, including information on whether they had been exposed to chemotherapy treatments and whether, given this variety of scenarios, they presented a clinical diagnosis of NP in any body region; (3) studies: This systematic review included research articles, research reports, and original research published in English or Spanish in peer-reviewed journals indexed in some of the databases used to compile the studies. Conversely, the exclusion criteria were as follows: (1) Population: studies involving animals; (2) studies analyzing other types of chronic pain; (3) studies: letters to the editor or comments that did not provide data relevant to our research.
2.3. Electronic Search
We systematically searched MEDLINE (via PubMed), Web of Science, Google Scholar, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and the Latin American and Caribbean Literature in Health Sciences (LILACS) from inception until January 2024. The search strategy included a combination of the following terms: “Cancer” (MeSH), “Neoplastic” (MeSH), “Tumor” (MeSH), “Neuropathic pain” (MeSH), “Cancer therapy” (non-MeSH), and “Immunotherapy” (non-MeSH), utilizing the Boolean connectors AND, OR, and NOT. For the PICO strategy, we extrapolated data to construct the following: Patients: Subjects with a diagnosis of cancer; Intervention: Treatment with immunotherapy; Comparison: Without immunotherapy; Outcomes: Presence of NP. The search strategies for each database are available in the Supplementary Material (Supplementary Table S1) .
2.4. Study Selection
Two authors (FD and JV) independently screened the titles and abstracts of references retrieved from the searches. We obtained the full text for references that either author considered potentially relevant. A third reviewer (HG) was involved if consensus could not be reached.
2.5. Data Collection Process
Two authors (JV and MO) independently extracted data on the outcomes of each study. The following data were extracted from the original reports: (I) authors and year of publication, (II) type of study and number of participants, (III) incidence and characteristics, (IV) location of cancer, (V) geographic region, (VI) average age, (VII) sex, and (VIII) treatment.
2.6. Assessment of Methodological Quality
The methodology of each study, as well as the outcomes, was measured using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool [ 11 ] during data extraction. ROBINS-I offers a comprehensive set of tools to assess and determine the risk of bias associated with confounding, participant selection, intervention measurements, deviations from the planned intervention, missing data, outcome measurements, and reported results. The ROBINS-I tool can be used in non-randomized cross-sectional and longitudinal studies, as quality is unaffected by the study design. Based on the literature on confounding, age, ethnicity/race, physical activity, and education were identified as the main confounders that needed to be appropriately adjusted for the study findings to be considered less risky. All areas are judged as being at low, moderate, severe, or critical risk of bias. Low risk indicates that a study is “similar to a successful randomized trial” in the area being evaluated. A moderate risk of bias means that the study is “good for a non-randomized study” but falls short of a full randomized trial. A very high risk of bias indicates that the study has “major problems”, while a very low risk of bias means the study is “too large...to provide useful information about the effects of the intervention”. If a domain does not contain enough information to determine whether it has a risk of bias, it is counted as having zero information. The total risk of bias for each article was the highest of all assessed fields [ 11 ].
3. Results
3.1. Selection of Articles
The search process yielded a total of 803 articles from various databases, aligning with the criteria and search terms established by our research team. A filtration process was applied, focusing on the titles and/or abstracts of these articles. Out of the initial pool, 98 articles were included, and 40 articles were selected for inclusion in the systematic review. These articles were chosen based on their comprehensive study of the sample, detailed statistical data for each variant, and their utilization of a clear methodology ( Figure 2 ).
A total of 40 articles were included in the final analysis. The total number of participants across all studies (N) was 7773. Of these participants, 2233 had NP associated with cancer or its treatments. The average age of the included participants was 52.49 [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].
3.2. Descriptive Results
Among the different types of research analyzed that address both the incidence and characteristics of NP in cancer patients, we observed that the prevalence of this type of pain varies according to the type of cancer and the treatment used. The types of cancer most frequently associated with NP are breast, lung, and colon cancer. Certain cancers with metastases in the bones, nervous system, or lymph nodes tend to present higher rates of NP ( Table 1 ).
Oncological treatments that patients undergo, such as chemotherapy, are related to the incidence of NP. In studies such as those conducted by Cofeen and Garzón-Rodríguez [ 21 , 49 ], a high incidence of NP is observed in cancers like colon and breast cancer, where treatments with neurotoxic agents are common and typically involved in advanced stages of cancer (III and IV). Studies by Maña (2011) and Jiang [ 14 , 27 ] document an association between radiotherapy received by patients with cancers in the neck, oral cavity, and esophagus and the appearance of NP. On the other hand, the studies by Bokhari and Maña (2011) [ 14 ] show that post-surgical NP is common in patients with breast cancer.
Regarding interventions and treatments for NP, several pharmacological approaches are mentioned, such as opioids, anticonvulsants (like entin or pregabalin), tricyclic antidepressants (like amitriptyline), and topical treatments in the affected area with lidocaine. In studies such as that of Smith [ 38 ], mindfulness was used as a treatment for NP, moving away from more conventional therapies such as pharmacological ones. Casanova [ 50 ] also presents a type of non-pharmacological treatment, pretreatment, and pilot study where graded motor imagery (GMI) and neural mobilization (NM) techniques were applied. For his part, Lee used “Calmare” therapy as an intervention for NP in oncological patients, showing another alternative to the previously mentioned drugs, which may help reduce the dependence that patients can develop on these medications.
Several of the analyzed studies demonstrate statistically significant findings regarding the reduction of DN or the improvement of the quality of life of treated patients. In the study by Jiang [ 27 ], pregabalin exhibited a significant reduction in pain scores on the Numeric Rating Scale (NRS) compared to the placebo group. Mañas 2011 (B) [ 48 ] also indicates that pregabalin not only decreased the intensity of NP but also reduced the necessity for patients to use other medications, such as benzodiazepines.
Some research highlights the relationship between NP and factors such as sleep disorders, quality of life, and anxiety in patients with DN. Harada [ 52 ] shows that patients with DN experience a deterioration in quality of life compared to those without neuropathy. Fontes, on the other hand, demonstrated that the decline in sleep quality was greater in individuals with NP during the first year of follow-up. Juwara, meanwhile, found a significant association between DN and anxiety, indicating that patients with anxiety reported higher levels of pain, suggesting that emotional factors can exacerbate the pain in these patients.
Comparing the reviewed studies shows the diversity of therapeutic approaches used for the management of neuropathic pain (NP) in cancer patients. Acquazzino (2016) [ 16 ] observed that 26% of patients treated with chemotherapy, particularly those with leukemia and lymphoma, experienced NP, although a direct treatment for this pain was not specified in his cohort. In contrast, a more structured pharmacological approach was implemented in his Australian study with pediatric patients, using opioids and anticonvulsants, mainly gabapentin, for NP related to solid tumors such as osteosarcoma and Ewing sarcoma. On the other hand, Fallon (2015) [ 19 ] in the United Kingdom explored a topical and noninvasive alternative, noting that a 1% menthol cream was effective in reducing the intensity of NP in 82% of patients, including cases of colorectal cancer, breast cancer, and multiple myeloma. These results underscore the adaptability of NP management, where treatment varies based on the type of cancer, the clinical context, and individual patient needs.
The reviewed studies reflect a variety of cancer types and approaches to the treatment of NP, emphasizing its management according to the clinical context. Garzón-Rodríguez et al. (2013) [ 21 ] in Spain focused on patients with breast and lung cancer, where NP was linked to tumor progression and treatment, although no precise therapy was specified. Gordillo-Altamirano et al. (2016) [ 25 ] in Ecuador, without specifying treatment, highlighted the negative impact of NP on the quality of life in patients with breast cancer and lymphoma. Golan-Vered and Pud (2012) [ 23 ] in Israel observed chemotherapy-induced peripheral neuropathy in breast cancer patients treated with paclitaxel, although they also did not specify a treatment. Regarding the treatment of NP, Haumann et al. (2016) [ 24 ] in the Netherlands compared the use of methadone and fentanyl in patients with NP, finding that methadone provided faster pain relief, especially in unspecified cancers. Conversely, treatments for NP in cancer patients depend greatly on the type and stage of the disease. Jain et al. (2014) [ 26 ] in India analyzed 300 patients with various cancers and found that 10% had postoperative NP, although they did not mention a specific treatment. Jiang (2019) [ 27 ] in China evaluated pregabalin in 128 patients with head and neck cancers, showing that this anticonvulsant was effective in significantly reducing pain. In Canada, Juwara (2019) [ 28 ] studied 195 patients with postoperative breast cancer and found that anxiety increased the frequency of NP without reporting a direct treatment. Lee et al. (2016) [ 31 ] in South Korea tested Calmare Therapy in 26 patients with various types of cancer, noting that this noninvasive technique reduced post-surgical and chemotherapy-induced NP. In Spain, López-Ramirez et al. (2016) [ 32 ] evaluated 5% lidocaine patches in 15 patients with different cancers, achieving effective relief of NP in 79.9% of cases. Collectively, these studies emphasize how approaches to treating NP vary based on the type of cancer and patient-specific factors.
The prevalence of NP in cancer patients varies considerably depending on the type of cancer, the treatment applied, and the individual characteristics of each patient. Cancers such as breast, lung, and colon, along with those with bone, nervous system, or lymph node metastases, show a higher incidence of NP, particularly in advanced stages. Cancer treatment, especially chemotherapy and radiotherapy, is closely associated with the occurrence of this type of pain, particularly when neurotoxic agents are used. Additionally, various therapeutic approaches, both pharmacological and non-pharmacological, have been identified for the management of NP, including opioids, anticonvulsants, tricyclic antidepressants, topical lidocaine, and innovative therapies such as mindfulness and Calmare therapy. The efficacy of these treatments varies depending on the clinical context and the type of cancer, making it crucial to personalize the therapy according to the individual needs of the patient. Furthermore, emotional factors such as anxiety and sleep disorders also play a significant role in the intensification of pain, highlighting the importance of a comprehensive approach in the management of NP. The findings underline the need for tailored treatment that considers not only the type of cancer but also the physical and emotional well-being of patients ( Figure 3 , Figure 4 and Figure 5 , Table 2 ).
3.2.1. Large Intestine Cancer
Among the types of cancer that we have been able to study in relation to NP, there is cancer that affects the large intestine. Nine articles were reviewed, all of which involved patients presenting NP; however, only five patients received treatment for this NP. In seven of the studies, the patients underwent chemotherapy, while in two studies, it is unspecified whether the patients received any type of oncological treatment. Additionally, it was noted that the stages of cancer varied according to the study: in one article, all stages were considered, while in four studies, patients in more advanced stages (III to IV) predominated.
3.2.2. Bone Cancer
Regarding bone cancer, six articles were reviewed, all of which involved patients presenting NP; however, only three reported a treatment for this pain. In four of the studies, the patients underwent chemotherapy or radiotherapy, while one study did not specify whether the patients received any oncological treatment. Furthermore, it was observed that the cancer stages of the involved patients varied according to the study. In three of the articles, all stages were considered, while two articles did not specify the cancer stage of their patients.
3.2.3. Soft Tissue Cancer
In relation to cancer affecting soft tissues, five studies were reviewed, all of which involved patients presenting NP; however, only two reported a treatment for this pain. In two of the studies, the patients had undergone chemotherapy or radiotherapy or were post-surgical patients, while in one study, only post-surgical patients were considered, and in another article, it was not specified whether the individuals underwent any treatment for cancer. Likewise, in three of the articles, the stages of the patients’ cancer were not specified. In one of the studies, all stages were considered, while in another, there was a predominance of patients in more advanced stages of cancer (III to IV).
3.2.4. Genital Cancer
Regarding cancer affecting the female genital organs, three studies were reviewed, all of which included subjects with NP; however, no article proposed a treatment for this pain. In one of the studies, patients had undergone chemotherapy or radiotherapy or were post-surgical patients, while in another study, no type of oncological treatment was specified, and in a third study, only patients who had undergone chemotherapy were considered. On the other hand, in two of the investigations, patients at all stages of cancer were considered, while one article focused specifically on patients with metastasis (stage IV).
3.2.5. Breast Cancer
Among all the articles reviewed, breast cancer is the most common type of cancer, being addressed by 25 of the studies. All patients in these studies had NP, but only 10 studies reported treatment for this pain. In six of the studies, patients had undergone chemotherapy or radiotherapy or were post-surgical patients. In five of the studies, only patients who received chemotherapy were considered, while in two articles, only patients who underwent radiotherapy were included, and in three studies, only post-surgical patients were examined. In three studies, patients had undergone only chemotherapy or radiotherapy, while in another five studies, it was not specified whether the subjects received any type of cancer treatment. Furthermore, it was observed that in 10 studies, the stage of cancer was not specified. In 10 articles, patients at all stages of this disease were considered, while in five studies, the focus was primarily on more advanced stages of cancer (stage IV) ( Figure 6 ).
3.2.6. Cervical Region Cancer
In relation to cancer affecting the neck, seven articles were reviewed, in which all subjects had NP; however, in only four of the studies was a treatment for this pain proposed. In two of the publications, the patients had been treated with chemotherapy or radiotherapy. In one of the studies, the patients were subjected only to chemotherapy, while in two articles, the individuals had received only radiotherapy, and in one study, they were only post-surgical patients. In one of the articles, it is not specified whether the subjects involved had undergone any type of oncological treatment. Similarly, in three of the studies, the stage of the patients’ cancer is not specified, while in two studies, individuals from all stages participated, and in two, they focused exclusively on patients with metastasis (stage IV).
3.2.7. Oral Cavity Cancer
Addressing the types of cancer affecting the oral cavity, four studies were reviewed, in which all patients presented NP, and in all the articles, some type of treatment for this pain was proposed. In one of the publications, individuals who had undergone chemotherapy or radiotherapy were considered, while in two articles, only individuals who received radiotherapy were included; one of the studies specified whether the people involved received any type of treatment for cancer. Regarding the stages of the patient’s cancer, in two articles, all stages were considered, while in one, they focused only on patients in stages III to IV, and in another publication, they did not specify the stage of cancer for the subjects involved.
3.2.8. Lung Cancer
Regarding lung cancer, 15 articles related to NP were reviewed. Only eight of them presented a treatment to reduce pain. In 10 of the publications, patients underwent chemotherapy; nine articles indicated that patients received radiotherapy, and four articles involved post-surgical patients and patients but did not specify patients with metastasis. Furthermore, cancer was also observed. One of the articles considered only patients with stages I to III; five studies addressed patients with all stages, i.e., I–IV; another five studies focused solely on patients with stage IV; two studies included only patients with stages III–IV; and only three studies did not specify ( Figure 4 and Figure 7 ).
3.2.9. Liver Cancer
In relation to liver cancer, four articles associated with NP were studied, and only one indicated a treatment to reduce pain. In all the articles studied, the patients were subjected to chemotherapy, two to radiotherapy, and two were post-surgical. On the other hand, the different stages of the cancers were also observed: three of them in stage IV and one article with patients in stages III–IV.
3.2.10. Hematologic Cancer
Regarding blood cancer, 12 articles were studied, all of which were related to NP, but only eight of them presented any treatment for this pain. Ten articles involved subjects undergoing chemotherapy, another six articles involved subjects undergoing radiotherapy, four articles reported subjects who were post-surgical, one article discussed patients with metastases, and two articles did not specify. Regarding the stage of cancer, three articles indicated that the subjects were in all stages, that is, from I–IV. Another two indicated only stage IV, four articles did not specify, one was in stage III, and finally, two articles were in stages III–IV ( Figure 5 and Figure 8 ).
3.2.11. Stomach Cancer
Regarding stomach cancer, four articles were studied, all of which were related to neuropathic pain, but only one presented a treatment to reduce pain. In three of the articles studied, it was stated that the patients underwent chemotherapy, two underwent radiotherapy, two were post-surgical, and only one did not specify. Speaking about the stage of cancer, two had patients in stage IV. Another article indicated that the patients had cancer at all stages (I–IV), and one article considered patients in stages III to IV.
3.2.12. Pancreatic Cancer
Regarding pancreatic cancer, three articles were collected, all of which reported patients presenting with neuropathic pain, but none mentioned treatment for this pain. In three of the articles, patients were presented as undergoing chemotherapy, two underwent radiotherapy, and two articles indicated that the patients were post-surgical. Regarding the stage of cancer, all three indicated that patients were in the terminal stage (IV).
3.2.13. Bile Duct Cancer
Within bile duct cancer, two articles were studied that were related to neuropathic pain, and neither discussed any treatment for this pain. In both studies, it was indicated that the patients underwent chemotherapy, but only one mentioned that the patients also received radiotherapy and were post-surgical. Regarding the stage of cancer, both articles indicated that the patients were in the terminal stage (IV).
3.2.14. Uterine Cancer
Regarding uterine cancer, four studies were collected, all of which dealt with neuropathic pain, and two of them presented any treatment for it. All articles indicated that the patients underwent chemotherapy; two had radiotherapy, three involved post-surgical patients, and one had metastasis. Speaking about the stages of cancer, three articles indicated that the patients were in stage IV and indicated that the patients were in stages III–IV.
3.2.15. Urinary Tract Cancer
Regarding genitourinary cancer, four studies were compiled, all of which were related to neuropathic pain, but three of them presented any treatment for this pain. Two articles indicated that the patients underwent radiotherapy, another article presented only post-surgical patients, one article involved patients undergoing chemotherapy chemotherapy, and finally, one did not specify. Regarding the stages of cancer, two articles indicated that the patients were in all stages, i.e., I–IV, and two did not specify.
3.2.16. Bowel Cancer
In relation to gastrointestinal cancer, five studies were examined, and all of them related to neuropathic pain, but only three of them presented any treatment for this pain. Concerning what the patients were subjected to, two articles indicated that the patients underwent radiotherapy, another two articles indicated that the subjects underwent chemotherapy, one article did not specify, and one specified post-surgical patients. Regarding the stages of cancer, three articles did not specify, but two of them indicated that the patients were in all stages, namely from I–IV.
3.2.17. Head Cancer
Within head cancer, six studies were compiled, all of which were related to NP; however, only three of them presented any treatment for this pain. Three articles indicated that the patients underwent radiotherapy, another three indicated that the patients underwent chemotherapy, another article presented post-surgical patients, and one did not specify. In relation to the stage of cancer, of the total studied, two articles indicated that the patients were in all stages (I–IV), another two were in only stage IV, and finally, another two were not specified.
3.2.18. Skin Cancer
Regarding skin cancer, two articles were studied, both of which were related to NP and also presented some treatment for this pain. One of them indicates that the patients underwent chemotherapy, and both of the patients underwent radiotherapy. Regarding the stage of cancer, both studies present patients who were in all stages, i.e., I–IV.
3.2.19. Thymus Cancer
In relation to thymus cancer, two articles were studied, and both were restudied. The NP also presented some treatments for this pain. One of them indicates that the patients underwent chemotherapy, and both patients underwent radiotherapy. In relation to the stage of cancer, both studies present patients who were in all stages, that is, from I–IV.
3.2.20. Nervous System Cancer
Within the field of nervous system cancer, three articles were studied, all of which were related to NP; however, only two of them presented any treatment for this pain. In two articles, the patients were subjected to chemotherapy; in all three articles, the patients were subjected to radiotherapy; and in only one article were there post-surgical patients. In relation to the stages of cancer, two articles indicate that the patients were in all stages, i.e., I–IV, and only one did not specify.
3.2.21. Lymphatic Cancer
Regarding lymph node cancer, five articles were studied, all of which were related to NP, but only three presented a treatment for it. Four of the articles studied indicate that their patients underwent chemotherapy, three other articles indicate that their patients underwent radiotherapy, two articles indicate that they included post-surgical patients and one of them did not specify. Regarding the duration of cancer, two articles indicated that the patients were in all stages, i.e., I–IV; one article indicated that their patients were in stages III and IV. Another article indicates only stage IV, and finally, the last article did not specify.
3.2.22. Ovarian Cancer
In relation to ovarian cancer, two articles related to NP were studied, both of which presented some treatment for this pain. Both articles indicate that their patients underwent chemotherapy, but only one of them states that their patients underwent radiotherapy. Regarding the stage of cancer, both articles indicate that their patients were in stages III and IV.
3.2.23. Esophageal Cancer
Within esophageal cancer, two studies were examined, both of which were related to neuropathic pain (NP), and both presented some treatment for this pain. Both articles indicate that the patients underwent chemotherapy, but only one article indicates that, in addition, their patients underwent surgery, with some having metastasis. Regarding the stages of cancer, one article indicates that it only involved patients with stage IV, while the other article mentions subjects in stages III and IV.
3.2.24. Prostate Cancer
Regarding prostate cancer, three studies were examined, only one of which had a treatment for NP. Two of the three articles involved patients who had undergone chemotherapy; two other articles indicate that their patients received radiotherapy, and one of the articles mentions post-surgical subjects. Concerning the stage of cancer, two articles indicate that the subjects were in the terminal stage, i.e., stage IV, while one of them does not specify.
3.2.25. Laryngeal Cancer
In relation to laryngeal cancer, two articles were examined regarding NP, and both presented a treatment for this pain. In both articles, the patients underwent radiotherapy, but only in one were there post-surgical subjects. Regarding the stage of this cancer, neither article specifies the stage.
3.2.26. Pharyngeal Cancer
In relation to pharyngeal cancer, three articles related to NP were examined; however, only one of them presented any treatment for this pain. In all three articles, the patients underwent radiotherapy, but only one article indicates that the patients also received chemotherapy, and some subjects were post-surgical. Concerning the stage of cancer, only one article indicates that the patients were in stage IV, while the other two articles do not specify.
3.3. Risk of Bias of Included Articles
The summary of the risk of bias in the included studies using the ROBINS-I tool is shown in Figure 6 . Of the included studies, four had a high risk of bias [ 12 , 19 , 32 , 40 ], while two had some concerns [ 13 , 17 ]. Those with serious risks encountered significant problems with the selection of study participants and also exhibited moderate bias in the classification of interventions, so these studies should be treated and analyzed with greater caution based on the interpretation of their results ( Figure 9 ).
4. Discussion
NP has neurophysiological principles that can be associated with a significant number of pathologies, which may accentuate the clinical symptoms of these patients. One of the conditions directly linked to the presence of NP is cancer. We have demonstrated that depending on the cancer type, NP may be observed to have a greater prevalence in certain cancers. Moreover, there is a higher prevalence of NP in patients who have undergone chemotherapy, with symptoms increasing or exacerbating in specific cancers that present NP due to chemotherapy.
Breast cancer stands out among the reviewed types of cancer as the one most frequently associated with NP. The management of NP is a crucial aspect, given its impact on the quality of life of patients. This pain can affect individuals both physically and emotionally, intensifying the suffering of those facing a serious prognosis. We found that 25 articles address breast cancer, involving a total of 5704 patients, making it the most prevalent cancer compared to the others included in the study. A relevant aspect of this type of cancer is its frequent association with advanced stages of the disease, especially stage IV, where treatment is more oriented toward palliative care than a curative intervention. The number of patients diagnosed with NP or experiencing recurrent symptoms increases. This lack of specific treatment for NP is reflected in our review, as only 10 of the 25 studies reviewed regarding breast cancer present a treatment for NP. Regarding the association of this type of pain with different interventions performed in cancers, we found 11 studies, including 703 patients who presented NP after surgery. Conversely, in a study that involved 359 patients, this type of pain associated with chemotherapy was documented. Furthermore, in a total of 670 patients, NP was observed as directly related to cancer. All of the above highlights the importance of addressing this type of pain, given its significant impact on the quality of life of patients. Another of the most frequent cancers associated with NP is lung cancer. Fifteen studies were reviewed, with a total of 4937 participants. An important characteristic of this pain is the high incidence rate of NP associated with cancer itself; 10 studies with 2100 participants detail this association. It is essential to know how many studies propose a treatment for pain related to this cancer; only eight indicated one. Likewise, NP associated with post-surgeries (related to cancer) was identified in six studies involving this parameter and 232 participants. Finally, NP associated with chemotherapy was documented in nine studies with 1877 participants. Lung cancer is particularly significant due to various predisposing factors, such as tobacco consumption, environmental smoke, electronic cigarettes, and cigarettes. Speaking of other cancers related to NP, we found blood cancer in 12 articles involving a total of 1865 participants, with only eight presenting a possible treatment for this pain. Eight studies specifically related to neuropathic pain due to blood cancer encompassing 402 patients with this pain. Conversely, only three studies involving a total of 52 patients address neuropathic pain post-surgery. Finally, there are four studies encompassing a total of 999 participants. It is vital to consider this cancer since it affects the production of erythrocytes and red blood cells and also impacts their function. Among various types are acute lymphocytic (or lymphoblastic) leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloicemia (CML) in addition to lymphoma (CML), myelomas, and others. Preventing the development of these cancers is essential as they progress quickly and can affect multiple body systems, weakening the immune system and leading to complications such as infections and bleeding. Furthermore, treatment can be expensive and carry high risk, negatively impacting the quality of life and emotional well-being of patients. Early detection and prevention, when possible, can significantly improve prognosis. Colorectal cancer also shows a notable association with NP, as evidenced by the nine reviewed articles that included a total of 1666 patients. Among these, five studies with 598 patients reported NP associated with chemotherapy treatments, highlighting the need to address this effect to improve patients’ lives. Additionally, three studies described the presence of NP after surgical interventions. Furthermore, two studies with 33 patients documented NP as directly associated with colorectal cancer. Regarding the treatment of NP, five of the studies proposed a treatment approach for this pain. In terms of the stages considered in these nine publications, five focused mainly on later stages (III–IV), while the remaining four (III–IV) did not specify the patients‘ stages.
Finally, in relation to the cancer with the highest prevalence of NP, those that presented the most NP were mammary gland, lung, colorectal, and blood cancers. Although a physiological relationship has not been established to explain why these regions with pathology could have a higher prevalence of NP, this could be associated with the fact that in the early stages, these cancers are often more silent, which is expressed through minimal evident symptoms. In higher stages, such as type IV, where metastasis has already occurred, it becomes more aggressive and may generate neuroplastic tissue changes that could be attributed to predisposing factors for NP. On the other hand, concerning cancer treatment, the highest predisposition to NP is observed after surgery for soft tissue cancer ( p = 0.001). After chemotherapy, there was a higher probability of NP in blood cancer, gastrointestinal cancer, and pharyngeal cancer. Finally, only two studies showed a greater difference regarding post-surgical and post-chemotherapy pain, specifically pharyngeal cancer and oral cavity cancer. All these results indicate that NP is present in several patients with cancer, which can be multifactorial and not due to a clear or defined onset ( Table 3 ).
Regarding previous review studies that have examined NP and its association with cancer, we identified two studies that associate NP with cancer. The article by Mulvey [ 54 , 55 ] revealed that various types of pharmacological and intervention treatments aimed at addressing NP are effective in patients with NP. The methodology of this review included 93 studies, of which only three are present in our study. This article reports that there is a lack of standardized guidelines for managing NP, constituting a barrier to effective treatment and diagnosis. While it establishes a relationship between NP and cancer, it focuses on treatment, whereas our review is centered on the characterization of the relationship between these two conditions and what should also be taken into consideration for managing patients with cancer. The study by Roberto et al. evaluated the prevalence of NP, concluding that 1 in 3 patients with cancer also report NP. This article examined 40 studies, three of which were included in our review. Conversely, our work encompasses 28 more recent articles than the publication of this review. The relationship we address in this study is treated very superficially and is based on only two studies, which is why our study differs significantly from the one mentioned above. Finally, in the article by Yon et al., the prevalence of NP and its effect on the quality of life are evaluated, with an emphasis on the pathophysiology and management of patients with NP and cancer. In conclusion, it is reported that the prevalence of NP reaches 40% of cancer patients, while in our study, it does not exceed 30% of patients with NP and cancer. It is also noted that this pain significantly impacts the quality of life of affected individuals, even more so than nociceptive pain. Furthermore, management is described as complex, including anticonvulsants, antidepressants, combined opioid therapy, topical agents, and intervention strategies. In relation to these previous studies, our review has a distinct and less-studied objective.
5. Limitations
This review was limited by the publication and authorship biases of the included studies. First, studies with differing results that were in non-indexed literature in the selected databases may have been excluded. Second, there could be limitations in the sensitivity and specificity of the searches. Finally, the authors personally selected articles. All of this increases the likelihood of excluding potential cases from countries outside of Asia and North America that are not reported in the scientific community.
6. Conclusions
The coexistence of cancer and neuropathic pain (NP) is evidenced in the literature. This duality of simultaneous conditions significantly alters patients’ quality of life. We believe that knowing the region affected by cancer has the highest probability of producing NP is crucial. In relation to this, when these types of cancer are diagnosed, the treating physician should suggest some form of preventive therapy to help reduce the risk of developing NP. A concerning factor is that certain therapies may increase the probability of NP. More studies are needed to address the pathophysiological events that mediate the presence of NP associated with these therapies, and its association should prompt new studies to enhance understanding of the condition, thus enabling the development of new guidelines for the prevention and effective treatment of NP associated with cancer.
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Supplementary Materials
The following supporting information can be downloaded at www.mdpi.com/article/10.3390/diagnostics15010116/s1 . Table S1: Details of the search strategy.
Conflicts of Interest
The authors declare no conflict of interest.
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