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Adverse Events

Dermatological & Mucosal Adverse Events

In this article we address the correlation between dermatological and mucosal adverse events. Mucocutaneous adverse events, including papulopustular rash, xerosis, pruritus, paronychia, hand-foot skin reaction, stomatitis, dry mouth, mouth and throat pain, taste alterations, oral burning sensation, oral ulceration, hair-, and ocular-, nose-, gastrointestinal, and genital- changes occur in the majority of patients during targeted anticancer therapies.

Lee at al. found a strong correlation between oral adverse events and hand-foot skin reaction (HFSR) in patients who were treated with sunitinib and sorafenib. A significant correlation was found between the occurrence of stomatitis and severity of HFSR reaction, although no significant correlation was found between HFSR severity and response to treatment. Oral adverse events were observed in 72% of the patients with severe HFSR (grade 3) and in 47% of the patients with moderate HFSR (grade 2).

Rash caused by TKIs or mTOR inhibitors affect between 9%–47% of the patients. Because there is a significant relationship between the occurrence of oral adverse events and the severity of HFSR in sunitinib- and sorafenib-treated patients, it is interesting to assess the potential for oral adverse events occurring with rash. Sonis et al. demonstrated a correlation between dermatological adverse events and mTOR inhibitor associated stomatitis. These data suggests that there may be more correlations found than published in the literature.

 

  1. What are the most common skin changes?
  2. What are the most common nail fold & nail changes?
  3. What are the most common hair changes?
  4. What are the most common mucosal changes?
  5. What are the most common non-mucocutaneous adverse events?
  6. How can you compare with chemo- & radiation therapy adverse event profile?
  7. How can you compare with the adverse event profile of hormonal therapy?
  8. What is the use of prospectively designed observational studies?
  9. What is the advantage from a multidisciplinary to an interdisciplinary approach?
  10. Who are the key role players?
  11. What is the need for education & active participation?
  12. What is the treatment of mild adverse events?
  13. What is the treatment of pain?
  14. What are dose modifications?
  15. What is a dose delay?
  16. What is a dose interruption?
  17. What is a dose reduction?
  18. What means early cessation?
  19. In Conclusion

 

What are the most common skin changes?

We describe the most common adverse events of targeted therapies treatments. The most common dermatological adverse events reported are: maculopapular and papulopustular rash, dry skin (xerosis cutis), pruritus (especially the scalp), skin cracks (fissures), and hand-foot skin reaction. These side effects will be discussed in detail in the chapters 8, 9 and 10.

There are several more dermatological adverse events known which are associated with targeted agents.35,36 Due to limited available information we will not discuss eczema, facial/periorbital edema and edema of the extremities, keratinocyte neoplasia: spinocellular carcinoma, keratoacanthoma, actinic keratosis (within sorafenib), keratosis pilaris-like follicular hyperkeratosis, photosensitivity, pigmentation changes, squamoproliferative lesions, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, subungual splinter hemorrhages, and yellow skin coloration.

What are the most common nail fold & nail changes?

There are a number of nail changes that are the result of side effect of treatment with targeted agents. About nail fold changes, nail plate changes, digit tip changes, paronychia, and pyogenic granuloma is extensive literature available.37-45 Despite these adverse nail changes being frequently mentioned in the literature, clinical trials about this disabling and painful adverse event are lacking. Based on expert opinion39 these are adverse events which can be managed effectively, although patients require thorough instruction and close monitoring. The nail fold and nail changes will be discussed in detail in the chapter 11.

What are the most common hair changes?

Hair changes are not as pronouncedly found as a side effect of targeted therapy as compared to that seen in some cytotoxic chemotherapy. However, hair changes can impact QoL.46-52 Trichomegaly, prolonged eyelashes, are the most common complication. Hair depigmentation is described with sunitinib therapy. Alopecia is also reported, but not to the degree as seen with cytotoxic chemotherapy. In addition, facial hypertrichosis, hirsutism, is described in women. In contrast, facial hair growth in men is frequently decreased during treatment with targeted agents.

People have two general hair types: vellus and terminal. Vellus hair is usually short, light-colored (pale), fine and barely noticeable, and develops on most of the body from childhood. In contrast, terminal hair (also referred to as androgenic hair) is more visible, and is generally longer, darker, and coarser than vellus hair; this is especially true for eyebrow hair and hair on the scalp. Puberty initiates this growth, and also of additional terminal hair in both sexes on the axillae, perineum, and legs, usually to a greater extent with men than women. The growth of androgenic hair is related to the level of male hormones (androgens) in the individual. Due to a normally higher level of androgens, men tend to have more androgenic hair than women.53 The hair changes will be discussed in detail in the chapter 12.

What are the most common mucosal changes?

Mucosal changes can be categorized into alimentary tract-, eye-, nasal-, and genital mucositis. Alimentary tract mucositis includes the oral and gastrointestinal mucosa, from the mouth to the anus. Stomatitis affecting oropharyngeal mucosa are common. Oral complications also includes dry mouth, taste alterations, burning sensation, and oral pain. Gastrointestinal adverse events include loose stool, diarrhea and malabsorption. An interdisciplinary team approach plays a crucial role in the supportive care in preventing the spiral of diarrhea. Eye changes include dysfunctional tear syndrome, meibomitis, blepharitis and conjunctivitis. Nasal mucosa changes includes nasal vestibulitis. Genital mucositis may develop. Severe mucosal ulcerations in combination with scrotal and perianal cutaneous aphthous-like ulcerations during temsirolimus therapy for advanced-stage renal cell carcinoma are reported.54

A growing number of cancer patients will be treated with targeted agents, most frequently as outpatients and over a long time span. This indicates a need for awareness and early recognition of mucosal complications not only among oncologists and oncology nurses, but also among community healthcare specialists, such as primary care physicians and dental professionals. Healthcare professionals should educate patients on the importance of early reporting of mucosal complaints.

What are the most common non-mucocutaneous adverse events?

Like with other systemic therapies, targeted agents can cause non-mucocutaneous adverse events. Hypertension is a common adverse event and there are many therapies being for management. Cardiotoxicity is a side effect that can probably be seen as a toxicity intensifier which may interfere with the recovery of previous cardiovascular damage, while any direct effect on cardiovascular function appears to be reversible.29,55,56 Fatigue is reported very often, and may be attributed to the agent, or due to other indirect effects such as dietary alterations, due to other medications or the underlying disease. In addition, the intensive treatment schedule can also cause fatigue. Interstitial lung disease is also reported, and while rare may be life threatening. Other non-mucocutaneous adverse events include hyperglycemia, hyperlipidemia, hypophosphatemia and hematologic toxicities. The list of non-mucocutaneous adverse events caused by targeted agents is still growing.

The non-mucocutaneous adverse events are beyond the scope of this book, but have to be taken into account. When patients have to address these adverse events in combination with the care for their skin and mucosa, it can be very time-consuming and increase the chance of dose-alteration or stopping the targeted therapy.

How can you compare with chemo- & radiation therapy adverse event profile?

The adverse events of targeted therapies are unique when compared to conventional anticancer cytotoxic chemotherapy. The adverse events from targeted agents are often compared to chemotherapeutic and radiotherapeutic regimes. However, the adverse events from these two regimes are cumulative. The more chemotherapy cycles or radio therapeutic sessions a patient receives, the more likely it will be that the severity of the adverse events will increase.

Knowledge of the adverse event profiles associated with targeted agents as well as proactive adverse event monitoring and treatment can help patients to better tolerate the given targeted therapy and optimize treatment outcome.

With targeted agents, adverse events appear to be cumulative too, if the first weeks of targeted therapy are considered. That is why many patients stop with their targeted therapy or have a dose interruption, most of the time followed by a dose reduction. Because of these dose modifications, it is not possible to track what would have happened with the adverse events if a patient would have continued the initial therapy. Moreover, many of the adverse events improve within a couple of weeks, despite continuation of therapy. Treatment of adverse events can help to decrease the severity and duration of the adverse events.

How can you compare with the adverse event profile of hormonal therapy?

While the signs and symptoms of targeted therapy-associated adverse events shares some characteristics to the adverse events from cytotoxic chemo- and radiation therapy, the adverse event onset and duration profile is comparable to the adverse effects of hormonal therapy. With chemo- and radiation therapy the adverse events are cumulative and increase with more treatment cycles. The adverse event profile of hormonal therapy is different. Most adverse events appear and, if adequately treated, may be resolved within the first 12 weeks of treatment. Effective treatment of these events are essential to ensure the compliance of patients and the continuing of antineoplastic treatment. Endocrine therapy is not associated with the more severe, acute toxicities of cytotoxic chemo- and radiation therapy, and may be taken for many years. Prevention and treatment of adverse events caused by long-term endocrine therapy is particularly important in the adjuvant setting, where patients are clinically cancer free. In this stage the efficacy benefits are not obvious while side effects may have a negative impact on daily life. In a palliative setting, patients experience more or less the decreasing effect of the symptoms where they had suffered from.

The targeted therapy-associated adverse events profile is comparable with those from hormonal therapy in onset and duration. Within the first weeks after initiation, many of the mucocutaneous side effects will develop. With proper skin and oral care, supported by medical interventions, many side effects will stabilize or resolve.

What is the use of prospectively designed observational studies?

Prospectively designed observational studies using well-defined terminology and appropriate assessment and grading tools are necessary to better characterize the prevalence and severity of oral and skin complications due to targeted therapy. The prevalence of oral and skin complications associated with targeted therapy may differ between agents and different routes and schedules of administration.

Combinations of targeted therapies, conventional cytostatic therapy and agents targeting growth factor receptors, such as EGFR, may result in enhanced anticancer efficacy.57 However, these combined treatment approaches, particularly those involving EGFR inhibitors, may increase the incidence and severity of mucosal and skin adverse events.17 For oral adverse events, a combination of basic oral care measures, pain treatment and topical therapy appears to be an effective approach to treatment, but well-designed prospective studies are required to substantiate the different treatment approaches.

An animal model of mucocutaneous adverse events would allow better characterization of early events and mechanisms driving its pathology. Moreover, investigations into the relationship between oral and non-oral adverse events, including those of the skin, may be helpful in obtaining a better understanding of potentially shared pathobiologic mechanisms and potentially lead to improved treatment strategies. In addition, new insights into mucocutaneous adverse event pathogenesis and advances made in their management may improve the treatment of mucocutaneous adverse events.

What is the advantage from a multidisciplinary to an interdisciplinary approach?

To date, many practices still work as individual providers and the different disciplines operate in isolation. Over the past years, progress has been made by treating the adverse event in a multidisciplinary setting. Interdisciplinary oncology teams, however, play a key role in providing patient education, instituting preventive measures and assuring early detection and intervention for patients on targeted therapy.

Multidisciplinary team approaches utilize the training, skills, and experience of individuals from different disciplines, with each discipline approaching the patient from their own perspective. Most often, this approach involves separate individual consultations. These may occur in a ‘one-stop-shop’ fashion with all consultations occurring as part of a ‘single appointment’ on one single day. It is common for multidisciplinary teams to meet regularly, in the absence of the patient, to ‘case conference’ findings and discuss future directions for the patients’ care. Multidisciplinary teams provide more knowledge and experience than disciplines operating in isolation.58

Interdisciplinary team approaches, as the word itself suggests, integrate separate discipline approaches into a single consultation and management plan. That is, the patient-history taking, assessment, diagnosis, intervention and short- and long-term management goals are conducted by the team, together with the patient, at one time.58 A common understanding and holistic view of all aspects of the patient’s care ensues, with the patient empowered to form part of the decision-making process, including the setting of long and short-term goals. Interdisciplinary teams have some obvious advantages over multidisciplinary, the most obvious being the patient-centered approach. When done well, it is an extremely efficient method of operating, with both time and cost savings from the lack of duplication and need for follow-up case conferencing.

Who are the key role players?

The adverse events of targeted agents can occur in many parts of the body. That’s why besides the social support system as outlined in paragraph 6.14, several disciplines play a key role in targeted therapy-associated adverse event management.

The medical specialists primary task is to determine the correct disease diagnosis, compile a treatment plan, explore potential adverse events, and perform dose modifications of the targeted agent if appropriate. Modifying treatment dosage should only be performed after adverse event treatment failure.

Nurses and nurse practitioners primary tasks are to provide patient education, written information and reliable resources, preventive measures, body inspection about first signs and symptoms, awareness of adverse events which may occur, adverse event measures, and early and ongoing communication.

Dentists and dermatologists are experts in oral and skin issues and can provide support in assessing and diagnosing the oral and dermatological adverse events. This includes detection by history, visual inspection, photographing, biopsy and culturing, depending on the signs and symptoms which may be present.

Ophthalmologists may be consulted with trichomegaly and when patients continue to complain about their eyes and adherent tissues. A major task is to inspect the eyeball for secondary damage.

In addition, pulmonologists can support in the assessment of lung adverse events including interstitial lung disease, a rare but serious targeted therapy-associated side effect. This is also the case for cardiologists when a decreased injection fraction or other cardiac events known with targeted agents occur. Pharmacist’s knowledge can be useful in issues about medication- and food interaction. Also employees from pharmaceutical companies can play a prominent role in side effect management by providing agent specific side effect treatment algorithms based on knowledge from clinical trials which are primary focusing on adverse events.

This enumeration is not the complete list of disciplines. Depending on the adverse event profile and the affected body parts, other disciplines may be consulted.

What is the need for education & active participation?

Successful management of adverse events relies on thorough and effective education of healthcare providers and patients. Adverse event symptoms should be managed in close partnership between both parties. Both are important and relies upon active participation of patients and a close provider-patient partnership.

Healthcare providers need to learn effective strategies to prevent adverse events and how to treat them once they occur and also when they worsen. In addition, healthcare providers need to have skills in identification, assessment, grading and monitoring adverse events. Education should include strategies for failure to effectively manage the adverse events and approach to targeted therapy, dose or schedule modification in order to maintain the planned therapy, and the goal of cancer therapy.

Patients need to be educated about how to recognize the symptoms of adverse events and how to proactively prevent and/or treat adverse events. In addition, patients need to be educated about treating adverse events at onset as treatment delay will reduce the effectiveness of the intervention.

What is the treatment of mild adverse events?

Patients experience a large variety of symptoms frequently and in various combinations. In general, mild to moderate side effects are expected to be bearable and rarely life threatening.59 Although these symptoms are mostly mild to moderate, they often cause a high level of symptom burden. Symptom burden is experienced differently in the individual patient, thus when considering treatment and the influence on health-related QoL, a self-reporting system of symptoms is the most reliable indicator of symptom presence and intensity.60-62 Because severe adverse events seldom occur it is important to focus on multiple mild adverse events. To improve decision making around managing symptoms and reduce dose modifications due to targeted therapy treatment, it is necessary to develop in depth insight into the relationship between symptoms, symptom burden and therapy decisions.

Dose reductions and treatment modifications are not only based on severe adverse events, but also due to multiple mild or moderate adverse events. Patients may experience several adverse events which are more or less successfully managed, however if another side effect develops, this can cause the patient to stop the therapy. Early identification and successful management in order to prevent progression of the adverse event may reduce interrupting or withholding lifesaving anticancer treatment.36,63,64 Optimal treatment with targeted therapies is limited by dose modifications due to adverse events. Improved insight into the relationship between adverse events and therapy decisions is needed. Using patient self-reported measurement methods helps to recognize symptoms and to differentiate among symptom intensities. This systematic approach might help to achieve the optimal dosing, which might improve progression free survival and overall survival.

What is the treatment of pain?

Pain is a common indirect adverse event of targeted therapies that may accompany other adverse events, like mucosal and skin injury. Deep fissures, hand-foot skin reaction, photosensitivity, desquamation, skin atrophy, paronychia, burning tongue and aphthous-like stomatitis for instance can cause much burden.

For mild to moderate pain of local oral and skin injury, topical therapies may provide considerable symptom relief and should be considered as improved symptom control without systemic agents may be possible or lower doses may be used for shorter periods.

For moderate to severe pain associated with targeted agents we prefer to prescribe NSAIDs instead of opioids, since lesions are more superficial. In addition, many targeted agents are provided in an outpatient setting, and may be prescribed the medication for long periods of time (till progression or unmanageable side effects). Hence we do not want them to be on medications that impose too many restrictions. But there are many patients who can’t tolerate NSAIDs. When NSAIDs are not tolerated, consider acetaminophen/paracetamol as maintenance therapy in combination with an immediate release oral opioid or fast acting fentanyl preparation (e.g. 50 microgram fentanyl nasal spray) to relief (oral) pain short-term, for instance before dinner. Fast acting fentanyl preparations are registered for patients who are already treated with opioids, they may also be considered in this population because of their short term pain relief. Since oral complaints can complicate administration of drugs by mouth, one should consider other kinds of administration routes, such as transdermal or intranasal routes.

What are dose modifications?

Optimal antitumor activity requires maintaining the optimal dose of targeted therapy in individual patients. When initiating an anticancer therapy, the treatment plan is based on data about kind of treatment, the optimal dose, and the most effective duration of therapy. Literature has been published showing rapid tumor growth in patients who stop treatment. Resultant, modifying targeted therapy dosing should be avoided in order to maintain the highest possible dose for the longest period. Dose modification may include dose delay, dose interruption, dose reduction and early cessation.

What is a dose delay?

Dose delay is a time interval during which there is a temporary cessation of the planed therapy. Often this means a delay for days or one to two weeks.

What is a dose interruption?

Dose interruption is some abrupt temporary cessation of the ongoing therapy, longer than a dose delay.

What is a dose reduction?

Dose reduction is an adjustment in the planned dosing of an ongoing therapy.

What means early cessation?

Early cessation is a continue stop of the therapy with the intention to not reinitiate the therapy again.

 

In Conclusion

In order to improve health-related QoL and adherence, adverse events should be prevented if possible and treated if necessary. Within targeted therapy, dose modifications are often performed because of the occurrence of adverse events often without even trying to treat them. It is essential to avoid stopping therapy because of adverse events, although dose modifications may be required based on individual safety and tolerability. Herein preventive measures and prompt treatment as soon as mucocutaneous adverse events appear are crucial. Prevention and management should be attempted in order to facilitate continuing targeted therapy.

 

 

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