Bernard J. Escudier, MD

The article by Posadas and Figlin on systemic therapy in advanced renal cell carcinoma (RCC) provides 

a very interesting and comprehensive review

 of our current knowledge concerning the treatment of RCC. As stated by the authors, this field has changed dramatically in the past 6 years, with the approval of six new drugs and at least two additional approvals coming in the very near future. However, after reading this article, readers might be somewhat disappointed by the lack of clear-cut recommendations regarding how they should treat specific patients presenting at their clinic.

One of the “advancing paradigms” referred to by the title of the review derives principally from the fact that approval has been provided, drug after drug-without, however, any attempt to prioritize the drugs. A good example of such a paradigm can be found in the recommendation for first-line treatment of clear-cell carcinoma, for which three regimens have been approved with the same level of evidence (sunitinib [Sutent], bevacizumab [Avastin] + interferon, and pazopanib [Votrient]). Head-to-head trials will certainly help define priorities to some degree, although guidelines will probably keep all the regimens as possible options in the future. However, one must wonder whether, if axitinib (Inlyta) and tivozanib are approved as first-line treatment when the data from ongoing phase III trials are presented, the other agents should remain as options.

Another important paradigm in RCC management derives from the lack of biomarkers for this disease. Although targeted therapy is currently the standard of care in RCC treatment, none of the targets have been shown to accurately predict the efficacy of the drugs we are using. This finding underlines the urgent need for validated biomarkers that can help physicians make the best choices for their patients. Similarly, although mechanisms of resistance to tyrosine kinase inhibitors (TKIs) are emerging-eg, production of cytokines such as interleukin (IL)-8, fibroblast growth factor (FGF), angiopoietin-many questions remain as to whether using drugs that block production of these cytokines (for example, dovitinib, which is currently being studied in vascular endothelial growth factor [VEGF]-refractory patients) will be able to overcome these resistance phenomena.

The authors have tried to define an algorithm for the management of advanced RCC in their Figure. Here there are some differences between the United States and Europe. In Europe, we feel that there is no evidence that non–clear-cell histology will benefit from temsirolimus (Torisel), and we still consider TKIs as the standard of care in this subgroup. Similarly, European RCC experts no longer use high-dose IL-2, based on the finding that no characteristics facilitate determination of which patients are suitable for this toxic treatment. Obviously, if new data from the SELECT trial reveal new information, this position will be quickly changed.

An important issue raised by the authors concerns the choice of subsequent treatment after first-line treatment has failed, which unfortunately is the case in the vast majority of patients. Two large phase III trials have positioned two new agents as standard-of-care in this setting, everolimus (Afinitor) and axitinib (which was recently approved by the US Food & Drug Administration [FDA] and is currently under examination by the European Medicines Agency [EMEA]). In order to provide help with clinical decisionmaking, a head-to-head study comparing those two drugs will be necessary, instead of indirect and biased intratrial comparisons. However, the field is moving so fast that new treatment options might make such a trial rapidly obsolete.

In fact, many new pathways are being explored, and the preliminary data are very exciting. Dovitinib, an FGF inhibitor, has impressive activity in heavily pretreated patients. Dual inhibition of cMET and VEGF, provided by drugs such as foretinib or cabozantinib, also looks very attractive. Similarly, the more potent inhibition of the Pi3K/Akt/mammalian target of rapamycin (mTOR) pathway is thought to be more active than that of the first-generation mTOR inhibitors (temsirolimus, everolimus). Whether this is confirmed by ongoing trials may change the landscape dramatically.

Finally, targeted immunotherapy has provided new hope in the management of RCC. CTLA-4 inhibitors, as well as inhibitors of PD-1 and PDL-1, have very promising activity, and the prospect of testing these drugs in early-stage disease appears very exciting. In addition, because of their different mechanism of action, these drugs might be safely combined with current drugs, thereby providing a major step forward toward the cure of metastatic disease. And this is very good news. Metastatic RCC now has a much longer overall survival, and the possibility of rendering this disease chronic-and some day curable-is approaching.

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Articles

The article by Posadas and Figlin on systemic therapy in advanced renal cell carcinoma (RCC) provides a very interesting and comprehensive review of our current knowledge concerning the treatment of RCC.

Metastatic RCC: Moving Towards a Chronic Disease

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Paralleling the increasing use of multikinase inhibitors in the field of cancer therapy, patients and clinicians are confronted with frequently occurring cutaneous side effects associated with the use of these new drugs. Two such targeted agents, sunitinib (Sutent) and sorafenib (Nexavar), were recently approved by the US Food and Drug Administration to treat patients with metastatic renal cell cancer (RCC). Cutaneous adverse effects associated with these drugs are sometimes distressing, partly because of their chronicity given the long-term duration of treatments, and can result in treatment interruption. Active collaboration between dermatologists and medical oncologists or urologists is urgently needed to characterize and treat these dermatologic side effects.

 gene products (serine-threonine kinases), including mutated B-Raf, as well as platelet-derived growth factor-beta (PDGFR-β), FLT

, and vascular endothelial growth factor receptor-2 and -3 (VEGFR-2 and -3). Sunitinib blocks VEGFR-1, -2, and -3, PDGFR-α and -β, Ret, Kit, and FLT

. Both drugs were recently approved by the US Food and Drug Administration (FDA) to treat patients with metastatic RCC,

 and sunitinib has also been approved for patients with imatinib (Gleevec)-resistant gastrointestinal stromal tumors.

 Furthermore, both drugs are currently being tested in various tumors (such as sorafenib for hepatocarcinoma) as single agents and in combination with chemotherapy, with promising preliminary results in several tumors. Numerous cutaneous side effects have been observed with these two molecules.

 Some side effects are common to the two drugs, such as hand-foot skin reaction (HFSR), xerosis, and subungual splinter hemorrhages (SSH), whereas others, like hair modifications, keratotic papules, and facial erythema, seem to be associated with the use of one or another of these targeted agents. Table 1 shows the association between the targeted receptors and the skin symptoms observed.

HFSR occurs in 30%−60% of patients receiving sorafenib and 15%−20% of patients treated with sunitinib,

 often appearing after 2 to 4 weeks of treatment. It seems to be dose dependent and rapidly disappears after treatment discontinuation.

HFSR usually presents as painful symmetric erythematous and edematous areas on the palms and soles, often preceded or accompanied by paresthesia (tingling sensations and intolerance to contact with hot objects); these sensations seem to be aggravated by a warm environment. HFSR can also affect the lateral sides of fingers or the periungual zones. Hyperkeratosis and desquamation are often associated. Painful hyperkeratotic areas on pressure points, surrounded by rings of erythematous and edematous lesions, are classically observed (Figure 1), and painful bullous lesions may be seen (Figure 2). Sole involvement can result in walking impairment. Preexistent sole hyperkeratosis seems to confer a predisposition to painful sole involvement and functional consequences. Although this syndrome can sometimes clinically resemble the more classic chemotherapy-induced acral erythema (AE), kinase inhibitor-induced HFSR has more localized and hyperkeratotic lesions, distinct from classic AE.

Histologic examination of HFSR shows epidermal changes suggestive of keratinocyte differentiation modifications. The granular layer is thinner or absent in several specimens, and some areas of parakeratosis are seen. Epidermal cells are swollen in the superficial stratum spinosum. Numerous mitoses are seen in the basal layers and also above the basal and suprabasal layers, where normally they should not be found physiologically. Dyskeratotic keratinocytes suggestive of apoptotic cells are observed.

As a preventive measure, patients with plantar hyperkeratosis are advised to have a pedicure prior to treatment. During treatment, however, shock absorbers can be used to relieve painful pressure points, and sandals seem to be helpful in some cases. Symptomatic treatment with over-the-counter emollient and keratolytic ointments (containing salicylic acid or urea) can be used. When grade 3 HFSR occurs (pain interfering with function), a dose reduction (to 50% of the dose) or treatment interruption for 1−2 weeks is recommended until symptoms return to grade 1. When treatment is resumed, the dose should be decreased by one level; the full dose should be returned after 3−4 weeks. As is the case with most of the other side effects occurring with kinase inhibitors, resuming treatment is not always associated with similar side effects, in our experience.

In our experience, multiple, painless distal SSH are frequently seen (in 40%−65% of patients) under fingernails (Figure 3) and less often under toenails of patients receiving multikinase inhibitors. First described in patients with infective endocarditis, SSH appear as linear black or red lines that actually look like wood splinters under the nails. They are formed and confined within the epidermis of the nailbed and consist of a mass of blood in a layer of squamous cells adhering to the undersurface of the nail. They are carried forward with nail growth and can be scraped away once they attain the free margin of the nail.

SSH are considered to be thrombotic or embolic in origin. Initially thought to be a typical sign of bacterial endocarditis, they have subsequently been reported to occur with various conditions,

 such as antiphospholipid syndrome, severe rheumatoid arthritis, thromboangiitis obliterans, and mitral stenosis; they also may occur at a high altitude or when arterial catheters are used. In addition, they may be seen in healthy patients, where they are more often confined to a single digit, and trauma seems to be the most common cause.

 Such traumatic SSH occur in the region where the nail plate separates from the nailbed, beneath which delicate, specialized, spiral capillaries are located and can easily rupture. Toxiderma is not usually an etiologic factor in SSH. SSH are rarely observed with imatinib and have not been reported with epidermal growth factor receptor (EGFR) inhibitors in the literature.

SSH may result from elective VEGFR blocking, which might prevent the physiologic repair of traumatized nailbed capillaries and facilitate the emergence of SSH.

 The hypothesis that nailbeds could offer a clinical monitoring window into the antiangiogenic effects of drugs that target VEGFR is being prospectively evaluated.

No therapeutic measure is needed for SSH, which are totally asymptomatic.

Skin dryness is a frequent complaint of patients treated with sorafenib and sunitinib. In our experience, skin dryness is reported in approximately 20%−30% of treated patients and is usually easy to treat symptomatically with skin emollient or body oil.

A face and scalp rash is seen in more than 50% of patients after 1 or 2 weeks of treatment with sorafenib, in our experience. It appears as an erythematous and squamous rash involving the mediofacial area and the scalp skin, sparing the periocular areas. Reminiscent of classic moderate seborrheic dermatitis, it is frequently preceded by or associated with scalp dysesthesia. This rash frequently fades or disappears after several weeks of treatment and usually does not require treatment; however, if patients request therapy, a topical emollient, 2% ketoconazole, or level 2 or 3 topical steroids can be prescribed for a short time, depending on the severity of symptoms.

In our patients, the texture of scalp hair is frequently modified with sorafenib treatment: hair becomes more brittle, finer, and curly, sometimes resembling hair modification associated with the use of EGFR inhibitors. Some patients have reported darkening of hair color.

Alopecia may occur in some patients treated with sorafenib or sunitinib, but it is rarely severe (Figure 4). As opposed to EGFR inhibitor-induced alopecia, it is not located on the frontotemporal areas but rather as diffuse hair loss. Spontaneous resolution of alopecia usually occurs despite continued sorafenib treatment, and interestingly, regrowing hair is often curlier than it was prior to sorafenib treatment (Figure 5).

Sunitinib frequently gives rise to hair depigmentation after 5−6 weeks of treatment. It is reversible as early as 2−3 weeks after treatment discontinuation. Successive depigmented and normally pigmented bands that are correlated respectively with periods on and off treatment can be observed.

 Sunitinib-induced hair depigmentation is probably due to the blockade of Kit signalling, which modulates the expression of the melanogenesis enzymes via the microphthalmia transcription factor.

Keratotic Papules, Kystic Lesions, and Keratoacanthomas

The prevalence of this side effect is not yet known; however, we and others have observed several cases of multiple keratotic papules, cystic cutaneous lesions (from milia cysts to more inflammatory lesions), and keratoacanthomas in patients receiving sorafenib.

 Keratoacanthomas are autoinvolutive epidermal tumors with borderline frontiers with squamous cell carcinomas. One case of squamous cell carcinoma in a patient treated with sorafenib has been reported.

 Further studies are ongoing to understand the mechanisms leading to these cystic lesions and keratoacanthomas. Cystic noninflammatory lesions do not require treatment, unless they become inflammatory and/or infected. Topical antibiotic treatments, such as topical clindamycin, metronidazole, or erythomycin, are then indicated.

Lesions suggestive of keratoacanthomas should be surgically removed.

Sunitinib is bright yellow, which may account for the yellowish skin coloration of patients treated with this drug. In our experience, yellowish skin is reported in about 30% of cases and is more visible in fair-skinned patients.

Periocular edema can be seen in sunitinib-treated patients. The preferential periocular location of the edema might be due to the high distension capacity of this skin area. Imatinib, which also targets PDGF and Kit receptors, is also known to be associated with edema, more frequently and severely than is sunitinib.

 Although the prevalent hypothesis explaining this symptom is the effect of PDGFR inhibition on interstitial fluid homeostasis, the exact mechanism leading to edema is not yet known. Moderate sunitinib periorbital edema does not usually require any treatment.

Inhibition of multikinase receptors results in a wide range of new and chronic cutaneous side effects. Some of these effects, like multiple subungual hemorrhages, facial erythema, moderate periocular edema, or hair modifications, are usually well tolerated. Nevertheless, physicians should be aware of them and should provide detailed information to their patients before introducing these drugs. Preventive measures can be taken for some of the skin effects, such as treatment of preexisting plantar hyperkeratosis to prevent HFSR.

Physicians also have to adapt the management of these cutaneous side effects in the context of long-term prescription of kinase inhibitors in renal cell cancer. Indeed, patients sometimes find it even more difficult to accept such chronic cutaneous side effects than acute and more severe effects. The study of these hitherto unknown side effects will provide useful information on skin, hair, and pigment cell physiology. Therefore, besides the mechanistic information generated as a result of their study, early recognition and symptomatic treatment of these associated cutaneous events should be critical aspects of the medical management of patients treated with kinase inhibitors. Synergistic collaboration between oncologists or urologists who treat patients with renal cell cancer and dermatologists is critical.

Paralleling the increasing use of multikinase inhibitors in the field of cancer therapy, patients and clinicians are confronted with frequently occurring cutaneous side effects associated with the use of these new drugs. Two such targeted agents, sunitinib (Sutent) and sorafenib (Nexavar), were recently approved by the US Food and Drug Administration to treat patients with metastatic renal cell cancer (RCC).

Bernard J. Escudier, MD

Articles

Metastatic RCC: Moving Towards a Chronic Disease

Cutaneous Side Effects of Multikinase Inhibitors Used in Renal Cell Cancer