Lung Cancer Update Issue 3, 2008

THOMAS J LYNCH, MD: We are accruing to a study evaluating two years of adjuvant erlotinib for patients with EGFR mutations (NCT00567359). We know the response rates in this population are extraordinarily high. The issue is, we don’t know what the long-term side effects are or the optimal duration of therapy. Patients develop significant rash. For patients who are really benefiting, the rash will burn out. It will not stay at that same level of intensity that you find in the first two months. In advanced disease, I have patients who have been on gefitinib and erlotinib for four, five, six or seven years.

Breast Cancer Update Issue 2, 2008

NANCY U LIN, MD: Some patients receiving the combination of capecitabine and lapatinib report fatigue or mild nausea, and there is the acneiform rash that is typical of any of the EGFR inhibitors. Typically, it appears over the lower part of the face and the upper chest.

Whether the rash is responding to treatment or going away on its own is hard to say, but we’ve used topical antibiotics with good results.

You definitely see hand-foot syndrome with capecitabine, and trial data suggest it may be worse with the addition of lapatinib.

Breast Cancer Update Issue 3, 2008

DR GRALOW: The rash we have seen secondary to lapatinib is located on the face and trunk. My group treats only patients with breast cancer, so we don’t have much experience with EGFR-targeted therapy. We’ve learned of some topical treatments that we can use. We don’t usually use oral antibiotics, but we have done so.

We’re getting better at managing the rash. From the patients’ standpoint, the rash is visible. They can tolerate it on their chest if they can cover it. When it’s on their face, however, they don’t like to be labeled or have people ask about it.

Renal Cell Cancer Update Issue 2, 2007

MARIO E LACOUTURE, MD: Dermatological side effects secondary to sorafenib and sunitinib are seen with high frequency. Data from Phase III randomized studies indicated that sorafenib led to a hand-foot skin reaction in 30 percent of patients, with Grade III to Grade IV severity in only five percent. With sunitinib, the development of the hand-foot skin reaction occurred in 20 percent of patients, and of those cases only five percent were Grade III to IV in severity.

Hand-foot syndrome also occurs with other agents, such as fluorouracil or pegylated doxorubicin. However, these seem to be clinically and histologically distinct from the hand-foot skin reaction occurring with sorafenib and sunitinib.

With more conventional agents, you have swelling, redness and pain diffusely through the palms and soles. With sorafenib and sunitinib, you have a thickening of the skin. This thickening, when it is subject to pressure, leads to bleeding underneath the thickened areas, causing significant pain for the patient.

Colorectal Cancer Update NSABP Education Session 2006

MICHAEL J O’CONNELL, MD: The toxicity associated with panitumumab, like cetuximab, is a cutaneous eruption — acneiform skin rash. Nearly 100 percent of the patients receiving panitumumab are reported to have some degree of skin rash. Infusion reactions have been uncommon with panitumumab. A variety of other side effects are seen infrequently — diarrhea, fatigue — but the major dose-limiting side effect has been skin rash.

TJ Lynch et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: An evolving paradigm in clinical management. Oncologist 2007;12:610-21.

If patients develop EGFRI-associated dermatologic toxicity, the following interventions are suggested, based on severity of the reaction:

Mild toxicities: Patients may not require any form of intervention; however, it may be appropriate to treat some mild toxicities with topical hydrocortisone (1% or 2.5% cream) or clindamycin (1% gel). The EGFRI dosage should not be altered for mild toxicities.

Moderate toxicities: Treatment is hydrocortisone (2.5% cream), clindamycin (1% gel), or pimecrolimus...(1% cream), with the addition of either doxycycline (100 mg, po twice a day [bid]) or minocycline (100 mg, po bid). The EGFRI dosage should not be altered for moderate toxicities.

Severe toxicities: A reduction in the EGFRI dose is recommended. Concomitant intervention is the same as for moderate toxicities — ie, hydrocortisone (2.5% cream), clindamycin (1% gel), or pimecrolimus (1% cream), with the addition of either doxycycline (100 mg, po bid) or minocycline (100 mg, po bid) — but with the addition of methylprednisolone dose pack. If toxicities do not sufficiently abate at 2-4 weeks, despite treatment, then interruption of EGFRI therapy is recommended, in accordance with prescribing information.

It is important to note that intervention for cutaneous toxicities needs to be maintained even when EGFRI therapy is decreased or is interrupted, because EGFRI-associated toxicities may have a very long duration, analogous to the prolonged tissue half-life of EGFRIs. Once the cutaneous reactions have sufficiently diminished in severity, or resolved, then EGFRI therapy may typically be re-escalated or restarted with a good degree of confidence that cutaneous toxicities may be more easily managed.

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RTP Satellite Symposium: Molecular Oncology 101 2008

DR LACOUTURE: I believe that — at least for most of the EGFR inhibitors right now — the possibility of having the discontinuation of these agents and the toxicities and reverting to a normal state would be better with the oral agents as opposed to the monoclonal antibodies.

We do seem to achieve a higher inhibition of the EGFR pathway with monoclonal antibodies, which may have greater antitumor activity by internalizing the receptor and, therefore, degrading it, and something that can also occur in skin. That may explain why we see a 17 to 20 percent rate of Grade III rash in the patients receiving the EGFR-inhibiting monoclonal antibodies versus approximately nine percent with the use of tyrosine kinase inhibitors.

Might I add that there’s a consistent story emerging across several classes of biologics, and that is that a pretty good link is evident between class-specific toxicity and efficacy. For example, with tamoxifen there is now evidence that if a patient experiences hot flashes, she has a better likelihood of getting benefit.

We have growing evidence with VEGF-targeting agents that hypertension is associated with survival. And, of course, with EGFR inhibitors, we’ve got evidence from multiple agents that rash is associated with improved outcome, so I believe the toxicities are becoming pretty good pharmacodynamic indicators of benefit.

Lung Cancer Update Issue 2, 2008

ROMAN PEREZ-SOLER, MD: The RADIANT study is evaluating adjuvant chemotherapy followed by erlotinib administered for two years to patients with non-small cell lung cancer (NSCLC) who have EGFR-positive disease as determined by IHC or FISH. The issue will be whether a patient can receive erlotinib for two years — if that would be tolerable. I believe it will be tolerable for most patients.

The first two months may be rough, but after two months of erlotinib, the majority will find that the toxicity subsides and the skin rash improves. A minority will need a dose reduction or will not be able to tolerate the drug.

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RTP Satellite Symposium: Molecular Oncology 101 2008

DR VENOOK: There’s an adjuvant study (NCCTG-N0147) evaluating FOLFOX with or without cetuximab for patients with Stage III colon cancer. That is a tough sell. These patients believe they are cured. They’re hedging their bets by taking more therapy, and we have trouble accruing patients and many drop out because they don’t want a rash. I believe their perception of the gain and what’s at stake is, as with most decisions by patients, the important factor.

However, in the advanced disease setting, patients tend to be much more forgiving of these kinds of toxicities. The perversion, of course, is the correlation with the degree of skin toxicity and efficacy of the agent. That may be favorable from a prognosis perspective, so in the waiting room, patients actually compare rashes and they are pleased when they have a bad rash.

DR LACOUTURE: With regard to the dermatologic problems that patients who are receiving cetuximab may encounter, I believe that by instituting early intervention and frequent follow-up, we can maintain the majority of patients on therapy, and that is associated with their overall sense of well-being and quality of life.

The two randomized trials in which the administration of tetracycline antibiotics was administered prophylactically showed a significant benefit. In one study, tetracycline at 500 milligrams twice daily showed a significant reduction in Grade II or worse rash.

A second trial evaluating oral minocycline at 100 milligrams twice daily for cetuximab-associated rash, published in the Journal of Clinical Oncology in December 2007, showed treatment reduced the number of lesions.

Renal Cell Cancer Update Issue 2, 2008

ROBERT A FIGLIN, MD: We participated in the study that evaluated sorafenib in older patients with advanced renal cell carcinoma and found no apparent difficulty administering sorafenib to patients older than age 65 compared to younger patients.

In my experience, older patients tolerate sorafenib better than sunitinib. We see less fatigue, hand-foot syndrome and hypertension with sorafenib.

I believe that some of the problem with the hand-foot syndrome that’s seen, specifically with the tyrosine kinase inhibitors, is that we don’t realize how much we traumatize our hands and feet every day through our normal activities and that angiogenesis is part of wound healing.

When we inhibit angiogenesis and inhibit wound healing, we also inhibit the ability of these hands and feet to get better. That’s why, when you stop these drugs for a period, the hands and feet get better quickly.

The single most important management strategy that my nurse tells me about all the time is anticipating the toxicities before they occur. We need to let patients know what they may experience when to call and then what to do. They should not wait until the toxicity is so robust that the only alternative is to stop the drug.

Once the patient is experiencing them, the easiest way to manage toxicities such as hand-foot syndrome is to stop the drug, restart at a lower dose and recognize that we may be able to escalate the dose later. However, the further the toxicity has developed, the longer the patient will be off of treatment before it reverses.

Renal Cell Cancer Update Issue 2, 2007

DR LACOUTURE: For patients who are receiving sorafenib and sunitinib, the hand-foot skin reaction tends to develop after the first month of therapy. With sorafenib, for which an administration of 400 milligrams twice daily is uninterrupted, you tend to see it earlier than with sunitinib, as the sunitinib regimen allows for a two-week drug holiday. Patients are able to recover from the tenderness and pain during that two-week drug holiday.

Flushing — the red face and the seborrheic dermatitis-like reaction — occurs within the first two to four weeks. Hand-foot skin reactions usually occur later, and they tend to become worse over time if the symptoms are not managed. For management, we have used high-concentration urea-containing preparations, such as urea 40 percent creams.

These are keratolytics, so they disrupt the outer layer of the skin, the stratum corneum. They seem to thin out that thickened skin layer that may be responsible for the increased pressure leading to the pain.

We also prescribe high-potency topical steroids, such as clobetasol ointment, as this will minimize the proliferation or the division of those skin cells. It will also decrease the underlying inflammation.

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