Answer (Gr 1): Continue but reduce dose to 120 mg

I would stop regorafenib therapy until the Grade 2 hand-foot syndrome resolved. Then I would restart therapy at 120 mg. For a patient experiencing Grade 1 hand-foot syndrome, I would continue treatment with regorafenib but at a reduced dose of 120 mg.

In my experience, patients on regorafenib experience much hand-foot syndrome and profound fatigue. If a patient is experiencing fatigue that is beginning to impact quality of life, I will continue with regorafenib therapy but at a reduced dose. A few patients have developed what seems to be pulmonary toxicity and I have had several patients admitted for presumed pneumonia, though there was no documented infection. Upon resumption of the same regorafenib dose, the patients again developed similar pulmonary symptoms.

If the patient developed Grade 1 or 2 hand-foot syndrome, I would stop regorafenib therapy. Once the toxicity resolved, I would either restart at 120 mg or 80 mg orally daily. I would also stop treatment if a patient were experiencing some fatigue that was interfering with his or her life. Once the fatigue resolved, I would restart regorafenib at 120 mg orally.

Answer (Gr 1): Continue but monitor weekly

If the patient developed Grade 2 hand-foot syndrome, I would hold treatment until the toxicity resolved. Thereafter, I would restart regorafenib at a reduced dose of 120 mg or 80 mg, depending on how brisk the recovery was. In my opinion, the patient’s quality of life during later lines of therapy is important.

I usually see my patients who are receiving regorafenib on a weekly schedule for the first month after initiating therapy because I am concerned about the toxic side effects of the drug. After the first month, I tend to see my patients every 2 weeks. If the patient developed Grade 1 hand-foot syndrome, I would continue with regorafenib while closely monitoring this side effect for a week.

Beyond the grade of the hand-foot syndrome, I am interested in discussing the emotional and physical effects of the drug with my patients. If the patient were having issues with hand-foot syndrome, even though it’s of Grade 1 intensity, I would dose reduce if the symptoms were still being experienced at the patient’s next weekly visit.

I have seen patients who discontinued regorafenib therapy because of fatigue. Often patients experience fatigue within the first week of treatment, and they are more vocal about this side effect than they are about hand-foot syndrome. Grading the level of fatigue is difficult. If the patient’s ECOG performance status has dropped on regorafenib, I will hold treatment and dose reduce. If the patient tells me that his or her quality of life has been noticeably affected by fatigue, I will reduce the dose.

Fatigue associated with regorafenib is unlike that induced by other cytotoxic agents, with which it’s experienced after receiving the drug for about 4 months. With regorafenib, I hear about it at the first week’s visit after initiating treatment.

For those patients who continue receiving treatment for 3 weeks, fatigue becomes a cumulative effect. It’s an effect observed with the tyrosine kinase inhibitors like sunitinib, sorafenib and regorafenib that inhibit the VEGF pathway. I believe it’s an off-target class phenomenon that keeps manifesting itself. I believe that at least 50% of my patients will voluntarily complain about fatigue while receiving regorafenib.

I never start regorafenib therapy at 160 mg because I believe that dose is intolerable. I usually start at 120 mg. In this clinical scenario, I would likely stop regorafenib until the Grade 1 or 2 hand-foot syndrome resolved. Then I would restart treatment at 80 mg orally daily with the hope to dose escalate. However, I am not sure that I would be able to do so. If the patient developed fatigue that was impacting quality of life, I would probably continue regorafenib but at a reduced dose. This is based on data suggesting that the side effects experienced will improve.

Answer (Gr 1): Continue but reduce dose

In the clinical scenario involving the 67-year-old patient who developed Grade 2 hand-foot syndrome, I would stop regorafenib therapy until the toxicity resolved. Then I would restart treatment at 120 mg PO orally daily. If the patient developed Grade 1 hand-foot syndrome, I would continue treatment with regorafenib but at a reduced dose.

Fatigue is a toxicity associated with regorafenib that I treat seriously. Even if the patient finds it tolerable, I stop treatment until symptoms resolve. Thereafter, I would restart regorafenib therapy at 120 mg orally daily. Fatigue is difficult to measure, and patients complain that it affects their quality of life. At the stage in which regorafenib is recommended, the patient’s quality of life is of high importance.

Answer (Gr 1): Continue but monitor weekly

If the 67-year-old patient developed Grade 2 hand-foot syndrome, I would stop regorafenib until the toxicity resolved. Then I would restart treatment at 120 mg orally daily.

If this patient developed Grade 1 hand-foot syndrome, I would not stop therapy after 1 week but would complete the first cycle of regorafenib. If the symptoms progressed to Grade 2 hand-foot syndrome in the second or third week of therapy, I would discontinue treatment.

For fatigue that is somewhat affecting the patient’s quality of life, I would probably ask the patient to continue therapy for 1 more week. If the patient could not tolerate treatment for this additional week, I would dose reduce without stopping regorafenib.

Answer (Gr 1): Continue but monitor closely

If the 67-year-old patient developed Grade 2 hand-foot syndrome after 1 week, I would stop regorafenib until the toxicity resolved. Then I would restart at 120 mg orally daily.

If the hand-foot syndrome were of Grade 1 intensity, I would probably continue with regorafenib therapy at 160 mg. However, I would closely monitor this patient and be prepared to dose modify by reduction or interruption in a week or couple of weeks.

If the patient is experiencing Grade 1 fatigue, I continue regorafenib at the same dose. However, I closely monitor the patient to ensure that the symptoms are not progressing.

Answer (Gr 1): Stop and resume at 120 mg

For a patient who developed Grade 2 hand-foot syndrome after 1 week, I would stop treatment until the symptoms resolved. Thereafter, I would restart at 80 mg orally daily.

If the patient developed Grade 1 hand-foot syndrome, I would stop therapy. Once toxicity resolved, I would restart regorafenib at 120 mg orally daily, depending on how bothersome it was for the patient. If a patient developed fatigue that was affecting quality of life, I would continue with regorafenib therapy but at a reduced dose to determine if this strategy would alleviate the symptoms. In general, I am more aggressive about dose reductions for patients experiencing more severe toxicities.