A DERMATOLOGIST'S PERSONAL PERSPECTIVE

Vivian W. Bucay, MD
Clinical Assistant Professor
Dept of Physician Assistant Studies
University of Texas Health Science Center - San Antonio, TX

As a dermatologist in clinical practice since 1991, I have had many opportunities to make a positive impact on patients' lives by being the first to diagnose and treat skin cancers, above all nonmelanoma skin cancers. Fortunately, almost every patient has had a good outcome, primarily because of early diagnosis and intervention. Like most dermatologists, I understand that if I encounter high-risk melanoma or advanced disease, clinical management will most often become the responsibility of surgical and medical oncologists, while I will navigate shallower waters, such as screening family members and reviewing pertinent but often confusing literature to assist the patient and family in making important decisions regarding treatment.

I have gained quite a new perspective on melanoma, however, since becoming an advanced melanoma patient myself in 2006. I have previously chronicled my personal battle with the disease twice before, first in San Antonio Medicine, a publication of the Bexar County Medical Society, in an issue dedicated to the physician as patient,¹ and second, in the 2008 Skin Cancer Foundation Journal, a publication targeted to the lay public.²

My purpose in this issue of The Melanoma Letter is twofold: to present treatment options for Stage III and Stage IV melanoma in the manner in which they became relevant for me, and to emphasize that good outcomes are not only possible, but becoming more attainable every day despite seemingly unfavorable odds.

DIAGNOSIS

On May 5, 2006, I asked my physician assistant (PA) to look inside my umbilicus to see whether or not she noticed anything unusual; I had noticed a white "residue" that appeared on dark clothing. There was no itching, bleeding, or tenderness, just a whitish discharge that had appeared intermittently for the previous few weeks. I had no recollection of any existing abnormality in the region, keeping in mind that I had seen my umbilicus at its peak convexity during each of my three pregnancies. Nonetheless, as I mentally reviewed the differential diagnosis — psoriasis, eczema, seborrheic dermatitis — melanoma was not on the list while I was undergoing a routine shave biopsy; my PA chose to do the biopsy for safety's sake despite noting nothing unusual herself.

So we were both surprised when we received the diagnosis by phone on May 10 from the dermatopathologist to whom I routinely send my patients' biopsies: amelanotic malignant melanoma, possibly metastatic. I suspected (or hoped) that it was a false positive produced by using a shave specimen rather than a full excisional biopsy. However, there was no error in the diagnosis, as immunohistochemistry proved positive for S-100, HMB-45, and MART-1.

I immediately contacted Alex Miller, MD, the surgical oncologist I have relied on over the years, and he was able to see me that same afternoon. Within the next two days, I had undergone a complete metastatic workup that included CT scans, PET-CT scans, endoscopy, colonoscopy, capsule endoscopy to visualize the small bowel, and MRI, all negative for metastatic disease. On May 16, I underwent wide excision of the umbilical region along with a sentinel node biopsy in the right groin. Histopathologic examination of the umbilicus confirmed a diagnosis of amelanotic melanoma, 3.3mm in thickness, with ulceration. A waiting period of about 4 days ensued during which we awaited the results of the sentinel node biopsy. With no clinically palpable lymph nodes and a series of negative studies, I was considering my treatment options as a Stage IIB patient, namely a year-long course of interferon alfa-2b, currently the only FDA-approved option for the adjuvant treatment of melanoma for Stage II and IIIB melanoma. Adjuvant therapy with interferon alfa-2b was approved in 1995 based on the results of the Eastern Cooperative Oncology Group (ECOG) 1684 study.³ Interferon has been proven to increase disease-free survival, but whether or not an increase in overall survival is attained remains a matter of debate.

A few days after surgery, the possibility of interferon treatment became a certainty when I was notified that the sentinel node was positive for micrometastases. According to the 2002 AJCC staging criteria, these findings placed me in Stage IIIB, with an average overall 5-year survival of 50 percent (see Table 1), according to statistics compiled by the American Cancer Society from a study of 40,000 patients diagnosed between 1988 and 2001.

I consulted with medical oncologist Ronald Drengler, MD, known in our medical community in San Antonio, TX, for his aggressive medical management of high-risk patients. Although the benefits of complete (therapeutic) lymph node dissection (CLND) in the absence of clinically palpable lymph nodes remains an area of continuous debate and controversy, I opted for this procedure, based on published reports.⁴ On May 30, I underwent radical dissection of the right groin. Histopathologic examination of an additional 28 nodes revealed micrometastatic disease in two of them.

Randomized controlled trials are ongoing to determine the effect of observation alone vs. immediate complete lymph node dissection in patients with positive sentinel lymph nodes. The data collected hopefully will shed further light on the role of initial aggressive surgical management.⁵

STAGE III TREATMENT OPTIONS

Multiple treatment options were presented to me, including observation alone, adjuvant therapy with high-dose interferon-alfa-2b, a (nonclinical) trial of biochemotherapy, or enrolling in a clinical trial. Dr. Drengler encouraged me to seek opinions at multiple institutions before committing to a treatment. During the recovery period from the CLND, I went to see Patrick Hwu, MD, at the M.D Anderson Cancer Institute in Houston, TX, as well as John Kirkwood, MD, at the University of Pittsburgh Hillman Cancer Center in Pittsburgh, PA. Both recommended that I undergo the FDA-approved high-dose intravenous (i.v.) interferon alfa -2b therapy for one month followed by subcutaneous injections for 11 months. Furthermore, Dr. Hwu mentioned Jeffrey Weber MD, PhD, then at the USC Norris Cancer Center in Los Angeles, CA (before being recruited to the H. Lee Moffitt Cancer Center in Tampa, FL), who was expected to begin a clinical trial evaluating the use of an anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody (ipililumab) as adjuvant therapy in high-risk melanoma.

A negative regulator of T-cell response, CTLA-4 can inhibit the body's antitumor response. An antibody to CTLA-4 could enhance the immune response against tumors by blocking the effect of this negative regulatory cytokine. The initial studies using an anti-CTLA-4 antibody were conducted in 14 patients with Stage IV melanoma at the National Cancer Institute (NCI) under lead researcher Steven Rosenberg, MD, PhD, and encouraging results were published in 2003.⁶.

Drs. Miller and Drengler also advised me to touch base with Dr. Weber about the anti-CTLA-4 therapy. I made the decision to begin treatment with high-dose interferon while awaiting notification about if and when the trial with Dr. Weber would begin. It was not a difficult decision. My HLA type excluded me from every other clinical trial available in the U.S. at that time, and, other than interferon, there was really nothing else. A wait and see approach was completely out of the question.

FROM STAGE IIIB TO STAGE IV

I completed one month of high-dose i.v. interferon and two months of subcutaneous interferon, when I received the news that I had been accepted for enrollment in the clinical trial with Dr. Weber. He had already seen objective tumor responses in patients with stage IV disease.⁷

My repeat CT scans and MRI performed in October 2006 as a prerequisite for inclusion in the trial remained negative for metastatic disease. From October 2006 through January 2007, I then commuted every two weeks between San Antonio and Los Angeles for either treatment or laboratory work. The infusion of anti-CTLA-4 was uneventful and well tolerated, especially compared to the serious flu-like side effects I'd experienced with interferon. As part of the study requirements, I underwent repeat CT scans on January 18, 2007, and received the news, again by telephone, that there were multiple pulmonary nodules bilaterally not seen on previous studies.

This was a rude surprise, because I was completely asymptomatic, working normal hours, planning my youngest daughter's bat mitzvah, etc. Drs. Drengler and Weber insisted on a lung biopsy, which I underwent on February 5, two days after the bat mitzvah. Two pulmonary nodules were biopsied by thoracoscopy; one was positive for melanoma, and one was suggestive of melanoma. Dr. Drengler arranged to have a portion of a specimen sent to the Molecular Profiling Institute (445 N. Fifth Street, Third Floor, Phoenix, AZ, 85004; phone 602-358-8900) for extensive immunohistochemistry and DNA microarray studies. These were performed to elucidate possible targets for therapy should additional therapy fail. Technically, I had failed two biologic therapies, a requirement for this specialized testing to be performed.

TREATMENT OPTIONS FOR STAGE IV DISEASE

With confirmed Stage IV disease, I was dropped from the anti-CTLA-4 trial and moved quickly to explore alternative treatment options. My husband, cardiologist Moises Bucay, MD, not only supported my desire to seek an appointment with Steven Rosenberg, MD, PhD, at the National Cancer Institute (NCI), but along with Dr. Drengler, coordinated the logistics to make it happen quickly.

We scheduled a February 27 appointment at NCI for me to be evaluated by Dr. Rosenberg and his team for inclusion in a clinical trial for stage IV melanoma patients. (See bethesdatrials.cancer.gov/clinical-research, which shows some of the ongoing clinical trials currently available.) I had been given the option of high-dose interleukin-2 (IL-2) infusions, an immunotherapy whose use was also pioneered by Dr. Rosenberg.⁸ It was first approved for use in Stage IV renal cell carcinoma patients and then in 1994 for Stage IV melanoma patients. However, I wanted to explore other options, given the relatively low success rate (around 6 percent) of IL-2 in achieving a complete response in stage IV patients. After another extensive evaluation at NCI, Dr. Rosenberg's team agreed to accept me in a clinical trial using a non-myeloablative lymphocyte-depleting regimen of chemotherapy followed by infusion of anti-tumor autologous lymphocytes (or some variation thereof), provided that I first undergo treatment with IL-2 and fail it. In this clinical trial, chemotherapeutic agents would be given to suppress the bone marrrow without completely ablating it. This contrasts with traditional methods incorporating totall-body irradiation to ablate all bone marrow in preparation for a marrow transplant. However, through good fortune, I never had to proceed to this therapy.

As agreed, I undertook the IL-2 therapy first, opting to receive it in San Antonio rather than at NIH because it is my home and because the nurses at the Methodist Hospital in San Antonio are experienced in managing IL-2 patients.

Interleukin-2 can be quite toxic and is usually administered over a 5 to 6 day period in the setting of a medical intensive care unit. It is given in one-week cycles; two cycles spaced one week apart constitutes a course of treatment. One month after the first course is completed, radiologic imaging studies are performed to assess the response of the tumor. Based on the outcome, the decision can be made whether or not to continue with another course of IL-2. I received my first course of IL-2 in March and was fortunate to see a 60 percent reduction in tumor volume by April. This was considered a partial response rate, and is seen in about 14 percent of patients who receive IL-2. In June, I tolerated another course of IL-2 and played the waiting game until August 1, 2007, when I would again undergo CT scans. There was not a day when I did not pray for membership in the "6 percent club," the group of complete responders. To date, a complete response has been equated with a durable remission. The CT scan was available for interpretation almost immediately after it was performed. I was led to the radiology reading room, where the radiologist read the study and showed me that the pulmonary nodules had completely disappeared - consistent with a complete response.

I have had repeat scans in October 2007, January 2008, April 2008 and August 2008; all have been negative for disease. Never one to look at statistics, I nonetheless was curious about what defines a durable remission, so I have allowed myself to look at survival rates for Stage IV melanoma patients treated with IL-2. For those achieving a partial response, median survival is 5 months; for those with a complete response, median survival is 10 years and counting. I hope to keep on counting.

DISCUSSION

I maintain that even though the appearance of the nodules in my lungs reclassified me as stage IV, it reflected an improved immune system that could now target the tumor burden which had been invisible in prior studies. Whether this belief is the result of denial or the consequence of extensive reading on immunotherapy, I have never regarded the appearance of the pulmonary nodules as disease progression.

I will try to explain. One of the side effects I had experienced from the anti-CTLA-4 infusion was an intermittent, generalized, erythematous, pruritic, urticarial eruption, which Dr. Weber called the "good rash," appearing in patients who had experienced a positive response to treatment. Immune-related adverse events also associated with a positive response to anti-CTLA-4 therapy include autoimmune colitis, hepatitis, nephritis, and hypophysitis, findings reported by Dr. Weber.⁹ Although I did not experience any of these autoimmune breakthrough phenomena, a differential white blood cell count performed every two weeks was consistently remarkable for a highly elevated proportion of eosinophils (comprising almost 50 percent of all white blood cells in the differential count, according to automated equipment that was highly sensitive to but not specific for eosinophils). In reality, these proved to be activated T-lymphocytes and not eosinophils at all; what was reported as eosinophilia was really the immune system's good response to the IL-2 - greatly increased production of activated T-lymphocytes. I concluded that this finding and the rash signified a vastly improved immune system. Unfortunately, adherence to the study criteria still dictated that I be excluded from the clinical trial.

Published reports now show that response to anti-CTLA-4 therapy can involve some unique characteristics which may account for the extended response time ("lag time") seen in patients. In fact, melanoma investigators presented data in 2008 at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting that support revised criteria to preclude patients with disease progression from being prematurely dropped from clinical trials involving agents that may result in a delayed immune response. In other words, patients would be allowed more time to mount an immune response.^{10, 11}

SUMMARY

Currently, other than routine imaging studies, physical examination, and some laboratory blood work such as following LDH levels, maintenance therapy for Stage IV melanoma patients does not exist. The standard treatment with IL-2 consists of four cycles or two courses. There is nothing to suggest that additional courses of IL-2 will confer an additional survival advantage. In fact, I had undergone a third course of IL-2 in September, 2007, during which I experienced severe side effects including capillary leak syndrome with prolonged edema, as well as an intensely pruritic episode of exfoliative erythroderma, and severe agitation, none of which I had experienced during the previous cycles.

It has become increasingly clear that in addition to aggressive surgical management, targeted immunotherapy will play an ever more important role in the management of high-risk and metastatic melanoma. Taking into account the new and compelling data that support the use of immunotherapy in treating advanced disease, it is now our responsibility to counsel patients regarding these new and promising treatment options. Although the adjuvant use of interferon alfa-2b for Stage II/III disease may not have lived up to expectations regarding increased survival, it has no doubt opened the gate to research for more effective treatments or advanced disease. I routinely encourage patients to participate in clinical trials when appropriate. A recent article published in the July 2008 issue of Practical Dermatology offers guidelines for management of intermediate risk melanoma;¹² it has been useful to me because the published data is presented clearly in a way that is readily applicable to daily clinical practice.

When I was first diagnosed with melanoma, I received numerous copies of Lance Armstrong's book Forget the Bike, his account of his experience and "defeat" of metastatic testicular cancer. I never managed to finish the book, perhaps because what I needed to know is stated early on: "People die…... Why we should go on, you might ask? Why don't we all just stop and lie down where we are? But there is another truth, too. People live. It's an equal and opposing truth."¹³ As physicians, we have the unique responsibility to help others gather all the facts they need to develop a personal strategy to achieve the best possible outcome in the fight against melanoma.

REFERENCES

1. Bucay VW. Ironic diagnosis changes life forever. San Antonio Medicine 2006; 59(10):32-33.
2. Bucay VW. A Dermatologist's Battle with Melanoma. The Skin Cancer Foundation Journal 2008; XXVI:52-56.
3. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14:7-17.
4. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355(13):1307-17.
5. Complete lymph node dissection or observation in treating patients with localized melanoma and sentinel node metastasis in patients who have undergone sentinel lymphadenectomy. Available from ClinicalTrials.gov Identifier: NCT00389571.
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10. Hody FS. The Global Ipilimumab Melanoma Study Group. Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. J Clin Oncol 2008; 26:134s.
11. Hamid O, Urba WJ, Yellin M, et al. Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma. J Clin Oncol 2007; 25:478s.
12. Yancovitz M, Polsky D. Answering the tough questions in melanoma care: a comprehensive guide to management of high risk intermediate melanoma. Practical Dermatology 2008; 5(7):30-5.
13. Armstrong L, Jenkins S. It's Not About the Bike: My Journey Back to Life. Berkley Books, New York, 2000; 3-4.