Melanoma is a rare but deadly form of skin cancer. The incidence of melanoma is on the rise, and is in fact increasing faster than any other cancer in the United States. In 2008, there will be an estimated 62,480 new cases of invasive melanoma diagnosed in the United States, accounting for 5% of all new cancer diagnoses in men and 4% of new cancer diagnoses in women. The number of new cases of melanoma has steadily increased for 30 years. These numbers do not include all of the cases of in situ melanoma, which are the melanomas that are confined within the outermost portion of the skin. This early form of melanoma accounts for an additional 50,000 cases per year.
Most melanomas develop in the skin, which includes nail beds, soles of the hands/feet, and scalp, but melanoma can also occur in the eye, or on mucosal surfaces such as the anal canal, rectum, and vagina. Because most cutaneous melanomas are visible, it is a cancer that is extremely amenable to early detection.
When diagnosed early, where melanoma is confined within the skin and is not associated with ulceration, survival rates are considered quite good. For Stage 0-IIb, the five-year survival rate varies from 67% to 100%. When ulceration is present in a thicker lesion (Stage IIc), the 5-year survival rate drops to 45%. When regional lymph nodes are involved (Stage III), the 5-year survival rate ranges from 24% to 69%, depending on the presence of ulceration in the primary lesion and the number and size of involved lymph nodes. When melanoma has spread outside of the regional lymph node basin (Stage IV) to other sub-cutaneous sites, distant lymph nodes, or other organs, most commonly the liver, lung, or brain, the 5-year survival rate drops to between 5% and 17%. The median survival for patients with Stage IV disease is only 6-9 months. Despite valiant attempts to identify new treatments and thus improve survival, this number has unfortunately remained low for over two decades (Balch et al, 2001).
The AJCC staging system for melanoma was revised in 2002 (Balch et al, 2001). Stage IV disease is further divided into three sub-groups: Group A includes individuals with sub-cutaneous and lymph node confined disease; Group B includes individuals with lung-confined disease; Group C is all patients with an elevated LDH level or other sites of metastatic disease. Survival differences in these groups were recently validated by Neuman et al. (2008).
Melanoma is considered an immunogenic disease. When a melanoma lesion is initially biopsied and/or removed from the skin, the presence of tumor infiltrating lymphocytes (Tils) is assessed. Tils represent infiltration of the cutaneous melanoma lesion by cells of the immune system. At the time of the original diagnosis, there can also be signs of regression, meaning that the original melanoma lesion has gotten smaller over time, indicating destruction of the melanoma tumor cells by cells from the patient’s immune system. Additionally, the incidence of melanoma is much greater in immunosuppressed individuals. These factors have led researchers to postulate that increasing the activity of the immune system will be a viable mechanism for treating melanoma. In fact, two of the three FDA-approved treatments for melanoma are immune stimulants.
Therefore, it is important to be aware of the ways that researchers believe immune function can be enhanced and the potential treatments on the horizon for melanoma. One target of immunotherapy is the Cytotoxic T Lymphocyte-Associated Antigen (CTLA4) receptor, which is found on the surface of T-cells. T-cells play an important role in immune surveillance, detecting non-self cells present within an individual. CTLA4 is an important down-regulator of T-cell proliferation. By blocking this receptor, T-cell division and replication can proceed unimpeded. Two agents, ipilimumab (MDX-010; Medarex, Princeton, New Jersey, USA, and Bristol-Myers Squibb, New York, New York, USA) and tremelimumab (CP-675,206; formerly known as ticilimumab; Pfizer, New York, New York, USA), are presently in advanced stages of testing in malignant melanoma. They have demonstrated efficacy in improving outcomes in patients with metastatic melanoma.
Systemic therapy remains the mainstay of treatment for Stage IV disease despite low efficacy rates. The NCCN guidelines provide recommendations for management of metastatic melanoma. These guidelines are based on current evidence and are reviewed regularly by a panel of experts. When a single site of metastatic disease is identified, resection of that site is recommended if feasible and if the patient is physically able to undergo surgery (Young et al, 2006). Following resection that renders the patient free of identifiable disease, he/she could undergo no further treatment and active observation for early detection of a recurrence, enrollment onto a clinical trial, or Interferon alpha 2-b which is approved for use in patients with Stage II-III melanoma at high risk for recurrence. If the patient is not a candidate for resection of all disease then observation or systemic therapy should be considered. Current recommendations for systemic therapy include referral to a clinical trial, which is preferred, dacarbazine or its oral form, temozolomide, high dose Interleukin-2, or other chemotherapy not currently FDA approved for the treatment of melanoma, which includes dacarbazine or temozolamide in combination with other agents, paclitaxel alone or in combination with cisplatin or carboplatin. In patients diagnosed with brain metastases, therapy to treat the brain lesion(s) should be instituted first followed by systemic therapy of the melanoma. If possible, providers are encouraged to refer patients to a clinical trial due to the low efficacy rates of currently available treatments.
Interferon alpha 2-b has been studied in several clinical trials. It was FDA-approved for the adjuvant treatment of high-risk melanoma, considered to be Stage IIb-IV resected disease. The pivotal trial leading to its approval was ECOG 1684, in which patients were randomized to receive high-dose interferon alpha 2-b for one year versus observation. Overall relapse-free survival was improved in the treatment arm from 0.98 years to 1.72 years, and an overall survival benefit of 9% was observed ( Kirkwood, 1996). In subsequent trials with high dose interferon, this survival benefit has not been observed. Interferon therapy is associated with toxicities which include flu-like symptoms, fever, chills, myalgias, nausea, vomiting, diarrhea, fatigue, depression, anorexia, elevation in LFTs, and myelosuppression. Ongoing clinical trials are underway to evaluate different dosing schedules and use in combination with other agents.
Interleukin-2 (IL-2) is another immune-modulating agent. IL-2 is FDA-approved for the treatment of Stage IV melanoma. Response rates range from 16-20%, with durable responses occurring in approximately 6% of patients treated (Rosenberg et al, 1998). These durable responses have been observed to last for up to 10 years. IL-2 must be administered by a team of highly qualified and experienced individuals. It is typically administered in an intensive care setting due to the toxicities. These include capillary leak syndrome, hypotension, renal dysfunction, flu-like symptoms, and rash, among others. Patients must be carefully selected to undergo this therapy due to the significant toxicity with which it is associated.
Dacarbazine is an intravenous chemotherapy FDA-approved for the treatment of metastatic melanoma. It has been studied in numerous clinical trials with response rates ranging from 5-28%, with a median response rate of 15%. Temozolomide is an oral agent, which demonstrates similar response rates with no significant difference noted in progression free survival or overall survival (Quirt et al, 2007). Temozolomide offers patients a convenient oral treatment regimen.
Other chemotherapy agents have also been shown to have an effect on melanoma. Nitrosureas have a response rate ranging from 10-20%; cisplatin 14-29%; paclitaxel 14%; and vincristine 12% (Wolchok, 2007).
Biochemotherapy, which is the combination of chemotherapeutic agents with immune modulating agents have been studied extensively in metastatic melanoma. While this combination has been shown to improve response rates, no benefit in overall survival has been observed. Side effects of biochemotherapy include severe and prolonged myelosuppression, flu-like syndrome, capillary leak syndrome, renal and hepatic dysfunction, and severe nausea/vomiting (Atkins, 2003).
Combination regimens, the most promising of which have been CVD (Cisplatin, Vinblastine, Dacarbazine) and Dartmouth (Carboplatin, Dacarbazine, Carmustine, and Tamoxifen) have not been demonstrated to be superior to single agent dacarbazine in Phase III clinical trials (Chapman et al, 1999).
Adoptive immunotherapy is also being studied extensively in patients with metastatic melanoma. In carefully selected patients, several small clinical trials have reported response rates as high as 50% (Dudley et al, 2002 and 2005; Heemskerk et al, 2008). Clinical trials are ongoing to improve the technique and examine response in larger samples of patients.
Throughout the oncology world, there is a great deal of interest in developing targeted therapy, with many currently under investigation. While some of the selected targets for therapy are proteins or cytokines, which have been identified as being altered in a particular disease, another target is identifying mechanisms to alter the function of the immune system. Several key pathways known to be altered in melanoma that are being examined include the mitogen-activated protein kinase ( MAPK) which includes raf, ras, PI3K, MEK; the retinoblastoma pathway (Rb); p53; and c-kit to mention a few. Because of the immunogenic nature of melanoma, there is particular interest in approaching therapy of this disease by targeting the immune system. Many targets exist, including CTLA4.
To understand the immune system targets of several new therapies for melanoma, it is essential for oncology nurses to first have a general understanding of the immune system. We will briefly review the components of the immune system, which are important to understanding the function of CTLA4 in modulating the immune system and its response to melanoma.
The immune system is divided into two main parts: the innate immune system (what we are born with) and the adaptive immune system (what we develop as a result of exposures). The immune system has several very unique and complex roles in defending our bodies, including the recognition of self versus non-self, active versus passive, general versus specific, among others. Cancer cells are self cells that have been altered in a slight but significant manner to allow them to undergo division and metastasis without detection by the host immune system. The rationale behind targeting the immune system is to help the cells of the immune system recognize the cancerous cells as being foreign and target them for destruction.
Dendritic cells are a type of B-cell; they are antigen presenting cells (APCs), which are responsible for activating T-cells and directing the adaptive immune system. After processing antigenic peptides intracellularly, dendritic cells then express those peptides, or proteins, on their cell surface for presentation to the T-cells. Helper T-cells are able to recognize these antigens as foreign and produce cytokines to activate a B-cell and/or T-cell response to that antigen. They also have the ability to differentiate into cytotoxic T-cells. Cytotoxic T-cells are activated by a specific antigen; amplify their replication, and specifically attack cells, which express the given antigen. B-cells can also recognize antigens that are presented to them by APC’s, such as dendritic cells. Lastly, Natural Killer Cells are an immune cell that is able to recognize non-self cells and to attack and destroy those cells.
Maturation of dendritic cells is essential for T-cell activation and therefore an effective immune response. Following recognition of a foreign antigen on the tumor cell surface, dendritic cells infiltrate into the tumor, process various proteins or antigens intracellularly, and then undergo maturation. Mature dendritic cells are then able to express those antigens on their cell surface via Major Histocompatibility Complex (MHC), and to release co-stimulatory cytokines. The dendritic cell then presents that foreign antigen to the T-cell receptor through the MHC. This binding sends a stimulatory signal to the T-cell for replication; secondary signals are sent to the T-cell through binding of the B7 on the dendritic cell to the CD28 receptor on the T-cell. This binding leads to T-cell replication. These activated t-cells can specifically target and destroy cells expressing the antigen.
There are a variety of factors which can inhibit the immune system’s ability to optimally recognize and destroy tumor cells. One mechanism is tumor-mediated inhibition of dendritic cell maturation. Tumors are also able to block the co-stimulatory signaling between B7 and CD28 which is essential for T-cell maturation. Without this second signal, the cytotoxic T-cell will proliferate but will not produce cytokines such as IL-2, which is essential for full activation. Tumors can also reduce expression of MHC expression, thereby reducing recognition by the cytotoxic T-cells.
Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA4) is a protein involved in T-cell expansion or replication and activation in response to an immune event. Following T-cell stimulation, T-cell proliferation is upregulated. Following successful response, CLTA4 is upregulated, which then sends an inhibitory signal to down-regulate or decrease T-cell proliferation and IL-2 production.
Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.
Two monoclonal antibodies targeting CTLA4 are currently in advanced stages of investigation for use in melanoma, ipilimumab (MDX-010; Medarex, Princeton, New Jersey, USA, and Bristol-Myers Squibb, New York, New York, USA) and tremelimumab (CP-675,206; formerly known as ticilimumab; Pfizer, New York, New York, USA). The efficacy rates and toxicity profiles of both drugs are quite similar.
Ipilimumab is a fully humanized IgG1 monoclonal antibody to CTLA4. It has been tested in both the adjuvant and the metastatic setting. Several phase I/II trials were conducted combining ipilimumab with vaccine therapies and other immune agents (Hodi, 2003; Phan, 2003; Attia, 2005; Maker 2005; Maker 2006). In a phase I trial combining ipilimumab with vaccine therapy in previously treated patients with metastatic disease, Attia et al (2005) report a 3.6% complete response rate and an 8.9% partial response rate with the 2 patients who achieved complete responses maintaining them at 30 and 31 months and the partial responders maintaining for 4-34 months. A Phase I trial conducted by Weber et al (2006) in the adjuvant setting administered ipilimumab at a dose of 3 mg/kg every 8 weeks for 12 months in combination with a vaccine, and reported that 19 of the 25 patients treated were alive at 12 months.
Ipilimumab has been studied in the first line setting in patients with metastatic disease at a dose of 3 mg/kg every 4 weeks for 4 total doses (Fischkoff et al, 2005). This study reported 5.4% of patients with a partial response and 10.8% of patients with stable disease. A phase II trial of ipilimumab administered in combination with dacarbazine (Fischkoff et al, 2005) demonstrated complete responses in 5.7% of patients durable at 17+ and 20+ months, partial responses in 11.4% of patients at 3 months up to 21+ months, and stable disease in 11.4% of patients lasting for 4-8 months. Another Phase II trial combined ipilimumab with IL-2 (Maker et al, 2005); this study demonstrates a complete response in 8.3% of patients with a duration of 13+ to 16+ months and a partial response in 13.9% of patients with a duration of 7 to 19+ months. This encouraging data led to several phase III trials.
In a Phase III trial, ipilimumab was administered alone or in combination with dacarbazine in the first line metastatic setting (Weber, 2007), 3 mg/kg every 3 weeks followed by 12 week rest and then every 12 week maintenance. Stable disease was seen in 39% of patients with the duration of response ranging between 99-379 days in responders (Weber, 2008).
A phase II single arm study of ipilimumab administered to patients with metastatic melanoma who had progressive disease following at least one line of prior therapy demonstrated an overall response rate of 5.8% and stable disease in 27.1% when evaluated by the independent review board; progression free survival at the 6-month follow up is 49.1% (O’Day, 2008).
Tremelimumab is a fully humanized IgG2 monoclonal antibody to CTLA4. This agent has also been studied in a multitude of Phase I-III clinical trials alone and in combination with other agents. In addition to clinical trials in melanoma, ongoing studies are examining the effect of this agent on other cancer types such as prostate cancer.
In the initial dose escalation study, 29 of the 39 study participants had metastatic melanoma. In this study, a single dose of tremelimumab was found to induce long-term remissions (36+ months) in some patients, complete responses in 2 patients and stable disease in 4 others (Ribas et al, 2005). Another phase I trial of tremelimumab with a redosing arm reported overall response rates of 8% in patients dosed at 10 mg/kg monthly and 7% in patients dosed at 15 mg/kg quarterly (Ribas et al, 2005). Another phase I trial was completed in patients with metastatic melanoma, where the primary end point was to identify changes in circulating cellular levels of tumor antigen-specific T-cells. While that level was not altered as a result of tremelimumab administration, 1/15 patient had a complete response, 2/15 had a partial response, and 3/15 had stable disease at 3+, 8+, and 11+ months (Ribas, 2006). An update of this trial demonstrated durable responses, of greater than 2 years, in 3 patients (Comin-Anduix, 2008).
A pilot study combining tremelimumab with autologous vaccination was also initiated. A total of 16 patients with metastatic disease were enrolled. Another trial combining tremelimumab with PF-3512676 is currently open and enrolling patients (Ribas et al, 2007).
A phase II study of tremelimumab, administered to patients with metastatic disease who had progression following at least one line of prior therapy, demonstrated an overall response rate of 8.3% and a clinical benefit rate (which includes stable disease) of 22.8%, with a mean overall survival of 10+ months (Kirkwood et al, 2008).
A Phase II study of tremelimumab administered in combination with IFN in patients with metastatic melanoma who had progressed on prior therapy demonstrates and overall response rate of 19% and plans to complete enrollment with additional patients (Tarhini, 2008).
Moving forward with tremelimumab, a dose of 15 mg/kg every 3 months was selected for use in subsequent trials due to the equivalent efficacy when compared with 10 mg/kg monthly and superiority in toxicity profile (Gomez-Navarro, 2006). A Phase III open-label, randomized, comparative study of tremelimumab and chemotherapy (temozolomide or dacarbazine) administered in the first line setting in patients with metastatic disease was recently halted early due to the lack of impact on overall survival between the two treatment arms. At the time the study closed, the median overall survival in the tremelimumab arm was 11.8 months and in the chemotherapy arm was 10.7 with a hazard ratio of 1.04 favoring the chemotherapy arm; however, additional subgroup analyses and continued follow up is planned (Ribas et al, 2008). A phase II clinical trial evaluating tremelimumab in second line therapy revealed an overall response rate of 8.3%, stable disease in 22.8%, and a duration of response of 9.7-13.5 months (Kirkwood et al, 2008).
In patients treated with these agents, there is a great deal of discussion about when disease status should be assessed. In most melanoma clinical trials, tumor evaluations are performed every 6-8 weeks due to the limited life expectancy of patients and the usual time for response from antineoplastic agents. However, many patients treated with anti-CTLA4 agents, who appear to have stable disease or even progressive disease at the initial analysis, go on to have tumor regression on subsequent evaluations at much later time periods than would normally be expected (Wolchok, 2008). Patients from these trials are described as having regression in the target lesions, or those identified at the start of the study to be used for response, but development of new lesions when disease is first assessed, only to have improvement by subsequent evaluations (5-6 months following initial treatment) and prolonged duration of response (Hamid et al, 2007). The key point to take away from this discussion is that the current approach to disease assessment for progression may need to be reevaluated in patients receiving this type of therapy. This will present an educational opportunity for oncology nurses familiar with the trial data.
Toxicities from this therapy are considered Immune Breakthrough Events (IBEs) or Immune-Related Adverse Events (IRAE) and include diarrhea, colitis, autoimmune hepatitis, maculopapular rash, pruritis, vitiligo, uveitis, and hypophysitis. These toxicities are related to activation of the immune response.
For the gastrointestinal events, patients generally present with diarrhea, which can quickly progress to colitis if untreated. In the early trials with these agents, there were reported cases of GI perforation and death. However, a treatment algorithm has been developed (Weber, 2007). If another cause has not been identified, grade 1-2 diarrhea should be treated symptomatically with loperamide or diphenoxylate and atropine. Therapy should be held until symptoms resolve to a grade 1. If symptoms of colitis are present with grade 2 diarrhea, budesonide or other moderate dose steroid can be added; for grade 3-4 diarrhea, high dose steroids should be initiated. For any patient on high dose steroids without a response in 5 days, an anti-TNF agent such as infliximab can be considered. It is important to note that use of high dose steroids for diarrhea/colitis or the other IBEs has not been associated with any abrogation of the anti-tumor response. Oncology nurses should ask patients to monitor the number of bowel movements daily. Patients should report any changes noted early. Patients with more frequent bowel movements should also be assessed for signs or symptoms of dehydration due to fluid loss. Intravenous fluids can be used to supplement oral intake if needed.
Autoimmune hepatic toxicity has also been seen. Patients typically remain asymptomatic but can have dramatic increases in the liver function tests and bilirubin levels. A treatment algorithm is available for guidance (Weber, 2007). Baseline LFTs and bilirubin levels should be assessed on all patients and monitored throughout the course of therapy. In a patient with normal values at baseline who presents with level ≥ grade 2, they should initially undergo intensified monitoring consisting of work up for autoimmunity and frequent LFT and bilirubin levels. Oral or intravenous steroids should be initiated in patients with prolonged elevation in levels. Patients with progressive elevation in levels should be admitted to the hospital for daily lab checks, started on IV steroids, progressing to mycophenolate mofetil, tacrolimus, and finally infliximab, if not reversing.
Hypophysitis is an inflammation of the pituitary glad. Patients experiencing hypophysitis generally present with endocrine symptoms, including fatigue, headache, diplopia, personality changes and loss of libido. Diagnosis is made with the use of laboratory tests for effective functioning of the pituitary gland, specifically thyroid function tests and blood levels of cortisol, testosterone and ACTH. Replacement therapy is effective in managing symptoms which were reversible in some cases. Oncology nurses need to be aware that hypophysitis is a common toxicity of anti-CTLA4 therapy. In patients presenting with symptoms of hypophysitis, laboratory studies should be evaluated and replacement therapy started if appropriate. Patients requiring replacement therapy will need education regarding the importance of this therapy in light of its potential duration.
Skin toxicities generally manifest as a maculopapular rash or pruritis. When biopsied, these areas have shown t-cell infiltrates. The rash can be effectively managed with topical steroids, topical antihistamines, and a short course of oral steroids, if needed. Oncology nurses can educate patients receiving anti-CTLA4 agents about the potential for skin toxicity as well as good skin hygiene as a mechanism of managing the side effects associated with rash and pruritis.
Uveitis is also seen when receiving treatment with these agents. Patients report itchy red eyes. Ophthalmologic evaluation reveals uveitis, which generally responds to topical steroidal drops.
Melanoma and the management of metastatic disease continue to be challenging in the United States and throughout the world. The treatment options available to patients are limited in their efficacy and often times are associated with numerous toxicities. Enrollment onto clinical trials is encouraged for patients with all types of malignancies, but especially so for melanoma. Targeted therapies, specific to melanoma cells or to the immune system as a whole, are sure to play a significant role in this evolution. As the basic science of melanoma continues to evolve, we will hopefully be better able to identify those patients most likely to benefit from particular therapies.
The anti-CTLA4 therapies highlight two important aspects of the changing landscape of oncologic therapies. First, many of the targeted therapies that have been developed have much different side effect profiles than traditional antineoplastic agents, making it imperative that oncology nurses are knowledgeable of the toxicities of each agent they are administering and their management. Second, the anti-CTLA antibodies present a challenge to us in our way of thinking about monitoring disease status and progression in patients with cancer. With immune targeted agents, we can no longer assume that the lack of a definitive response at first evaluation means that a person’s disease is resistant to that therapy. Delayed responses have been seen in many patients and prolonged, durable responses have been seen in those same patients. Throughout the course of melanoma treatment, nurses must remain continually aware of the devastatingly poor prognosis associated with metastatic disease and initiate supportive care measures quickly and seamlessly when appropriate.
As newer treatments for the melanoma continue to be tested and developed, oncology nurses must be aware of the characteristics of the disease that make it both difficult and unique to treat. They must be aware of the treatments that their patients are receiving and the potential side effects to effectively and skillfully manage the toxicities and facilitate early intervention to prevent progression to life threatening complications.
Grading of Common Side Effects of Anti-CTLA4 Antibodies
|Grade 1||Grade 2||Grade 3||Grade 4||
|Rash||Rash Macular or papular eruption or erythema without associated symptoms||Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of body surface area (BSA)||Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of body surface area (BSA)||Severe, generalized erythroderma or macular, papular or vesicular eruption; desquamation covering ≥ 50% BSA Generalized exfoliative, ulcerative, or bullous dermatitis||Death|
|Diarrhea||Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline||Increase of 4 – 6 stools per day over baseline; IV fluids indicated <24hrs; moderate increase in ostomy output compared to baseline; not interfering with ADL collapse)||Increase of ≥ 7 stools per day over baseline; incontinence; IV fluids ≥ 24 hrs; hospitalization; severe increase in ostomy output compared to baseline; interfering with ADL||Life-threatening consequences (e.g., hemodynamic||Death|
|Colitis||Asymptomatic, pathologic or radiographic findings only||Abdominal pain; mucus or blood in stool||Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs||Life-threatening consequences (e.g., perforation, bleeding, ischemia, necrosis, toxic megacolon)||Death|
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