Update #10 – Guest Blogger Dr. Schwam breaks big news about starting a new treatment

Hey everyone,

As the title suggests, my dad wrote a guest blog post (thanks dad!) about my appointment at MGH today. Before I let him take it away I just wanted to mention that the past few days have been really rough for me. I have been feeling really sad (for reasons I both can and cannot explain),  as well as excessively tired and unmotivated. These are all common side effects of interferon, which I was hoping to avoid, but alas they got to me, seemingly out of nowhere. As a person who prides herself on not taking life too seriously and finding the humor in every situation, this has been very upsetting.

The good news is we are going to stop treatment with interferon, not because of the side effects I just mentioned (which could be a reason to stop treatment later on had I stayed in it) but because my oncologist went to a conference that unveiled some new, very promising results for another standard treatment drug (approved by the FDA in 2015 to treat patients with stage 3 disease) called ipilimumab or “Ipi” (yervoy). You can read the press release here. While this is good news overall, I am very scared about potential autoimmune side effects of Ipi (colitis, hepatitis, etc) and hate the idea of possibly needing to go on systemic steroids to treat these side effects. However, as you will read later, I know that I have to try this drug if I want the best chance at surviving long-term and relapse-free. So unless any new breakthrough data appears in the next couple of weeks I will likely be starting Ipi next month. 

-Elana

Hi everyone,

It never occurred to me that someday I might be blogging, but Elana is feeling both the pressure of school and the effects of interferon, and she asked me to do this update, so here goes.  I’m Eric Schwam, the senior member of the Schwam family, and I’m incredibly proud to be Elana’s dad.  As Elana mentioned earlier in her blog, I’m also a medical doctor, an emergency physician, to be exact.  That makes me the appropriate person in the family to do this update, considering how technical it is.  I should say that the field of melanoma treatment is pretty far from what I do in the ER.  To be at all educated, I had to do a lot of reading on the subject.  I’m certainly not an expert, but maybe I should be considered a highly educated layperson.  I’m going to try to explain all this to the rest of you.

If for whatever reason, you want to become even more informed on this topic, I have included the section on “Adjuvant immunotherapy for melanoma” at the bottom of this blog.  Not an easy or enjoyable read, however.  If you want to read an excellent book on the history of cancer treatment (not much specifically about melanoma), I can recommend “The Emperor of all Maladies” by Siddhartha Mukherjee (he won the Pulitzer prize for it) or the Ken Burns PBS documentary on the book.

So today I accompanied Elana to her appointment at MGH.  We thought that as scheduled, she would be starting the subcutaneous dosing of interferon, and in fact we spent the first hour with Riley discussing that topic, until Dr. Lawrence popped into the room with news from an oncology conference 4 days ago.  (Somehow the news media skipped this important breaking news in favor of the latest exposé on Donald Trump.)  Based on this new information, he suggested that we stop interferon and switch to Yervoy (ipilimumab, or “Ipi”). He said it is what he would do, if he were in her shoes.

Ipi is another immune therapy for melanoma.  It is not chemotherapy, in the usual sense of the word.  Like Keytruda (pembrolizumab), it blocks the tumor’s resistance to destruction by the patient’s immune system, but it does so by a different molecular mechanism. It is called a CTL-4 inhibitor.  Ketruda is a PD-1 inhibitor.  They are both sometimes called checkpoint inhibitors.  Ipi was always an option for Elana.  Some cancer centers use it instead of interferon, and some (like MGH) shy away  from it.  The reason for this disparity is that there has been only one clinical trial completed.  It demonstrated improved short term survival but at a pretty high cost in terms of side effects.  If you go revving up the immune system to attack a tumor, the immune system can attack normal tissues as well; these are called “autoimmune” reactions.  In this trial, 90% of the patient’s experienced some side effect, about 1/3 of these were considered serious, and 5% were life threatening.  So that is the reason for the differing opinions on its use for stage III disease.  Do you count on the theoretical promise of the drug to improve survival, or do you fear serious the side effects?  Dr. Lawrence feels that the new data have won him over to Ipi.  These new data are Ipi’s longer term survival  rates.  Patient’s in the placebo arm had a 5 year survival rate of 54%, but patient’s treated with Ipi had a 65%  5 year survival rate, even those who couldn’t tolerate taking  the drug for very long.

So what’s wrong with interferon?  It is still an option.  The caveat with interferon is that the data that support it are mixed.  That is the problem with a lot of human clinical trials.  You can’t treat patients like lab rats.  You can’t force them into rigid treatment protocols, regardless of the consequences, all in the name of science.  As a result, the outcome data from these trials can be messy and open to multiple interpretations.   Interferon became the standard of care in the USA because of its safety and modest effectiveness.

No one knows what is the right thing to do now, least of all me.   So much of this is like rolling dice, with potentially huge consequences.  Elana said to me that she does not want to start Ipi, but she knows she has to.  It is her decision.

Ipi Treatment timeline:

They will wait a few weeks to let the interferon wash out of her system and then Ipi  will be given via IV infusion for 90 minutes every 3 weeks for 4 doses, followed by every 3 months for 3 years.

For all of you out there, I want you to know that when she starts Ipi, my beautiful, sweet and strong daughter will need your continued support more than ever.

Eric

Stop reading here unless you want a a very dense scientific explanation about adjuvant therapy for melanoma written for physicians and researchers.

Adjuvant immunotherapy for melanoma from UpToDate

Author: Jeffrey A Sosman, MD

Section Editor

Michael B Atkins, MD

Deputy Editor

Michael E Ross, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2016. | This topic last updated: Sep 08, 2016.

INTRODUCTION — Surgical excision is the treatment of choice for early cutaneous melanoma and is curative in most cases. However, some patients will subsequently relapse with disseminated disease. High-risk features in the primary tumor and regional lymph node metastasis define patient subsets that are at increased risk for recurrent disease.

Adjuvant immunotherapy with interferon alfa (IFNa) prolongs disease-free and overall survival in selected patients at increased risk for disease dissemination. High-dose IFNa continued for one year has been the standard of care for patients with resected node-positive melanoma (stage III) and should be considered for patients with negative nodes and an increased risk of recurrence (stage IIB and IIC (table 1A-B)). More recently, the checkpoint inhibitor ipilimumab has been shown to significantly decrease the rate of recurrence, and this may offer an alternative to interferon.

A number of other approaches have been studied to reduce the risk of recurrence in patients thought to be at high risk for relapse. These include adjuvant chemotherapy with agents such as dacarbazine [1-3]; nonspecific immune adjuvants such as Bacillus Calmette-Guerin (BCG) vaccine [1,4,5], Corynebacterium parvum [5-7], or levamisole [8-10]; and hormonal agents such as megestrol acetate. However, none of these agents, used either alone or in various combinations, proved beneficial when compared with either observation or placebo in randomized clinical trials.

The use of adjuvant immunotherapy with IFNa and ipilimumab will be reviewed here, along with a brief discussion of other experimental approaches to adjuvant therapy.

MECHANISM OF ACTION — The rationale for the use of adjuvant interferon alfa (IFNa) as therapy following disease resection is based upon early clinical studies that demonstrated antitumor activity in patients with metastatic melanoma. Both animal model and histologic evidence suggest that the effects of IFNa are mediated through effects on host cells rather than through a direct effect on tumor cells [11,12].

In a murine melanoma model, intact signaling pathways are necessary in the host immune system for IFNa to induce tumor regression; if these are not present, tumor growth is not inhibited by IFNa [11]. By contrast, an intact signaling pathway within the tumor was not required for tumor regression in response to IFNa.

Additional evidence comes from a clinical research study in which single-agent high-dose IFNa was administered as a neoadjuvant for four weeks to patients with palpable regional lymphadenopathy; this was followed by a complete lymphadenectomy [12]. Tumor responses were documented in 11 of 20 patients (55 percent). Tumor samples from patients who responded to IFNa had increased numbers of CD11c- and CD3-positive cells within their tumors and a decrease in the number of CD83-positive cells compared with those who did not respond to IFNa.

RISK STRATIFICATION AND ADJUVANT THERAPY — The decision of whether or not to recommend adjuvant therapy depends heavily upon the risk of disease recurrence based upon the stage at diagnosis (algorithm 1). Consensus recommendations have been published by the Society for Immunotherapy of Cancer (SITC) based upon a systematic review of the literature [13]. These guidelines use risk stratification as the basis for decision recommendations.

Staging and prognosis — The extent and characteristics of the primary tumor and regional lymph node involvement allow classification of patients into different risk categories. The Tumor, Nodes, Metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) (table 1A-B) incorporates the most important determinants of prognosis [14,15]. (See “Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma”.)

  • For the primary tumor (T), increasing tumor thickness, an increased mitotic rate, and the presence of ulceration (ie, the loss of the epidermal layer overlying the primary tumor) are associated with an increased risk of relapse (figure 1).
  • The presence of lymph node involvement is associated with a significant increase in risk of recurrence, and this is further subdivided based upon the number and extent of lymph node disease (figure 2).

Low-risk patients — The majority of patients diagnosed with melanoma present with stage I or IIA disease (localized tumor either ≤4 mm in thickness without ulceration or ≤2 mm in thickness with ulceration). In these patients, surgery is usually curative, and adjuvant therapy is not indicated except in the context of a formal clinical trial (figure 3) [13].

High-risk node-negative (stage IIB or IIC) disease — Patients without lymph node involvement but with high-risk features in their primary tumor are at increased risk for recurrence and disease dissemination. High-risk primary tumors include those with tumor >4 mm thick or ulceration. The majority of the SITC consensus panel recommended either one year of high-dose interferon alfa (IFNa) or inclusion in a clinical trial, although observation is an acceptable alternative (figure 3). There are no data to support the use of pegylated interferon (IFN) in this setting.

Microscopic involvement of one lymph node — Patients with stage III disease based upon the presence of microscopic involvement in only one lymph node are at higher risk than those without lymph node involvement but are at lower risk than those with more extensive lymph node disease. Available evidence from clinical trials supports several options, including high-dose IFNa, pegylated IFN, participation in a clinical trial, or observation. In the SITC consensus statement, the majority of the panel recommended one year of high-dose IFNa. Other options included pegylated IFN for up to five years, participation in a clinical trial, or observation. The optimal duration of treatment with pegylated IFN is not well defined; the median on the European Organization for Research and Treatment of Cancer (EORTC) trial was 16 to 18 months, although the intent was to treat for five years (figure 4) [16].

Macroscopic or multiple lymph node involvement — For patients with more extensive lymph node disease, one year of adjuvant therapy with high-dose IFNa is considered the standard approach for patients who are not enrolled in a clinical trial (figure 4) [13].

Contraindications to interferon — A high-dose IFNa regimen for one year can be associated with significant side effects. (See ‘Treatment-related toxicity’ below.)

Thus, patients who are being offered adjuvant IFNa should have a good performance status without significant depression or a history of psychiatric disorder. IFNa is also not appropriate for those with a history of an autoimmune disorder.

INTERFERON — The use of adjuvant immunotherapy with interferon alfa (IFNa) in patients considered to be at high risk for recurrence following their initial surgical resection is based upon the results of numerous clinical trials. These trials have used differing doses and schedules of IFNa, and the trials have varied in the definition of high risk for the patients that were included.

Meta-analysis — The most extensive data come from a meta-analysis that included data from 14 randomized trials published between 1990 and 2008, which included a total of 8122 patients [17]. In 12 of the 14 trials, patients were randomly assigned to IFNa and to either observation or placebo; in the other two trials, IFNa was compared with a GM2-KLH vaccine that was considered to be inactive.

  • Disease-free survival with IFNa was significantly prolonged overall (hazard ratio [HR] for recurrence 0.82, 95% CI 0.77-0.87). These results were consistent across different patient subsets or based upon the IFNa dose and schedule, and there was no statistically significant heterogeneity between clinical trials.
  • Overall survival (for which data were available for 12 of 14 trials) was significantly improved with IFNa (HR for death 0.89, 95% CI 0.83-0.96).

High-dose IFNa trials — A high-dose schedule of IFNa has been the most widely used and is generally considered the standard approach for patients who are to receive adjuvant IFNa. This has been extensively studied in multiple large cooperative group trials.

ECOG 1684 — In the Eastern Cooperative Oncology Group trial (ECOG 1684), 287 patients with melanomas >4 mm in depth (stage IIB) or subclinical or clinically apparent regional node involvement (stage III) were randomly assigned to one year of high-dose IFNa-2b or close observation [18]. The IFNa treatment schedule consisted of intravenous therapy at a dose of 20 million units/m2 five days per week for four weeks followed by 10 million units/m2 subcutaneously three times weekly for an additional 11 months.

At a median follow-up of nearly seven years, the following statistically significant benefits were noted in the IFNa arm:

  • A nine-month prolongation in relapse-free survival (RFS, median 1.7 versus 1.0 years), with an 11 percent absolute increase in RFS at five years (37 versus 26 percent)
  • A one-year prolongation in median survival (3.8 versus 2.8 years), with a 9 percent absolute increase in survival at five years (46 versus 37 percent)

In a subsequent analysis, the improvement in overall survival was no longer statistically significant [19]. Treatment benefit appeared to be confined to patients with lymph node involvement, with a doubling of RFS in these subgroups. Although patients without nodal involvement (T4NO stage IIB, (table 1A-B)) did not appear to benefit, there were too few patients in this subgroup to make any meaningful assessment.

Intergroup E1690 — The Intergroup protocol E1690 compared high-dose IFNa (as in the E1684 protocol) with low-dose IFNa (as in the World Health Organization [WHO] 16 protocol) or observation [20]. The eligibility criteria for this study were similar to those for ECOG 1684, except that patients with clinically normal regional nodes were not required to undergo staging lymph node dissections. As a result, approximately 25 percent of the 642 patients had deep primary tumors with undefined nodal status.

The following findings were noted:

  • Both the high-dose IFNa and the observation arms had significantly better survival than was observed in the respective study populations treated in ECOG 1684. A subtle selection bias over time probably accounts for this “study effect.”
  • A significant RFS benefit was noted for high-dose IFNa relative to observation (HR 1.28). This benefit was particularly large for patients with melanoma involving two to three lymph nodes. Low-dose IFNa produced an intermediate result relative to observation (HR 1.19, p = 0.17).
  • There was no overall survival benefit associated with high-dose IFNa relative to either low-dose IFNa or observation. It is uncertain why the RFS benefit observed with high-dose IFNa failed to translate into an overall survival benefit. One contributing factor was the extraordinarily high salvage rate among patients relapsing off the observation arm. In a retrospective review of the data, many such patients were treated with further surgery and either IFNa- or interleukin-2 (IL-2)-containing regimens following relapse. (See “Interleukin-2 and experimental immunotherapy approaches for advanced melanoma”.)

Intergroup E1694 — Intergroup E1694 compared high-dose IFNa-2b with the GM2-KLH vaccine in resected stage IIB and III melanoma patients, the same population studied in ECOG 1684 and 1690 [21]. The trial was closed prematurely when interim analysis disclosed a significantly worse RFS and overall survival for patients treated with the GM2-KLH vaccine compared with the high-dose IFNa (HR 1.47 and 1.52, respectively).

The initial interpretation of this trial was that the GM2-KLH vaccine was no worse than observation and that the vaccine thus served as a control group for the high-dose IFNa. A subsequent trial found that the vaccine did not improve overall survival compared with observation alone. (See “Interleukin-2 and experimental immunotherapy approaches for advanced melanoma”, section on ‘Ganglioside vaccines’.)

ECOG 1697 — The use of a brief induction course of IFNa without maintenance therapy was formally studied in ECOG 1697, in which patients with largely stage IIA melanoma were randomly assigned to high-dose IFNa for four weeks or to observation, without further maintenance. A planned interim analysis after enrollment of 1150 patients found no evidence of improvement in either RFS or overall survival, and accrual to the trial was discontinued [22]. These results suggest that the four-week high-dose interferon (IFN) induction schedule alone is insufficient to produce improvement in relapse-free or overall survival even in patients with intermediate-risk melanomas.

Biochemotherapy — Intensive biochemotherapy was evaluated as an alternative to high-dose IFNa in a phase III cooperative group trial (S0008) and may constitute an alternative to high-dose IFNa in carefully selected patients [23]. The trial randomly assigned 432 patients with high-risk melanoma to either three cycles of cisplatin, vinblastine, dacarbazine, IL-2, and IFNa given over a nine-week period or to high-dose IFNa for one year.

  • At a median follow-up of 7.2 years, the biochemotherapy regimen significantly prolonged RFS (median 4.0 versus 1.9 years and five-year RFS rate 48 versus 39 percent, HR 0.75, 95% CI 0.58-0.97). However, there was no significant difference in the overall survival (five-year rate 56 percent for both treatment arms, HR 0.98, 95% CI 0.74-1.31).
  • The toxicity profiles of the two regimens differed substantially. For the biochemotherapy regimen, grade 3 or 4 toxicity was observed in 76 percent of cases and consisted primarily of hematologic and gastrointestinal toxicity. Neurologic, psychiatric, and hepatic toxicities were the most frequent with high-dose IFNa. Biochemotherapy toxicities were limited to the nine-week treatment period, while IFNa toxicities were distributed across the year of treatment.

Intermediate- and low-dose IFNa trials — Multiple trials have evaluated lower doses of adjuvant IFNa-2a or -2b, either alone or in combination with IL-2, to determine whether similar effectiveness could be achieved with decreased toxicity and expense [16,24-27]. Although some of these trials demonstrated a benefit in RFS for the IFN arm relative to placebo [25], particularly in patients with melanomas 1.5 to 4 mm thick, this benefit was lost once treatment stopped, raising the possibility that prolonged treatment may be necessary. Overall, these trials have demonstrated either no benefit or less benefit than that seen with the high-dose IFNa schedule.

More recently, ECOG examined the effect of more prolonged low-dose IFN treatment in intermediate-risk melanoma. In a phase III trial, 850 patients with resected melanoma ≥1.5 mm thick and clinically negative regional lymph nodes were randomly assigned to either 18 or 60 months of low-dose IFNa [26]. Longer duration of adjuvant interferon (60 months) did not significantly improve rates of relapse-free, distant-metastasis free, or overall survival compared with the 18 months of treatment (73 versus 76, 80 versus 82, and 85 versus 86 percent, respectively).

Treatment-related toxicity — Administration of adjuvant high-dose IFNa is associated with numerous adverse effects, including acute constitutional symptoms, chronic fatigue, myelosuppression, and neurologic and psychologic effects, which are experienced to some degree by the majority of patients (table 2) [28].

  • Granulocytopenia occurs in the majority of patients and may be severe enough in 20 to 60 percent to warrant dose modification. Infections are uncommon, suggesting a different mechanism of myelosuppression than that seen with cytotoxic chemotherapy.
  • Liver toxicity resulted in two early deaths in ECOG trial 1684 but has not been a cause of death in the United States cooperative group trials since vigilant monitoring and dose modification guidelines were mandated.
  • Fatigue is common and was present in 70 to 100 percent of patients in large trials. Fatigue can increase in severity with duration of therapy and can be debilitating.
  • Mild to moderate depression and impaired cognitive function are commonly reported, while mood instability (alternating mania and depression) occurs less often. A history of mood or psychiatric disorders is a risk factor for neuropsychiatric effects. The use of antidepressants (either therapeutically or prophylactically) may facilitate completion of the full planned course of therapy.
  • Thyroid dysfunction (both hypothyroidism and hyperthyroidism) may appear during the course of IFNa therapy. It typically is autoimmune in nature and usually resolves within 6 to 12 months of stopping treatment. Studies suggest that thyroid dysfunction may be associated with a significantly enhanced chance of therapeutic benefit.

Patients should be monitored closely during therapy. During the initial four-week induction period with IFNa, this should include weekly blood counts, liver function tests, and metabolic panels. These should then be repeated on a monthly basis for patients being treated on the high-dose IFNa regimen.

The majority of these effects can be managed with appropriate supportive care and/or dose reduction if toxicity is severe [28]. Most adverse reactions resolve with treatment discontinuation.

Autoimmunity — Multiple manifestations of autoimmunity, including thyroid dysfunction, vitiligo, and the development of autoantibodies, occur in 15 to 30 percent of patients who are treated with IFNa [29]. Whether the immunotherapy can induce an autoimmune response and whether this is important for the development of an antitumor effect is uncertain, and different analyses have yielded conflicting results. The role that differences in IFN doses and schedules play in these disparate outcomes remains to be sorted out.

  • A direct relationship between the development of autoimmunity and the prevention of relapse in high-risk patients receiving adjuvant IFNa was supported in the results from a correlative study [30]. As part of a larger study, immunologic responses were assessed in 200 patients who were randomly assigned to induction therapy with IFNa for four weeks with or without maintenance therapy with IFNa for an additional 48 weeks. Overall, 52 patients (26 percent) developed antithyroid, antinuclear, or anticardiolipin autoantibodies or clinical manifestations of autoimmunity (eg, vitiligo, thyroiditis).

The development of autoimmunity was associated with a striking improvement in both disease-free and overall survival [30]. At a median follow-up of 46 months, patients with evidence of autoimmunity had statistically significant, marked reductions in the rate of relapse (13 versus 73 percent in those without autoimmunity) and of overall mortality (4 versus 54 percent). Multivariate analysis showed that the only independent prognostic factors were the development of autoimmunity and regional lymph node involvement at presentation; the specific treatment arm did not influence outcome. Similarly, in ECOG trials E2696 and E1694, the development of autoimmunity following IFNa therapy as manifested by the development of autoantibodies was associated with an improved outcome [31].

  • By contrast, a retrospective analysis of two randomized trials comparing intermediate-dose interferon with observation found that the appearance of autoantibodies was not strongly associated with an improved relapse-free interval [32]. This study analyzed 355 patients from the European Organization for Research and Treatment of Cancer (EORTC) 18952 and the Nordic Interferon trial, all of whom were negative for anticardiolipin, antithyroglobulin, and antinuclear antibodies at baseline [24,33]. Although the frequency of seroconversion increased with interferon treatment in both trials, the difference was not statistically significant when corrected for the duration of time patients were followed. Similarly, a subset analysis from the EORTC 18991 trial of 220 patients who were autoantibody negative at treatment initiation found that the appearance of autoimmune antibodies was neither prognostic nor predictive for an improved outcome in patients treated with pegylated IFN [34].

Because autoimmunity may not be observed until months after the initiation of treatment, there is no way at present to identify prospectively those patients who are more likely to benefit from adjuvant IFNa, and alternative methods are needed to predict who will respond to adjuvant therapy [29].

Pegylated IFNa-2b — Pegylated IFNa has been developed to decrease the frequency with which IFNa is administered while maintaining a high level of exposure. Pegylated IFNa has been evaluated as an adjuvant following primary resection of melanoma in two phase III trials [16,35]:

  • In the EORTC 18991 trial, 1221 patients with stage III melanoma (N1 or N2 disease) were randomly assigned to pegylated IFNa or observation. The pegylated IFNa was given weekly for eight weeks (6 mcg/kg per week subcutaneously) and then as maintenance (3 mcg/kg per week) through five years. At a median follow-up of 7.6 years, the seven-year RFS was significantly increased with pegylated IFNa compared with observation (39.1 versus 34.6 percent, HR 0.87, 95% CI 0.76-1.00, p = 0.055) [36]. There was no difference in overall survival (p = 0.57). The most frequent grade 3 or 4 side effects with pegylated IFNa were fatigue, hepatotoxicity, and depression (16, 11, and 6 percent of cases, respectively).
  • In a second trial, 909 patients were randomly assigned to pegylated IFNa (180 mcg subcutaneously weekly) or IFNa (3 million units three times per week), each for 24 weeks [35]. There was no significant difference in the five-year distant metastasis-free survival, disease-free survival, or overall survival.

IPILIMUMAB — The use of ipilimumab as an adjuvant for high-risk melanoma is based upon the results of a large trial in which ipilimumab significantly decreased the rate of recurrence compared with placebo. Additional follow-up from this trial will be required to assess the impact on the rate of distant metastases and overall survival.

In the European Organization for Research and Treatment of Cancer (EORTC) 18071 trial, 951 patients were randomly assigned to either ipilimumab or placebo [37]. All patients had stage III melanoma, and 80 percent had stage IIIB or IIIC disease. The other 20 percent had stage IIIA disease with melanoma >1 mm diameter in the sentinel lymph node. Treatment with ipilimumab was given at a dose of 10 mg/kg every three weeks for four doses, then every three months for three years unless toxicity or relapse prevented its continuation. Placebo was given on the same schedule. The primary endpoint of the trial was relapse-free survival (RFS).

At a median follow-up of 2.7 years, results included the following:

  • The median RFS was significantly increased with ipilimumab compared with placebo (median, 26 versus 17 months, three-year RFS 46.5 versus 34.8 percent, hazard ratio [HR] 0.75, 95% CI 0.64-0.90). Overall, there were 234 events in those treated with ipilimumab (49 percent) compared with 294 in those assigned to placebo (62 percent).
  • Toxicity associated with adjuvant ipilimumab was quite significant. Immune-related side effects were observed in 90 percent of patients treated with ipilimumab, including 36.5 with grade 3 events and 5.5 percent with grade 4 events. The most common treatment-related adverse events were dermatologic, gastrointestinal, endocrine, and hepatic (63, 46, 38, and 25 percent of patients, respectively). Primarily because of toxicity, only one-half of the patients assigned to ipilimumab received more than the initial 12 weeks of therapy, and only 29 percent of the patients remained on therapy beyond one year. (See “Toxicities associated with checkpoint inhibitor immunotherapy”.)
  • There were five treatment-related deaths (three due to colitis, one to myocarditis, and one to multiorgan failure with Guillain-Barre syndrome) in patients treated on the ipilimumab arm.

Based upon the results of this trial, adjuvant ipilimumab was approved at a dose of 10 mg/kg by the US Food and Drug Administration (FDA) in October 2015. However, overall survival data from this trial is not yet available. Furthermore, the dosage used in this trial (10 mg/kg) is different from standard does used for metastatic disease (3 mg/kg) and, thus, may be associated with increased toxicity.

A second phase III trial is comparing ipilimumab at two doses (the 10 mg/kg dose used in the EORTC 18071 trial or the standard 3 mg/kg dose approved for patients with stage IV disease) versus high-dose interferon (ECOG 1609, NCT01274338). It has overall survival and RFS as co-primary endpoints, with data anticipated to be mature in two to three years.

INTERFERON VERSUS IPILIMUMAB — There currently are no data from randomized trials comparing interferon with ipilimumab. Although the initial data with ipilimumab demonstrate that the recurrence-free survival benefit seems to be at least of similar magnitude to what has been achieved with interferon, there are no long-term data on the impact on survival. Furthermore, ipilimumab can be associated with severe or life-threatening side effects, particularly at the doses used in the adjuvant setting.

A phase III trial (Eastern Cooperative Oncology Group [ECOG] 1609, NCT01274338) is comparing ipilimumab at two doses (the 10 mg/kg dose used in the EORTC 18071 trial and the standard 3 mg/kg dose approved for patients with stage IV disease) versus high-dose interferon, and the results from this along with additional follow-up from the EORTC 18071 trial will be important in determining the roles of each of these agents as adjuvant therapy.

EXPERIMENTAL APPROACHES — Several alternative approaches are being studied as an alternative to high-dose interferon alfa (IFNa) or ipilimumab.

Anti-PD-1 antibodies — Checkpoint inhibition using antibodies that target the programmed cell death-1 protein ([PD-1] nivolumab, pembrolizumab) significantly prolongs overall survival in patients with advanced melanoma. Both of these approaches are now being studied in an adjuvant setting. (See “Immunotherapy of advanced melanoma with immune checkpoint inhibition” and “Principles of cancer immunotherapy”.)

Checkpoint inhibitors targeting PD-1 or the PD-1 ligand also have significant clinical activity in patients with advanced melanoma.

  • A phase III trial comparing nivolumab with ipilimumab has completed enrollment for patients who have had complete resection of stage IIIB/C or IV melanoma (NCT02388906). Results are pending.
  • A phase III trial comparing pembrolizumab with placebo is ongoing in patients with high-risk stage III melanoma following complete resection (NCT02362594).
  • A phase III cooperative group trial (S1404) comparing pembrolizumab with high-dose IFN is ongoing in patients with high-risk stage III or IVA disease following complete resection.

Bevacizumab — Bevacizumab was studied as an adjuvant in a phase III trial in which 1343 patients with resected stage IIB, IIC, or III disease were randomly assigned to one year of treatment (7.5 mg/kg every three weeks) or observation [38].

At a median follow-up of 25 months, there was no significant difference in overall survival, the primary endpoint of the trial (hazard ratio [HR] 0.97, 95% CI 0.78-1.22). However, there was a statistically significant increase in the disease-free interval (one-year and two-year disease-free rates 77 versus 70 and 59 versus 57 percent, respectively, HR 0.83, 95% CI 0.70-0.98) and a statistically insignificant trend toward improved distant metastasis-free survival (HR 0.88, 95% CI 0.73-1.06, p = 0.18).

Interpretation of the trial and the potential role of bevacizumab will require further follow-up to assess the five-year overall survival rate.

GM-CSF — Granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to demonstrate a benefit in a multicenter trial in patients with high-risk stage III or completely resected stage IV melanoma [39]. In this trial, 815 patients were randomly assigned to GM-CSF or placebo. Patients who were HLA-A2-positive were randomly assigned to peptide vaccination or placebo in combination with their GM-CSF or placebo; patients who were HLA-A2-negative received only GM-CSF or placebo. There was no statistically significant difference in either overall survival (five-year survival rate 52 versus 49 percent, HR 0.94, 95% CI 0.77-1.15) or relapse-free survival (five-year relapse-free survival rate 31 versus 27 percent, 11.4 versus 8.8 months, HR 0.88, 95% CI 0.74-1.04) when GM-CSF was compared with placebo. There was also no benefit associated with the use of the peptide vaccine.

Other — The development of molecularly targeted drugs for patients with metastatic melanoma is leading to the evaluation of these newer agents in an adjuvant setting for high-risk patients with melanoma. (See “Immunotherapy of advanced melanoma with immune checkpoint inhibition” and “Molecularly targeted therapy for metastatic melanoma”.)

There currently are no data to support the use of these agents in an adjuvant setting. However, several large phase III trials are assessing the role of these and other approaches as an alternative to standard high-dose interferon (IFN) [40]:

  • Vemurafenib versus placebo (NCT01667419)
  • Dabrafenib plus trametinib versus observation (NCT01682083)
  • Pegylated IFN versus observation in patients with ulcerated melanoma >1 mm (European Organization for Research and Treatment of Cancer [EORTC] 18081, NCT01502696)
  • Mage 3 vaccine versus placebo

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

  • Beyond the Basics topics (see “Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)” and “Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)”)

SUMMARY AND RECOMMENDATIONS

  • Patients who have undergone a definitive resection of cutaneous melanoma generally do well. However, subsets of patients at increased risk of recurrence can be defined based upon the characteristics of the primary tumor (thickness, mitotic rate, ulceration) or the presence of lymph node metastases. (See ‘Risk stratification and adjuvant therapy’ above.)
  • Multiple clinical trials have demonstrated that adjuvant treatment with interferon alfa (IFNa) can prolong disease-free survival and overall survival in high-risk groups, although such treatment can be associated with significant toxicity. One large randomized trial has shown that adjuvant ipilimumab can significantly reduce the rate of recurrence compared with placebo, although additional long-term follow-up will be required to assess the impact on survival. There currently are no results from randomized trials directly comparing interferon and ipilimumab. (See ‘Interferon’ above and ‘Ipilimumab’ above and ‘Interferon versus ipilimumab’ above.)
  • For patients at low risk of recurrence (no lymph node involvement and tumor ≤4 mm in thickness without ulceration or ≤2 mm in thickness with ulceration, stage IIA (table 1A-B)), we suggest not using adjuvant therapy since there is a high probability of cure, and there is no evidence that adjuvant therapy improves the prognosis (figure 3). (See ‘Low-risk patients’ above.)
  • Adjuvant immunotherapy may be indicated for patients at increased risk of recurrence (algorithm 1):
  • For patients with increased risk of recurrence based upon characteristics of the primary tumor (>4 mm thick, the presence of ulceration, or a mitotic rate ≥1/mm2) but without lymph node metastases (stages IIB or IIC), we suggest adjuvant IFNa (figure 3) (Grade 2B). Alternative options include observation or participation in a clinical trial. (See ‘High-risk node-negative (stage IIB or IIC) disease’ above and ‘Meta-analysis’ above.)
  • For patients with regional lymph node involvement (stage III), the extent of lymph node disease should be incorporated into the treatment recommendation (figure 4):

-If disease is limited to microscopic involvement of a single lymph node (N1a disease), we suggest adjuvant immunotherapy (Grade 2B). Alternatives include clinical trial participation or observation. (See ‘Microscopic involvement of one lymph node’ above and ‘Meta-analysis’ above.)

-If there is macroscopic involvement of a lymph node or if there is involvement of more than one node (N1b, N2, or N3 disease), we recommend adjuvant immunotherapy (Grade 1B). Alternatives include clinical trial participation, especially trials with an active control arm. (See ‘Macroscopic or multiple lymph node involvement’ above and ‘Meta-analysis’ above.)

  • Options for adjuvant immunotherapy include high-dose interferon and ipilimumab. The choice between these two agents should consider the specific side effects associated with each drug as well as the more limited long-term data associated with ipilimumab.
  • For patients who are treated with adjuvant IFNa, we suggest one year of therapy with the high-dose schedule used in the Eastern Cooperative Oncology Group trial (ECOG) 1684 trial (Grade 2C). This trial used intravenous IFNa (20 million units/m2 five days per week for four weeks) followed by 10 million units/m2 subcutaneously three times weekly for an additional 11 months. Alternative schedules (lower doses, shorter duration of therapy, or in combination with other agents) have not been demonstrated to be equally effective and are not recommended. One large clinical study suggests that pegylated IFNa is an alternative for patients with lymph node involvement.
  • For patients who are treated with adjuvant ipilimumab, the approved dose is 10 mg/kg every three weeks for four doses, followed by every 12 weeks for three years unless toxicity or relapse prevented its continuation. There are no data on the 3 mg/kg schedule in the adjuvant setting. (See ‘Ipilimumab’ above.)

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REFERENCES

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2              Karakousis CP, Emrich LJ. Adjuvant treatment of malignant melanoma with DTIC + estracyt or BCG. J Surg Oncol 1987; 36:235.

3              Banzet P, Jacquillat C, Civatte J, et al. Adjuvant chemotherapy in the management of primary malignant melanoma. Cancer 1978; 41:1240.

4              Morton DL, Eilber FR, Holmes EC, et al. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann Surg 1974; 180:635.

5              Lipton A, Harvey HA, Lawrence B, et al. Corynebacterium parvum versus BCG adjuvant immunotherapy in human malignant melanoma. Cancer 1983; 51:57.

6              Balch CM, Smalley RV, Bartolucci AA, et al. A randomized prospective clinical trial of adjuvant C. parvum immunotherapy in 260 patients with clinically localized melanoma (Stage I): prognostic factors analysis and preliminary results of immunotherapy. Cancer 1982; 49:1079.

7              Lipton A, Harvey HA, Balch CM, et al. Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma. J Clin Oncol 1991; 9:1151.

8              Loutfi A, Shakr A, Jerry M, et al. Double blind randomized prospective trial of levamisole/placebo in stage I cutaneous malignant melanoma. Clin Invest Med 1987; 10:325.

9              Spitler LE. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol 1991; 9:736.

10           Parkinson DR. Levamisole as adjuvant therapy for melanoma: quo vadis? J Clin Oncol 1991; 9:716.

11           Lesinski GB, Anghelina M, Zimmerer J, et al. The antitumor effects of IFN-alpha are abrogated in a STAT1-deficient mouse. J Clin Invest 2003; 112:170.

12           Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol 2006; 24:3164.

13           Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol 2013; 10:588.

14           Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27:6199.

15           Melanoma of the Skin. In: American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.325.

16           Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 2008; 372:117.

17           Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102:493.

18           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.

19           Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004; 10:1670.

20           Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18:2444.

21           Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19:2370.

22           Agarwala SS, et al. Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697) (abstract #8505). J Clin Oncol 2011; 29:527s.

23           Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma–an intergroup study of cancer and leukemia Group B, Children’s Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol 2014; 32:3771.

24           Eggermont AM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 2005; 366:1189.

25           Grob JJ, Dreno B, de la Salmonière P, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998; 351:1905.

26           Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol 2010; 28:841.

27           Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 2012; 30:3810.

28           Hauschild A, Gogas H, Tarhini A, et al. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer 2008; 112:982.

29           Koon H, Atkins M. Autoimmunity and immunotherapy for cancer. N Engl J Med 2006; 354:758.

30           Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006; 354:709.

31           Krauze MT, Tarhini A, Gogas H, Kirkwood JM. Prognostic significance of autoimmunity during treatment of melanoma with interferon. Semin Immunopathol 2011; 33:385.

32           Bouwhuis MG, Suciu S, Collette S, et al. Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. J Natl Cancer Inst 2009; 101:869.

33           Hansson, J, Aamdal, S, Bastholt, L, et al. Results of the Nordic randomized adjuvant trial of intermediate-dose interferon alfa-2b in high-risk melanoma. Eur J Cancer 2007; 6(suppl 5):4.

34           Bouwhuis MG, Suciu S, Testori A, et al. Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies–EORTC 18991. J Clin Oncol 2010; 28:2460.

35           Eigentler TK, Gutzmer R, Hauschild A, et al. Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial. Ann Oncol 2016; 27:1625.

36           Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 2012; 30:3810.

37           Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 16:522.

38           Corrie PG, Marshall A, Dunn JA, et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol 2014; 15:620.

39           Lawson DH, Lee S, Zhao F, et al. Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). J Clin Oncol 2015; 33:4066.

40           http://www.clinicaltrials.gov/ (Accessed on June 08, 2012).

Topic 7615 Version 46.0

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4 thoughts on “Update #10 – Guest Blogger Dr. Schwam breaks big news about starting a new treatment

  1. Lisa Gaulin

    Hey Elana and the newest blogger! I did subject myself to read the unabridged portion. The therapy sounds very much like what my patients in the MS(multiple sclerosis)center rely on as DMT(disease modifying therapy). Interferons have been used since the mid to late 90’s and more recently the pegylated interferon-Plegridy is a once every 14 day sc med, was FDA approved about 2 yrs ago. Our patients who have tried, usually 2 or more DMT’s, with continued disease progression or are intolerant to the side effects are then considered for chemotherapuetic-like medications-Tysabri, Lemtrada, Zinbryta. All of these carry the kinds of concerns your new med has for the auto-immune backlash. You are one tough cookie ! And you got this!

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    Reply
  2. Ed Bobrow

    I start by telling you that you have some of your Grandpa George’s tenacity and Bravery. I know how tough as well as loving he was. He would be so proud of the fight you are making and of your folks who support you so well.

    I loved your Grandpa and Grandma dearly. Diapered your mom and love her as dearly. We were all family!

    You have them and a great Dad all in you. They were tough fighters as well!

    LOVE from a Family Friend that loves you all,
    Ed

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    Reply
    1. schwambomb Post author

      Ed you are the sweetest and thank you for that post, it brought tears to my eyes. Thanks for loving my family so much and I hope to run into you one of these days!

      Like

      Reply
  3. Pingback: Update #11 -Buhbye Interferon, Hello Ipilimumab and other stories from the past 3 weeks | Schwaming Cancer

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