Patient-reported treatment-related symptom burden for patients with advanced melanoma in Canada

This was a qualitative, non-interventional study to explore patients’ experiences of treatment for advanced melanoma (stages III and IV) in Canada, conducted in the winter of 2014/2015. During the study time period, CTLA-4, BRAF, and PD-1 inhibitors were only available as single agents in cases of advanced disease. PD-1 inhibitors were introduced just as this study was initiated so its uptake was low in the patient population. Neither the use of these single agents in the curative/adjuvant setting nor the use of combination regimens in any setting were reimbursed by the publicly funded healthcare system. Thus, their use was limited to patients who were participating in clinical trials.

Recruitment was facilitated by Canadian patient advocacy associations who made initial contact with members and determined study eligibility. Patients were recruited from seven provinces: Alberta, British Columbia, Manitoba, New Brunswick, Ontario, Quebec, and Saskatchewan. Patients met all of the following inclusion criteria: had advanced melanoma (stage III or IV, self-report of doctor diagnosis), 18 years of age or above, spoke English or French, and were willing and able to participate in the study and give written informed consent.

Individual interviews were conducted in either English or French by one of five trained interviewers and were conducted in a single session lasting 45 to 60 min, during which patients shared their stories and answered questions about their experiences with treatment for advanced melanoma. Interviews conducted in French were translated by a professional translation service provider to ensure proper language translation of the French-Canadian language into English. The interviews were audio-recorded and transcribed verbatim using a professional linguist and superior machine-assisted rapid translation that ensures accuracy and consistency in the translation process.

Prior to the interview, patients received an overview of the study, the patient information letter, and the informed consent form. Patients completed a demographic health information form including detailed questions related to diagnosis and treatment course. The interview was guided by open-ended questions (see Table 1) from a semi-structured interview guide.

Interview questions for this study were designed based on a literature review and collaboration with clinical experts and patient advocacy groups. The interview guide is a set of questions exploring patients’ general experience of the effects of melanoma and its treatment in terms of symptoms and quality of life. Questions designed to elicit personal experience without leading the patient were developed to allow patients to describe their experiences spontaneously. For example, “First, will you describe what it has been like for you since you were diagnosed with advanced melanoma?” and, “Please describe any changes in how your body feels or functions since you were diagnosed with advanced melanoma?” Patients were queried about specific symptoms and impacts on functioning or well-being if not mentioned spontaneously.

Transcripts were coded and analyzed to identify themes important to patients, using a grounded theory method that identified important concepts from the narrative data without applying an a priori theoretical model [34, 35]. This allowed for the elicitation of patients’ described experiences rather than applying themes developed by researchers, as in traditional content analysis [36]. Grounded theory is widely used for analyzing exploratory qualitative data [37, 38].

An initial code book was developed by the research team, reflecting the overall structure of the interview guide. Codes were created to capture key concepts in the guide. For example, for a probe asking about diarrhea as a side effect of treatment, a code for the experience of diarrhea was created. Codes were created separately for symptoms that were mentioned spontaneously and those mentioned in response to a probe.

After the first two transcripts were coded independently by all researchers, the coding scheme was refined to capture new, emerging symptoms, experiences, and HRQL impacts. Each transcript was then coded by one researcher and independently reviewed by another. Discrepancies and changes to the coding scheme were harmonized among the research team, ensuring reliability of coding. All data was analyzed using ATLAS.ti. [39]

The study included 29 adult patients with advanced melanoma. Most (n = 18; 62%) were female; mean age 52 (range = 28–69). Twenty patients (69%) reported stages III or IV melanoma at diagnosis. At the time of the interview, 22 (76%) reported stages III or IV, three (10%) reported being in remission, and four (14%) had achieved no evidence of disease (NED). Patients’ sociodemographic and clinical characteristics are shown in Table 2.

We observed 13 unique treatment journeys involving drug therapies, and one patient who had radiotherapy only. In the following sections, we summarize the experiences of patients representing four major therapy groups:

Counts and percentages of the treatment experiences represented are shown in Table 3. The TRSs reported by patients in our sample are shown in Table 4 and detailed results are described below.

Ten patients (34%) received between one and four cycles of cytotoxic chemotherapy (nine DTIC, one temozolomide),¹ and none of these patients experienced remission.

Nausea was the most commonly reported TRS for patients who had received DTIC and was described as being the most severe right after intravenous infusions, often continuing between infusions. Two patients described these infusions as being painful experiences.

Fatigue and flu-like symptoms such as chills were other common TRSs among chemotherapy patients. Patients who reported fatigue described it as debilitating and thus having a significant impact on their overall health-related quality of life:

“I still have the side effects. Some days, I am going back to bed for the entire afternoon, it will make me feel better, I just need to sleep. There is still a lot of fatigue.”

A patient who received temozolomide similarly referred to a profound burden on their physical functioning:

“That was the most physically debilitating part…it actually like physically knocked me on my butt for the entire week that I had to take the pill…I couldn’t move. I couldn’t function.”

Mental health impacts from chemotherapy were less common but included sadness over having to avoid social contact due to germs or feelings of burdening others:

“…you just feel like you’re a burden on the entire world, right? Because there’s nothing you can do.”

The most commonly reported physical TRSs attributed to ipilimumab were skin rash, diarrhea or constipation, fatigue, and itching. While most described skin rash and fatigue as annoyances, two patients reported serious fatigue that had a greater impact on their daily functioning, as one patient’s quote describes representatively:

“And there was a lot a fatigue, I was always tired. I couldn’t spend half a day without lying down. If I got up at 8 a.m., I had to lay down at 10 a.m., then again at 12 p.m. I had to lay down every two hours because I was so tired.”

Although less common, gastrointestinal problems such as chronic diarrhea or constipation were described as particularly bothersome and often limiting of their ability to be away from home, in addition to being painful and irritating. Severe diarrhea was implicated in three of the previously mentioned cases where patients needed to cease ipilimumab treatment and switch to PD-1 inhibitor treatment.

Two patients specifically mentioned that they had experienced far worse side effects with prior treatment and did not feel that the ipilimumab TRSs placed as much burden on their functioning:

“And that’s when he got me into the Yervoy [ipilimumab] trial, and … it was a complete about-face, because taking that drug, it does—didn’t make me sick. I could —you know, I was tired from it and had some other physical side effects, but I could still function and—you know, carry on kind of sort of semi-normal, I suppose.”

No impacts on mental health functioning or social functioning attributed to ipilimumab were reported.

Eight patients (28%) had received or were currently receiving one or more of the following BRAF inhibitors: vemurafenib (n = 4), dabrafenib (n = 5), or the MEK inhibitor binimetinib plus dabrafenib (n = 1), generally as the second line of therapy after chemotherapy.

Although five patients were told by their doctors that the BRAF inhibitor would be effective for 6 to 9 months, these patients had been taking their medication for up to 3 years with no evidence of cancer at the time of the interview. One patient had serious TRSs from vemurafenib and switched to dabrafenib, which was tolerable. Two patients did not have a successful treatment response to dabrafenib; one switched to ipilimumab and the other switched to dabrafenib plus binimetinib.

A majority of patients reported TRSs of fatigue, hair loss, and diarrhea or constipation as side effects associated with BRAF inhibitors. Additionally, roughly half reported experiencing nausea, sun sensitivity, sleep disturbance, skin rashes, itching, pervasive pain, and joint pain. TRSs unique to vemurafenib were a loss of appetite and callouses on feet, while side effects unique to dabrafenib were muscular pain, headaches, chills, and difficulty concentrating. No unique TRSs were reported for the combination therapy of dabrafenib and binimetinib.

Patients who reported skin rash as a TRS of a BRAF inhibitor described the rashes as being severe and typically developing at the start of treatment, causing patients to stop and re-start the therapy. Five patients experienced severe fatigue and other side effects such as anxiety and memory loss that significantly affected their quality of life, requiring a dose reduction. One patient called the TRSs “horrendous” when at the full dose. Yet, all five were willing to continue treatment given reductions in tumor sizes and other positive treatment responses. The following quote from a patient on dabrafenib is consistent with this majority sentiment:

“The diagnosis itself didn’t really affect my body as much the surgeries and the chemicals that they pumped into me. The latest on the dabrafenib that I had was very painful. It affected my skeletal system and my muscle function. It was very painful and—but it was doing a good job, so you tolerate it. You know, and they give you pills to help counter everything else, but it—but that really did incapacitate me, that one.”

With respect to BRAF and MEK inhibitors, patients reported fewer effects on mental health functioning compared to physical health functioning. There were only two reports of a specific mental health side effect, and only five patients reported any at all. One patient reported experiencing anxiety about whether the treatment would continue to be effective after the duration of action suggested by their doctor (6 to 9 months) had passed.

There were two reports of impacts on social functioning that were attributed specifically to side effects from taking a BRAF inhibitor. One lamented about the difficulty of raising a young daughter and participating in activities with her due to aches, pains, fatigue, and sun sensitivity. Another patient related not feeling well enough to drive to a friend’s home an hour away and being limited to short visits with friends.

Four patients (14%) received a PD-1 inhibitor, three of whom received pembrolizumab, and the other was unspecified. All four received the treatment as second- or third-line therapy and either through a clinical trial or an early access program because the drugs had not been approved in Canada at the time of this study. All of these patients had previously received DTIC and/or ipilimumab, during which their advanced melanoma either did not respond or had returned.

All PD-1 inhibitor patients reported a positive response to treatment in terms of reduced number and size of tumors.² Patients attributed few TRSs to PD-1 inhibitor treatment and described them as mild. One patient reported diarrhea and dry mouth after the seventh pembrolizumab treatment. Another mentioned itchy, inflamed toes. A third patient spoke of fatigue that was concurrent with pembrolizumab therapy, but could not be certain it had been caused by the treatment. Two of the pembrolizumab-treated patients reported damage to the thyroid, which they understood to be a consequence of “amping up” the immune system to treat the melanoma.

Patients described their overall experience with PD-1 inhibitors as generally tolerable, separately reporting that they felt “good,” “great,” or “healthy” throughout. One patient was surprised and very pleased about feeling better early in the pembrolizumab treatment regimen:

“And so, you know, actually, before the second infusion three weeks later, I felt symptom-free.”

Another patient expressed pleasure that the administration of pembrolizumab was less burdensome than their previous therapy:

“The ipilimumab was an hour and a half infusion. This [pembrolizumab] is a half hour. So time-wise, it has been beautiful.”

In terms of mental health functioning, one patient reported a change in mood concurrent with their pembrolizumab treatment, but they could not attribute it specifically to the drug or to the cumulative impact of advanced melanoma. No other impact on mental health functioning was specifically associated with PD-1 inhibitors. When prompted, all patients reported that they had not felt any impact of PD-1 inhibitor treatment on cognition, feeling depressed or sad, or feeling anxious. Additionally, there were no specific reports of impacts on social functioning, even after probing questions were asked.