Docetaxel (Castration-Naive Metastatic Prostate Cancer)

A New Standard of Care as Older Drug Moves to Front Line

Docetaxel has long been part of the treatment armamentarium for castration-resistant metastatic prostate cancer but has only fairly recently become a standard of care, albeit technically off label, for castration-naive metastatic prostate cancer.^1-5 The diagnosis of metastatic castration-naive prostate cancer has been increasing, attributable, at least in part, to recent advances in imaging, as well as to successful prostate cancer screening efforts.⁶

The CHAARTED trial found that among men with castration-naive metastatic prostate cancer who had a high volume of disease, the combination of ADT with six cycles of docetaxel prolonged median overall survival by an unprecedented 17 months compared with androgen-deprivation therapy (ADT) alone, and it yielded a better prostate-specific antigen (PSA) response and longer times to clinical disease progression and recurrence.^7,8 A meta-analysis pooling data from this trial with data from the similar STAMPEDE⁹ and GETUG-AFU 15¹⁰ trials for men with castration-naive metastatic prostate cancer (irrespective of disease volume) also showed an overall survival benefit.^11,12 Guidelines from the National Comprehensive Cancer Network (NCCN)⁴ and the American Society of Clinical Oncology (ASCO)¹³ recommend the combination of ADT with docetaxel, among other options, as systemic therapy for castration-naive metastatic disease. The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer (NCCN Guidelines®) distinguish between low- versus high-volume disease, suggesting that evidence of benefit for docetaxel in patients with low-volume disease is less certain.

Selecting Patients

Choose patients for docetaxel wisely. To me, that means choosing patients who are chemofit and have a high burden of disease.

“Choose patients for docetaxel wisely. To me, that means choosing patients who are chemofit and have a high burden of disease,” recommended Christopher J. Sweeney, MBBS, a medical oncologist at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston, referring to men with castration-naive prostate cancer. “We need to give patients the option of choosing a chemotherapy approach or a hormone approach,” he continued, “describing the risks and benefits of both.”

Chemofit patients are those free of comorbidities that would limit safe receipt of docetaxel, meaning they have adequate bone marrow function, do not have neuropathy or liver dysfunction, and are able to tolerate the fatigue that the drug can induce, he elaborated. In trials, roughly 50% to 60% of patients with metastatic prostate cancer were fit enough to receive chemotherapy. “It may be closer to 60% in the hormone-sensitive setting, where men haven’t been on the hormone therapy for years and are just starting treatment. They are a little bit younger and a little bit fitter, generally,” he told JNCCN 360.

On the basis of the CHAARTED trial findings, high-volume disease is defined by the presence of visceral metastases and/or four or more bone metastases including one that is extra-axial (beyond the pelvis and vertebral column),^7,8 according to Dr. Sweeney, who started using docetaxel in this setting in 2005 for the trial.

Educating Patients

“It’s important to provide upfront education to patients prior to starting docetaxel, including a discussion of the common potential side effects,” recommends Joanne Chien, MSN, RN, GNP-BC, an advanced practice provider in Medical Urologic Oncology at the Stanford Cancer Center, Palo Alto, California. “I like to keep the information succinct and try to use lay terms, so patients can understand what to expect but are not overwhelmed.” Patient education before starting docetaxel typically lasts 20 to 30 minutes and highlights common side effects as well as the importance of timely and early management.

As docetaxel frequently causes neutropenia, patients are counseled to have a working thermometer at home, monitor for fever, and alert the care team promptly if one occurs. “I tell patients they can generally live a normal life, but we do talk about good hand hygiene. I caution them to stay away from people who are sick and be alert for any spiking fever between 7 and 10 days after their infusion—when the absolute neutrophil nadir occurs and infection risk is highest,” Ms. Chien said. “Washed fruit and vegetables are generally safe; however, I would advise patients to avoid raw fish or uncooked products to limit the risk of infection.”

“We also educate patients about using take-home medications and empower them to manage side effects at home,” she told JNCCN 360. The team typically prescribes three antinausea medications targeting different receptors in the brain. “In this castration-naive setting using docetaxel, we normally don’t give steroids upfront. Patients will be premedicated with dexamethasone on the day of treatment in the infusion center, and if during the course of chemotherapy they develop water retention, we will then provide additional outpatient dexamethasone to help reduce it. And if they develop intolerable side effects, then we add prednisone as well.”

“Of note, I let my patients know they need to listen to their bodies. If they experience something unusual, they need to let us know,” emphasized Ms. Chien, who has been using docetaxel for castration-naive metastatic prostate cancer since 2015. “Patients may experience uncommon side effects or side effects we are unaware of.”

Tailoring Treatment Choice

Given the numerous similarly efficacious options for treating hormone-sensitive metastatic prostate cancer,^4,14–16 treatment should be tailored to the individual patient, according to Dr. Sweeney. In addition to chemofitness and disease volume, the metastatic presentation (whether de novo or relapsed after local therapy), patient preference, and cost come into play.

“We have a conversation to work out which drug will be best for which patient. By and large, it really isn’t about whether to use ADT plus docetaxel. It’s about whether to use ADT plus the other available agents—apalutamide, enzalutamide, and abiraterone,” he explained.^17-20 Still another option is ADT plus radiation to the prostate if the patient has a low burden of cancer.”²¹

Dr. Sweeney identified three main patient groups with somewhat different treatment options:

• “A patient who has a lot of cancer on a scan at first presentation has a poor outlook,” he noted. In this population, docetaxel, enzalutamide, apalutamide, and abiraterone have been shown to be effective. If the patient is chemofit, all of them are an option; if not, all but docetaxel are options.
• “If the patient has a low burden of disease and an intact prostate, the options are pretty much all of the above, with maybe slightly less evidence for docetaxel. But there is also the option of radiation to the prostate,” Dr. Sweeney pointed out. “These treatments all have their pros and cons, with varying degrees of certainty for possible benefits.”
• “If a patient has a relapse after local therapy, the only drugs for which benefit has been shown are apalutamide and enzalutamide. We don’t see any benefit with docetaxel in that group,” he noted. And benefit of abiraterone in this population is unclear.

“Laying out the options, some patients would rather get the side effects of chemotherapy out of the way if they are fit for that treatment. And they are most likely to be fit for it when they are starting hormone therapy rather than years later when they are older or may be more fragile,” Dr. Sweeney observed. “So, they will just be given six cycles of docetaxel and then be put on testosterone suppression alone, versus being on hormone therapy continuously for 3, 4, 5 years and then receiving docetaxel later.”

Recognizing that oral hormone therapy can be expensive and may entail out-of-pocket costs ranging from $0 to $10,000, depending on insurance coverage, “The decision about treatment also depends on what a patient can afford and access,” Dr. Sweeney added. “In contrast to ongoing hormone therapy, docetaxel is given for a finite period, and it has been found to be more cost-effective than abiraterone.”²²

“We tailor the treatment to the individual patient,” Ms. Chien concurs, noting that at her center, the decision often comes down to docetaxel versus abiraterone. The latter has advantages such as its oral pill form, convenience, and slightly more favorable toxicity profile. In contrast, Ms. Chien described the disadvantages of abiraterone, which include adverse effects such as severe hypertension, the need for concomitant prednisone (leading to bone loss when taken long term), and possibly greater financial toxicity.

We find that in patients who are fit and have a high volume of disease, docetaxel is a good choice compared with abiraterone given the shorter duration of therapy.

“We find that in patients who are fit and have a high volume of disease, docetaxel is a good choice compared with abiraterone given the shorter duration of therapy,” she said. “Patients can get the chemo out of the way, and we save the abiraterone for later, when the disease becomes castration-resistant.”

Preventing and Managing Adverse Effects

Docetaxel has well-established, generally manageable adverse effects.⁵ Compared with peers on ADT alone, patients on ADT plus docetaxel experience poorer quality of life while receiving the chemotherapy but better quality of life longer term.²³

“I tell patients that docetaxel is a chemotherapy that’s overall well tolerated,” Ms. Chien explained. “They can expect fatigue and nail changes (brittleness and discoloration), but there is minimal nausea and often thinning of the hair rather than hair loss. They may also experience water retention and leg edema, as well as tearing of the eyes.” Adverse effects frequently reported in trials—neuropathy, stomatitis, and diarrhea—have been minimal among her patients.

Before each docetaxel infusion, patients should have bloodwork and visit with a team member who conducts an assessment. “We review lab results with them and provide reassurance before the next cycle of treatment,” she said. At her infusion center, all patients receive premedications consisting of an antinausea agent and dexamethasone either orally or intravenously. Additionally, the incidence and/or severity of infusion reactions may be prevented or reduced by slowing the infusion rate.

The standard dose of docetaxel for castration-naive metastatic prostate cancer is 75 mg/m² every 3 weeks, for six cycles. About 85% of patients in the CHAARTED trial were able to complete all six cycles without any dose reduction.^7,8 “In real-world experience, it’s probably a little less, maybe 75%,” Dr. Sweeney noted.

Providers can improve the odds of completing treatment by offering anticipatory guidance, he pointed out. “Encourage patients to follow a good diet and get exercise and rest. I tell them to get up, move, do some exercise, hydrate, eat a decent breakfast, build in a nap during the day if they are feeling tired, and then get up and go again,” he recommended. “I also let them know about the possible need for dose adjustments, because the standard dose may be too much.”

Neutropenia

In the CHAARTED trial, the most common grade 3 or 4 adverse events among patients receiving combination ADT and docetaxel were related to neutropenia (seen in 12.1% of patients), febrile neutropenia (6.1%), and infection with neutropenia (2.3%).⁷

When docetaxel is administered, the NCCN Guidelines recommend use of myeloid growth factors based on patients’ risk of neutropenic fever.²⁴ “We don’t give a growth factor to everybody in this setting. But if a patient is at higher risk for an infection, perhaps because he is 65 years or older, for example, we tend to add the growth factor to prevent neutropenic episodes,” Ms. Chien agreed.

When patients do develop a fever, Ms. Chien’s infusion center uses a low-risk neutropenic fever protocol in appropriate cases. “The goal is triaging and treating patients in the outpatient setting with IV fluids and antibiotics when possible, instead of admitting everybody to the ED,” she explained. “For this protocol, we use the Multinational Association for Supportive Care in Cancer [MASCC] febrile neutropenic risk stratification²⁵ to calculate the risk of neutropenic fever. In addition, we use lactate level, which can be an indicator of risk.”

Fatigue

The main side effect patients have with docetaxel is that for the first week after the infusion, they feel fatigued and have a little less energy.

“The main side effect patients have with docetaxel is that for the first week after the infusion, they feel fatigued and have a little less energy to get out and do things,” Dr. Sweeney reported. This side effect can be marked, as 4.1% of patients in the CHAARTED trial experienced fatigue that was grade 3 or 4 in severity.⁷

Patients receiving docetaxel may develop fatigue for three main reasons, according to Ms. Chien: the chemotherapy itself, the anemia it induces, and the concomitant ADT. “This is definitely our number one side effect because all those factors combine to make patients feel tired,” she agreed.

“If patients’ anemia is reasonably stable, we watch it and counsel them about maintaining and increasing physical activity, for example, taking 30-minute walks twice a day, to combat fatigue,” she said. “I encourage them by telling them their body will adapt if they keep moving and get some exercise.”

Nausea

“I agree that docetaxel has low emetogenic potential, as indicated in the NCCN Guidelines,” Ms. Chien told JNCCN 360. Nonetheless, her center’s protocol is to provide three lines of antinausea medications proactively for patients to take home: ondansetron, prochlorperazine, and low-dose lorazepam. “However, in my experience, patients rarely need to use them,” she added.

Patients are instructed to take ondansetron as the first-line antiemetic. “If patients report they are sensitive to smells, gag easily, and have a history of motion sickness, they could be at higher risk for developing chemo-induced nausea, so I counsel them to use the medication prophylactically: take ondansetron in the morning before breakfast and at night before dinner,” she said. “If they don’t have any nausea for a couple days, it’s okay to reduce to once a day or even none, and use prochlorperazine in between if needed or if they could not tolerate the side effects of ondansetron such as constipation and headache. The goal is to find the balance between quality of life and managing side effects.”

Lorazepam can cause drowsiness, so patients are instructed to use it at night and not to operate any machines or drive when they are using it. On the other hand, this medication can also help them sleep.

Peripheral Edema

In Ms. Chien’s experience, leg edema occurs in about 20% to 25% of patients treated with docetaxel. She instructs patients to weigh themselves regularly during chemotherapy to detect any weight gain and routinely assesses them for perceived leg heaviness and pain.

“I ask them to elevate their legs and to exercise, both to overcome fatigue and to increase circulation,” she explained. “If they have gained a lot of weight, we add take-home dexamethasone, asking them to take it the day before, the day of, and the day after chemotherapy.”

Peripheral Neuropathy

Docetaxel can cause both sensory and motor neuropathy; signs and symptoms usually are cumulative, but they resolve after treatment discontinuation.²⁶ In the CHAARTED trial, 1% of patients experienced grade 3 or 4 neuropathy of some type.⁷

The patient and physician should talk about peripheral neuropathy at every visit and consider a dose reduction if it starts to emerge.

“The patient and physician should talk about peripheral neuropathy at every visit and consider a dose reduction if it starts to emerge,” Dr. Sweeney recommended. “Pain can be managed with medications, but it also is an indication that the dose of docetaxel may need to be reduced.”

“I’ve found peripheral neuropathy to be relatively mild,” Ms. Chien reported. “I always ask patients how much it affects their daily function and quality of life. If it doesn’t disrupt sleep or otherwise bother them, we just monitor it, because we know it will lessen after treatment. However, if it progresses to grade 2 or 3, we would discuss dose-reducing or delaying chemotherapy, and treat neuropathy with gabapentin.

Stomatitis

Patients on docetaxel may report they have developed mouth sores or dry mouth, or that food doesn’t taste good, according to Ms. Chien. “It’s part of the routine physical to examine the patient’s oral cavity to rule out any fungal infection that needs to be treated with nystatin oral mouth rinse. If mouth sores develop, we first recommend an oral rinse consisting of warm water mixed with salt or baking soda. In more severe cases, we order ‘magic mouthwash,’ a compound usually containing liquid lidocaine, diphenhydramine, and an antacid.”

Delivering Multidisciplinary Care

A multidisciplinary team approach is key to successfully managing castration-naive metastatic prostate cancer, including administering chemohormonal therapy.⁶ “We engage the urologist to ensure that he or she is sending the patients through. Moreover, the urologist can continue to manage the leuprolide injections while the medical oncologist gives the chemotherapy,” Dr. Sweeney told JNCCN 360. “That’s one very successful way of coordinating care among relevant specialists.”

“We work with specialists to support the patient’s personal needs,” Ms. Chien noted. She may refer to social workers, who provide psychosocial support and help with logistic issues such as transportation to the infusion center. Other patients may need home support and/or referral to palliative care professionals.

The palliative care specialists are the experts in managing side effects if they become more complicated or multifactorial.

“The palliative care specialists are the experts in managing side effects if they become more complicated or multifactorial, and they add tremendous value in patient care by helping with symptom management,” she elaborated. “Patients’ issues may not be due to docetaxel alone. They may have other, preexisting chronic conditions, and now they have cancer, too. We try to help them through this journey every step of the way.”

DISCLOSURES

Christopher J. Sweeney, MBBS, was principal investigator (study chair) of the CHAARTED trial and co–study chair of the ENZAMET trial. He also reported research and consulting relationships with Dendreon, Janssen, Sanofi, Astellas, Pfizer, and Bayer.

Joanne Chien, MSN, RN, GNP-BC, reported no conflicts of interest.

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