“Providing hope when there is little to hope for is hard,” noted Hyman B. Muss, MD, Professor of Medicine and the Mary Jones Hudson Distinguished Professor of Geriatric Oncology at the University of North Carolina at Chapel Hill and the Lineberger Comprehensive Cancer Center. At the 2023 Miami Breast Cancer Conference, Dr. Muss shared his many years of experience in treating patients with breast cancer at the end of life.1 For “the determined few,” this may include one final, well-tolerated chemotherapy regimen, and for all patients, it should be marked by “being kind, honest, and available,” he said.
The Reality of the Disease
Although outcomes in metastatic breast cancer have steadily improved, median overall survival for all patients remains about 3 years, and by 5 years, about 25% of patients are alive; at 10 years, this drops to just 10%. “It may be a little better, with some of the newer drugs—CDK [cyclin-dependent kinase] inhibitors, antibody-drug conjugates, and immunotherapy—but not dramatically,” Dr. Muss added.
Hyman B. Muss, MD
Subsequent lines of treatment often do not keep metastatic breast cancer at bay for long. A 2015 study of 472 patients evaluated progression-free survival according to different lines of treatment.2 For chemotherapy and endocrine therapy combined, median progression-free survival was 9.0 months with first-line therapy, 4.4 months after second-line therapy, 4.0 months after third-line treatment, and 3.0 months with the fourth line of treatment.
Despite the Odds, Many Patients Remain ‘Hopeful’
Patients with metastatic breast cancer typically understand their illness is not curable, but many are hopeful they will “do well,” he noted. “They see ads on TV for new drugs, and they get excited, and that’s appropriate.”
Patients with metastatic breast cancer usually do not progress “linearly” through Kübler-Ross’ five stages for dealing with the end of life, stated Dr. Muss. “My own bias looks like this: Patients deny, they’re hopeful, and then they are not hopeful. They come back to see you when they see something encouraging on TV or a friend is getting some potion. Now they’re optimistic again. It’s never linear in real life.”
Dr. Muss continued: “We have also learned, from an elegant study by the late Dr. Jane Weeks, who died of metastatic breast cancer, that the doctors who patients like the most tend to give the least accurate prognostic information.3 And patients who do not accept the incurable nature of their cancer are more likely to have less trust in their doctors and to look to alternative belief systems. We want our patients to like us, and we are afraid to disclose what their survival is likely to be,” he said.
However, a survey of 126 patients with metastatic cancer who had variable prognoses suggests that it may be far better for physicians to be forthcoming.4 In that study, 98% said they wanted their physician to be “realistic, give an opportunity to answer questions, and acknowledge the patient as an individual when discussing prognosis.” They said the best doctors’ behavior reflected expertise, especially for pain control, whereas the worst behavior reflected nervousness, communication first with family and then the patient, and use of euphemisms.
Not All Patients Are the Same
In Dr. Muss’ experience, there are several types of attitudes patients may express. There are those who are “content with the news” and accept their physicians’ word that the time for hospice has come. There is a considerable “middle group for whom the conversation keeps on going” about new drugs they hear about. Finally, there are a certain percentage who “refuse to give up” until they are faced with the undeniable fact that nothing else can help them. None of these attitudes, he said, “is right or wrong.”
Last Lines of Treatments
“The question is what do you do for the patient after you get to this point?” Dr. Muss observed that “a determined few want treatment to the end.” Especially in heavily treated patients, the goal is to control the disease and manage symptoms with the least toxicity.
He described three approaches he has taken in this regard. According to Dr. Muss, whatever treatment approach one takes should be grounded in science. “More and more patients are sophisticated and can look things up on PubMed…. The worst thing you could do would be to prescribe something of questionable value or homeopathic doses that don’t work at all. With this approach, patients will lose all trust in you at a very bad time in their lives.”
One regimen is low-dose cyclophosphamide and methotrexate. In a study of 63 patients who have had prior chemotherapy and a good performance status, researchers evaluated oral cyclophosphamide at 50 mg/d plus and methotrexate at 2.5 mg twice daily on days 1 and 2.5 There were 12 responses (2 complete responses), for a response rate of 19%, and 8 patients were stable for more than 24 weeks. Median time to disease progression was 3 months, and the treatment was tolerated, with five patients experiencing grade 3 adverse events (one with anemia, five with elevated transaminase levels). Three patients had grade 2 nausea or vomiting, and a few had mild hair loss.
“This is an easy regimen to give. These drugs are approved and are inexpensive,” Dr. Muss noted.
Metronomic liposomal doxorubicin is another option whereby the drug is administered routinely at low doses. This agent was evaluated in a study of 44 patients of whom 13% had HER2-positive disease, 76% had received at least two prior chemotherapy regimens, and 51% had had prior anthracyclines.6 Treatment with liposomal doxorubicin at 20 mg/m2 every 2 weeks resulted in an 18% response rate (all partial responses) and a 45% clinical benefit rate, with median progression-free survival of 4.2 months and median overall survival of 17.6 months. There were no grade 3 or 4 hematologic or nonhematologic toxicities; two patients developed grade 2 hand-foot syndrome. “Toxicity was minimal with this regimen. For patients with a poor performance status, starting metronomic liposomal doxorubicin at 15 mg/m2 may be a good option,” added. Dr. Muss.
Metronomic eribulin is another approach, as shown in a study that incorporated smaller doses (0.9 mg/m2 on days 1, 8, and 15 every 28 days) than were used in the registrational phase III EMBRACE trial.7 The study included 59 patients, 22% of whom had HER2-positive disease. All had received prior taxanes, 67% had received anthracyclines, and 80% had received at least two prior chemotherapy regimens. The response rate was 15%, including one complete response, and 48% achieved clinical benefit. Median progression-free survival was 3.5 months, and median overall survival was 14.3 months. Grade 3 or 4 neutropenia was reported in 19%, grade 3 peripheral neuropathy was noted in 5%, and treatment discontinuation because of toxicity was reported in 3%.
Life Lessons Learned
Dr. Muss summarized the lessons he has learned from treating patients with breast cancer at the end of life. “When metastases are detected, we want a soft landing. I tell patients, ‘We can’t get rid of this for good, but we may be able to treat you with something that will provide hope. Of course, you look at the tail of the Kaplan-Meier curves and always hope that patients will be on that tail.”
He continued: “You wait for questions and cheerlead within reason. As time goes on, you introduce existential issues, always framing things positively. You make sure the patient’s directives are clear, and when possible, you offer ways the patient can give back.” For example, Dr. Muss described the Lineberger tumor donation program into which patients can donate tumor samples for research after their deaths. “Many patients accept this and are happy to do it as a way to give back,” he shared.
“When there is little to be hopeful for, reinforce that you will always be there for them and that there is always something to be done in terms of pain control and other symptoms. I remind people that miracles happen without doctors and that making peace is important, such as by writing letters to family and friends,” Dr. Muss concluded. The Stanford University website (med.stanford.edu/letter/friendsandfamily.html) offers help to patients to compose such letters.
DISCLOSURE: Dr. Muss reported no conflicts of interest.
REFERENCES
1. Muss HB: Metronomic chemotherapy, hope, and end-of-life care. Invited Lecture. 2023 Miami Breast Cancer Conference. Presented March 3, 2023.
2. Bonotto M, Gerratana L, Iacono D, et al: Treatment of metastatic breast cancer in a real-world scenario: Is progression-free survival with first line predictive of benefit from second and later lines? Oncologist 20:719-724, 2015.
3. Weeks JC, Catalano PJ, Cronin A, et al: Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 367:1616-1625, 2012.
4. Hagerty RG, Butow PN, Ellis PM, et al: Communicating with realism and hope: Incurable cancer patients’ views on the disclosure of prognosis. J Clin Oncol 23:1278-1288, 2005.
5. Colleoni M, Rocca A, Sandri MT, et al: Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: Antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73-80, 2002.
6. Munzone E, Di Pietro A, Goldhirsch A, et al: Metronomic administration of pegylated liposomal-doxorubicin in extensively pre-treated metastatic breast cancer patients: A mono-institutional case-series report. Breast 19:33-37, 2010.
7. Chalasani P, Farr K, Wu V, et al: Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer. Breast Cancer Res Treat 188:91-99, 2021.
