Many cancer clinical trials focus on testing new treatments or testing treatments in new settings, with the hope that these treatments will lead to improvements in survival. A second type of trial looks at whether using less treatment or a less invasive form of treatment can provide similar benefits to standard care while coming with less severe side effects. Trials that test whether less is more when it comes to treatment are called de-escalation trials.
Results from a variety of de-escalation trials were presented at the 2018 San Antonio Breast Cancer Symposium (SABCS), which took place Dec. 4-8.
“De-escalation of cancer treatment in general is an important topic,” said Elaine Schattner, a patient advocate, journalist and physician from New York City who attended the meeting and spoke to Cancer Today about the topic. “It matters to patients. Many now are alive and are suffering from side effects of what turned out to be too much therapy.”
Some trials are testing whether patients can take a lower dose of a drug or take a drug for a shorter period while still receiving similar benefits to those provided by the standard treatment. The TAM-01 trial, whose results were presented at SABCS Dec. 6, looked at the effects of a low dose of tamoxifen in patients who received surgery for hormone-sensitive noninvasive breast conditions, including ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and atypical ductal hyperplasia (ADH).
Currently, individuals with precancerous conditions that put them at high risk for invasive breast cancer are often advised to take 20 milligrams of tamoxifen per day for five years. For patients who are postmenopausal, an aromatase inhibitor or raloxifene can also be an option. However, many people stop taking risk-reducing therapies or choose not to start them because they come with a variety of side effects, such as hot flashes, sleep problems, vaginal dryness and pain during sex. In rare cases, tamoxifen leads to dangerous side effects, including blood clots and endometrial cancer.
The researchers randomly assigned 500 patients with DCIS, LCIS or ADH to receive a low dose—5 milligrams—of tamoxifen per day or a placebo for three years. After following the patients for a median of around five years, the researchers found that those who received low-dose tamoxifen had about half the risk of recurrence or developing a new breast cancer or precancerous condition as those who received the placebo—a similar level of benefit as seen in earlier trials of the 20-milligram dose. Risk of recurrence or new disease was 5.5 percent in patients who took the low dose of tamoxifen and 11.3 percent in those who received the placebo.
Further, patients who took the low dose of tamoxifen experienced few side effects. Patients using the 5-milligram dose of tamoxifen did not report hot flashes, vaginal dryness or pain during intercourse at a rate significantly higher than patients taking the placebo. And taking the low dose of tamoxifen did not appear to increase the rate of endometrial cancer or blood clots.
“When you look at drug development, we rush these drugs out and don’t pay attention to the dose that’s needed,” said Virginia Kaklamani, leader of the Breast Cancer Program at UT Health San Antonio, during a press conference she moderated. Providing a lower dose and reducing side effects could mean that more patients are able to tolerate the drug and stay on it.
Kaklamani said that based on the results, she would offer a lower dose of tamoxifen to patients with LCIS and LDH and consider the lower dose in patients with DCIS if they were having trouble tolerating the higher dose due to side effects.
No company makes 5 milligram tamoxifen tablets currently, but study leader Andrea De Censi said in the press conference that patients can either take 10 mg pills every other day or cut the pills in half. De Censi is director of the medical oncology unit at the National Hospital E.O. Ospedali Galliera – S.C. Oncologia Medica in Genoa, Italy.
Of course, the decision of whether to shorten therapy or reduce the dose of a drug is not always clear-cut. The PHARE trial, for which results were presented at SABCS Dec. 5, investigated whether those with early-stage HER2-positive breast cancer should take six months of the targeted therapy Herceptin (trastuzumab) after surgery instead of taking the drug for a year. The trial was a non-inferiority trial, meaning that it was set up to determine if taking the shorter duration of Herceptin was no worse for disease-free survival than taking the standard year-long course of therapy. The researchers concluded that the standard of care should still be 12 months of Herceptin. These results contrast with those of the PERSEPHONE trial, presented earlier this year, which concluded that taking Herceptin for six months wasn’t substantially less effective than taking it for a year.
A Less Invasive Option
Surgical oncologists are also exploring treatment de-escalation. At SABCS on Dec. 6, researchers presented the long-term results of the AMAROS trial, which investigated whether some early-stage breast cancer patients can avoid surgery to remove lymph nodes in their armpits and instead receive radiation therapy to the area.
Twenty years ago, it was standard for women with early-stage breast cancer to receive surgery to remove large numbers of lymph nodes in their armpits to determine if the cancer had spread beyond the breast and to reduce risk of recurrence. Today, it’s common to avoid extensive lymph node surgery in some patients by first performing sentinel node biopsies—biopsies done on the first lymph nodes into which the area with the tumor drains.
Most recently, studies including the AMAROS trial have investigated whether it’s safe to avoid extensive lymph node surgery in some patients even when cancer is found in sentinel nodes.
The AMAROS trial was limited to patients with small tumors who didn’t have any cancer in their lymph nodes detectable by ultrasound or when examined by touch. The patients received sentinel node biopsies. They were randomly assigned before their sentinel node biopsy to receive either radiation or extensive surgery to remove the lymph nodes. They only received the treatment if the biopsy detected cancer.
Ten years after treatment, the patients assigned to receive radiation had similar rates of recurrence to the armpit region, distant metastasis-free survival, and overall survival compared to those who had surgery to remove their lymph nodes. For patients receiving radiation therapy, overall survival was 81.4 percent, while it was 84.6 percent for those who had surgery. The same trial previously showed that five years after treatment, patients were significantly more likely to be diagnosed with lymphedema if they received surgery to remove their lymph nodes than if they got radiation instead.
Some other randomized trials have recently shown that survival and disease-free survival are similar for patients with limited lymph node metastases whether they received surgery to remove the lymph nodes in their armpits or no further surgery in the area.
“This is really the beauty of this sort of de-escalation in therapy where you’re improving the morbidity of our patients … without compromising their outcomes,” said Kaklamani, the moderator of a press conference where the results were discussed.
The Patient Perspective
Stacey Tinianov, who was diagnosed with breast cancer in 2013, is in favor of research that will help improve quality of life for patients but says she prefers other terms to de-escalation. “I don’t look at it as de-escalation per se. I really look at it as, ‘What is the right treatment for you?’” she said.
Patients will need to work with their doctors to choose the best therapy. Alongside learning about their cancer’s biology, patients need to determine their own definition of quality of life, said Tinianov, a patient advocate and patient and community engagement consultant living in Santa Clara, California, who attended the SABCS meeting.
Schattner, the physician-turned-patient advocate, said that patients can make sure they’re getting the best treatment for them by asking a lot of questions. “Before signing on to treatment, a patient should ask her or his doctor, ‘What are my options? What would happen to me if I didn’t take this treatment? Is there a lesser treatment or a less toxic treatment that I might take?’”
The answer may be that more extensive treatment will be more effective. “There are some patients for whom de-escalation might be a mistake,” Schattner said.
Even for patients who conclude that they need more rather than less treatment, having data to back up that decision may be helpful. “Any research that can be done that will inform future patients’ decisions to take more and not less would be very valuable, in the sense that it could spare others the toxicity of those extra treatments,” said Schattner. “Those who would do poorly if they did not get extra treatment would feel confident of their decision to take more because they would know that they needed it and that they were more likely to benefit from that extra treatment.”
December 12, 2018