Deborah Abrams Kaplan

Bob Schulz knew something was wrong when he had a hard time walking up the hill while golfing in December 2018. At 73, he still walked the 18 holes at the Albuquerque, New Mexico, golf course every week. After a chest X-ray, his doctor sent him to the hospital immediately. Two liters of fluid were removed from Scholz’s lungs several times during his four-day hospital stay. Extensive testing revealed malignant pleural effusion, or excess fluid and cancer cells between the tissues separating the lungs from the chest cavity.

Bob Scholz received a diagnosis of diffuse large B-cell lymphoma in 2018.

Scholz sought a second opinion at The University of Texas MD Anderson Cancer Center, in Houston, a 13-hour drive away. There, he received a diagnosis of diffuse large B-cell lymphoma. He and his wife, Cindy, quickly packed up and moved to Houston for six months of R-CHOP chemotherapy, a combination of five drugs infused to kill cancer cells.

After chemotherapy, Scholz thought he was cancer-free, but in late 2020 he lost his voice completely, which sent him back to his oncologist at MD Anderson. A positron emission tomography scan revealed a recurrence of lymphoma in his throat, lung and liver. This time his doctor offered him treatment through a clinical trial for natural killer (NK) cell therapy, a type of infusion therapy that uses the body’s natural killer immune cells or donor NK cells, which are grown into larger quantities and sometimes genetically engineered with additional targeting abilities.

Scholz and his wife, Cindy, moved to Houston so he could receive treatment at The University of Texas MD Anderson Cancer Center.

NK cells are a type of white blood cell in the immune system that can kill cancer and virally infected cells. “They have the innate ability to recognize and attack cells infected with viruses or cancer cells,” says Dr. Sarah Holstein, a multiple myeloma researcher and an associate professor of internal medicine at the University of Nebraska Medical Center in Omaha. However, cancer cells can sometimes evade NK cells’ ability to interact with and kill cancer cells. “The idea behind NK cell therapy is to augment the body’s natural NK cell response and increase it and, hopefully, lead to a more direct cell-killing effect against the cancer cell,” she explains.

Over the past two decades, researchers have studied various ways to do this; for example, by collecting the patient’s NK cells, growing them and then reinfusing them. When using the patient’s cells, it’s called an autologous adoptive transfer. Doctors also are growing cells from donors, called allogeneic adoptive transfer. These cells come from sources such as cell lines, peripheral blood or pluripotent stem cells, which can be found in neonatal foreskin or the umbilical cord, for example. Pluripotent stem cells have the ability to differentiate into many types of mature cells and can develop into NK cells or other needed cell types. “One cell in the lab can produce millions of NK cells,” says Dr. Paolo Strati, an assistant professor in the department of lymphoma and myeloma and the department of translational molecular pathology at MD Anderson Cancer Center. More recently the field has evolved to study genetically engineered NK cells, such as chimeric antigen receptor (CAR)-NK cells, that have the ability to recognize a specific target on the cancer cell.

Prior to his diagnosis, Scholz enjoyed golfing every week.

Following three days of chemotherapy to prepare his immune system, the doctors gave Scholz three infusions of modified NK cells. He finished his treatment in early 2021 and is in remission. “I’m thankful every day about how fortunate I was to go there. I’m thankful to have that kind of a place with treatments with that chance of success,” he says.

Dr. Jeffrey Miller, a professor of medicine in the division of hematology, oncology and transplantation at the University of Minnesota in Minneapolis, has been researching NK cell treatments for more than 25 years. He published a paper in 2005 about administering haploidentical allogeneic NK cells, which were taken from a related donor, to patients. The research showed that the cells can persist and expand in the body and may have a treatment role. His 2014 update, which was published in 

, included 57 patients with relapsed/refractory acute myeloid leukemia (AML). Researchers used the immunotoxin interleukin (IL)-2 diphtheria toxin fusion to deplete T regulatory cells and thereby help improve NK cell growth rates. In the study, successful NK cell expansion correlated with remission. Patients were given NK cells, cytokines and lymphodepleting therapy.

“There was excitement in the field when we started to see (complete) response rates between 25% and 40% with those updates,” Miller says. “These were patients who progressed after standard therapy and had no other options.” The response allowed some patients to become eligible for allogeneic bone marrow transplants, even when they were not previously eligible.

Today, researchers are trying different trial designs, including an NK multidose strategy from allogeneic cells. “We couldn’t do it when we had to collect cells from individual donors. That only gave us one cell dose,” Miller explains. Allogeneic cells can be expanded much faster, allowing for multiple doses and freezer storage until needed. Some trials are now giving up to six weekly doses of these off-the- shelf cell products, and doctors can infuse the cells in an cell expansion correlated with remission. Patients were given NK cells, cytokines and lymphodepleting therapy.

Nancy Gessmann received a diagnosis of multiple myeloma after seeing her primary care doctor for back pain and a fever.

Today, researchers are trying different trial designs, including an NK multidose strategy from allogeneic cells. “We couldn’t do it when we had to collect cells from individual donors. That only gave us one cell dose,” Miller explains. Allogeneic cells can be expanded much faster, allowing for multiple doses and freezer storage until needed. Some trials are now giving up to six weekly doses of these off-the- shelf cell products, and doctors can infuse the cells in an outpatient clinic instead of during a hospital stay. “The cells are thawed at the bedside and given, and the patients are watched for a few hours for allergic reactions,” Miller says.

The idea behind multidosing is that NK cells don’t persist in the body for as long as T cells, which are used in CAR-T cell therapy. “Think of it as a living drug,” Holstein says. “Once you put them in, those engineered cells persist and continue to fight against the tumor, should there be any remaining tumor cells that flare up again.” Researchers don’t think the NK cells can live as long as T cells, “but we don’t know if they need to live that long. Perhaps they’re super effective early on and we don’t need them to persist,” Holstein says.

In her multiple myeloma research, Holstein led a study that explored the use of off-the-shelf NK cell therapy given shortly after the time of a stem cell transplant. “There are data showing that early recovery of the patient’s own NK cells after a stem cell transplant is associated with improved outcomes. It is hypothesized that this early recovery of NK cells is contributing to the killing off of residual myeloma cells,” she says. By giving multiple doses of off-the-shelf NK cells — or allogeneic cells — researchers are hoping to boost the effect, ensuring that there’s enough time for NK cells to attack any errant myeloma cells during the critical bone marrow recovery time. “At this time, we’re not sure yet if this approach is effective,” Holstein explains.

Although more recent trials are studying multiple dosing, earlier trials such as Holstein’s used one dose. That’s partly because it was difficult to grow enough cells for multiple doses per patient, even using donor cells. Nancy Gessmann was 59 years old when she enrolled in Holstein’s earlier trial in 2017.

She hadn’t heard of multiple myeloma before back problems and a fever sent her to her primary care doctor in Harlan, Iowa, in 2016. After receiving her diagnosis, Gessmann sought treatment an hour away at the University of Nebraska Medical Center, where she received chemotherapy followed by a stem cell transplant in May 2017.

During her 18 days in the hospital for the transplant, she received a single dose of allogeneic NK cells as part of Holstein’s phase 1 study, along with a series of seven cytokine shots (they help stimulate the NK cells) to help the cells expand. “It gave me hope that if there was anything out there that could help me, it was worth trying,” she explains. Aside from feeling tired after the transplant and growth factor shots — which are given to aid the therapy — Gessmann does not think she experienced any side effects from the NK cell infusion.

With the clinical trial, “I had the opportunity to possibly help myself, my family and others. I benefited from clinical research done by others before me with stem cell transplants and chemotherapies. Others helped my treatment plan and made it easier for me. I’m paying it forward,” Gessmann says.

NK cell therapy may have advantages over T cells. Infused CAR-T cells will recognize a cancer cell and attack it. One attack method involves releasing toxins called cytokines, which can lead to a hyperinflammatory state known as cytokine release syndrome (CRS). CRS is caused when a large number of cytokines, proteins made by some immune cells, are quickly released into the blood from immune cells. They can lead to CRS symptoms such as fever, but patients can also experience low blood pressure, low blood oxygen and neuro- toxicities such as difficulty finding words, and severe issues such as a seizure or coma. About 10% of patients receiving CAR-T cell therapy for lymphoma experience severe CRS, and 40% experience severe neurotoxity. “It’s a real problem; hence, we need to look into different treatments,” Strati says.

NK cells potentially can be less toxic than, and as effective as, T-cell therapy. “Treatment for me was extremely easy, and the results were great,” Scholz says. “It wasn’t like serious chemotherapies. I didn’t feel real good for a couple of days, but it was minor. There were no repercussions from treatment.”

The good thing about NK cells compared with T cells, Miller says, is that NK cells don’t induce graft-versus-host disease, which is when infused allogeneic T cells attack the patient’s healthy cells. NK cells are missing the mechanism in T cells that cause it. For NK therapy, “as far as we know, no known neurotoxicity or CRS has been reported in any consistent way today,” Miller says.

The CAR technology also is being used for some NK cell treatments. With CAR, “we engineer NK cells in the lab,” Strati says. “We make them able to recognize specific proteins on top of lymphoma.” Using donor cells, both CAR-T and CAR NK cells can be available to patients more quickly than the patient’s cells.

The first in-human trial in the United States with CAR NK cells was for relapsed/refractory CD19-positive B lymphoid malignancies. The trial encoded NK cells to recognize CD19 and express cytokine IL-15 to improve persistence. Results were published in a 2020 New England Journal of Medicine study, and it continues to receive a lot of attention, Holstein says. The phase 1 and 2 study showed proof of concept that CAR-NK therapy is possible and effective. Of the 11 patients, 8 had a response and 7 had a complete remission.

Researchers developed data for NK cells having a similar cancer-killing strategy but different recognition pattern as T cells, leading to “a crazy interest in NK cells,” Miller says. “Until the past decade, people mostly ignored NK cells.”

It’s not just academic labs pursuing them but also cell companies with their own constructs and expansion strategies. The field opened up considerably with the ability to grow billions of cells for off-the-shelf usage in the past 10 years.

Given the multibillion dollar market for anticancer anti- body therapy and the ability of cell therapy companies to genetically manipulate cells with CARs, “I would expect we’re going to see somebody close to clinical approval in the next three to five years,” Miller says.

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Donna Pinto began getting mammograms at age 40 because her grandmother died of breast cancer at 50. In 2010, a suspicious mammogram led Pinto, then 44, to a needle biopsy in her right breast. The pathology showed ductal carcinoma in situ (DCIS), considered the earliest form of breast cancer. DCIS refers to abnormal cells found only inside a milk duct.

Pinto’s surgeon wasn’t quite convinced, thinking the results might indicate atypical ductal hyperplasia, a marker for women who might have a risk factor for developing breast cancer.
A subsequent surgical biopsy showed intermediate-grade DCIS. Pinto was given two treatment options: full mastectomy or partial mastectomy with seven weeks of daily radiation.

She held off on treatment as she dove into research that revealed varying medical opinions, some saying to avoid treatment unless the diagnosis was high-risk DCIS, and that low- and intermediate-grade DCIS were potentially overtreated and more studies were needed. “That was different from the information I received,” says Pinto, who chose active surveillance.

With a rise in breast cancer screening has come a rise in DCIS diagnoses, which make up 20% to 25% of all breast cancers in the United States. More than 60,000 women each year receive a diagnosis of the condition. Labeled a stage 0 cancer, DCIS is considered pre-invasive.

How to treat DCIS continues to be debated and researched by the medical community. That’s because preventing an invasive breast cancer diagnosis in women with DCIS does not appear to reduce the chances of dying from breast cancer, which has led to concerns about overtreatment. In 20% to 30% of patients who don’t receive treatment, DCIS will progress to invasive breast cancer, according to Dr. Mridula George, a medical oncologist treating breast cancer at Rutgers Cancer Institute of New Jersey.

A month after the surgical biopsy, Pinto had a breast MRI followed by two mammograms over the next 18 months. The second mammogram showed potentially invasive cancer, so Pinto underwent two lumpectomies, the second to clean up the margins, which potentially
had cancer cells. 

The diagnosis was low- or intermediate-grade DCIS; a second pathology opinion downgraded it to low-grade. Because the margins were still potentially positive, her doctor again encouraged her to get a mastectomy or at least undergo three weeks of radiation. “I felt like I was being bullied,” she says. “I found a new doctor.”

The Oncotype DX Breast DCIS Score test, which was new at the time, showed that Pinto was at low risk of developing invasive cancer. Her DCIS has not progressed in 11 years. She started the website DCIS411.com to support and educate other women with the diagnosis.

The discussion about de-escalating surgery for low-grade DCIS and early-stage invasive breast cancer is not new, but there’s a continuing research focus to determine when it’s safe for women to avoid surgery.

Doctors tend to recommend lumpectomy for localized DCIS as a first treatment approach. After surgery, the patient often receives breast radiation. Mastectomy is not typically recommended, says Dr. Alastair Thompson, chief of breast surgery and a researcher at Baylor College of Medicine in Houston. The patient may also be given anti-hormonal therapy or an endocrine medication for longer-term protection against progression and future breast changes.

National Comprehensive Cancer Network (NCCN) guidelines call for performing a lumpectomy at a minimum for DCIS at any stage. “One thing to understand about medicine is that changing practice has to be based on evidence that shows it is not going to be detrimental 

to the patient in terms of future risk of invasive cancer,” George says. Currently, physicians cannot accurately predict which patients are at increased risk of progression to invasive cancer.

Women who decline breast surgery can consider taking anti-estrogen (hormonal) therapy to decrease the risk of progression if the cancerous cells express the estrogen or progesterone receptor. So far, preliminary studies support this approach for lower-grade DCIS, but larger studies are needed. “Most patients are more receptive to having the surgery versus taking a pill (long term),” George says. Hormonal therapy has potential side effects. For instance, tamoxifen, the treatment of choice for premenopausal women, can cause fatigue, hot flashes, and a small risk of developing blood clots or uterine cancer.

Women who receive a DCIS diagnosis in their 30s and 40s or have a family history of breast cancer may want to get genetic testing, George says. Those with mutations such as BRCA1 or BRCA2 have an increased risk of DCIS turning into invasive breast cancer, and a bilateral mastectomy might be recommended. A patient who takes that route would not need radiation or hormonal therapy if the tumor is estrogen- or progesterone-receptor positive, George says.

“It’s ironic that, in the 1990s, the data was saying we can do breast conservation, and surgeons who didn’t grow up with that were uncomfortable with it. Women wanted to conserve their breasts,” says Dr. Benjamin Anderson, a breast surgeon at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle. “Now, the pendulum has swung. More women want bilateral mastectomies, and surgeons are saying you don’t need to do that.”

Researchers in clinical trials are investigating whether surgery offers a benefit. For instance, the COMET trial, which began in 2016, is comparing surgery with or without radiation, as well as with or without endocrine therapy, to active surveillance with or without endocrine therapy for five years. Researchers want to determine which groups of women with low-risk DCIS might be spared from surgery. Thompson, one of the trial’s co-principal investigators, says they’ve recruited 568 of the 1,200 participants needed. “It will be awhile before we determine what the answer is,” Thompson says. After recruiting ends, it will take at least two years of follow-up to reach the first reporting point to determine results.

Two European trials tried to answer the same question but closed early because not enough patients were recruited. “Most folks know they want one treatment or the other and are not willing to be randomized,” Thompson says. A Japanese trial is offering active monitoring and tamoxifen, not surgery.

Thompson is also involved with the Precision collaboration, which builds on multiple studies conducted over the past 20 years in the United States, the United Kingdom and Europe. It aims to distinguish features of those with DCIS who will progress versus those who won’t.

The most common form of breast cancer, invasive ductal carcinoma, makes up 80% of all breast cancer diagnoses. It occurs when cancer that began in a milk duct moves into the breast tissue.

There’s flexibility in managing DCIS because the mortality rate is relatively low, according to Anderson. “(But) with invasive breast cancer, now you’re talking about a different arena,” he says.

Treatments include breast surgery, chemotherapy, radiation therapy, targeted therapy and/or hormonal therapy, depending on the cancer subtype. “These treatment options are used to reduce the chance of the cancer coming back and trying to prevent stage 4 cancer, which is not curable,” George says. Not all women need all three approaches.

Women with invasive breast cancer typically get neoadjuvant therapy, which is drug treatment before surgery, to shrink the tumor. Multidrug treatments are so effective in 30% to 50% of some subtypes, particularly for breast cancer that is human epidermal growth factor receptor 2 (HER2) positive or triple-negative, that the cancer 

will disappear, so there’s no tumor left at the operation, Thompson says.

Treatment used to be more difficult for those with HER2-positive invasive cancers. Drugs such as Herceptin (trastuzumab) and Perjeta (pertuzumab) have been game changers, Anderson says. Some patients have evidence of a complete pathological response, meaning the absence of any detectable cancer on samples of affected breasts and lymph nodes. “Those are the patients we say we might not have to operate on,” he says, though radiation would still be used. This approach is being verified in ongoing clinical trials but is not the current standard of care.

Women with invasive breast cancer typically get a sentinel lymph node biopsy, a procedure to remove the nodes to determine if cancer cells are present. It’s usually done during lumpectomy or mastectomy to look for cancer spread. Experts don’t recommend eliminating the procedure, because it helps with cancer staging and assessing the risk of disease recurrence based on the number of positive lymph nodes, George says.

Currently, not all patients get axillary lymph node dissection, which removes anywhere from 10 to 40 lymph nodes. Lymphedema is a possible long-term side effect of lymph node surgery, affecting 20% to 30% of patients. Excess fluid buildup causes swelling, usually in the arms and legs but sometimes affecting other parts of the body. Patients with one or two positive nodes who had breast-conserving surgery will get radiation, so dissection may not be done, George says. If the patient did not respond to neoadjuvant systemic therapy and has positive node involvement, axillary lymph node dissection will be considered.

“The group we now struggle with is those with mastectomies and one or two positive sentinel nodes,” says Dr. Lee Wilke, director of the breast center and a breast surgeon at the University of Wisconsin Health in Madison, because these women may not all get radiation. “The question is, is it safe to not remove the axillary nodes?”

Without surgery, it is difficult to determine if all cancer cells are eliminated from the tumor bed. Imaging cannot detect everything, and needle biopsies can miss spots. “There is no strong agreement as to what is the best form of imaging and biopsy to give you a very accurate assessment,” Thompson says. Leaving behind tumor cells is a missed opportunity to offer treatment that potentially protects against future cancer growth or spread.

Imaging might include mammogram, ultrasound, MRI or PET scans. Biopsies can be done with a small or big needle, with multiple passes necessary. “Bigger needles give a better idea of what’s there, but these biopsies are not trivial things to go through,” Thompson says, and there can be false negatives. At the moment, there’s no gold standard for assessing whether any cancer remains.

“If we don’t operate, we don’t have a good way of knowing if everything is gone,” he says.

Women with triple-negative breast cancer who experience a complete clinical response, with nothing seen in the breast or lymph nodes on biopsy, may in the future be advised to avoid surgery but still get radiation, Thompson says. At present, physicians still operate to prove nothing is left, he adds.

Liquid biopsy, which evaluates the blood for cancer cells, is approved for patients with stage 4 disease because the cancer has already spread. No liquid biopsy tests are approved for cancer stages 1 to 3 but are under active investigation to see if they can detect microscopic disease or predict who may have a higher chance of recurrence.

“The holy grail will be the ability to detect cancer cells in the blood and know whether there’s evident cancer still remaining,” Wilke says. Residual disease may or may not be seen in a liquid biopsy: “It’s like looking for a needle in a haystack.”

In 2007, Valerie Fraser learned she had two different cancers in the same breast: invasive ductal carcinoma and inflammatory breast cancer. Inflammatory breast cancer is rare, at 1% to 5% of all breast cancers. The diagnosis came after Fraser developed a quarter-size rash in her
left breast, which eventually swelled, doubling in size, resulting in multiple workups. Her cancer was HER2 positive, and she was treated with Herceptin, followed by Herceptin and chemotherapy. After chemotherapy, her breast looked normal again, and imaging showed a complete response with no evidence of tumors. In spite of this, doctors recommended the normal treatment — surgery and radiation — to kill any remaining cancer cells. At that time, biopsies were not done to look for a pathological complete response, she says, though she would have considered that approach.

Like Pinto, Fraser spent a lot of time researching her disease. She says the risk of recurrence for inflammatory breast cancer is greatest in the first two years, and getting radiation and mastectomy after chemotherapy would have eliminated these options if the cancer recurred later. Therefore, she decided to proceed with careful monitoring. She also continued with Herceptin, and 13 years later has had no recurrence. Fraser went on to become a research advocate and, with her oncologist, founded the Inflammatory Breast Cancer International Consortium (ibcic.org) to bring researchers together throughout the world to advance the science, medicine and treatment options.

Avoiding surgery was not a hard decision, Fraser says, though she knows it’s a psychologically difficult one for many women because they don’t know if they had a pathological complete response to treatment. Clinical guidelines for surgical treatment of invasive breast cancer have not changed in recent years, and surgery is still recommended, Thompson says.

However, neither DCIS nor invasive breast cancer is one condition, Thompson says: “What we as a community tend to do is group people together and assume they’re all the same.” Treatment decisions must be individual, with patients and their doctors being mindful that evidence for subgroups in both cancer types can benefit from a specific approach rather than an across-the-board decision.

George has patients in their 80s and 90s who opted to forgo invasive breast cancer surgery. They may take hormonal therapy if appropriate and follow up more frequently. These older patients with early stage cancers are more likely to die from other causes, she says.

With shared decision-making, doctors review the risks and benefits of each approach, and the patient decides what to do. “As physicians, we work with patients to make sure they are comfortable with whatever approach they take. We don’t have a crystal ball to know whether it’s right or wrong,” Wilke says.

Today, treatment is more personalized based on cancer type, stage, genetics, age and comorbidities. Twenty years ago, a conversation about breast cancer treatment would have taken her 30 minutes; now it can take an hour and a quarter or longer, Wilke says. “It’s a lot to factor in,” she says. “It’s important for people to understand they have a lot of options.”

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When Christopher Schade noticed blood in his urine in 2010, he found himself at the beginning of a long and challenging road.


A urologist found a tumor in his bladder, and Schade, now 66, received a diagnosis of urothelial cancer, the most common form of bladder cancer. The doctor removed the tumor and inserted chemotherapy into Schade’s bladder in the recovery room.

During a follow-up CT scan a year later, doctors saw no problems with Schade’s bladder, but found enlarged lymph nodes in his abdomen and neck area that turned out to be cancerous, likely spread from the bladder cancer. This time, Schade was treated with systemic platinum-based chemotherapy.

A stiff neck sent Schade back to the doctor in 2015, and that, too, was diagnosed as a recurrence of cancer in his lymph nodes. Offered chemotherapy or a clinical trial with two immunotherapies, Schade recalled his treatment in 2011, which he described as “not a pleasant experience.” He was working in the garage door business then, and chemotherapy’s side effects, which included the loss of his hair and physical strength, interfered. 

“I struggled to make it into work and function normally,” he says. So, in 2015, Schade chose the clinical trial, receiving a combination of Imfinzi (durvalumab) and tremelimumab for one year. Fortunately, the immunotherapy worked, shrinking his tumors, with side effects that included treatable pancreatitis and pneumonitis, both conditions caused by inflammation triggered by the immune-activating effect of the drugs.

Imfinzi is one of five immunotherapies approved by the Food and Drug Administration (FDA) for treatment in cases where bladder cancer progresses after chemotherapy. All the drugs are checkpoint inhibitors, meaning they interfere with the activity of proteins cancer uses to keep the immune system quiet so that it won’t attack. The treatment allows the body to more effectively recognize and fight the disease.

Similar to the others in its class, Imfinzi was approved in 2017 to treat patients with locally advanced (inoperable) or metastatic bladder cancer experiencing disease progression after responding to initial, or first-line, treatment with a platinum-based chemotherapy.
In addition, a couple of these drugs are available to patients with recurrent advanced or metastatic disease who cannot receive chemotherapy. But now, some patients have the opportunity to receive immunotherapy sooner, while they are still experiencing disease control from chemotherapy, as a means of prolonging their response.

Bavencio (avelumab), also approved in 2017 to treat disease progression or recurrence after chemotherapy, received the green light in June for use as a maintenance treatment, to be administered to patients with stable or improved disease immediately after first-line platinum-based chemotherapy for bladder cancer that, at initial diagnosis, was locally advanced or metastatic. This means that, after the completion of chemotherapy, eligible patients will no longer have to wait until their cancer returns to be considered for immunotherapy in order to lengthen or extend remission.

Metastatic bladder cancer is a challenging disease to treat, says Dr. Petros Grivas, a medical oncologist at UW Medicine in Seattle, an associate professor at the University of Washington and lead researcher of the JAVELIN Bladder 100 phase 3 trial that led to Bavencio’s approval by the FDA for this maintenance use. The prognosis for those whose disease is metastatic when first diagnosed is poor, and giving patients immunotherapy treatment earlier, when their cancer has responded to 

chemotherapy and not yet progressed, was shown to prolong overall survival, meaning the time from the start of treatment until death, and to delay disease progression.

The most common first-line treatment for metastatic bladder cancer is chemotherapy that combines a platinum agent — cisplatin or, if the patient cannot tolerate it, carboplatin — with gemcitabine, a chemotherapy that doesn’t contain platinum, Grivas says. For many types of solid tumors, including bladder cancer, this type of treatment is given for a set number of cycles, typically four to six, rather than indefinitely, as the treatment doesn’t cure cancer that has spread to distant locations in the body and can cause side effects.

After receiving up to six cycles of treatment, a patient with metastatic bladder cancer continues to see the doctor for follow-up visits to monitor for cancer progression. “Unfortunately, the vast majority of patients will develop progression of their cancer, usually within a period of months,” says Dr. Matthew Galsky, a medical oncologist at the Icahn School of Medicine at Mount Sinai in New York City. “It was always sort of a strange approach to stop treatment in the context of a metastatic cancer,” he says, “but we didn’t have anything better that would offer a favorable risk-benefit profile. Giving a treatment holiday seemed to be the best approach.”

Now, patients who have stable or improved disease after completing chemotherapy can potentially receive Bavencio to maintain those health benefits.

The JAVELIN Bladder 100 trial data showed a significant overall survival benefit for patients who received Bavencio immediately following chemotherapy compared with those who did not. The median overall survival for those who received Bavencio plus best supportive care was 21.4 months, compared with 14.3 months for those in the group that received best supportive care alone. “The study showed a very significant difference in terms of overall survival, as well as progression-free survival,” meaning the time from the start of treatment until disease worsened, Grivas says. It is expected that the results will change the standard of care for this population of patients. “It’s really exciting news for patients and their families,” Grivas says.

Under previous treatment guidelines, about 25% to 

55% of patients received another therapy if their disease progressed after initial chemotherapy. A patient might not receive treatment if their cancer was progressing too quickly or they were not fit enough for treatment, Grivas says. Making Bavencio available as a maintenance treatment will allow more patients to receive immuno

patients finishing first-line chemotherapy have a disease that is stable or improved, he says, and the majority of them will be eligible to receive immunotherapy. Exceptions include those who have active autoimmune disease or immunosuppression.

The use of Bavencio as a maintenance treatment exemplifies an important strategy in improving care for metastatic bladder cancer: moving FDA-approved drugs to an earlier therapy phase so they can have a larger impact, Galsky says.

There are two other key approaches, he adds. One involves identifying combination regimens capable of overcoming resistance to immunotherapies given alone. The other is using biomarkers — genetic alterations specific to patients or their cancers — to better identify who should receive which treatment. Based on analyses of the number of mutations in a patient’s tumor and whether the mass expresses the immune-dampening protein PD-L1, “there is some resurgence of interest in trying to better identify subgroups of patients who might do quite well with (checkpoint inhibitors) alone,” Galsky says.

Not surprisingly, the five immunotherapies already approved to treat disease that flares up after chemotherapy are attractive candidates to move to an earlier treatment setting, Galsky says. In addition to JAVELIN Bladder 100, Galsky led a second trial testing that concept. The randomized phase 2 study compared the immunotherapy Keytruda (pembrolizumab) given as maintenance versus placebo after first-line chemotherapy. This strategy is called switch maintenance therapy because, when initial treatment ends, the patient is switched to a different treatment for maintenance therapy, as is done with Bavencio.

The trial met its main goal of showing better progression-free survival, as well as higher response rates, with Keytruda. While it did not show a significant overall survival benefit, which was a secondary goal, “that’s probably mostly related to the smaller sample size and the fact that the study was underpowered to show a survival 

improvement,” Galsky says. His study also allowed patients with cancer that progressed on the placebo to instead get Keytruda, known as “crossover,” which may have diminished the observable overall survival benefit.

In some cancer types, such as lung cancer, chemotherapy may work better in combination with immunotherapy than 

it does alone in some patients, Grivas says, but that hasn’t been the case with metastatic bladder cancer. In that disease, he says, chemotherapy can help shrink or control the tumor, potentially allowing the immunotherapy to work better afterward. “These are all theoretical concepts,” Grivas says. “I don’t think we have a good answer for why the back-to-back approach seems to work better, so far, compared to the combination approach.”

One clinical trial, IMvigor130, did test chemotherapy in combination with immunotherapy to treat bladder cancer. Patients received platinum-based chemotherapy with or without 

(atezolizumab) as a first-line treatment. 

The study showed prolonged progression-free survival but on interim analysis did not show a significant overall survival benefit, Grivas says. He is watching for longer-term follow-up results from this and several other trials testing chemotherapy/immunotherapy combinations, including CheckMate901, which is investigating the immunotherapies Opdivo (nivolumab) and Yervoy (ipilimumab) with or without chemotherapy.

The immunotherapies approved to treat metastatic bladder cancer that worsens or comes back after chemotherapy, including Bavencio, target the PD-L1 and PD-1 signaling pathways, chains of chemical reactions that send messages to cells from their environment that suppress the immune response to tumors. Targeting these pathways stops the proteins PD-L1 and PD-1 from binding together and may boost the body’s immune response against cancer cells.

About half the patients in the JAVELIN Bladder 100 trial had a high level of expression of PD-L1 in their tumor, and they experienced a greater degree of overall survival benefit. However, an overall survival benefit also was seen to a smaller degree that was not statistically significant in patients with PD-L1-negative tumors, Grivas says. Because of that, he says, every patient completing platinum-based chemotherapy who has stable or improved disease should be considered for Bavencio maintenance treatment, as long as they don’t have any uncommon contraindications.

Even though patients both with and without PD-L1 expression in their tumors should be offered Bavencio maintenance, “biomarkers are the holy grail,” Grivas says, and many studies are looking at gene alterations that might help define which patients are best suited for immune checkpoint inhibitor therapy. Across the five immunotherapies approved for metastatic bladder cancer, “most of the studies suggest that PD-L1 expression has some ability to enrich for responses, but that hasn’t necessarily informed practice in most clinical disease states of bladder cancer because of the lack of great alternative treatment options,” Galsky says.

That said, the JAVELIN Bladder 100 researchers are working to identify data on different biomarkers in the tumor tissues that were examined in their trial, and they hope to present that data soon.

Carefully selecting patients for a specific checkpoint inhibitor is important, as these drugs have side effects, including a high cost that might not be entirely covered by health insurance. “It is extremely important to develop clinically useful biomarkers to guide treatment decisions,” says Dr. Sangeeta Goswami, an assistant professor of genitourinary oncology at The University of Texas MD Anderson Cancer Center in Houston. Using initial biopsy samples to identify a tumor’s genetic and immune attributes can help determine if a patient is a good candidate for a specific treatment, she says.

The rates of overall response to immunotherapies for bladder cancer, meaning the proportion of tumors that shrink or stay stable when treated, range from 17% to 25%, Goswami says. “One of the major questions is why the majority of patients aren’t responding to single-agent immune checkpoint therapy,” she says. According to Goswami, it’s important to start looking at combinations of a tumor’s genetic and immunological attributes to help predict response.

One promising biomarker is mutational burden, or a tumor’s number of genetic mutations, which research shows is potentially associated with a higher response rate to immunotherapy. IMvigor130 has also shown that when patients have both high tumor mutational burden and high PD-L1 expression, they experience improved progression-free survival compared with patients who have only one of the biomarkers, or neither of them. A proportion of patients who participated in the IMvigor130 study had this combination and markedly better outcomes with checkpoint inhibitors alone versus chemotherapy, Galsky says. 

Patients in the IMvigor130 trial received Tecentriq plus chemotherapy, Tecentriq alone or chemotherapy alone as a first-line treatment for metastatic bladder cancer. “A combination of those two biomarkers is emerging as a potentially powerful way to predict which patients would be best suited for immune checkpoint blockade, but further validation of that is required,” Galsky says.

To further parse which patients respond to immunotherapy for metastatic bladder cancer, Goswami and her colleagues used genetic sequencing data to find that patients who responded to treatment with checkpoint inhibitors in two previously conducted phase 2 trials were more likely to have the ARID1A gene mutation. This mutation is present in about 25% of patients with metastatic bladder cancer, 35% of those with endometrial cancer and 50% of those with ovarian cancer, she says. 

Goswami also observed that patients whose tumors had a higher expression of CXCL13, a protein involved in antibody-producing B cell immune activation, experienced improved overall survival. She hypothesized that since both biomarkers are important on their own, combining them could increase their ability to predict better treatment response. Using data from the same two trials, CheckMate 275 and IMvigor 21, she found that patients with both mutations experienced improved overall survival compared with those who had either biomarker individually or the absence of both.

Given that a minority of patients respond to immunotherapy, targeting the right patient, when possible, is important. “Increasing the response rate will change the landscape of treatment for these patients,” Goswami says.

While side effects occur with immunotherapy, they aren’t different in the maintenance setting compared with other settings. The Bavencio side effects in the JAVELIN Bladder 100 trial were similar to those already known to be associated with immunotherapy, Grivas says, and no new safety issues were found during the trial. 

The most common serious side effects observed in the trial, which occurred more frequently in the group that took Bavencio, were urinary tract infection, anemia, the presence of blood in urine, fatigue and back pain. No severe side effects or deaths were reported. Diarrhea and rash are also fairly common side effects of checkpoint inhibitors.

“These are drugs that will be used when patients progress anyway,” Galsky notes, so individuals who take maintenance immunotherapy may simply experience side effects a few months earlier than they would have otherwise.

Warren Buikema, now 73, experienced some side effects after he received immunotherapy for progressive bladder cancer in 2018.

He initially received a diagnosis in 2016 after experiencing burning with urination. His first treatments consisted of surgery to remove the tumor and insertion of Bacillus Calmette-Guérin (BCG), a type of immunotherapy for earlier-stage cancer, into the bladder.

During a regular follow-up, the doctor found lesions in Buikema’s bladder that weren’t healing and eventually became cancerous. In 2018, Buikema entered a clinical trial, receiving a combination of chemotherapy and the immunotherapy Opdivo (nivolumab). To avoid further cancerous lesions, Buikema had his bladder surgically removed in 2019.

Likely as a result of the immunotherapy, Buikema was told, he experienced thyroid problems leading to the need for thyroid replacement medication. While the immunotherapy treatment left him feeling foggy and disconnected for a short time following its administration, he says, that side effect wasn’t bad.

Despite the possibility of side effects, Galsky believes that immunotherapy maintenance treatment in patients with advanced or metastatic bladder cancer is a true breakthrough and worth strong consideration by patients and their doctors.

“In general, the results seem favorable enough to change practice, in my opinion,” he says of Bavencio maintenance. “This is the largest degree of benefit in terms of overall survival that we’ve seen in a randomized phase 3 trial for metastatic urothelial cancer.” “This is a very exciting time in the bladder cancer area, because we’ve been doing chemotherapy for the last 30 to 40 years,” Goswami adds. “We now have so many options. We have to make it more personalized to see how we sequence therapy and how we know what biomarkers to use for treatment.”

Patients with advanced or metastatic bladder cancer, after responding to initial treatment with chemotherapy, may preserve their health improvements by starting immunotherapy immediately.

Immunotherapy Just After Chemo May Allow Some Patients with Bladder Cancer to Maintain Health Benefits

When Bill Warner received a diagnosis of a possible bile duct tumor in December 2012, he underwent an endoscopic retrograde cholangiopancreatography (ERCP). This procedure uses a duodenoscope, a tubular, flexible endoscope with a light, camera and biopsy tools.

Doctors were unable to biopsy during several ERCP procedures, and after additional testing, he had surgery in February 2013 to remove and test part of the tumor in his liver. He and his wife, Carla Warner, breathed a sigh of relief when the results were benign. Their relief was short-lived.

Within a few weeks, Bill had a low-grade fever and didn’t feel well. Blood tests revealed carbapenem-resistant Enterobacteriaceae (CRE) bacteria.

“As the infection became stronger and stronger, he became weaker,” Carla says. The former concrete mixer driver lost 60 pounds over the next eight months and experienced weakness, delusions and “unbelievable pain,” she says. The only antibiotics that could treat the infection either caused kidney damage or made him vomit. Bill died from the infection in November 2013 at age 55.

CRE are, by definition, bacteria resistant to the carbapenem class of antibiotics, the last-resort treatment for severe infections. Mortality rates for those infected with CRE and related superbugs are up to 50%.

At the time, Carla and her husband’s doctors did not know how Bill had acquired the infection. Then, in spring 2015, while getting ready for work, she caught a morning television news segment that linked a child’s CRE infection to a duodenoscope used during ERCP. “His story was almost identical to ours. It was deja vu,” she says. Friends and family started texting: “Are you watching the news? Isn’t this what Bill had?”

Carla requested her husband’s medical records and found the duodenoscope maker and model. According to testimony before the Food and Drug Administration (FDA) and a 2015 

story, the model used, an Olympus TJF-Q180V, was later associated with similar infections. It turned out that duodenoscopes from several manufacturers had designs that did not allow complete cleaning and disinfecting of tiny crevices in the movable elevator mechanism, even when medical centers followed manufacturers’ cleaning recommendations.

The FDA, researchers and device manufacturers are looking at updated disinfection or sterilization guidelines to minimize risks going forward, as well as design changes, such as manufacturers making disposable parts or instruments. The strategies vary in popularity and acceptance, with associated cost concerns.

Although CRE infections from duodenoscopes made the biggest news splash, other endoscopes have been associated with infection transmission, too, though to a lesser extent. Recent research in the journal 

showed that bronchoscopes, inserted through the nose or mouth to inspect the lungs, may have a higher risk of transmitting superbugs like CRE or other multidrug-resistant organ- isms than previously thought. This seems to be connected to procedures used for reprocessing — disinfecting or sterilizing &mdash; the scopes. In certain circumstances, current reprocessing guidelines and instructions may not be enough to eliminate the low risk of transmission.

A handful of cases in 2016 linked gastroscopes, which are used to inspect the stomach, to superbug infections, and a few reports suggest that, although also a low risk, improperly reprocessed colonoscopes could expose patients to CRE infections, said Lawrence Muscarella, a consultant in quality improvement and health care safety who holds a doctorate in bioengineering and works with health care organizations and device manufacturers on causes of infection and prevention.

All of this poses a concern for those who have or had cancer and require repeated scoping. It also affects people predisposed to cancer who need ongoing surveillance, patients with unexplained gastrointestinal symptoms and those who simply get routine screening colonoscopies.

About half a million ERCPs are performed in the U.S. each year, and that’s just a fraction of 56 million upper endoscopies. In addition, 19 million colonoscopies are performed, according to an analysis conducted by iData Research.

“Any time there’s an invasive procedure, regardless of the type, there’s always a risk of bacterial translocation,” says Dr. Elizabeth Robilotti, an infectious disease specialist at Memorial Sloan Kettering Cancer Center. There are two ways to get an infection. The first, translocation, occurs when normally present bacteria move from their regular environment to another part of the body. Bacteria could travel from, say, the colon to the prostate during a transrectal prostate biopsy procedure or from the gut or skin into the blood, where there is no barrier to the development of infection. Although the risk exists, it’s exceedingly rare in healthy people, she says, and even rare in immuno- compromised individuals.

The other way to be infected is by acquiring someone else’s bacteria from an improperly reprocessed endoscope.

Remaining CRE bacteria are not inherently resistant to endoscopic cleaning, Robilotti says; rather, the cleaning process does not always allow full access to the instrument. “Cleaning

of the duodenoscope is a recognized challenge,” she says.

The bronchoscope’s design is less complex, but if the device is not properly serviced, it can pose a risk of transmitting CRE even when cleaned according to manufacturers’ instructions, Muscarella says.

A study he co-authored found that damage and inadequate maintenance were risk factors for bronchoscopes exposing patients to bacteria. Bacteria can be deposited in tiny cracks and tears, out of reach of cleaning processes, and grow in a resistant biofilm. The risk is low, and exposure does not guarantee infection, Muscarella adds.

The bacteria causing the CRE outbreaks were likely present in health care facilities before becoming drug-resistant, so infected patients received successful antibiotic treatment or recovered on their own. As recently as 20 years ago, bacteria like Klebsiella and E. coli, which today may be considered CRE, were susceptible to several types of antibiotics, according to Muscarella. “Transmissions may have been happening, but in the past, they were eradicated by the antibiotics or the patient’s own immune system,” he says.

The wide use of antibiotics and the constant development of new ones to address resistance has led to a long list of “superbugs.”

The chances of passing along bacteria on endoscopes can be reduced in several ways: repeating the disinfection, implementing sterilization or using partially or completely disposable endoscopes.

Flexible endoscopes are considered semicritical devices that normally come in contact with mucous membranes but not blood or otherwise sterile tissue. Although the FDA prefers that they be sterilized, it requires only disinfection. However, in spite of health care facilities following manufacturers’ directions for disinfecting flexible endoscopes, including duodenoscopes, the FDA reported in a 2018 study that up to 3% of duodenoscopes tested were considered reprocessing failures after being found positive for high-concern organisms, and up to 3% tested positive for low-concern organisms. The agency had expected a total failure rate of less than 0.4%. After cleaning with brushes and a detergent, high-level disinfection includes immersing an instrument in a liquid chemical germicide for the FDA-recommended amount of time, at the right concentration and temperature. The agency suggests repeating the process to ensure that it is done properly.

Some health care organizations are switching their protocol to sterilizing, instead of disinfecting, flexible endoscopes. When it comes to duodenoscopes, the FDA recommends sterilization over high-level disinfection when possible and practical, though availability of this method is limited. Sterilization can be difficult because the heat can damage components. One technique uses pressurized steam, but for more delicate instruments, organizations can use a low-temperature liquid chemical processing system, a sporicidal technology. Ethylene oxide gas is another sterilization option.

In 2018, North Dakota’s Altru Health System was the first to sterilize the duodenoscope. “I’m encouraged to know that there are some hospitals out there that are using sterilization (for these instruments),” Carla Warner says.

“If tested, these should not grow any type of bacteria or show any signs of leftover biomatter.”

Some hospitals may be reluctant to sterilize bronchoscopes or rigid endoscopes, Muscarella says, especially if the central reprocessing area is in the basement, requiring more careful tracking and monitoring of the instruments. When scopes are reprocessed closer to procedure rooms, they spend less time out of commission for cleaning, so the hospital can keep a lower inventory of them, he says.

Using sterilized equipment, even if not mandated by the FDA, can still be cost-effective, according to Carla. If hospitals realize that sterilization is a deciding factor for patients, they can highlight the practice in their advertising, she says.

To give duodenoscopes a safety update, the FDA recommends that health care systems transition to instruments with disposable components, such as end caps, or to fully disposable devices, allowing for more effective reprocessing or eliminating the need for it.

Currently, five manufacturers offer disposable end caps, and singleuse duodenoscopes are entering the market. The FDA approved a Boston Scientific model in December 2019. Disposable bronchoscopes are available, Muscarella says, but not widely used in the U.S.

One problem with disposable devices is cost and who pays it. The Boston Scientific single-use duodenoscope is expected to cost $3,000, and insurance coverage is not yet guaranteed, according to 

. Hospitals already own reusable scopes at upward of $40,000 each. “(If insurance doesn’t cover a disposable scope,) the burden could shift onto the patient to decide whether to purchase it themselves, and that doesn’t typically happen in medicine,” Muscarella says.

If hospitals can’t negotiate the price, disposable instruments could be too expensive, he says.

Other concerns with disposable scopes include reuse for economic reasons. Inexpensive disposable equipment is discarded, Muscarella says, but there could be a financial incentive to reuse costly single-use devices, which is counter to their purpose. Also, disposable scopes would not prevent infections caused by bacteria’s movement from one part of the body to another. “The infection rate is not entirely eliminated by single-use endoscopes, but clearly, it would prevent patient-to-patient trans- mission,” Muscarella says.

Patients don’t always know what to ask their doctors regarding recommended endoscopies.

When Carla had to schedule a spinal fusion after her husband died, she asked the doctor to explain each step from beginning to end, telling her how every item in the operating room would be reprocessed, which ones would have been sterilized, and which would be new or unused. “He was a little taken aback by the question, and it was something he had not discussed with a lot of patients,” she says. She also asked why he chose to work at that hospital.

When he said it was because of lower infection rates, she was satisfied. After she shared her reasons for asking such detailed questions, the doctor said, “I should be having this discussion with all my patients.”

Carla recommends also asking about the equipment and model numbers, steps taken to clean the endoscopes, whether the scopes are sterilized or disinfected, and whether they are inspected with a borescope, a small instrument that helps detect tears and defects that can harbor bacteria. Not all physicians understand how reprocessing works because they are involved only with the procedure, but Carla encourages physicians to visit the central reprocessing area to learn. “The first red flag for me is if a physician can’t tell me the steps, they take to make sure the patient is safe,” she says. If the medical staff, including the receptionist, do not take concerns seriously and provide answers, patients should find a new doctor or facility, she says.

Muscarella agrees that patients have some control and power because they can decide where to have procedures done. They can tell doctors or clinics that they plan to call several facilities and choose the one that best meets their requirements. For instance, patients could look for a facility with a robust safety program, which could include using a certain type of endoscope or sterilizing instruments instead of disinfecting them.

These conversations are one positive result of the infection outbreaks, says Andrea Dwyer, director of the Colorado Colorectal Screening Program and adviser to the patient advocacy group Fight Colorectal Cancer. In addition to asking about procedure risk, “it’s OK to ask how many procedures the doctor does per year, the volume — and, if something happens, how to follow up and who to follow up with,” she says.

Infection following an endoscopic procedure could occur within 24 hours or longer, says Robilotti. During diagnosis, doctors consider the severity of the illness and may test for infection in multiple sites, such as blood, urine and possibly bile, if a bile drain is involved. “We have to put the whole clinical picture together to establish if certain signs or symptoms are from an infection,” he says, and, if so, where it arose.

Determining causality is important. If a patient develops an infection but does not inform the doctor who performed the endoscopy or tell the doctor treating the infection about prior procedures, the doctors may not connect the dots. One remedy is for the doctor’s office or clinic to contact patients after the procedure and ask if they have any infection symptoms. “The FDA is reporting reduced infection rates,” Muscarella says, “but if the medical facility doesn’t track all infections, then the risk could be underreported.”

The risk of getting an infection from a diagnostic procedure is real. But when a doctor recommends an endoscopy, it’s important to consider the risk versus benefit, Dwyer says. Colonoscopies, for example, carry a small risk of complications but a high rate of effectiveness for identifying potentially cancerous polyps.

In spite of her husband’s death from the CRE infection, “I will never advocate for someone to go against what their physician recommends they need in treatment,” Carla says. What if her own doctor recommended an ERCP?

“I wouldn’t say I would not do the procedure,” she says. “I’d have to do my research really well. If I couldn’t find a satisfactory local provider, I’d go somewhere else that has technologies available for true sterilization.”

Bacteria lingering on endoscopes can lead to drug-resistant infections. Before getting scoped, patients should ask how they will be protected.
 

Deborah Abrams Kaplan

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