EditorialPublication Exclusive

Research reveals fine line between ‘one more try’ and ‘a bridge too far’

“I think we may be going a bridge too far.” 

– Lt. Gen. Frederick Browning, prior to the First Allied Airborne Army’s unsuccessful attempt to seize the bridge at Arnhem, Netherlands, during World War II

 

Over the last few months, I have been taking care of a 19-year-old woman with refractory Hodgkin’s lymphoma.

She originally presented with advanced-stage disease and received treatment with ABVD chemotherapy, a common regimen that consists of doxorubicin, bleomycin, vinblastine and dacarbazine.

John Sweetenham

Repeat imaging after four cycles showed responding disease; however, at completion of six cycles of therapy, repeat imaging showed clear evidence of disease progression.

In view of this, she underwent three cycles of ESHAP — etoposide, methylprednisolone, cytarabine and cisplatin — and then received high-dose therapy and an autologous stem cell transplant. Three months after her transplant, follow-up imaging showed FDG-avid disease in the lung. She was referred to our clinic, where a biopsy confirmed persistent Hodgkin’s lymphoma.

Emerging evidence supports a role for allogeneic transplantation in this setting. Although the interpretation of these data is complicated by their mostly retrospective nature and selection bias, most would agree that allogeneic transplantation offers the best chance of cure in this situation, although there is considerable uncertainty about how much of a chance that really is.

It is widely agreed that the outcome for transplantation is better if the patient’s disease is responding to a salvage regimen. The expression “bridging” therapy has thus been born, referring to cytoreductive therapy prior to allogeneic transplant.

Consistent with this concept, this patient was treated with bridging brentuximab vedotin (Adcetris, Seattle Genetics). Meanwhile, her relatives were tissue typed.

After three cycles, she had an excellent radiologic response. After five cycles, when her sibling donor had been identified, further imaging showed progressive disease at several sites. In a further attempt to bridge, we have now begun treatment with nivolumab (Opdivo, Bristol-Myers Squibb). It is too early to assess her response to this therapy, but I have already thought about what the next “bridge” might be if this one fails.

So far, this woman has remained remarkably well, with excellent tolerance of her therapy and largely asymptomatic disease. This — coupled with her young age — has made decisions about bridging therapy pretty straightforward so far, and there is no question that we should continue to try to get her to transplant. But, as I have contemplated the next steps for this patient, it poses the question of how many attempts at bridging therapy are reasonable, and what constitutes “a bridge too far.”

Lack of literature

There isn’t much published literature to help. Most of the studies that have assessed changing pre-transplant cytoreductive regimens have been in the context of autologous stem cell transplant, where the data indicate that all salvage regimens are relatively equal. If a patient has disease that does not respond to one of these regimens, they are unlikely to get a meaningful response to another — and even if they do, the chances that this will convert into long-term DFS after transplant are very small.

In the context of allogeneic transplantation, we have few such data, and one could reasonably expect that switching to different bridging therapies with completely novel mechanisms of action is more likely to be successful than simply changing chemotherapy regimens. Even so, there must come a point when the writing is on the wall that a patient has refractory disease and that no intervention is likely to help.

As I have pondered this, my attention turned to a recent study from The University of Texas MD Anderson Cancer Center in which researchers compared the attitudes of hematologic and sold tumor oncology specialists toward end-of-life care. Although my patient is probably not in the “end-of-life” realm at the moment, the message from this study is nevertheless highly relevant.

Using a questionnaire-based approach, including clinical vignettes, investigators explored the attitudes of oncologists and advanced-practice clinicians toward various aspects of end-of-life care. Researchers analyzed the results according to whether the providers specialized in solid tumors or hematologic malignancies.

The results showed those of us with a primary interest in leukemia, lymphoma and myeloma are less comfortable discussing death and dying, less likely to refer to hospice and more likely to report a sense of failure when we cannot alter the course of a patient’s disease. We also are more likely to recommend systemic therapy to our patients in the last month of life.

Consistent with these observations, previous studies have demonstrated higher rates of admission to the ICU and higher rates of hospitalization at the end of life in patients with hematologic malignancies than solid tumors.

The investigators did not provide explanations for the difference in attitudes, but they advocated for specific interventions aimed at specialists in hematologic malignancies to improve end-of-life care.

Potential explanations

It is fairly easy to construct hypotheses for why attitudes may differ.

On the whole, hematologic neoplasms are highly responsive, often to multiple lines of therapy. They frequently affect a younger age group than solid tumors, and they often are treated with high-complexity/high-intensity regimens such as stem cell transplantation, instilling a culture of aggressive treatment as the standard in these diseases.

The responsive nature of these diseases makes relapse or recurrence seem particularly devastating, and the availability of an increasing number of treatment options makes “one more try” an attractive proposition for us and — usually — our patients.

This is reinforced by the fact that, in contrast to most solid tumors, hematologic malignancies often will respond — at least transiently — to multiple lines of therapy. Even when the prospect of cure is small, we can tell our patients that we may have a chance to improve their quality of life in their remaining days ... or can we?

A recent study led by researchers at Weill Cornell Medical College — restricted to patients with advanced, metastatic solid tumors — showed that the use of palliative chemotherapy in these end-stage patients was not associated with improved quality of life near death. In patients with a good baseline performance status, chemotherapy produced worse quality of life near death. Although patients with hematologic malignancies were not included in this study, it is difficult to come up with an explanation for why the outcome would differ.

For now, I will continue to treat my patient in the hope that we will find a regimen or drug that will allow her the best chance to get to an allogeneic transplant. I believe that to be her best curative option, but use the word “believe” deliberately, because the data for the effectiveness of stem cell transplant after multiple salvage regimens of this type are not available. I recognize that this approach might differ if she were 59 years old rather than 19, — my enthusiasm for multiple bridging therapies might be lower.

Data show those of us taking care of patients with hematologic malignancies are slow to recognize when it is time to modify goals of care. Addressing that will require convincing evidence from focused research in these patients that we are truly over-treating at the end of life; novel interventions to inform us of how to change our attitudes and practice, if appropriate; and open-mindedness on our part to the possibility of going a bridge too far.

“I think we may be going a bridge too far.” 

– Lt. Gen. Frederick Browning, prior to the First Allied Airborne Army’s unsuccessful attempt to seize the bridge at Arnhem, Netherlands, during World War II

 

Over the last few months, I have been taking care of a 19-year-old woman with refractory Hodgkin’s lymphoma.

She originally presented with advanced-stage disease and received treatment with ABVD chemotherapy, a common regimen that consists of doxorubicin, bleomycin, vinblastine and dacarbazine.

John Sweetenham

Repeat imaging after four cycles showed responding disease; however, at completion of six cycles of therapy, repeat imaging showed clear evidence of disease progression.

In view of this, she underwent three cycles of ESHAP — etoposide, methylprednisolone, cytarabine and cisplatin — and then received high-dose therapy and an autologous stem cell transplant. Three months after her transplant, follow-up imaging showed FDG-avid disease in the lung. She was referred to our clinic, where a biopsy confirmed persistent Hodgkin’s lymphoma.

Emerging evidence supports a role for allogeneic transplantation in this setting. Although the interpretation of these data is complicated by their mostly retrospective nature and selection bias, most would agree that allogeneic transplantation offers the best chance of cure in this situation, although there is considerable uncertainty about how much of a chance that really is.

It is widely agreed that the outcome for transplantation is better if the patient’s disease is responding to a salvage regimen. The expression “bridging” therapy has thus been born, referring to cytoreductive therapy prior to allogeneic transplant.

Consistent with this concept, this patient was treated with bridging brentuximab vedotin (Adcetris, Seattle Genetics). Meanwhile, her relatives were tissue typed.

After three cycles, she had an excellent radiologic response. After five cycles, when her sibling donor had been identified, further imaging showed progressive disease at several sites. In a further attempt to bridge, we have now begun treatment with nivolumab (Opdivo, Bristol-Myers Squibb). It is too early to assess her response to this therapy, but I have already thought about what the next “bridge” might be if this one fails.

So far, this woman has remained remarkably well, with excellent tolerance of her therapy and largely asymptomatic disease. This — coupled with her young age — has made decisions about bridging therapy pretty straightforward so far, and there is no question that we should continue to try to get her to transplant. But, as I have contemplated the next steps for this patient, it poses the question of how many attempts at bridging therapy are reasonable, and what constitutes “a bridge too far.”

Lack of literature

There isn’t much published literature to help. Most of the studies that have assessed changing pre-transplant cytoreductive regimens have been in the context of autologous stem cell transplant, where the data indicate that all salvage regimens are relatively equal. If a patient has disease that does not respond to one of these regimens, they are unlikely to get a meaningful response to another — and even if they do, the chances that this will convert into long-term DFS after transplant are very small.

In the context of allogeneic transplantation, we have few such data, and one could reasonably expect that switching to different bridging therapies with completely novel mechanisms of action is more likely to be successful than simply changing chemotherapy regimens. Even so, there must come a point when the writing is on the wall that a patient has refractory disease and that no intervention is likely to help.

As I have pondered this, my attention turned to a recent study from The University of Texas MD Anderson Cancer Center in which researchers compared the attitudes of hematologic and sold tumor oncology specialists toward end-of-life care. Although my patient is probably not in the “end-of-life” realm at the moment, the message from this study is nevertheless highly relevant.

PAGE BREAK

Using a questionnaire-based approach, including clinical vignettes, investigators explored the attitudes of oncologists and advanced-practice clinicians toward various aspects of end-of-life care. Researchers analyzed the results according to whether the providers specialized in solid tumors or hematologic malignancies.

The results showed those of us with a primary interest in leukemia, lymphoma and myeloma are less comfortable discussing death and dying, less likely to refer to hospice and more likely to report a sense of failure when we cannot alter the course of a patient’s disease. We also are more likely to recommend systemic therapy to our patients in the last month of life.

Consistent with these observations, previous studies have demonstrated higher rates of admission to the ICU and higher rates of hospitalization at the end of life in patients with hematologic malignancies than solid tumors.

The investigators did not provide explanations for the difference in attitudes, but they advocated for specific interventions aimed at specialists in hematologic malignancies to improve end-of-life care.

Potential explanations

It is fairly easy to construct hypotheses for why attitudes may differ.

On the whole, hematologic neoplasms are highly responsive, often to multiple lines of therapy. They frequently affect a younger age group than solid tumors, and they often are treated with high-complexity/high-intensity regimens such as stem cell transplantation, instilling a culture of aggressive treatment as the standard in these diseases.

The responsive nature of these diseases makes relapse or recurrence seem particularly devastating, and the availability of an increasing number of treatment options makes “one more try” an attractive proposition for us and — usually — our patients.

This is reinforced by the fact that, in contrast to most solid tumors, hematologic malignancies often will respond — at least transiently — to multiple lines of therapy. Even when the prospect of cure is small, we can tell our patients that we may have a chance to improve their quality of life in their remaining days ... or can we?

A recent study led by researchers at Weill Cornell Medical College — restricted to patients with advanced, metastatic solid tumors — showed that the use of palliative chemotherapy in these end-stage patients was not associated with improved quality of life near death. In patients with a good baseline performance status, chemotherapy produced worse quality of life near death. Although patients with hematologic malignancies were not included in this study, it is difficult to come up with an explanation for why the outcome would differ.

For now, I will continue to treat my patient in the hope that we will find a regimen or drug that will allow her the best chance to get to an allogeneic transplant. I believe that to be her best curative option, but use the word “believe” deliberately, because the data for the effectiveness of stem cell transplant after multiple salvage regimens of this type are not available. I recognize that this approach might differ if she were 59 years old rather than 19, — my enthusiasm for multiple bridging therapies might be lower.

Data show those of us taking care of patients with hematologic malignancies are slow to recognize when it is time to modify goals of care. Addressing that will require convincing evidence from focused research in these patients that we are truly over-treating at the end of life; novel interventions to inform us of how to change our attitudes and practice, if appropriate; and open-mindedness on our part to the possibility of going a bridge too far.