Editorial

Adjuvant treatment of pancreatic cancer: Hobson’s choice or Morton’s fork?

As some of you know, I have a broad background in general oncology, but my real expertise is in the domain of genitourinary malignancy.

It has been some time since I needed to make independent decisions about clinical management of gastrointestinal malignancy, beyond acting as a ward attending on the inpatient service.

It was, thus, quite challenging when a close friend recently asked my opinion about the state of the art of adjuvant treatment of resected node-negative pancreatic cancer, a problem facing his brother.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

Some years ago, a very close friend posed the same question. After reviewing the literature, I advised against wasting his time and resources. Sadly, he ignored my advice, had several months of toxic adjuvant chemotherapy, showed demonstrable progression before the end of his course of treatment, and died just a few months after starting his chemotherapy.

In the more recent situation, having acknowledged my lack of personal expertise in this domain, I did agree to review the literature to see what had changed.

Varying takes

I started, as is often the case, with a look at HemOnc Today for its various reports of breaking news in the field, and UpToDate (truth in disclosure, I edit its bladder cancer section).

I found an excellent review by David Ryan, MD, who concluded that he would recommend adjuvant chemotherapy even for T1 tumors without local nodal involvement. This view was based upon his take on the literature, citing data from a series of randomized and nonrandomized trials. This also seems to have been the general consensus from the experts in the field with whom I have discussed the issue in the past few days, in addition to the guidelines from ASCO, National Comprehensive Cancer Network and European Society for Medical Oncology.

Nonetheless, I have reviewed the old and recent literature, and I’m not so sure this makes perfect sense to me when looking at the big picture — particularly as the “take” on the literature seems to vary widely.

From my perspective, the factors that need to be considered include the potential for permanent cure, length of absolute survival, TWIST (time without symptoms of tumor or treatment), extent of toxicity and cost, in addition to patient-related issues, such as age, comorbidity and performance status.

In this context, I should perhaps comment that it has never seemed logical to factor in DFS, as one might expect treatment with even minimal anticancer effect to delay the recurrence of disease for a short period based simply on tumor growth kinetics. The potential benefit of delayed recurrence is balanced by the earlier introduction of toxicity and cost, and becomes moot if randomized trials suggest equivalence of OS.

The usual word salad of acronyms appears to dominate the field of adjuvant studies in pancreatic cancer, and it seems some of the key studies are represented by the ESPAC 1-4 series, CONKO-1, RTOG 9704 and JSAP-02.

These studies have attempted to assess the impact of chemotherapy alone or chemoradiation after radical pancreatectomy, or they have compared different approaches to chemotherapy head-to-head.

As this is only an editorial and not a detailed review of the literature, I will content myself by summarizing the data:

  • Surgical pancreatectomy with T1 disease, clean margins and negative nodes is most likely to produce the hallmark of success;
  • When reported, higher T stage, N-positive disease and higher levels of circulating CA 19-9 are associated with substantially worse outcomes within each study;
  • Single-agent gemcitabine is less toxic and less expensive than combination regimens, but also less effective than adjuvant therapy;
  • Gemcitabine-capecitabine, compared with gemcitabine alone, improves median survival by an average of 2.5 months (with overlapping confidence intervals) but is more toxic. Five-year survival is less than 30% in each arm, hardly a “win” for adjuvant therapy;
  • If one considers the published major trials, the “positive” arms do not exceed 30% 5-year survival nor median survival of 3 years, a disappointing outcome for adjuvant studies;
  • The role of adjuvant chemoradiation is unclear, but it may have an impact in selected patients; and
  • Few studies have addressed cost of 6 months of adjuvant therapy.

Clinical trials and cost considerations

So where does this leave us? Well, firstly it tells us that physicians should actively encourage their patients to participate in the available cancer trials, given that the extant “standards” (eg, self-proclaimed by ESPAC-4) are highly imperfect and mostly not associated with cure.

This means more than just telling them that trials exist, but rather defining very clearly the very poor likelihood of success from current approaches and the reasons for considering the available trials.

This is particularly important in view of the number of potentially useful trials that have closed early because of poor accrual, and because it may be helpful to future patients.

Reviewing the literature suggests that adjuvant chemotherapy may well give a little benefit to the patient who wishes to “take no prisoners” and give a maximum effort to fighting the cancer. However, the outcomes depend on extent of disease and the other factors above, and these data need to be specified in any discussion with a patient and associated family.

It also behooves physicians involved in this clinical setting to be clearly aware of the costs of treatment to the system, but more importantly to the individual patient. A 10% co-pay for a treatment that might cost a total of $200,000 can be crippling to the average working family in the United States and simply may not seem worthwhile to some patients faced with the outcome data above.

Many physicians like to claim to be purists, and to be above discussion of fiscal issues, focusing just on the patient and the treatment. However, in this escalating cost environment, when the fiscal consequences have become so draconian, I do not believe this to be ethical.

Sadly, the patient sits somewhere between Hobson’s choice and Morton’s fork.

To remind you, Thomas Hobson (1544-1631) had an extensive stable of horses, suggesting to his customers that they could choose their mounts; in reality, house rules required customers to take the horse closest to the door, so there was really no choice at all.

Similarly, Archbishop John Morton (circa 1420-1500) is believed to have held the view that a person living modestly must be saving money and, thus, could afford taxes, whereas a person living in lavish style was probably rich and, thus, could afford taxes.

As caring clinicians, we must take care not to place our patients with pancreas cancer, following complete resection, into a situation in which they have no choice, predicated on a false dilemma.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.

Disclosure: Raghavan reports no relevant financial disclosures.

As some of you know, I have a broad background in general oncology, but my real expertise is in the domain of genitourinary malignancy.

It has been some time since I needed to make independent decisions about clinical management of gastrointestinal malignancy, beyond acting as a ward attending on the inpatient service.

It was, thus, quite challenging when a close friend recently asked my opinion about the state of the art of adjuvant treatment of resected node-negative pancreatic cancer, a problem facing his brother.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

Some years ago, a very close friend posed the same question. After reviewing the literature, I advised against wasting his time and resources. Sadly, he ignored my advice, had several months of toxic adjuvant chemotherapy, showed demonstrable progression before the end of his course of treatment, and died just a few months after starting his chemotherapy.

In the more recent situation, having acknowledged my lack of personal expertise in this domain, I did agree to review the literature to see what had changed.

Varying takes

I started, as is often the case, with a look at HemOnc Today for its various reports of breaking news in the field, and UpToDate (truth in disclosure, I edit its bladder cancer section).

I found an excellent review by David Ryan, MD, who concluded that he would recommend adjuvant chemotherapy even for T1 tumors without local nodal involvement. This view was based upon his take on the literature, citing data from a series of randomized and nonrandomized trials. This also seems to have been the general consensus from the experts in the field with whom I have discussed the issue in the past few days, in addition to the guidelines from ASCO, National Comprehensive Cancer Network and European Society for Medical Oncology.

Nonetheless, I have reviewed the old and recent literature, and I’m not so sure this makes perfect sense to me when looking at the big picture — particularly as the “take” on the literature seems to vary widely.

From my perspective, the factors that need to be considered include the potential for permanent cure, length of absolute survival, TWIST (time without symptoms of tumor or treatment), extent of toxicity and cost, in addition to patient-related issues, such as age, comorbidity and performance status.

In this context, I should perhaps comment that it has never seemed logical to factor in DFS, as one might expect treatment with even minimal anticancer effect to delay the recurrence of disease for a short period based simply on tumor growth kinetics. The potential benefit of delayed recurrence is balanced by the earlier introduction of toxicity and cost, and becomes moot if randomized trials suggest equivalence of OS.

PAGE BREAK

The usual word salad of acronyms appears to dominate the field of adjuvant studies in pancreatic cancer, and it seems some of the key studies are represented by the ESPAC 1-4 series, CONKO-1, RTOG 9704 and JSAP-02.

These studies have attempted to assess the impact of chemotherapy alone or chemoradiation after radical pancreatectomy, or they have compared different approaches to chemotherapy head-to-head.

As this is only an editorial and not a detailed review of the literature, I will content myself by summarizing the data:

  • Surgical pancreatectomy with T1 disease, clean margins and negative nodes is most likely to produce the hallmark of success;
  • When reported, higher T stage, N-positive disease and higher levels of circulating CA 19-9 are associated with substantially worse outcomes within each study;
  • Single-agent gemcitabine is less toxic and less expensive than combination regimens, but also less effective than adjuvant therapy;
  • Gemcitabine-capecitabine, compared with gemcitabine alone, improves median survival by an average of 2.5 months (with overlapping confidence intervals) but is more toxic. Five-year survival is less than 30% in each arm, hardly a “win” for adjuvant therapy;
  • If one considers the published major trials, the “positive” arms do not exceed 30% 5-year survival nor median survival of 3 years, a disappointing outcome for adjuvant studies;
  • The role of adjuvant chemoradiation is unclear, but it may have an impact in selected patients; and
  • Few studies have addressed cost of 6 months of adjuvant therapy.

Clinical trials and cost considerations

So where does this leave us? Well, firstly it tells us that physicians should actively encourage their patients to participate in the available cancer trials, given that the extant “standards” (eg, self-proclaimed by ESPAC-4) are highly imperfect and mostly not associated with cure.

This means more than just telling them that trials exist, but rather defining very clearly the very poor likelihood of success from current approaches and the reasons for considering the available trials.

This is particularly important in view of the number of potentially useful trials that have closed early because of poor accrual, and because it may be helpful to future patients.

Reviewing the literature suggests that adjuvant chemotherapy may well give a little benefit to the patient who wishes to “take no prisoners” and give a maximum effort to fighting the cancer. However, the outcomes depend on extent of disease and the other factors above, and these data need to be specified in any discussion with a patient and associated family.

It also behooves physicians involved in this clinical setting to be clearly aware of the costs of treatment to the system, but more importantly to the individual patient. A 10% co-pay for a treatment that might cost a total of $200,000 can be crippling to the average working family in the United States and simply may not seem worthwhile to some patients faced with the outcome data above.

PAGE BREAK

Many physicians like to claim to be purists, and to be above discussion of fiscal issues, focusing just on the patient and the treatment. However, in this escalating cost environment, when the fiscal consequences have become so draconian, I do not believe this to be ethical.

Sadly, the patient sits somewhere between Hobson’s choice and Morton’s fork.

To remind you, Thomas Hobson (1544-1631) had an extensive stable of horses, suggesting to his customers that they could choose their mounts; in reality, house rules required customers to take the horse closest to the door, so there was really no choice at all.

Similarly, Archbishop John Morton (circa 1420-1500) is believed to have held the view that a person living modestly must be saving money and, thus, could afford taxes, whereas a person living in lavish style was probably rich and, thus, could afford taxes.

As caring clinicians, we must take care not to place our patients with pancreas cancer, following complete resection, into a situation in which they have no choice, predicated on a false dilemma.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.

Disclosure: Raghavan reports no relevant financial disclosures.