Original Research

The dominant limb is the limb preferred for performing an activity that requires one hand or for performing the more demanding part of an activity that requires both hands. For example, most playing card dealers use their dominant limb to distribute cards (the more demanding part of the activity) and their nondominant limb to hold the rest of the pack (the less demanding activity). Although a relationship between nocturnal hand paresthesias and daily hand activities has been known for more than a century, it was not until more recently that it was recognized that unilateral carpal tunnel syndrome (CTS) more commonly involves the dominant limb.^1,2

Among people with CTS, the dominant limb tends to be affected earlier and, in the setting of bilateral involvement, more severely.^3,4 This relationship, however, is not absolute. In 1983, Falck and Aarnio reported that CTS could be more pronounced on the nondominant side whenever upper extremity usage requirements, especially occupational requirements, stressed that limb to a greater extent than they stressed the dominant limb.⁵

Regarding occupation, particular CTS risk factors and associations have been reported. One study found that the most common work-related risk factor was repetitive bending and twisting of the hands and wrists.⁶ In another study, the incidence of CTS was almost 10-fold higher among workers performing high force, high repetition jobs than among those performing low force, low repetition jobs.^7-10 A meta-analysis identified a strong causal relationship between forceful, repetitive work and development of CTS.¹¹ A more recent and controversial study found no association between heavy use of computers and CTS.¹² In 1911, Hart reported an association between repetitive gripping and thenar atrophy.¹³ Although he misattributed the association to trauma of the recurrent thenar motor branch, 2 of the 3 described patients reported a period of episodic hand paresthesias preceding the development of thenar eminence atrophy and thus more likely had typical CTS.

Background

The present study was prompted by the clinical and electrodiagnostic (EDX) features of a 27-year-old right-hand–dominant man who presented to the EDX laboratory for assessment of bilateral hand paresthesias. The patient reported episodic bilateral hand tingling that was much more pronounced on the left (nondominant) side. Consistent with his report, EDX assessment revealed bilateral CTS that involved the nondominant limb to a much greater extent than that of the dominant limb. As a blackjack dealer, the patient was using his nondominant hand to “tightly grip 2 decks of cards” and the dominant hand to distribute those cards.

Similar history and EDX patterns (bilateral CTS more pronounced on nondominant side) were subsequently noted in 2 other patients, both of whom were using their nondominant limb to perform an activity that required sustained gripping. One of these patients was a minnow counter. He was using his nondominant hand to firmly grip the top of a bucket and the dominant hand to “deal” the fish into separate tanks. The other patient was a mason. He was using his nondominant hand to firmly hold a brick or stone in place and the dominant hand to apply cement. The clinical and EDX features of these 3 patients suggested that sustained gripping might be a significant risk factor for development of CTS. That all 3 of these patients were using their dominant hand for a repetitive activity (dealing) further suggested that, compared with repetitive activity, sustained gripping was more significant as a risk factor for development of CTS.

As unilateral CTS typically occurs on the dominant side, and bilateral CTS typically is more pronounced on the dominant side, the term backward CTS is applied to cases in which unilateral CTS occurs on the nondominant side or bilateral CTS involves the nondominant side to a greater extent than the dominant side.

Although many investigators have purported an association between CTS and a particular upper extremity activity, their conclusions are limited by use of poorly validated symptom surveys, use of faulty epidemiologic methods, selection of a specific basis for clinical diagnosis (eg, isolated hand pain), or lack of EDX confirmation. Associations between a particular activity and development of CTS are best addressed by studies that include both clinical and EDX assessments and that fully characterize the individual hand usage patterns.

Methods

This study identified the upper extremity usage patterns associated with development of CTS among patients found in the EDX laboratory to have backward CTS (unilateral CTS in nondominant limb or bilateral CTS involving nondominant limb more than dominant limb). Thus, whenever patients who were referred to the EDX laboratory for upper extremity studies were noted to have backward CTS, an extensive upper extremity usage assessment was immediately performed. Both the EDX studies and the upper extremity usage assessments were performed by the author during the same encounter.

All patients had initial screening sensory and motor nerve conduction studies performed: median sensory, recording the second digit; ulnar sensory, recording the fifth digit; superficial radial, recording the dorsum of hand; median motor, recording the thenar eminence; and ulnar motor, recording the hypothenar eminence. As CTS was suspected in all cases, median and ulnar palmar nerve conduction studies were performed as well. All these studies were performed using previously reported techniques, and all collected values were compared with EMG laboratory control values.^14,15 In all patients, the median nerve conduction studies were performed bilaterally. Approval from an ethics board or an institutional review board was not needed because this study did not involve personal information or identifiable images.

To avoid identifying small, chance asymmetries related to hypothyroidism and other conditions that produce bilateral CTS, the author predefined the degree of asymmetry required for study inclusion to identify only large asymmetries. Because the EDX manifestations of CTS typically reflect features of demyelination before those of axon loss, the required asymmetries were predefined using peak sensory and distal motor latency values. For study inclusion, the median nerve latency value recorded from the nondominant limb needed to exceed the value recorded from the dominant limb by 0.6 msec for the median palmar responses, 1.0 msec for the median digital sensory responses, or 1.0 msec for the median motor responses.

Excluded from the study were patients who reported being ambidextrous, those who had changed hand dominance at any age and for any reason, those with a history of upper extremity trauma or surgery, and those with EDX findings indicating a concomitant neuromuscular disorder. In addition, patients with diabetes mellitus or any other condition associated with bilateral CTS were excluded.

Results

From the approximately 2,000 upper extremity EDX studies performed over a 30-month period, the author identified 21 patients who met the inclusion criteria (Table 1). Of these 21 patients, 15 (71%) had bilateral CTS and 6 (29%) had unilateral CTS. Sixteen of the 21 patients used their nondominant hand, through a significant portion of the day, to perform an activity that required sustained gripping (Table 2).

Of these 16 patients, 14 reported that the sustained gripping activity was related to their occupation: pipe fitter (4 patients), card dealer (4), professional driver (2), grocery store clerk (1), wire stripper (1), bakery worker (1), and motel room cleaner (1). In their jobs, the pipe fitters were continually cutting pipe during their entire 8-hour shift—using the nondominant hand to tightly grip a pipe while using the dominant hand to direct an electrically powered blade through it. Of the card dealers, 1 was a professional playing card dealer (not the dealer whose case prompted this study), 1 distributed store coupons into containers, and 2 distributed pieces of mail into bins (referred to as casing the mail). All the card dealers used their nondominant hand to tightly grip items that the dominant limb distributed. The professional drivers used their nondominant hand to grip the steering wheel. The grocery store clerk used her nondominant hand to grip shopping items while moving them across a barcode detector. The wire stripper used her nondominant hand to tightly grip bundles of wire while holding a tool in the dominant hand to snip or strip them. The bakery worker continually used her nondominant hand to squeeze off pieces of dough from a mound. And the motel room cleaner used her nondominant hand to grip the side of a bathtub while scrubbing the tub with her dominant hand (she estimated she cleaned bathtubs for about 25% of her 8-hour shift).

Of the 2 patients who reported sustained gripping unrelated to occupation, 1 was baby-sitting her grandson 5 days per week. She carried him, grasping his buttock with her nondominant hand, while performing her daily activities. She estimated she carried the child a minimum of 2 hours a day. After several weeks, she noted episodic tingling in the nondominant hand, yet she continued carrying him for another 7 months, at which point she sought medical care. The other patient, a student in a stress relief class, was instructed to repetitively open and tightly close her nondominant hand for 10 minutes 4 or more times per day. After several weeks, she noted episodic tingling in the exercised, nondominant hand.

Of the 5 patients who denied performing an activity that required sustained gripping, 2 used their nondominant limb to enter data into a computer while turning pages with the dominant limb. A piano teacher, used her nondominant limb to strike piano keys while sitting to the right of her pupils; and a typist, consistently slept with the dorsal aspect of the nondominant hand pressed into her cheek, resulting in sustained wrist flexion throughout the night. One patient could not identify an activity performed with her nondominant limb both frequently and for prolonged periods.

Discussion

As with other syndromic disorders, CTS is associated with several clinical features, the presence of which correlates with the severity of median nerve involvement. During the earliest stage of CTS, episodic hand tingling (a positive symptom) is commonly reported. This tingling typically is more pronounced at night and during relaxation. In addition, many patients come to recognize that their hand tingling is precipitated by activities that involve sustained upper extremity elevation (eg, driving with a limb resting on upper portion of steering wheel; reading with upper extremities maintained in forward abduction) and that lowering a symptomatic limb relieves its tingling.

With progression, negative symptoms appear (eg, numbness and then weakness and wasting). Unfortunately, as the negative symptoms replace the positive ones, affected individuals may become less symptomatic and mistakenly believe their condition is improving. Features of autonomic fiber involvement may also be present but are less reliably elicited. Isolated hand pain is an uncommon manifestation of CTS because pain more commonly occurs later in the course and for this reason tends to be accompanied by other features of CTS.

The clinical features of CTS correlate with its underlying pathology. As demyelination precedes axon disruption pathologically, the clinical features of demyelination (episodic paresthesias) precede those of axon loss (numbness, weakness, wasting). However, clinical features may go unrecognized or be dismissed by the patient. Moreover, there is substantial variation in type, intensity, and frequency of symptoms.^16,17

The EDX features of CTS correlate with its underlying pathology and pathophysiology. As demyelination (loss of insulation) increases the capacitance of the membrane and increases internodal current leakage, conduction velocity is reduced. As severity worsens and pathology changes from predominantly demyelination to predominantly axon loss, the individual nerve fiber action potentials, which make up the compound responses being recorded, are lost. As a result the amplitude and negative area under the curve values decrease. Thus, the EDX features of demyelination (eg, prolonged latencies) precede those of axon loss (eg, amplitude, negative area under the curve reduction).

As with other focal mononeuropathies, the sensory responses tend to be affected earlier and to a greater degree than do the motor responses. Consequently, the EDX features of CTS typically follow a standard progression. The median palmar responses are involved sooner and to a greater degree than the median sensory responses recorded from the digits, which in turn tend to be involved earlier and to a greater degree than are the median motor responses.

Awareness of this relationship dictates the severity of the lesion and helps in the recognition of a cool limb and in the avoidance of a false-positive study interpretation. In a cool limb, the fingers are cooler than the wrists. Thus, the peak latency of the median digital sensory response is delayed to a greater extent than the ipsilateral median palmar response (the opposite of the CTS pattern). Accordingly, whenever this pattern is identified, the hand must be warmed or rewarmed and the studies repeated. The hand is also warmed or rewarmed whenever the median motor response is delayed out of proportion to that of the median palmar response.

Conclusion

Cases of CTS mainly in the nondominant limb provide an opportunity to identify particular limb usage patterns that might be associated with CTS. Of the present study’s 21 affected patients, 16 were using their nondominant limb to perform activities that required sustained gripping. Fourteen of the 16 activities were related to occupation. These findings strongly suggest an association between activities that require sustained gripping and development of CTS.

That the card dealers simultaneously used their nondominant hand for sustained gripping and the dominant hand for the repetitive activity of dealing suggests that sustained gripping is a stronger risk factor than repetitive activity for the development of CTS—an unanticipated finding. Interestingly, in a 2001 study that suggested repetitive activity might not be a CTS risk factor, there was a higher incidence of CTS among computer users working with a mouse—an activity that requires sustained gripping.¹²

Episodic hand tingling during mouse use likely reflects impaired blood flow to the median nerve, which occurs when carpal tunnel pressure approaches or exceeds 20 to 30 mm Hg.¹⁸ Placement of a hand on a mouse increases intracarpal pressure from 3 to 5 mm Hg (wrist in neutral position) to 16 to 21 mm Hg, whereas mouse use increases intracarpal pressure to 28 to 33 mm Hg.^18-20 

The dominant limb is the limb preferred for performing an activity that requires one hand or for performing the more demanding part of an activity that requires both hands. For example, most playing card dealers use their dominant limb to distribute cards (the more demanding part of the activity) and their nondominant limb to hold the rest of the pack (the less demanding activity). Although a relationship between nocturnal hand paresthesias and daily hand activities has been known for more than a century, it was not until more recently that it was recognized that unilateral carpal tunnel syndrome (CTS) more commonly involves the dominant limb.^1,2

Among people with CTS, the dominant limb tends to be affected earlier and, in the setting of bilateral involvement, more severely.^3,4 This relationship, however, is not absolute. In 1983, Falck and Aarnio reported that CTS could be more pronounced on the nondominant side whenever upper extremity usage requirements, especially occupational requirements, stressed that limb to a greater extent than they stressed the dominant limb.⁵

Regarding occupation, particular CTS risk factors and associations have been reported. One study found that the most common work-related risk factor was repetitive bending and twisting of the hands and wrists.⁶ In another study, the incidence of CTS was almost 10-fold higher among workers performing high force, high repetition jobs than among those performing low force, low repetition jobs.^7-10 A meta-analysis identified a strong causal relationship between forceful, repetitive work and development of CTS.¹¹ A more recent and controversial study found no association between heavy use of computers and CTS.¹² In 1911, Hart reported an association between repetitive gripping and thenar atrophy.¹³ Although he misattributed the association to trauma of the recurrent thenar motor branch, 2 of the 3 described patients reported a period of episodic hand paresthesias preceding the development of thenar eminence atrophy and thus more likely had typical CTS.

Background

The present study was prompted by the clinical and electrodiagnostic (EDX) features of a 27-year-old right-hand–dominant man who presented to the EDX laboratory for assessment of bilateral hand paresthesias. The patient reported episodic bilateral hand tingling that was much more pronounced on the left (nondominant) side. Consistent with his report, EDX assessment revealed bilateral CTS that involved the nondominant limb to a much greater extent than that of the dominant limb. As a blackjack dealer, the patient was using his nondominant hand to “tightly grip 2 decks of cards” and the dominant hand to distribute those cards.

Similar history and EDX patterns (bilateral CTS more pronounced on nondominant side) were subsequently noted in 2 other patients, both of whom were using their nondominant limb to perform an activity that required sustained gripping. One of these patients was a minnow counter. He was using his nondominant hand to firmly grip the top of a bucket and the dominant hand to “deal” the fish into separate tanks. The other patient was a mason. He was using his nondominant hand to firmly hold a brick or stone in place and the dominant hand to apply cement. The clinical and EDX features of these 3 patients suggested that sustained gripping might be a significant risk factor for development of CTS. That all 3 of these patients were using their dominant hand for a repetitive activity (dealing) further suggested that, compared with repetitive activity, sustained gripping was more significant as a risk factor for development of CTS.

As unilateral CTS typically occurs on the dominant side, and bilateral CTS typically is more pronounced on the dominant side, the term backward CTS is applied to cases in which unilateral CTS occurs on the nondominant side or bilateral CTS involves the nondominant side to a greater extent than the dominant side.

Although many investigators have purported an association between CTS and a particular upper extremity activity, their conclusions are limited by use of poorly validated symptom surveys, use of faulty epidemiologic methods, selection of a specific basis for clinical diagnosis (eg, isolated hand pain), or lack of EDX confirmation. Associations between a particular activity and development of CTS are best addressed by studies that include both clinical and EDX assessments and that fully characterize the individual hand usage patterns.

Methods

This study identified the upper extremity usage patterns associated with development of CTS among patients found in the EDX laboratory to have backward CTS (unilateral CTS in nondominant limb or bilateral CTS involving nondominant limb more than dominant limb). Thus, whenever patients who were referred to the EDX laboratory for upper extremity studies were noted to have backward CTS, an extensive upper extremity usage assessment was immediately performed. Both the EDX studies and the upper extremity usage assessments were performed by the author during the same encounter.

All patients had initial screening sensory and motor nerve conduction studies performed: median sensory, recording the second digit; ulnar sensory, recording the fifth digit; superficial radial, recording the dorsum of hand; median motor, recording the thenar eminence; and ulnar motor, recording the hypothenar eminence. As CTS was suspected in all cases, median and ulnar palmar nerve conduction studies were performed as well. All these studies were performed using previously reported techniques, and all collected values were compared with EMG laboratory control values.^14,15 In all patients, the median nerve conduction studies were performed bilaterally. Approval from an ethics board or an institutional review board was not needed because this study did not involve personal information or identifiable images.

To avoid identifying small, chance asymmetries related to hypothyroidism and other conditions that produce bilateral CTS, the author predefined the degree of asymmetry required for study inclusion to identify only large asymmetries. Because the EDX manifestations of CTS typically reflect features of demyelination before those of axon loss, the required asymmetries were predefined using peak sensory and distal motor latency values. For study inclusion, the median nerve latency value recorded from the nondominant limb needed to exceed the value recorded from the dominant limb by 0.6 msec for the median palmar responses, 1.0 msec for the median digital sensory responses, or 1.0 msec for the median motor responses.

Excluded from the study were patients who reported being ambidextrous, those who had changed hand dominance at any age and for any reason, those with a history of upper extremity trauma or surgery, and those with EDX findings indicating a concomitant neuromuscular disorder. In addition, patients with diabetes mellitus or any other condition associated with bilateral CTS were excluded.

Results

From the approximately 2,000 upper extremity EDX studies performed over a 30-month period, the author identified 21 patients who met the inclusion criteria (Table 1). Of these 21 patients, 15 (71%) had bilateral CTS and 6 (29%) had unilateral CTS. Sixteen of the 21 patients used their nondominant hand, through a significant portion of the day, to perform an activity that required sustained gripping (Table 2).

Of these 16 patients, 14 reported that the sustained gripping activity was related to their occupation: pipe fitter (4 patients), card dealer (4), professional driver (2), grocery store clerk (1), wire stripper (1), bakery worker (1), and motel room cleaner (1). In their jobs, the pipe fitters were continually cutting pipe during their entire 8-hour shift—using the nondominant hand to tightly grip a pipe while using the dominant hand to direct an electrically powered blade through it. Of the card dealers, 1 was a professional playing card dealer (not the dealer whose case prompted this study), 1 distributed store coupons into containers, and 2 distributed pieces of mail into bins (referred to as casing the mail). All the card dealers used their nondominant hand to tightly grip items that the dominant limb distributed. The professional drivers used their nondominant hand to grip the steering wheel. The grocery store clerk used her nondominant hand to grip shopping items while moving them across a barcode detector. The wire stripper used her nondominant hand to tightly grip bundles of wire while holding a tool in the dominant hand to snip or strip them. The bakery worker continually used her nondominant hand to squeeze off pieces of dough from a mound. And the motel room cleaner used her nondominant hand to grip the side of a bathtub while scrubbing the tub with her dominant hand (she estimated she cleaned bathtubs for about 25% of her 8-hour shift).

Of the 2 patients who reported sustained gripping unrelated to occupation, 1 was baby-sitting her grandson 5 days per week. She carried him, grasping his buttock with her nondominant hand, while performing her daily activities. She estimated she carried the child a minimum of 2 hours a day. After several weeks, she noted episodic tingling in the nondominant hand, yet she continued carrying him for another 7 months, at which point she sought medical care. The other patient, a student in a stress relief class, was instructed to repetitively open and tightly close her nondominant hand for 10 minutes 4 or more times per day. After several weeks, she noted episodic tingling in the exercised, nondominant hand.

Of the 5 patients who denied performing an activity that required sustained gripping, 2 used their nondominant limb to enter data into a computer while turning pages with the dominant limb. A piano teacher, used her nondominant limb to strike piano keys while sitting to the right of her pupils; and a typist, consistently slept with the dorsal aspect of the nondominant hand pressed into her cheek, resulting in sustained wrist flexion throughout the night. One patient could not identify an activity performed with her nondominant limb both frequently and for prolonged periods.

Discussion

As with other syndromic disorders, CTS is associated with several clinical features, the presence of which correlates with the severity of median nerve involvement. During the earliest stage of CTS, episodic hand tingling (a positive symptom) is commonly reported. This tingling typically is more pronounced at night and during relaxation. In addition, many patients come to recognize that their hand tingling is precipitated by activities that involve sustained upper extremity elevation (eg, driving with a limb resting on upper portion of steering wheel; reading with upper extremities maintained in forward abduction) and that lowering a symptomatic limb relieves its tingling.

With progression, negative symptoms appear (eg, numbness and then weakness and wasting). Unfortunately, as the negative symptoms replace the positive ones, affected individuals may become less symptomatic and mistakenly believe their condition is improving. Features of autonomic fiber involvement may also be present but are less reliably elicited. Isolated hand pain is an uncommon manifestation of CTS because pain more commonly occurs later in the course and for this reason tends to be accompanied by other features of CTS.

The clinical features of CTS correlate with its underlying pathology. As demyelination precedes axon disruption pathologically, the clinical features of demyelination (episodic paresthesias) precede those of axon loss (numbness, weakness, wasting). However, clinical features may go unrecognized or be dismissed by the patient. Moreover, there is substantial variation in type, intensity, and frequency of symptoms.^16,17

The EDX features of CTS correlate with its underlying pathology and pathophysiology. As demyelination (loss of insulation) increases the capacitance of the membrane and increases internodal current leakage, conduction velocity is reduced. As severity worsens and pathology changes from predominantly demyelination to predominantly axon loss, the individual nerve fiber action potentials, which make up the compound responses being recorded, are lost. As a result the amplitude and negative area under the curve values decrease. Thus, the EDX features of demyelination (eg, prolonged latencies) precede those of axon loss (eg, amplitude, negative area under the curve reduction).

As with other focal mononeuropathies, the sensory responses tend to be affected earlier and to a greater degree than do the motor responses. Consequently, the EDX features of CTS typically follow a standard progression. The median palmar responses are involved sooner and to a greater degree than the median sensory responses recorded from the digits, which in turn tend to be involved earlier and to a greater degree than are the median motor responses.

Awareness of this relationship dictates the severity of the lesion and helps in the recognition of a cool limb and in the avoidance of a false-positive study interpretation. In a cool limb, the fingers are cooler than the wrists. Thus, the peak latency of the median digital sensory response is delayed to a greater extent than the ipsilateral median palmar response (the opposite of the CTS pattern). Accordingly, whenever this pattern is identified, the hand must be warmed or rewarmed and the studies repeated. The hand is also warmed or rewarmed whenever the median motor response is delayed out of proportion to that of the median palmar response.

Conclusion

Cases of CTS mainly in the nondominant limb provide an opportunity to identify particular limb usage patterns that might be associated with CTS. Of the present study’s 21 affected patients, 16 were using their nondominant limb to perform activities that required sustained gripping. Fourteen of the 16 activities were related to occupation. These findings strongly suggest an association between activities that require sustained gripping and development of CTS.

That the card dealers simultaneously used their nondominant hand for sustained gripping and the dominant hand for the repetitive activity of dealing suggests that sustained gripping is a stronger risk factor than repetitive activity for the development of CTS—an unanticipated finding. Interestingly, in a 2001 study that suggested repetitive activity might not be a CTS risk factor, there was a higher incidence of CTS among computer users working with a mouse—an activity that requires sustained gripping.¹²

Episodic hand tingling during mouse use likely reflects impaired blood flow to the median nerve, which occurs when carpal tunnel pressure approaches or exceeds 20 to 30 mm Hg.¹⁸ Placement of a hand on a mouse increases intracarpal pressure from 3 to 5 mm Hg (wrist in neutral position) to 16 to 21 mm Hg, whereas mouse use increases intracarpal pressure to 28 to 33 mm Hg.^18-20 

The dominant limb is the limb preferred for performing an activity that requires one hand or for performing the more demanding part of an activity that requires both hands. For example, most playing card dealers use their dominant limb to distribute cards (the more demanding part of the activity) and their nondominant limb to hold the rest of the pack (the less demanding activity). Although a relationship between nocturnal hand paresthesias and daily hand activities has been known for more than a century, it was not until more recently that it was recognized that unilateral carpal tunnel syndrome (CTS) more commonly involves the dominant limb.^1,2

Among people with CTS, the dominant limb tends to be affected earlier and, in the setting of bilateral involvement, more severely.^3,4 This relationship, however, is not absolute. In 1983, Falck and Aarnio reported that CTS could be more pronounced on the nondominant side whenever upper extremity usage requirements, especially occupational requirements, stressed that limb to a greater extent than they stressed the dominant limb.⁵

Regarding occupation, particular CTS risk factors and associations have been reported. One study found that the most common work-related risk factor was repetitive bending and twisting of the hands and wrists.⁶ In another study, the incidence of CTS was almost 10-fold higher among workers performing high force, high repetition jobs than among those performing low force, low repetition jobs.^7-10 A meta-analysis identified a strong causal relationship between forceful, repetitive work and development of CTS.¹¹ A more recent and controversial study found no association between heavy use of computers and CTS.¹² In 1911, Hart reported an association between repetitive gripping and thenar atrophy.¹³ Although he misattributed the association to trauma of the recurrent thenar motor branch, 2 of the 3 described patients reported a period of episodic hand paresthesias preceding the development of thenar eminence atrophy and thus more likely had typical CTS.

Background

The present study was prompted by the clinical and electrodiagnostic (EDX) features of a 27-year-old right-hand–dominant man who presented to the EDX laboratory for assessment of bilateral hand paresthesias. The patient reported episodic bilateral hand tingling that was much more pronounced on the left (nondominant) side. Consistent with his report, EDX assessment revealed bilateral CTS that involved the nondominant limb to a much greater extent than that of the dominant limb. As a blackjack dealer, the patient was using his nondominant hand to “tightly grip 2 decks of cards” and the dominant hand to distribute those cards.

Similar history and EDX patterns (bilateral CTS more pronounced on nondominant side) were subsequently noted in 2 other patients, both of whom were using their nondominant limb to perform an activity that required sustained gripping. One of these patients was a minnow counter. He was using his nondominant hand to firmly grip the top of a bucket and the dominant hand to “deal” the fish into separate tanks. The other patient was a mason. He was using his nondominant hand to firmly hold a brick or stone in place and the dominant hand to apply cement. The clinical and EDX features of these 3 patients suggested that sustained gripping might be a significant risk factor for development of CTS. That all 3 of these patients were using their dominant hand for a repetitive activity (dealing) further suggested that, compared with repetitive activity, sustained gripping was more significant as a risk factor for development of CTS.

As unilateral CTS typically occurs on the dominant side, and bilateral CTS typically is more pronounced on the dominant side, the term backward CTS is applied to cases in which unilateral CTS occurs on the nondominant side or bilateral CTS involves the nondominant side to a greater extent than the dominant side.

Although many investigators have purported an association between CTS and a particular upper extremity activity, their conclusions are limited by use of poorly validated symptom surveys, use of faulty epidemiologic methods, selection of a specific basis for clinical diagnosis (eg, isolated hand pain), or lack of EDX confirmation. Associations between a particular activity and development of CTS are best addressed by studies that include both clinical and EDX assessments and that fully characterize the individual hand usage patterns.

Methods

This study identified the upper extremity usage patterns associated with development of CTS among patients found in the EDX laboratory to have backward CTS (unilateral CTS in nondominant limb or bilateral CTS involving nondominant limb more than dominant limb). Thus, whenever patients who were referred to the EDX laboratory for upper extremity studies were noted to have backward CTS, an extensive upper extremity usage assessment was immediately performed. Both the EDX studies and the upper extremity usage assessments were performed by the author during the same encounter.

All patients had initial screening sensory and motor nerve conduction studies performed: median sensory, recording the second digit; ulnar sensory, recording the fifth digit; superficial radial, recording the dorsum of hand; median motor, recording the thenar eminence; and ulnar motor, recording the hypothenar eminence. As CTS was suspected in all cases, median and ulnar palmar nerve conduction studies were performed as well. All these studies were performed using previously reported techniques, and all collected values were compared with EMG laboratory control values.^14,15 In all patients, the median nerve conduction studies were performed bilaterally. Approval from an ethics board or an institutional review board was not needed because this study did not involve personal information or identifiable images.

To avoid identifying small, chance asymmetries related to hypothyroidism and other conditions that produce bilateral CTS, the author predefined the degree of asymmetry required for study inclusion to identify only large asymmetries. Because the EDX manifestations of CTS typically reflect features of demyelination before those of axon loss, the required asymmetries were predefined using peak sensory and distal motor latency values. For study inclusion, the median nerve latency value recorded from the nondominant limb needed to exceed the value recorded from the dominant limb by 0.6 msec for the median palmar responses, 1.0 msec for the median digital sensory responses, or 1.0 msec for the median motor responses.

Excluded from the study were patients who reported being ambidextrous, those who had changed hand dominance at any age and for any reason, those with a history of upper extremity trauma or surgery, and those with EDX findings indicating a concomitant neuromuscular disorder. In addition, patients with diabetes mellitus or any other condition associated with bilateral CTS were excluded.

Results

From the approximately 2,000 upper extremity EDX studies performed over a 30-month period, the author identified 21 patients who met the inclusion criteria (Table 1). Of these 21 patients, 15 (71%) had bilateral CTS and 6 (29%) had unilateral CTS. Sixteen of the 21 patients used their nondominant hand, through a significant portion of the day, to perform an activity that required sustained gripping (Table 2).

Of these 16 patients, 14 reported that the sustained gripping activity was related to their occupation: pipe fitter (4 patients), card dealer (4), professional driver (2), grocery store clerk (1), wire stripper (1), bakery worker (1), and motel room cleaner (1). In their jobs, the pipe fitters were continually cutting pipe during their entire 8-hour shift—using the nondominant hand to tightly grip a pipe while using the dominant hand to direct an electrically powered blade through it. Of the card dealers, 1 was a professional playing card dealer (not the dealer whose case prompted this study), 1 distributed store coupons into containers, and 2 distributed pieces of mail into bins (referred to as casing the mail). All the card dealers used their nondominant hand to tightly grip items that the dominant limb distributed. The professional drivers used their nondominant hand to grip the steering wheel. The grocery store clerk used her nondominant hand to grip shopping items while moving them across a barcode detector. The wire stripper used her nondominant hand to tightly grip bundles of wire while holding a tool in the dominant hand to snip or strip them. The bakery worker continually used her nondominant hand to squeeze off pieces of dough from a mound. And the motel room cleaner used her nondominant hand to grip the side of a bathtub while scrubbing the tub with her dominant hand (she estimated she cleaned bathtubs for about 25% of her 8-hour shift).

Of the 2 patients who reported sustained gripping unrelated to occupation, 1 was baby-sitting her grandson 5 days per week. She carried him, grasping his buttock with her nondominant hand, while performing her daily activities. She estimated she carried the child a minimum of 2 hours a day. After several weeks, she noted episodic tingling in the nondominant hand, yet she continued carrying him for another 7 months, at which point she sought medical care. The other patient, a student in a stress relief class, was instructed to repetitively open and tightly close her nondominant hand for 10 minutes 4 or more times per day. After several weeks, she noted episodic tingling in the exercised, nondominant hand.

Of the 5 patients who denied performing an activity that required sustained gripping, 2 used their nondominant limb to enter data into a computer while turning pages with the dominant limb. A piano teacher, used her nondominant limb to strike piano keys while sitting to the right of her pupils; and a typist, consistently slept with the dorsal aspect of the nondominant hand pressed into her cheek, resulting in sustained wrist flexion throughout the night. One patient could not identify an activity performed with her nondominant limb both frequently and for prolonged periods.

Discussion

As with other syndromic disorders, CTS is associated with several clinical features, the presence of which correlates with the severity of median nerve involvement. During the earliest stage of CTS, episodic hand tingling (a positive symptom) is commonly reported. This tingling typically is more pronounced at night and during relaxation. In addition, many patients come to recognize that their hand tingling is precipitated by activities that involve sustained upper extremity elevation (eg, driving with a limb resting on upper portion of steering wheel; reading with upper extremities maintained in forward abduction) and that lowering a symptomatic limb relieves its tingling.

With progression, negative symptoms appear (eg, numbness and then weakness and wasting). Unfortunately, as the negative symptoms replace the positive ones, affected individuals may become less symptomatic and mistakenly believe their condition is improving. Features of autonomic fiber involvement may also be present but are less reliably elicited. Isolated hand pain is an uncommon manifestation of CTS because pain more commonly occurs later in the course and for this reason tends to be accompanied by other features of CTS.

The clinical features of CTS correlate with its underlying pathology. As demyelination precedes axon disruption pathologically, the clinical features of demyelination (episodic paresthesias) precede those of axon loss (numbness, weakness, wasting). However, clinical features may go unrecognized or be dismissed by the patient. Moreover, there is substantial variation in type, intensity, and frequency of symptoms.^16,17

The EDX features of CTS correlate with its underlying pathology and pathophysiology. As demyelination (loss of insulation) increases the capacitance of the membrane and increases internodal current leakage, conduction velocity is reduced. As severity worsens and pathology changes from predominantly demyelination to predominantly axon loss, the individual nerve fiber action potentials, which make up the compound responses being recorded, are lost. As a result the amplitude and negative area under the curve values decrease. Thus, the EDX features of demyelination (eg, prolonged latencies) precede those of axon loss (eg, amplitude, negative area under the curve reduction).

As with other focal mononeuropathies, the sensory responses tend to be affected earlier and to a greater degree than do the motor responses. Consequently, the EDX features of CTS typically follow a standard progression. The median palmar responses are involved sooner and to a greater degree than the median sensory responses recorded from the digits, which in turn tend to be involved earlier and to a greater degree than are the median motor responses.

Awareness of this relationship dictates the severity of the lesion and helps in the recognition of a cool limb and in the avoidance of a false-positive study interpretation. In a cool limb, the fingers are cooler than the wrists. Thus, the peak latency of the median digital sensory response is delayed to a greater extent than the ipsilateral median palmar response (the opposite of the CTS pattern). Accordingly, whenever this pattern is identified, the hand must be warmed or rewarmed and the studies repeated. The hand is also warmed or rewarmed whenever the median motor response is delayed out of proportion to that of the median palmar response.

Conclusion

Cases of CTS mainly in the nondominant limb provide an opportunity to identify particular limb usage patterns that might be associated with CTS. Of the present study’s 21 affected patients, 16 were using their nondominant limb to perform activities that required sustained gripping. Fourteen of the 16 activities were related to occupation. These findings strongly suggest an association between activities that require sustained gripping and development of CTS.

That the card dealers simultaneously used their nondominant hand for sustained gripping and the dominant hand for the repetitive activity of dealing suggests that sustained gripping is a stronger risk factor than repetitive activity for the development of CTS—an unanticipated finding. Interestingly, in a 2001 study that suggested repetitive activity might not be a CTS risk factor, there was a higher incidence of CTS among computer users working with a mouse—an activity that requires sustained gripping.¹²

Episodic hand tingling during mouse use likely reflects impaired blood flow to the median nerve, which occurs when carpal tunnel pressure approaches or exceeds 20 to 30 mm Hg.¹⁸ Placement of a hand on a mouse increases intracarpal pressure from 3 to 5 mm Hg (wrist in neutral position) to 16 to 21 mm Hg, whereas mouse use increases intracarpal pressure to 28 to 33 mm Hg.^18-20 

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

eAppendix

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

eAppendix

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

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