Optimal Chemotherapy Dosing in a Bilateral Lower Extremities Amputee With Metastatic Pancreatic Adenocarcinoma

The dosing of cytotoxic chemotherapy is often based on a measurement of body surface area (BSA). Although the use of BSA has been shown to be a poor estimate of drug metabolism, because it does not account for interpatient variability in complex biologic processes such as enzymatic activity,¹ it remains a standard when prescribing chemotherapy.² The use of BSA-based dosing is further complicated in certain scenarios, including obesity and loss of a limb, because these patients are underrepresented in drug development and clinical trials.³ In this report, we describe a patient who underwent bilateral traumatic lower leg amputations and later presented with metastatic pancreatic cancer. He did not initially respond to a dose-adjusted regimen that accounted for his amputations but subsequently showed evidence of disease response when nonadjusted BSA was used to guide treatment.

CASE REPORT

A 55-year-old man who underwent traumatic bilateral lower extremity amputations 22 years ago presented with abdominal pain. The injuries to the lower extremities had necessitated below-the-knee amputation of the right leg and above-the-knee amputation of the left leg. The patient, who had recently diagnosed diabetes, had biopsy-proven AJCC IV pancreatic adenocarcinoma of the tail of the pancreas with metastases to the liver and peritoneum, associated with an elevated CA 19-9 of 52,481 U/mL. In addition to the bilateral amputations, the finding pertinent to this presentation on physical examination was tender hepatomegaly. FOLFIRINOX therapy was recommended.⁴

To account for the patient's amputations in calculating the BSA for chemotherapy, the “rule of nines” of burn medicine was used. The patient's preamputation BSA was calculated according to the preamputation body weight shown in the available records, considering that the patient retained his same body habitus and prior height. The BSA was then reduced by 18%, a 9% reduction to account for each lower extremity amputation.^5,6 Because of concerns of toxicity from the FOLFIRINOX regimen, the dose was then further reduced by 20% on the basis of our reported experience of tolerance to FOLFORINOX in our patient population.⁷ The patient tolerated the treatment well; however, a restaging computed tomographic (CT) scan showed stable disease.

At that point, the patient's chemotherapy dosage was again adjusted based on a preamputation BSA that was not reduced to account for his amputations, with the 20% overall reduction applied. A restaging CT scan after 2 months showed evident partial response by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).⁸ CA 19-9 showed an initial increase followed by a decrease that was commensurate with the partial response (Table 1). The patient was thereafter continued on FOLFIRINOX.

Table 1.

RECIST 1.1 and Ca19-9 results

Criteria	Baseline	First assessment after 4 cycles of therapy based on amputee BSA	Second assessment after 4 cycles of therapy based on nonamputee BSA
RECIST 1.1 measurement, cm	12.8	12.1	8
% RECIST change		−5.5	−37.5
CA 19-9, U/mL	52,481	85,573	30,245

DISCUSSION

The formula for calculating BSA is based on the work of Du Bois and Du Bois,⁹ who, in 1916, compartmentalized each body segment and assigned each a linear equation. The use of BSA-adjusted dosages is intended to limit drug toxicity by attempting to account for drug elimination based on body size. However, body size alone is not responsible for metabolism and elimination of cytotoxic medications. Some studies have found a 4-to 10-fold variation in cytotoxic drug clearance due to baseline enzymatic activity and genetic and environmental factors.¹⁰ The adjustment of chemotherapy based on BSA remains the standard of care, to optimize drug exposure while minimizing potential toxicities, even though an accurate estimate of BSA may lead to an inaccurate dose up to 40% of the time, with 10% of patients being overdosed and up to 30% underdosed, according to one study.¹ This discrepancy in dosing is due to the failure of BSA to account for numerous other variables in drug elimination, including the patient's sex, hepatic and renal function, obesity, nutritional status, concurrent medications and herbal supplements, and disease etiology, in addition to the previously mentioned differences observed in enzymatic activity.

Calculations of BSA are further complicated in several clinical situations, including obesity, cachexia, and limb amputation. Rising levels of obesity and diabetes, coupled with improved long-term survival in cardiac disease, portend a likely increase in patients with leg amputations who present with cancers that necessitate initiation of systemic therapy.¹¹ A literature search revealed no unifying guidelines on either the dosing of cytotoxic agents in patients who have undergone leg amputation or the role of adjusting BSA for chemotherapy in these patients. When calculating the dose of chemotherapy in the presence of amputation, many physicians borrow the rule of nines from burn medicine as a way to estimate BSA.⁶ The rule provides a practical estimate for the percentage of BSA and divides the body into areas of roughly 9% of BSA. This method allows for a convenient estimation of BSA reduction, which is necessary in patients who have undergone amputation. However, there is no evidence to support this practice; in fact, some have argued that amputated limbs may not contribute significantly to altered drug metabolism, and therefore no adjustment in BSA is necessary.¹²

The rule of nines was devised as a way to rapidly estimate BSA in determining emergency management of critically injured burn patients. It is therefore not surprising that its role in carefully calculated BSA measurements for cytotoxic treatment is limited. Studies that compared the estimated BSA obtained from the rule of nines to direct measurement and have found significant differences.¹³ The rule is also limited in situations involving partial limb amputations, as in this case. In addition, the use of the rule to adjust total BSA for amputations assumes that the lost limb (and therefore tissue, blood, and plasma) will affect the volume of distribution (V_D) of the drug, and therefore its pharmacokinetics. However, the change in V_D may not be as clinically significant as many of the other factors already mentioned that affect drug metabolism—namely, hepatic and renal function, obesity, enzymatic activity, and concurrent medications that may also affect enzymatic activity. In our patient, the possibility that the response to FOFLFORINOX was already evolving in the right direction, with stable disease after the first 2 months of therapy, despite the rise in CA19-9, which is not necessarily a reliable predictive marker,¹⁴ is not ruled out.

Quite apart from the general limitations of both BSA and the rule of nines is the specific difference in metabolism of the individual agents in FOLFIRINOX. One study found that the clearance of irinotecan varied as widely as 34% among patients after correction for BSA and concluded that BSA and other body-size measures (ie, ideal body weight) were unrelated to clearance and metabolism of the drug.¹⁵ Because BSA does not account for complicated metabolic processes such as differing levels of enzymatic activity, the ideal adjustment to BSA (and therefore dosages of cytotoxic medications) in patients who have undergone leg amputation remains unclear. Certainly, the experience of this patient shows that BSA reduction to account for amputation can result in subtherapeutic doses of chemotherapy. Especially since the risk of underdosing is already a consideration when basing chemotherapy on BSA,¹ there is clearly a need for further research, to establish clinical guidelines for the treatment of malignancy in patients who have undergone amputation.