In NWTS-5, dosages of

chemotherapy agents for Wilms tumor patients who are less than 30 kg were

converted from mg/m2

to mg/kg. By assuming the average 1-m2 child weighs 30 kg,

the dose/m2 can be divided by 30 to arrive at a dose/kilogram, which can be used in

dosing calculations. This adjustment lowers the dose by 20% to 50% in children who

weigh less than 15 kg. In NWTS-5, infants younger than 12 months of age received

doses that were further reduced by halving the milligram/kilogram dose.

Interaction of Chemotherapy with Radiation

CASE 95-2, QUESTION 3: Are there any dosing precautions required because of potential interactions

between B.N.’s treatments?

Another medication-related problem that may arise in B.N. is the interaction of

dactinomycin and doxorubicin with radiation therapy.

42–46 Two effects have been

reported. One is acute enhancement of radiation effects, and the other is recurrence

(recall) of radiation effects up to several weeks later, especially to skin and mucous

membranes. Because B.N. is to receive abdominal and lung irradiation during his

chemotherapy treatment, concurrent doses of dactinomycin and doxorubicin will need

to be reduced by 50%, and held if wet desquamation of the skin at the radiation site

occurs. In many of the Ewing sarcoma and rhabdomyosarcoma protocols,

dactinomycin or doxorubicin is stopped during concurrent radiation treatments.

Doxorubicin Cardiotoxicity in Pediatrics

CASE 95-2, QUESTION 4: When B.N. receives lung radiation for his metastases, how will it affect the

doxorubicin he is scheduled to receive?

Although it is well known that mediastinal radiation can increase the risk of

anthracycline-induced cardiac toxicity,

47

the only adjustment for B.N. would be a

temporary reduction of doxorubicin doses (same reductions as described in Case 95-

2, Question 3). The total doxorubicin dose should be limited to no more than 5 mg/kg

(150 mg/m2

in larger children). In earlier Wilms tumor studies, the risk of congestive

heart failure was 4.4% at 20 years, or up to 17.4% in patients who relapsed and

received more doxorubicin.

48 Thus, cardiovascular toxicity can develop as long as

20 years after therapy is completed, with an apparent decrease in left ventricular

wall thickness and increased ventricular afterload, probably related to inadequate

numbers of myocytes.

49 These reports emphasize the need to minimize chemotherapy

in patients with good prognosis, as the Wilms tumor studies are doing. New

recommendations include better standardization of cardiac monitoring and

continuation of monitoring throughout life in survivors of childhood cancer who

receive cardiotoxic agents.

Dactinomycin Hepatotoxicity

CASE 95-2, QUESTION 5: B.N. is to receive vincristine 0.05 mg/kg weekly for 10 weeks; doxorubicin 1.5

mg/kg at weeks 3 and 9; 1 mg/kg at weeks 15 and 21; and dactinomycin 0.045 mg/kg at weeks 0, 6, 12, 18, and

24. During the third week of treatment, his alanine aminotransferase (ALT) is elevated to 78 units/dL. Is this

related to his drug therapy?

Early in the NWTS-4, an increased incidence (14.3%) of severe hepatotoxicity

(elevation of alanine aminotransferase or ALT 10 times normal with or without

ascites) was reported with the pulse-intensive dactinomycin doses (0.060

mg/kg/single dose) in patients receiving no abdominal radiation.

50 Subsequently,

dactinomycin doses were reduced. Still, the incidence of hepatotoxicity in patients

receiving the newer 0.045-mg/kg pulse doses (3.7%), as well as those receiving the

standard 0.015 mg/kg/day for 5 days (2.8%), remained elevated relative to the

NWTS-3 results (0.4%),

p. 2007

p. 2008

which used the same 0.015 mg/kg/day for 5 days.

51 The reasons for the increased

hepatotoxicity are not known. Liver function usually returns to baseline within 1 to 2

weeks after discontinuation of chemotherapy, although more severe problems with

sinusoidal obstructive syndrome (hepatopathy, veno-occlusive disease) have also

been reported.

33 Chemotherapy was restarted in some patients, although frequently at

lower doses or without dactinomycin. B.N. should be monitored closely in case his

liver enzymes continue to rise, especially because he will receive abdominal

radiation treatments that may increase the risk of hepatic toxicity. If his ALT rises to

2 to 5 times normal, or his total bilirubin is 3 to 5 mg/dL, doses of all three of his

drugs should be reduced by 50%. If his ALT or bilirubin rises above 2 to 5 times

normal, the drugs should be withheld until laboratory values return to lower than the

aforementioned ranges.

Osteosarcoma

DEFINITION, EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND COURSE OF

THE DISEASE

Osteosarcoma is a malignant osteoid-producing bone tumor that occurs most

commonly in adolescents or young adults in the second or third decade of life.

52–54 A

second peak incidence occurs in patients older than 50 to 60 years old. The most

common manifestation at diagnosis is pain at the site, which can sometimes be

present for several weeks to months. It occurs most frequently in the metaphyseal

ends of the distal femur, proximal tibia, or proximal humerus, but it can occur in the

flat bones as well.

The age range and bones involved suggest a malignant response associated with

normal childhood growth spurts. Osteosarcoma has been associated with Paget

disease in the elderly, another condition with rapid bone turnover.

53 Radiation from

treatments or nuclear disasters has also been linked to osteosarcoma. Mutation of the

retinoblastoma gene increases the risk of osteosarcoma, and retinoblastoma survivors

and carriers need to be monitored for osteosarcoma. There are a number of other

uncommon inherited conditions that are associated with an increased risk of

osteosarcoma.

Typical staging systems are not used for osteosarcoma; however, presence of

clinically detectable metastatic disease at diagnosis, resectability of the tumor, and

tumor grade (high vs. low) are important to outcomes. Low-grade tumors are not

likely to metastasize and are not treated with chemotherapy in contrast to high-grade

tumors. Clinically detectable metastases are present in 15% to 20% of patients,

usually in the lungs but occasionally in the same or other bones. If surgery alone is

used for treatment, 80% of patients will die within 5 years of recurrent metastatic

disease, indicating the presence of subclinical micrometastases at the time of

diagnosis.

52–54 The degree of tumor necrosis at surgical resection is an indicator of

chemosensitivity of the tumor and risk of relapse. Greater than 90% necrosis at the

time of surgery after six cycles of neoadjuvant chemotherapy is associated with a

70% to 80% chance of long-term survival for non-metastatic disease, with survival

dropping to around 50% for non-metastatic disease with less than 90% necrosis.

CLINICAL PRESENTATION AND DIAGNOSIS

Because osteosarcoma usually presents close to a joint in long bones, it most

commonly presents with pain or a limp. It is often thought to be an athletic injury at

first. In some patients, a broken arm or leg will occur, bringing attention to the mass

on radiographs. Diagnosis is based on pathology from a biopsy, which should be

obtained by the surgeon performing the definitive surgery; therefore, the biopsy tract

can be resected with the tumor.

TREATMENT OVERVIEW

Although surgery is the main treatment of the primary tumor, chemotherapy is used to

prevent development of metastases in patients with high-grade osteosarcoma. Drugs

frequently used for osteosarcoma include high-dose methotrexate, cisplatin,

doxorubicin, and ifosfamide. Regimens have changed minimally in the last 25 years,

with the current standard treatment in COG being cisplatin and doxorubicin

alternating with two cycles of high-dose methotrexate. Neoadjuvant chemotherapy is

commonly given for 6 cycles and continued after surgery for 12 more cycles (for a

total of 29 weeks). The tumor is relatively resistant to radiation therapy, which is

usually reserved for cases in which local control cannot be achieved surgically.

54

Surgical procedures usually fit into two categories: limb preservation or salvages, or

amputation with prosthetics. There are a number of versions of each type of

surgery.

52,53 When chemotherapy is used with surgery in non-metastatic patients, longterm (2–5 years) disease-free survival is 50% to 85%.

52–54

ROLE OF CHEMOTHERAPY IN TREATMENT

CASE 95-3

QUESTION 1: G.C. is an 18-year-old man with a 2- to 3-month history of left shoulder pain. A tumor is found

on radiograph, and biopsy confirms a high-grade conventional osteosarcoma of the left proximal humerus. No

apparent metastases are found with CT and bone scans. Renal function, left ventricular ejection fraction, and

hearing tests are all within normal limits. G.C. begins neoadjuvant chemotherapy consisting of high-dose

methotrexate alternating with cisplatin and doxorubicin. Six cycles of this chemotherapy (cisplatin/doxorubicin

twice and high-dose methotrexate 4 times) will be given before his surgery, after which he will receive two

more cycles of cisplatin/doxorubicin, each followed by two cycles of methotrexate, then two more cycles of

doxorubicin, each followed by two cycles of methotrexate. What is the goal of chemotherapy? What is the role

of presurgical (neoadjuvant) chemotherapy in G.C.?

Because G.C.’s osteosarcoma is in his proximal humerus, the surgeon can remove

the primary tumor using one of the various operations described in the literature.

52,53

Limb salvages typically work well in the upper extremities, with fewer

complications than when they are used for lower extremities. Because patients with

osteosarcoma usually die from metastases, the goal of the chemotherapy is to

eradicate micrometastases, which are present more than 80% of the time, as

discussed in the previous section. Neoadjuvant chemotherapy of osteosarcoma was

developed to treat micrometastases while waiting for limb salvage surgeries to be

arranged, performed, and healed. Neoadjuvant therapy may improve limb-sparing

surgery by shrinking the tumor; it also allows histologic grading of the response to

initial chemotherapy at surgery, a prognostic factor for risk of relapse (see Case 95-

3, Question 2). However, no convincing evidence to date indicates that disease-free

survival is better for patients who receive neoadjuvant chemotherapy relative to

those who receive their chemotherapy as adjuvant therapy.

54

In G.C., a titanium bone

implant was placed where the diseased humerus was removed. The ease of doing this

surgery may have been enhanced by neoadjuvant chemotherapy–induced shrinkage of

the tumor.

PROGNOSTIC FACTORS

CASE 95-3, QUESTION 2: At surgery, G.C.’s tumor shows excellent histologic response, shown by 99%

necrosis of the tumor sample. At diagnosis, his LDH was 220 units/L. How do these prognostic factors affect

the choice of therapy in osteosarcoma?

p. 2008

p. 2009

Conventional staging systems do not correlate well with prognosis for most bone

cancers. Clinically apparent metastases or a location that does not allow complete

surgical removal of the primary tumor are associated with a poor prognosis.

52–54

Newer surgical techniques and treatments have improved the prognosis with 20% to

30% of metastatic patients cured using neoadjuvant chemotherapy and surgery. Other

potential prognostic factors have been identified; however, few of these factors have

been used to stratify patients to different treatment regimens. G.C. has a minimally

elevated LDH consistent with a relatively small tumor mass, although this is not used

to stratify for treatment. The percentage necrosis of the tumor at surgery correlates

with risk of recurrence. In current studies, patients with greater than 90% tumor

necrosis after six cycles of neoadjuvant chemotherapy are considered good risk and

are treated with standard chemotherapy such as G.C. is receiving. Patients whose

tumors have less necrosis at surgery are considered to be standard risk, and they have

a higher risk of treatment failure. No treatment modifications to date have

demonstrated better outcomes for these patients than the good risk protocol described

above.

DELAYED CLEARANCE AFTER HIGH-DOSE METHOTREXATE

CASE 95-3, QUESTION 3: After reconstructive surgery using a titanium implant, G.C. restarts his

chemotherapy. During his fourth cycle of chemotherapy, after high-dose methotrexate is given, G.C.’s peak

methotrexate concentration is 1,300 micromolar (μM) and the 72-hour concentration is 0.22 μM (normal, <0.1

μM at 72 hours). Recorded urine-specific gravities are less than 1.010, urine pH is between 7 and 8, and urine

output is greater than 2 to 3 mL/kg/hour, which, according to guidelines, suggest a reduced risk of methotrexateinduced nephrotoxicity. His creatinine has increased from 0.9 to 1.1 mg/dL (creatinine clearance of 106

mL/minute/1.73 m

2

); however, he does not have any signs or symptoms of methotrexate toxicity in spite of his

delayed clearance. Leucovorin rescue (15 mg IV every 6 hours beginning at hour 24) is continued. What

potential problems could be causing his retention of methotrexate?

Accumulations of protein-containing fluids (called third-spaces), such as pleural

effusion and ascites, or GI obstruction, may retain methotrexate and slow the terminal

excretion.

55–58 Slow excretion of methotrexate allows more proliferating cells to be

exposed to methotrexate during the S phase of the cell cycle, increasing the

cytotoxicity and resulting in more mucositis and myelosuppression. Many drugs

interact with methotrexate, which can also slow its excretion. Cisplatin reportedly

reduces the excretion of methotrexate because of nephrotoxicity, especially at

cumulative cisplatin doses greater than 300 mg/m2

.

59 G.C. has received four doses of

120 mg/m2

(480 mg/m2

total dose) of cisplatin, which may have contributed to the

reduced methotrexate excretion. He has not received concomitant nephrotoxins, such

as aminoglycosides or amphotericin B. Weak organic acids, such as salicylates,

nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, or trimethoprim–

sulfamethoxazole (TMP–SMX), can compete with methotrexate for renal tubular

secretion via the organic anion transport system.

59,60 Proton pump inhibitors are

thought to more directly inhibit transporter proteins and have been reported to delay

methotrexate excretion.

59,61

Although G.C.’s serum creatinine appears to be the same that it was at diagnosis

(1.1 mg/dL), serum creatinine is not always a good indicator of renal function, so it is

possible that G.C. has had some renal damage that is not apparent from his serum

creatinine concentrations.

29 A measured creatinine clearance was 176

mL/minute/1.73 m2 at diagnosis, and a repeat at this point is 106 mL/minute/1.73 m2

.

Even measured creatinine clearance may not always be accurate when compared

with Cr-ethylenediaminetetraacetic acid measurement of glomerular filtration rate.

29

Although the reduced renal clearance may be contributing, it is not clear why G.C. is

retaining methotrexate; future courses of methotrexate need close monitoring.

LEUCOVORIN RESCUE

CASE 95-3, QUESTION 4: How long should leucovorin be administered to G.C.?

Leucovorin is a tetrahydrofolate that bypasses methotrexate’s block of

dihydrofolate reductase and reduces the toxicities of high-dose methotrexate. It,

therefore, can be used as a form of methotrexate rescue. Cytotoxic effects of

methotrexate depend on concentration and duration of exposure.

62 Many high-dose

methotrexate protocols continue leucovorin rescue until serum methotrexate

concentrations are 0.1 μM, which would be expected to occur approximately 72

hours after a 12 g/m2 dose infused over 4 hours. Because G.C. has delayed

methotrexate clearance with persistence of methotrexate levels still above 0.1 μM at

72 hours, prevention of GI and bone marrow cytotoxicity may require continuation of

leucovorin rescue until methotrexate concentrations are less than 0.05 μM.

62 For

G.C., methotrexate concentrations did not fall below 0.1 μM until 108 hours after his

dose; thus, leucovorin was continued 24 hours past that time to ensure presence until

methotrexate fell below 0.05 μM. Other considerations may also be important in

patients receiving leucovorin rescue. Because of the competitive nature of leucovorin

rescue, higher leucovorin doses may be needed for patients with excessively high

methotrexate concentrations.

Petros and Evans

56 describe in Figure 95-1 that the methotrexate concentrations

(those above the blue-shaded area) place patients at high risk for methotrexate

toxicity if given the usual low-rescue doses of leucovorin.

56,63–69 Methotrexate doses

(12 g/m2

) infused over 4 hours are designed to produce peak methotrexate

concentrations in the blood of 1,000 μM, followed by less than 10 μM at 24 hours, 1

μM at 48 hours, and 0.1 μM at 72 hours. Higher concentrations may result in greater

toxicity and additional leucovorin doses may be necessary. If G.C.’s methotrexate

concentrations had remained more than 1 μM 48 hours after the beginning of the

infusion, current COG recommendations are to increase the leucovorin dose to 15

mg/m2 every 3 hours until methotrexate concentrations fall below 0.5 μM. If

concentrations exceed 5 μM 48 hours or more after the methotrexate dose, higher

doses of leucovorin are recommended (150 mg/m2 every 3 hours). Oral leucovorin

administration should not be used when the patient has emesis or requires large oral

doses (>50 mg), which are often poorly absorbed.

56

If a patient on high-dose

methotrexate experiences renal failure and has elevated concentrations of

methotrexate, glucarpidase (carboxypeptidase G2) may be used in addition to the

leucovorin. Glucarpidase hydrolyzes methotrexate into inactive compounds and is

very effective at quickly lowering methotrexate concentrations; however, it generally

needs to be administered within the first 96 hours after the methotrexate dose. In spite

of rapid reduction of methotrexate concentrations, it is not clear the extent to which it

lowers morbidity or mortality from the high levels and delayed clearance.

70

Figure 95-1 Composite semi-logarithmic plot of serum methotrexate (MTX) concentrations versus time. Several

research groups have proposed threshold MTX concentrations over time that enable clinicians to identify patients

at “high risk” for experiencing toxicity after high-dose MTX plus conventional low-dose leucovorin administration.

Data for the figure were obtained from reports of (▴) Evans,

63

(▵) Tattersal,

64

(○) Isacoff,

65

(○) Isacoff,

66

()

Nirenberg,

67

() Stoller,

68 and (▾) Rechnitzer.

69

(Source: Petros WP, Evans WE. Anticancer agents. In: Burton

ME et al, eds. Applied Pharmacokinetics & Pharmacodynamics. 4th ed. Philadelphia, PA: Lippincott Williams &

Wilkins; 2006:617.)

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Hematopoietic cell transplantation (HCT) is a life-saving medical

procedure involving the infusion of hematopoietic stem cells into a

patient, the HCT recipient, to treat malignant and nonmalignant diseases

and/or restore normal hematopoiesis and lymphopoiesis.

Case 101-1 (Question 1),

Case 101-2 (Question 1)

In autologous HCT, the donor and recipient are the same individual,

eliminating the need for pretransplantation and posttransplantation

immunosuppression. Autologous hematopoietic cells must be obtained

(i.e., harvested) before the myeloablative preparative regimen is

administered and subsequently stored for administration after the

preparative regimen.

Case 101-1 (Questions 2, 3)

Post-transplantation pharmacotherapy for autologous HCT includes

hematopoietic growth factors to stimulate the proliferation of committed

progenitor cells and to accelerate hematopoietic recovery.

Case 101-1 (Question 6),

Case 101-2 (Question 8)

Common complications after autologous HCT are infections and organ

failure, which occur in less than 5% of patients. The most common

cause of death after autologous HCT is recurrence of the primary

disease.

Case 101-1 (Question 5)

Allogeneic HCT involves the transplantation of hematopoietic stem cells

obtained from a donor’s bone marrow, peripheral blood progenitor cells

(PBPCs), or umbilical cord blood to a patient. The donor for an

allogeneic HCT may be an unrelated or related individual.

Histocompatibility determination between donors and recipients must be

performed through human leukocyte antigen (HLA) typing. The

preparative regimen is, in part, determined by the degree of mismatch

between the donor and the recipient.

Case 101-2 (Questions 2, 3)

The function of the preparative regimens for autologous HCT is to

eradicate residual malignancy. The function of the preparative regimen

in allogeneic HCT is to eradicate the residual malignancy, but also to

provide immunosuppression, allowing the transplanted stem cells to

grow and create a graft-vs.-tumor effect.

Case 101-1 (Question 4)

Choice of preparative regimens for HCT depends on factors such as

underlying disease, degree of HLA matching, stem cellsource, patient

age, and comorbid conditions. Preparative regimens differ in intensity

Case 101-2 (Questions 5, 6)

and are distinguished as myeloablative or nonmyeloablative.

Post-transplantation immunosuppressive therapy is necessary for

allogeneic HCT to prevent both graft rejection and acute and/or chronic

graft-vs.-host disease (aGVHD/cGVHD). Some immunosuppressants

require therapeutic drug monitoring to ensure effectiveness while

minimizing toxicity.

Case 101-2 (Question 7),

Case 101-4 (Question 1),

Case 101-5 (Questions 1–9)

Post-transplantation complications of myeloablative preparation regimens

such as hemorrhagic cystitis, mucositis, and Sinusoidal obstructive

syndrome (SOS)/

veno-occlusive disease (VOD) require pharmaceutical management.

Case 101-2 (Questions 8, 9),

Case 101-3 (Questions 1–9)

Opportunistic infections are a major cause of morbidity and mortality

after myeloablative and nonmyeloablative HCT. The primary pathogens

vary based on the time post-transplant and include bacterial, fungal, and

viralspecies.

Case 101-6 (Questions 1–3),

Case 101-7 (Questions 1–5)

Long-term complications of HCT include cGVHD, endocrine

dysfunction, and secondary cancers.

Case 101-5 (Questions 7–9),

Case 101-8 (Question 1)

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