Chapter 1: Adrenocortical Cancer

Peter F. Lebowitz; Tito Fojo

INTRODUCTION

Listen

Epidemiology

| Download (.pdf) | Print

Epidemiology

Incidence:

0.5 to 2.0 cases per one million population

Stage at Presentation

Deaths:

0.2% of cancer deaths

Stage I:

Median age:

Bimodal median, at age 4 years and ages 40–50 years

Stage II:

29%

Male to female ratio:

1:1.3

Stage III:

19%

Stage IV:

49%

Cohn K et al. Surgery 1986;100:1170–1177

Wooten MD, King DK. Cancer 1993;72:3145–3155

Pathology

Unlike renal cell carcinoma, adrenocortical cancer stains positive for vimentin
>20 mitoses per HPF—median survival 14 months

≤20 mitoses per HPF—median survival 58 months
Tumor necrosis—poor prognosis
Vascular invasion—poor prognosis
Capsular invasion—poor prognosis

Weiss LM et al. Am J Surg Pathol 1989;13:202–206

Survival After Complete Resection

| Download (.pdf) | Print

Survival After Complete Resection

5-Year Actuarial Survival

Stages I–II

54%

Stage III

24%

1-Year survival

Stage IV

Icard P et al. Surgery 1992;112:972–980; discussion 979–980

Icard P et al. World J Surg 1992;16:753–758

Work-up

CT scan of chest, abdomen, and pelvis to determine extent of disease
MRI of abdomen may help to identify and follow liver metastases
If IVC is compressed, consider IVC contrast study, ultrasound, or MRI to assess disease involvement before surgical exploration, although apparent extent of involvement should not deter exploration
Serum and 24-hour urinary cortisol; 24-hour urinary 17-ketosteroid
Additional studies can be performed to determine the functional status of the tumor including: serum estradiol, estrone, testosterone, dehydroepiandrosterone sulfate (S-DHAS), 17-OH-progesterone, and androstenedione

Staging

| Download (.pdf) | Print

Staging

Stage I

<5-cm tumor confined to adrenal

Stage II

>5-cm tumor confined to adrenal

Stage III

Positive lymph nodes or local invasion with tumor outside adrenal in fat or adjacent organs

Stage IV

Distant metastasis

Macfarlane DA. Ann R Coll Surg Engl 1958;23:155–186

Sullivan M et al. J Urol 1978;120:660–665

Expert Opinion

Primary therapy: Primary therapy is complete surgical resection
Surgery and Radio Frequency Ablation (RFA) as therapies for recurrences: When possible, local recurrences should be addressed surgically. Some advocate surgical resection of metastatic disease, and although it may improve survival, firm evidence is lacking. Radio frequency ablation may be used as an alternative if the recurrence is deemed amenable to ablation and has an expendable margin. Just as incomplete resections should not be embarked on, neither should incomplete ablations be performed
Management of excess hormone production: Excess hormone production should not be ignored. Manage severe hypercortisolism aggressively. Because chemotherapy is usually ineffective, treatment of hormonal excess should not be delayed in expectation that chemotherapy will reduce the tumor burden and improve symptoms. Instead, use steroidogenesis inhibitors either singly or in combination. Mitotane is the cornerstone of any strategy and should be started as soon as a diagnosis has been made. Use mitotane at the highest tolerable dose. However, because a therapeutic mitotane level and steady state will not be reached for several months, other agents must be initiated concurrently. In patients with LFT results not more than 3 times normal range, begin therapy with ketoconazole, mindful of the potential for a pharmacokinetic interaction with other drugs. If LFTs are elevated, if an aggressive ketoconazole dose escalation is unsuccessful in controlling symptoms, or if toxicity develops, use metyrapone^✫, either alone or in combination with ketoconazole. Cortisol levels must be monitored frequently to adjust steroidogenesis inhibitor drug doses and to avoid adrenal insufficiency, which occurs infrequently in patients with cortisol-producing tumors. Should adrenal insufficiency occur, hydrocortisone and mineralocorticoid replacement should be instituted as indicated below
- Mitotane: Refer to section describing mitotane as a regimen for ACC
- Ketoconazole: In patients with ACC and frank Cushing syndrome, treatment can start with 200 mg/dose given 3 or 4 times per day. The dose can then be increased by 400 mg/day every few days to a maximum single doses of 1200–1600 mg administered 3 or 4 doses per day (ie, total daily doses = 3600–6400 mg) while monitoring liver function. Because ketoconazole requires stomach acidity for absorption, proton pump inhibitors should be avoided, and achlorhydria should be suspected in elderly individuals who do not respond to therapy
- Metyrapone^✫: Metyrapone is begun at a low dose of 500–1000 mg (250–500 mg 2–4 times daily) and is escalated every few days to the maximum daily dose. The dose needed to inhibit cortisol production ranges from 500–6000 mg/day, although little is gained with total daily doses greater than 2000 mg
Chemotherapy for unresectable, advanced, and recurrent disease: Chemotherapy is recommended for patients with metastatic disease, although evidence of survival benefit is not and will never be available. EDP (etoposide + doxorubicin + cisplatin) plus mitotane or streptozocin plus mitotane should be used as first-line therapy. "Novel targeted therapies" that may seem attractive have not been proved and should not be substituted for these chemotherapies that have known activity in ACC
Adjuvant mitotane: A recent analysis of 177 patients with ACC compared the outcome in 47 patients treated with adjuvant mitotane therapy with 130 patients who received no additional therapy (Terzolo et al., 2007). Surprisingly, when used at "more tolerable" daily doses of 2000–3000 mg, the authors reported that mitotane demonstrated significant benefit in the adjuvant setting. However, the results of this retrospective nonrandomized study must be viewed cautiously. Because the advantage was confined to time to recurrence and not to overall survival, the value of adjuvant mitotane is diminished. Furthermore, the short follow-up period of patients treated with mitotane leaves the conclusions in doubt. The lack of convincing evidence and the difficulty of administering mitotane has often guided a recommendation that "adjuvant" mitotane therapy should be used only in cases where a tumor cannot be fully removed surgically or in patients with a high likelihood of recurrence; that is, large tumors with extensive necrosis, capsular, lymphatic, or venous invasion, a high mitotic or Ki67 labeling index, and small or questionable surgical margins. Until further data are available, this continues to be the most reasonable approach
Long-term mitotane monotherapy: Administer mitotane long-term only to patients who tolerate it well and experience a therapeutic response or those who are at high-risk for recurrence. The optimal duration of therapy is not known: a recommendation of "indefinite" is most conservative. Prolonged therapy is often made possible by the fact that after months of therapy body stores are finally saturated, and the dose needed to maintain serum levels is then markedly reduced. In this case the tolerability improves markedly. However, suboptimal therapy (judged by serum mitotane levels) that is limited by side effects should not be continued; in this setting there is little chance of benefit in the face of continued toxicity. Although suboptimal therapy cannot be accurately defined, blood levels of 10–14 mg/L are often cited as optimal based on two small studies, but lower levels are likely of some value; a clinical observation also noted in the recent retrospective analysis of adjuvant mitotane (Terzolo et al., 2007)

REGIMEN: MITOTANE (o,p′-DDD)

Listen

Regimen: Mitotane (o,p′-DDD)

Luton J-P et al. N Engl J Med 1990;322:1195–1201

Mitotane 2000–20,000 mg/day; administer orally as a single dose or in 2–4 divided doses

Glucocorticoid replacement is necessary in all patients:

Hydrocortisone 15–20 mg; administer orally every morning, plus:

Hydrocortisone 7.5–10 mg; administer orally every afternoon around 4 PM

Mineralocorticoid replacement is also recommended:

Fludrocortisone acetate 100–200 mcg/day; administer orally every morning, or:

Fludrocortisone acetate 100 mcg/day; administer orally every morning and every evening

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Mitotane is available in the United States for oral administration in tablets that contain 500 mg mitotane. Lysodren (mitotane tablets). Bristol-Myers Squibb Company, Princeton, NJ

Patient Population Studied

A study of 59 patients with adrenocortical carcinoma treated with mitotane at different times in relation to surgery

Efficacy (N = 37)

| Download (.pdf) | Print

Efficacy (N = 37)

Overall response rate

22%

Stable disease >12 months

Clinical benefit rate

27%

Complete responses have been reported in other studies but are rare

Toxicity

| Download (.pdf) | Print

Toxicity

Adverse Event

% Patients

No. of Patients

Anorexia/nausea

Vomiting

Diarrhea

Skin rash

Confusion/sleepiness

100

Ataxia

Depression

Dysarthria

Tremor

Visual disturbance

Leukopenia

Van Slooten H et al. Eur J Cancer Clin Oncol 1984;20:47–53

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Dose Modification

General Guidelines:

First step with most side effects, especially if they occur as mitotane dose is advanced: (1) stop mitotane; (2) wait up to 7 days for symptoms to resolve; (3) restart mitotane at lower dose (500–1000 mg/day less than previous dose) or at previously tolerated dose; (4) increase dose in 500-mg/day increments at 1-week intervals

Anorexia

Nausea/vomiting

Administer mitotane in divided doses, and/or most of dose before bedtime. Crush tablets and dissolve in vehicle. Use antiemetics as needed. Reassess adrenal replacement

Diarrhea

Administer as divided doses. Use loperamide or diphenoxylate/atropine

Altered mental status

Stop therapy. Follow general guidelines. Obtain imaging study only if symptoms persist after 1 week off therapy

Skin rash

If not severe, continue mitotane and treat rash with local measures and antipruritics

Therapy Monitoring

Check mitotane level at least every 4 weeks initially. Patients receiving long-term mitotane therapy can have monitoring reduced to every 2–3 months
Adrenal function can be monitored by measuring ACTH, but this alone is not reliable and should be interpreted together with clinical assessment
Response assessment: Initially every 6–8 weeks. Patients receiving long-term mitotane therapy can have monitoring reduced to every 3–6 months

Notes

Begin mitotane administration at a low dosage, usually no more than 2000 mg/day
Increase dose in increments of 500 mg to a maximum of 1000 mg/day, usually at intervals of not less than 1 week
Do not increase mitotane if a patient is experiencing side effects; follow General Guidelines in the Treatment Modifications section. Although mitotane is considered to have low to no emetogenic potential, it often produces low-grade nausea that is difficult to tolerate because it occurs every day. In some patients, chronic administration of antiemetics is required. See Chapter 39
The optimal dosage is not known; however, mitotane levels should be monitored with a goal of attaining a level of 14–20 mcg/mL. Levels greater than 20 mcg/mL are usually associated with intolerable side effects
A dosage of 4000–6000 mg/day usually results in a therapeutic level of mitotane in most patients after 6–10 weeks; however, some patients tolerate or require doses as high as 10,000–12,000 mg/day
Therapeutic levels can be achieved more quickly by administering higher doses and by increasing doses more aggressively, but this strategy usually fails because of side effects that result
With long-term administration of mitotane, the dosage required to maintain a therapeutic level may be substantially less, even as low as 500–1000 mg/day
Chronic administration results in adrenal insufficiency requiring steroid replacement therapy, as recommended in Regimen. Some physicians prefer to begin replacement therapy at the time mitotane therapy is started; others wait until there is evidence of incipient adrenal insufficiency, usually 6–8 weeks after the start of therapy. Replacement therapy is recommended with twice-daily hydrocortisone and with once- or twice-daily fludrocortisone replacement. Measuring ACTH levels to monitor the adequacy of replacement therapy is of limited value, because normal ACTH levels are difficult if not impossible to achieve. Patients should be instructed to obtain and wear identification that warns health care providers about possible adrenal insufficiency
Even without effecting a reduction in tumor size, mitotane may reduce circulating hormone levels, so that mitotane therapy can be continued solely to control the signs and symptoms of hormonal excess. Furthermore, if, after a period of mitotane administration, there is evidence of disease progression, discontinuing mitotane will result in a recurrence of the signs and symptoms of hormonal excess. The latter may appear gradually as mitotane is slowly cleared, but may eventually be worse than before mitotane therapy because of interval growth of the tumor. In these patients, consider continuing mitotane or begin an alternate drug to control hormonal excess

Haak HR et al. Br J Cancer 1994;69:947–951

Hoffman DL, Mattox VR. Med Clin North Am 1972;56:999–1012

Van Slooten H et al. Eur J Cancer Clin Oncol 1984;20:47–53

REGIMEN: CISPLATIN + MITOTANE

Listen

Regimen: Cisplatin + Mitotane

Bukowski RM et al. J Clin Oncol 1993;11:161–165

Hydration: ≥2000 mL 0.9% Sodium Chloride injection (0.9% NS), at ≥100 mL/hour before and after cisplatin administration. Also encourage increased oral fluid intake. Monitor and replace magnesium/electrolytes as needed

Cisplatin 75–100 mg/m²; administer intravenously in 50–250 mL of 0.9% NS over 30 minutes on day 1 every 3 weeks (total dosage per cycle = 75–100 mg/m²)

Mitotane^✫ 4000 mg/day; administer orally, continually

Glucocorticoid replacement is necessary in all patients:

Hydrocortisone 15–20 mg; administer orally every morning, plus

Hydrocortisone 7.5–10 mg; administer orally every evening, continually

Mineralocorticoid replacement is also recommended

Fludrocortisone acetate 100–200 mcg/day; administer orally every morning, or

Fludrocortisone acetate 100 mcg/day; administer orally every morning and every evening, continually

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1: HIGH. Potential for delayed symptoms

Emetogenic potential on days with mitotane alone: MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Mitotane is available in the United States for oral administration in tablets that contain 500 mg mitotane Lysodren (mitotane tablets). Bristol-Myers Squibb Company, Princeton, NJ

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Dose Modification

CrCl 30–50 mL/min (0.5–0.83 mL/s)

Hold cisplatin until CrCl ≥50 mL/min (≥0.83 mL/s), then reduce dose to 75 mg/m² if previous dose was 100 mg/m² or 60 mg/m² if previous dose was 75 mg/m²

CrCl <30 mL/min (<0.5 mL/s)

Discontinue cisplatin

Unacceptable GI or neuromuscular side effects from mitotane

Reduce mitotane to 2000 mg/day

Unacceptable side effects from mitotane at 2000 mg/day

Reduce mitotane to 1000 mg/day

Unacceptable side effects from mitotane at 1000 mg/day

Discontinue mitotane

CrCl, creatinine clearance

Patient Population Studied

A trial of 42 patients with metastatic or residual adrenocortical carcinoma because complete resection was not possible. Prior therapy with mitotane was allowed

Efficacy (N = 37)

| Download (.pdf) | Print

Efficacy (N = 37)

Complete response

2.7%

Partial response

27%

Median response duration

7.9 months

Median time to response

76 days

Toxicity (N = 36)

| Download (.pdf) | Print

Toxicity (N = 36)

Adverse Event

% G1/2

% G3/4

Hematologic

Anemia

Leukopenia

Thrombocytopenia

—

Nonhematologic

Nausea/vomiting

Diarrhea

—

Mucositis

—

Increased bilirubin

—

Renal

Peripheral neuropathy

Myalgias

N = 36, but reported as percent of 37 eligible patients

Therapy Monitoring

CBC with leukocyte differential count, serum creatinine and electrolytes, serum magnesium, and LFTs on day 1
Response assessment: Repeat imaging studies every 2 cycles; 24-hour urine cortisol and 17-ketosteroids with each cycle, if abnormal at baseline
Mitotane level at least every 4 weeks initially. A level of 14–20 mcg/mL is desirable
Adrenal function can be monitored by measuring ACTH, but this alone is not reliable and should be interpreted together with clinical assessment

ADVANCED OR METASTATIC ADRENAL CANCER REGIMEN: ETOPOSIDE + DOXORUBICIN + CISPLATIN + MITOTANE (EDP-M)

Listen

Advanced or Metastatic Adrenal Cancer Regimen: Etoposide + Doxorubicin + Cisplatin + Mitotane (EDP-M)

Fassnacht M et al. N Engl J Med 2012;366:2189–2197

Mitotane 500–5000 mg/day; administer orally, continually

If possible, mitotane is started a minimum of 1 week before cytotoxic treatment is initiated. The ultimate goal is to attain mitotane concentrations in blood of 14–20 mcg/mL over time, as tolerated, trying not to exceed these values as side effects worsen with higher values. Note that side effects may preclude this range from being attained
Initiate treatment with doses of 1000–1500 mg per day at bedtime to minimize sedative effects during waking hours, and escalate doses as tolerated
Large daily doses may be divided in ≥2 doses

Doxorubicin 40 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 4 weeks (total dosage/cycle = 40 mg/m²)

Prehydration for cisplatin: ≥500 mL 0.9% sodium chloride injection (0.9% NS) per day; administer intravenously at ≥100 mL/hour for 2 consecutive days, starting before cisplatin on days 3 and 4

Cisplatin 40 mg/m² per day; administer intravenously in 50–500 mL of 0.9% NS over 30–60 minutes for 2 doses on 2 consecutive days, days 3 and 4, every 4 weeks (total dosage/cycle = 80 mg/m²)

Posthydration for cisplatin: ≥500 mL 0.9% NS per day; administer intravenously at ≥100 mL/hour for 2 consecutive days, after cisplatin on days 3 and 4. Encourage increased oral fluid intake. Monitor and replace magnesium and electrolytes as needed

± Mannitol diuresis: May be given to patients who have received adequate hydration

Mannitol 12.5–25 g may be administered by intravenous injection before or during cisplatin administration, or

Mannitol 10–40 g; administer intravenously over 1–4 hours before or during cisplatin administration, or may be prepared as an admixture with cisplatin

Note: Diuresis with mannitol requires maintaining hydration with intravenously administered fluid during and for hours after mannitol administration

Etoposide 100 mg/m² per dose; administer intravenously diluted to a concentration within the range 0.2–0.4 mg/mL in 5% dextrose injection or 0.9% NS over at least 60 minutes for 3 consecutive days, on days 2, 3, and 4, every 4 weeks (total dosage/cycle = 300 mg/m²)

Glucocorticoid replacement is necessary in all patients taking mitotane

Hydrocortisone 15–20 mg orally every morning, plus:

Hydrocortisone 7.5–10 mg orally every evening

Mineralocorticoid replacement is also recommended:

Fludrocortisone acetate 100–200 mcg/day orally every morning, or:

Fludrocortisone acetate 100 mcg/day orally every morning and every evening

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1: MODERATE

Emetogenic potential on day 2: LOW

Emetogenic potential on days 3 and 4: HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

| Download (.pdf) | Print

Patient Population Studied

Patients with histologically confirmed adrenocortical carcinoma not amenable to radical surgical resection who had not received any previous treatment with cytotoxic drugs, except mitotane, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. One hundred fifty-one patients received etoposide + doxorubicin + cisplatin + mitotane

Age (y)

Median

Range

51.9

19.0–76.2

Sex—Number (%)

Male

Female

60 (39.7)

91 (60.3)

Tumor stage—Number (%)

III

151 (100.0)

Endocrine symptoms—Number (%)

Cushing syndrome ± other symptoms

Conn syndrome only

Virilization only

Feminization only

No symptoms

Missing data

60 (39.7)

2 (1.3)

6 (4.0)

3 (2.0)

70 (46.4)

10 (6.6)

ECOG performance status score—Number (%)

73 (48.3)

64 (42.4)

13 (8.6)

1 (0.7)

Time since primary diagnosis—Months

Median

Range

7.3

0–183.7

Number of affected sites^✫

Median

Range

1–7

^✫The following sites were calculated as separate sites of adrenocortical carcinoma: adrenal gland (including local recurrence), liver, lung, bone, peritoneum, retroperitoneum, pleura, mediastinum, central nervous system, soft tissue, spleen, and ovary

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Dose Modification

Day 1 WBC <1000/mm³ or platelet count <100,000/mm³ or G >2 nonhematologic toxicity

Delay chemotherapy until WBC ≥1000/mm³ and platelet count ≥100,000/mm³, or nonhematologic toxicity G ≤1 for a maximum delay of 2 weeks

>2-week delay in reaching WBC >1000/mm³ or platelet count >100,000/mm³ or for resolution of non-hematologic toxicity to G ≤1

Discontinue therapy

G4 ANC or G ≥3 platelet counts

Reduce dosages of all drugs by 25% except mitotane

Creatinine clearance <50 to 60 mL/min

Hold cisplatin until creatinine clearance >50–60 mL/min

Efficacy

| Download (.pdf) | Print

Efficacy

Efficacy in the Intention-to-Treat Population

Randomized Comparison versus Streptozocin + Mitotane^✫

Variable

EDP-M (N = 151)^†

Sz-M (N = 153)^†

P-Value

Type of response—no. (%)

Complete response

2 (1.3)

1 (0.7)

Disease-free by time of surgery^‡

4 (2.6)

2 (1.3)

Partial response

29 (19.2)

11 (7.2)

Stable disease^§

53 (35.1)

34 (22.2)

Progressive disease

43 (28.5)

88 (57.5)

Did not receive treatment

3 (2.0)

4 (2.6)

Not evaluable for response

17 (11.3)

13 (8.5)

Objective response

Number of patients

% (95% CI)

23.2 (16.7–30.7)

9.2 (5.1–14.9)

<0.001

Disease control^✫✫

Number of patients

% (95% CI)

58.3 (50.0–66.2)

31.4 (24.1–39.4)

<0.001

EDP-M (N = 151)^†

Sz-M (N = 153)^†

HR [95%CI]; P-Value

Progression-free survival

5.0 months

2.1 months

0.55

[0.42–0.68];

<0.001

Overall survival^††

14.8 months

12.0 months

0.79

[0.61–1.02];

0.07

^✫Responses according to Response Evaluation Criteria in Solid Tumors (RECIST)

^†EDP + M = etoposide + doxorubicin + cisplatin + mitotane; Sz + M = streptozocin + mitotane

^‡Surgery performed >PR to study treatment; not included in PR category

^§Stable disease was defined as no disease progression for at least ≥8 weeks and no objective response to treatment. Confirmatory scans were not required for this determination, according to the study protocol

Objective response = CR + PR

^✫^✫Disease control + CR + PR + SD

^††Patients classified according to first-line therapy, but they were allowed to receive the alternate therapy in second line

Toxicity

| Download (.pdf) | Print

Toxicity

Event

Number of Patients (%)

Any serious adverse event

86 (58.1)

Adrenal insufficiency

5 (3.4)

Bone marrow toxicity

17 (11.5)

Cardiovascular or thromboembolic event

10 (6.8)

Fatigue or general health deterioration

8 (5.4)

Gastrointestinal disorder

6 (4.1)

Impaired liver function

Impaired renal function

1 (0.7)

Infection

10 (6.8)

Neurologic toxicity

5 (3.4)

Respiratory disorder

9 (6.1)

Other

15 (10.1)

Therapy Monitoring

CBC with leukocyte differential count, serum creatinine and electrolytes, serum magnesium, and LFTs on day 1 of each cycle
Response assessment: Repeat imaging studies every 2 cycles; 24-hour urine 17-ketosteroids and cortisol with each cycle if abnormal at baseline
Mitotane level at least every 4 weeks initially. A level of 14–20 mcg/mL is desirable but may not be attained
Adrenal function can be monitored by measuring ACTH, but this alone is not reliable and should be interpreted together with clinical assessment

REGIMEN: DOXORUBICIN

Listen

Regimen: Doxorubicin

Decker RA et al. Surgery 1991;110:1006–1013

Doxorubicin 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 3 weeks to a maximum cumulative lifetime dosage of 500 mg/m² (total dosage per cycle = 60 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: HIGH

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 31 patients with unresectable adrenocortical carcinoma with ECOG PS 0–3. Fifteen of the 31 patients had been treated with mitotane immediately before doxorubicin

Efficacy (N = 31)

| Download (.pdf) | Print

Efficacy (N = 31)

Response Rate

No. of Patients

Initial treatment with chemotherapy (doxorubicin); no prior mitotane

19%

Tumor did not respond, or progressed when treated with mitotane

Toxicity (N = 31)

| Download (.pdf) | Print

Toxicity (N = 31)

% Mild/Moderate

% Severe

Hematologic

Any hematologic

Nonhematologic

Nausea/vomiting

Diarrhea

Skin/mucosa

Neurologic

Hepatic

Bear HD et al. J Clin Oncol 2003;21:4165–4174

Therapy Monitoring

CBC with leukocyte differential count, serum creatinine, electrolytes, and LFTs on day 1
Response assessment: Repeat imaging studies every 2 cycles; 24-hour urine cortisol and 17-hydroxycorticosteroids with each cycle if abnormal at baseline

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Dose Modification

Day 1 ANC <1500/mm³, platelet count <75,000/mm³

Delay chemotherapy until ANC >1500/mm³ and platelet counts >75,000/mm³ for a maximum delay of 2 weeks. Use filgrastim or pegfilgrastim in subsequent cycles if delay for low ANC

Febrile neutropenia

Filgrastim or pegfilgrastim in subsequent cycles

Febrile neutropenia on filgrastim or pegfilgrastim

Reduce doxorubicin dosage by 25%

G ≥3 Nonhematologic toxicity

Hold therapy until resolution to G1. Reduce doxorubicin dosage by 25% if recovery occurs in <2 weeks

Bear HD et al. J Clin Oncol 2003;21:4165–4174

Notes

The recommended limit for total cumulative lifetime doxorubicin dosage of 450–500 mg/m² may be exceeded, provided that adequate cardiac monitoring is conducted before every or every other chemotherapy cycle

ADVANCED OR METASTATIC ADRENAL CANCER REGIMEN: STREPTOZOCIN + MITOTANE (Sz-M)

Listen

Advanced or Metastatic Adrenal Cancer Regimen: Streptozocin + Mitotane (Sz-M)

Fassnacht M et al. N Engl J Med 2012;366:2189–2197

Mitotane 500–5000 mg/day; administer orally, continually

If possible, mitotane is started a minimum of 1 week before cytotoxic treatment is initiated. The ultimate goal is to attain mitotane concentrations in blood of 14–20 mcg/mL over time, as tolerated, trying not to exceed these values as side effects worsen with higher values. Note that side effects may preclude this range from being attained
Initiate treatment with doses of 1000–1500 mg/day at bedtime to minimize sedative effects during waking hours, and escalate doses as tolerated
Large daily doses may be divided in ≥2 doses

Hydration for streptozocin (all cycles): 1000 mL 0.9% sodium chloride injection (0.9% NS) per day; administer intravenously with 500 mL given before streptozocin and 500 mL given after streptozocin

First cycle: Streptozocin 1000 mg/day; administer intravenously in 50–500 mL of 0.9% NS or 5% dextrose injection (D5W) over 30–60 minutes for 5 doses on 5 consecutive days, days 1–5, every 3 weeks (total dose/cycle = 5000 mg)

Second and subsequent cycles: Streptozocin 2000 mg; administer intravenously in 50–500 mL of 0.9% NS or D5W over 30–60 minutes on day 1, every 3 weeks (total dose/cycle = 2000 mg)

Glucocorticoid replacement is necessary in all patients taking mitotane

Hydrocortisone 15–20 mg orally every morning, plus:

Hydrocortisone 7.5–10 mg orally every evening

Mineralocorticoid replacement is also recommended:

Fludrocortisone acetate 100–200 mcg/day orally every morning, or:

Fludrocortisone acetate 100 mcg/day orally every morning and every evening

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH each day streptozocin is administered. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Event

Dose Modification

Day 1 WBC <1000/mm³ or platelet count <100,000/mm³ or G >2 nonhematologic toxicity

Delay chemotherapy until WBC ≥1000/mm³ and platelet count ≥100,000/mm³, or nonhematologic toxicity G ≤1 for a maximum delay of 2 weeks

>2-week delay in reaching WBC, >1000/mm³ or platelet count >100,000/mm³, or for resolution of nonhematologic toxicity to G ≤1

Discontinue therapy

G4 ANC or G ≥3 platelet counts

Reduce streptozocin dose by 25%

Creatinine clearance <50–60 mL/min

Hold streptozocin until creatinine clearance >50–60 mL/min

Patient Population Studied

| Download (.pdf) | Print

Patient Population Studied

Patients with histologically confirmed adrenocortical carcinoma not amenable to radical surgical resection who had not received any previous treatment with cytotoxic drugs, except mitotane, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. One-hundred fifty-three patients received streptozocin + mitotane

Age (y)

Median

Range

50.0

18.8–72.8

Sex—Number (%)

Male

Female

61 (39.9)

92 (60.1)

Tumor stage—Number (%)

III

1 (0.7)

152 (99.3)

Endocrine symptoms—Number (%)

Cushing syndrome ± other symptoms

Conn syndrome only

Virilization only

Feminization only

No symptoms

Missing data

64 (41.8)

3 (2.0)

7 (4.6)

2 (1.3)

68 (44.4)

9 (5.9)

ECOG performance status score—Number (%)

72 (47.1)

60 (39.2)

21 (13.7)

Time since primary diagnosis—Months

Median

Range

4.5

0–111.6

Number of affected sites^✫

Median

Range

1–8

Efficacy

| Download (.pdf) | Print

Efficacy

Efficacy in the Intention-to-Treat Population

Randomized Comparison vs. Etoposide + Doxorubicin + Cisplatin + Mitotane^✫

Variable

EDP-M (N = 151)^†

Sz-M (N = 153)^†

P-Value

Type of response—no. (%)

Complete response

2 (1.3)

1 (0.7)

Disease-free by time of surgery^‡

4 (2.6)

2 (1.3)

Partial response

29 (19.2)

11 (7.2)

Stable disease^§

53 (35.1)

34 (22.2)

Progressive disease

43 (28.5)

88 (57.5)

Did not receive treatment

3 (2.0)

4 (2.6)

Not evaluable for response

17 (11.3)

13 (8.5)

Objective response

Number of patients

% (95% CI)

23.2 (16.7–30.7)

9.2 (5.1–14.9)

<0.001

Disease control^✫^✫

Number of patients

% (95% CI)

58.3 (50.0–66.2)

31.4 (24.1–39.4)

<0.001

EDP-M (N = 151)^†

Sz-M (N = 153)^†

HR [95% CI]; P-Value

Progression-free Survival

5.0 months

2.1 months

0.55

[0.42–0.68];

<0.001

Overall Survival^††

14.8 months

12.0 months

0.79

[0.61–1.02];

0.07

^✫Responses according to Response Evaluation Criteria in Solid Tumors (RECIST)

^†EDP + M = etoposide + doxorubicin + cisplatin + mitotane; Sz + M = streptozocin + mitotane

^‡Surgery performed >PR to study treatment; not included in PR category

^§Stable disease was defined as no disease progression for at least 8 weeks and no objective response to treatment. Confirmatory scans were not required for this determination, according to the study protocol

Objective response = CR + PR

^✫✫Disease control + CR + PR + SD

^††Patients classified according to first-line therapy, but they were allowed to receive the alternate therapy in second line

Therapy Monitoring

CBC with leukocyte differential count, serum creatinine, electrolytes, and LFTs on day 1; obtain creatinine clearance on day 1 if an elevation in serum creatinine is observed
Twenty-four–hour urine for protein on day 1
Response assessment: Repeat imaging studies every 2 cycles; 24-hour urine 17-ketosteroids and cortisol with each cycle if abnormal at baseline
Mitotane level at least every 4 weeks initially. A level of 14–20 mcg/mL is desirable, but may not be attained
Adrenal function can be monitored by measuring ACTH, but this alone is not reliable and should be interpreted together with clinical assessment

Toxicity

| Download (.pdf) | Print

Toxicity

Event

Number of Patients (%)

Any serious adverse event

62 (41.6)

Adrenal insufficiency

1 (0.7)

Bone marrow toxicity

3 (2.0)

Cardiovascular or thromboembolic event

Fatigue or general health deterioration

7 (4.7)

Gastrointestinal disorder

12 (8.1)

Impaired liver function

7 (4.7)

Impaired renal function

6 (4.0)

Infection

4 (2.7)

Neurologic toxicity

4 (2.7)

Respiratory disorder

5 (3.4)

Other

13 (8.7)

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Chapter 1: Adrenocortical Cancer

Send Email

Citation

Jump to a Section

INTRODUCTION

Expert Opinion

REGIMEN: MITOTANE (o,p′-DDD)

Notes

REGIMEN: CISPLATIN + MITOTANE

ADVANCED OR METASTATIC ADRENAL CANCER REGIMEN: ETOPOSIDE + DOXORUBICIN + CISPLATIN + MITOTANE (EDP-M)

REGIMEN: DOXORUBICIN

ADVANCED OR METASTATIC ADRENAL CANCER REGIMEN: STREPTOZOCIN + MITOTANE (Sz-M)

Pop-up div Successfully Displayed