17 - Soft Tissue Sarcomas

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 17 - Soft Tissue Sarcomas

Chapter 17

Soft Tissue Sarcomas

Robert S. Benjamin

I. Classification and approach to treatment

A. Types of soft tissue sarcomas

The soft tissue sarcomas are a group of diseases characterized by neoplastic proliferation of tissue of mesenchymal origin. Thus, they differ from the more common carcinomas, which arise from epithelial tissue. Sarcomas can arise in any area of the body and from any origin; however, they most commonly arise in the soft tissue of the extremities, trunk, retroperitoneum, or head and neck area. There are more than 20 different types of sarcomas, classified according to lines of differentiation toward normal tissue. For example, rhabdomyosarcoma shows evidence of skeletal muscle fibers with cross-striations, liposarcoma shows fat production, and angiosarcoma shows vessel formation. Precise characterization of the types of sarcoma is often impossible, and these tumors are called unclassified sarcomas. All of the primary bone sarcomas may arise in soft tissue, leading to such diagnoses as extraskeletal osteosarcoma, extraskeletal Ewing's sarcoma, and extraskeletal chondrosarcoma. A common diagnosis in the recent past was malignant fibrous histiocytoma (MFH). This tumor is characterized by a mixture of spindle (or fibrous) cells and round (or histiocytic) cells arranged in a storiform pattern with frequent areas of pleomorphic appearance and frequent giant cells. There is no evidence of differentiation toward any particular tissue type. Many tumors previously called pleomorphic fibrosarcoma, pleomorphic rhabdomyosarcoma, and so forth were classified as MFH. As immunohistochemistry and molecular diagnostic techniques have improved, many of the tumors previously classified as MFH have been reclassified as pleomorphic something else. Furthermore, there are strong opponents of the term MFH since there is no evidence that the tumors have histiocytic origin, and pleomorphic tumors previously classified as MFH are now frequently referred to as unclassified high grade pleomorphic sarcomas.

B. Metastases

Metastatic spread of all sarcomas tends to be through the blood rather than through the lymphatic system. The lungs are by far the most frequent site of metastatic disease. Local sites of metastasis by direct invasion are the second most common area of involvement, followed by bone and liver. (Liver metastases are common with intra-abdominal sarcomas, especially gastrointestinal stromal tumors [GISTs], however, and metastases to soft tissue are common with myxoid liposarcomas.) Central nervous system (CNS) metastases are extraordinarily rare except in alveolar soft-part sarcoma.

C. Staging

Staging of sarcomas is complex and demands an expert sarcoma pathologist. Tumors have been staged

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according to two systems: the American Joint Committee on Cancer (AJCC) staging system and the Musculoskeletal Tumor Society staging system. The new International Union Against Cancer (UICC)/AJCC staging system with international acceptance takes portions from each of the older systems and more appropriately identifies patients at increased risk of metastatic disease. Further revisions to this system are still under way, and a final, widely accepted system is still not in place. Since current and earlier publications still refer to the older systems, however, all will be included.

  • The old AJCC staging system

    • Tumor grade. The primary determinant of stage is tumor grade.

      • Grade 1 tumors are stage I.

      • Grade 2 tumors are stage II.

      • Grade 3 tumors are stage III.

      Any tumor with lymph nodemetastases is automatically stage III.

      Any tumor with gross invasion of bone, major vessel, or major nerve is stage IV.

    • Stage. Further divisions of stages I to III into A and B are based on tumor size.

      • A = tumor smaller than 5 cm

      • B = tumor size 5 cm or larger

      In stage III, lymph node metastases are classified as IIIC. In stage IV, local invasion is called IVA, and IVB represents distant metastases.

  • The Musculoskeletal Tumor Society staging system. The Musculoskeletal Tumor Society stages sarcomas according to grade and compartmental localization. The Roman numeral reflects the tumor grade.

    • Stage I: low grade

    • Stage II: high grade

    • Stage III: any-grade tumor with distant metastasis

    The letter reflects compartmental localization. Compartments are defined by fascial planes.

    Stage A: intracompartmental (i.e., confined to the same soft tissue compartment as the initial tumor)

    Stage B: extracompartmental (i.e., extending outside of the initial soft tissue compartment into the adjacent soft tissue compartment or bone)

    A stage IA tumor is a low-grade tumor confined to its initial compartment, a stage IB tumor is a low-grade tumor extending outside the initial compartment, and so forth.

  • The new AJCC staging system. The stage is determined by tumor grade, tumor size, and tumor location relative to the muscular fascia. There are now four tumor grades.

    • Grade 1: well differentiated

    • Grade 2: moderately differentiated

    • Grade 3: poorly differentiated

    • Grade 4: undifferentiated

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    Tumor size is now divided as less than or equal to 5 cm or more than 5 cm (in the old AJCC system, it was less than 5 cm or more than or equal to 5 cm).

    • T1 = less than or equal to 5 cm

    • T2 = greater than 5 cm

    Tumor status is subdivided by location relative to the muscular fascia.

    • Ta = superficial to the muscular fascia

    • Tb = deep to the muscular fascia

    The AJCC stage grouping is as follows:

    Stage I T1a, 1b, 2a, 2b N0 M0 G1 2
    Stage II T1a, 1b, 2a N0 M0 G3 4
    Stage III T2b N0 M0 G3 4
    Stage IV Any T N1 M0 Any G
    Any T N0 M1 Any G

    The new staging system divides patients according to necessary therapy.

    Stage I patients are adequately treated by surgery alone.

    Stage II patients require adjuvant radiation therapy.

    Stage III patients require adjuvant chemotherapy.

    Stage IV patients are managed primarily with chemotherapy, with or without other modalities.

D. Evaluation

Patients are evaluated and followed up according to the plan in Table 17.1.

E. Primary treatment

  • Surgery and radiotherapy. Treatment of the primary tumor involves surgery with or without radiation therapy. If radiation therapy is not used, surgery must be radical. Although this may often involve amputation or complete excision of the involved muscle group from origin to insertion, more and more frequently, wide local resection is performed, with or without adjuvant radiation, depending on stage and extent of negative margins.

  • Adjuvant chemotherapy. The role of adjuvant chemotherapy remains controversial, with both positive and negative results reported. A meta-analysis of individual patient data indicated a highly significant decrease in the risk of disease recurrence (either local or distant) and death in patients treated with adjuvant chemotherapy; thus, some investigators believe that adjuvant therapy is clearly indicated for patients whose histologic type, grade, or location is known to convey a poor prognosis. The meta-analysis confirms a survival benefit for patients with primary sarcomas of the extremities as well as increased local or distant disease-free interval for all patients treated with doxorubicin (Adriamycin)-based adjuvant chemotherapy. A recent Italian cooperative group study using epirubicin and ifosfamide for patients with current stage III disease also demonstrated survival and disease-free survival advantage for patients treated with chemotherapy; however,

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    the statistical significance of the survival advantage was lost with further follow-up.

Table 17.1. Soft tissue sarcoma evaluation

Testsa Initial During Treatment Follow-up (if no evidence of disease)
History and physical examination X Before each treatment Year 1: q2 months; years 2, 3: q3 months; year 4: q4 months; year 5: q6 months; then yearly
CBC, differential, and platelet countsb X Twice weekly Yearly
Electrolytesb X Before each treatment
Chemistry profileb X Before each treatment q4 months
Urinalysis If giving ifosfamide As indicated by symptoms
PT, APTT, fibrinogen X
Chest radiograph X Before each treatment Same as for history and physical examination
CT scan chest If chest radiograph appears normal To confirm chest radiograph findings (if initially abnormal) or for surgical planning If chest radiograph becomes equivocal
MRI primary (if not intra-abdominal), or X Preoperatively
Ultrasound primary Year 1: q4 months; years 2, 3: q6 months
PET-CT X Every two to three cycles if preoperative therapy is given
CT of abdomen and pelvis If myxoid liposarcoma or retroperitoneal or pelvic primary tumor If baseline, every third cycle If baseline, year 1: q4 months; years 2, 3: q6 months
ECG If cardiac history
Cardiac nuclear scan (for ejection fraction) If cardiac history If doxorubicin dose is to exceed standard limits for schedule Yearly for 2 years, then as clinically indicated
Central venous catheter X
Bone marrow or screening MRI of spine and pelvis If small cell tumor
Bone scan If indicated by history
Plain film If indicated by history
CBC, complete blood cell count; PT, prothrombin time; APTT, activated partial thromboplastin time; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; ECG, electrocardiography; X, procedure to be done; , procedure not needed.
aTests may be ordered more frequently based on clinical indications.
bRequired more frequently if patient is on a medical treatment program.

F. Prognosis

Prognosis is related to stage, with a 5-year survival rate of 99% for new AJCC/UICC stage I, 82% for stage II, and 52% for stage III. Corresponding rates of disease-free survival at 5 years are 78% for stage I, 64% for stage II, and 36% for stage III. Long-term results are still worse. The survival rate for stage IV disease is less than 10%; however, a definite fraction of patients in this category can be cured. Most patients with stage IV disease, if left untreated, die within 6 to 12 months; however, there is great variation in actual survival, and patients may go on with slowly progressive disease for many years.

G. Treatment response

Response to treatment is measured in the standard manner for solid tumors with the addition of tumor necrosis, both radiologically and pathologically, but there are increasing examples where good responses are missed by standard criteria, and newer approaches to computed tomography (CT) and magnetic resonance imaging (MRI) evaluation and the use of positron emission tomography (PET) are becoming more frequent.

  • Complete remission. This implies complete disappearance of all signs and symptoms of disease.

  • Partial remission. Standard response evaluation criteria in solid tumors (RECIST) criteria (Chapter 2, Section IV.B.1) are generally employed. This requires a 30% or greater decrease in measurable disease, calculated by comparing the sum of the longest diameters of all lesions before and after therapy. When disease can be followed objectively by MRI or CT, marked tumor necrosis attributable to chemotherapy demonstrated by imaging or pathology is considered at least the equivalent of a partial response by RECIST criteria.

  • Stable disease or improvement. Lesser degrees of tumor shrinkage are categorized by some physicians as stable disease and by others as improvement or minor response. Stable disease implies a less than 20% increase in disease for at least 8 weeks. There is increasing recognition that stable disease or improvement that persists for a minimum of 4 months is at least as meaningful for ultimate patient benefit as partial response. For all response categories, no new disease must appear during response.

  • Progression. New disease in any area or a 20% or more increase in measurable disease constitutes progressive disease.

  • Survival. All patients whose disease responds objectively to chemotherapy survive longer than patients with progressive disease, and the degree of prolongation of survival is directly proportional to the degree of antitumor response that can be measured.

II. Chemotherapy

A. General considerations and aims of therapy

Although there are numerous types of soft tissue sarcomas, there are few differences among them regarding responsiveness to a standard soft tissue sarcoma regimen. GISTs and alveolar

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soft-part sarcomas and, to a lesser extent, clear cell sarcomas and epithelioid sarcomas respond less frequently to standard regimens than do the other soft tissue sarcomas. GISTs, in particular, should not be treated with doxorubicin- and ifosfamide-based chemotherapy. GISTs are usually characterized by mutated c-Kit and have a high response rate with prolonged remissions after treatment with imatinib at 400 mg daily. Patients who do not respond or who have a relapse after initial therapy may respond to higher doses up to 800 mg in divided doses daily or to sunitinib. Angiosarcomas can respond to paclitaxel, while other sarcomas do not. Two tumors Ewing's sarcoma and rhabdomyosarcoma particularly in children, are responsive to dactinomycin, vincristine, or etoposide. The other tumors are not. The goal of therapy for patients with advanced disease is primarily palliative, although a small fraction (~20%) of patients who achieve complete remission are, in fact, cured. The first aim, therefore, is to achieve complete remission. Several investigators, including the author, have shown that the prognosis is the same whether complete remission is obtained by chemotherapy alone or by chemotherapy with adjuvant surgery, that is, surgical removal of all residual disease. Short of complete remission, partial remission causes some palliation, with relief of symptoms and prolongation of survival by approximately 1 year. Any degree of improvement or stabilization of previously advancing disease likewise increases survival.

B. Effective drugs

The most important chemotherapeutic agent is doxorubicin, which forms the backbone of all combination-chemotherapy regimens. Ifosfamide, an analog of cyclophosphamide that has documented activity even in patients who are refractory to combinations containing cyclophosphamide, is usually included in front-line chemotherapy combinations. It is always given together with the uroprotective agent mesna to prevent hemorrhagic cystitis. Dacarbazine (DTIC), a marginal agent by itself, adds significantly to doxorubicin in prolonging remission duration and survival as well as in increasing the response rate. Cyclophosphamide adds marginally, if at all, but is included in some effective regimens.

The key to effective sarcoma chemotherapy is the steep dose response curve for doxorubicin. At a dose of 45 mg/m2, the response rate is lower than 20% as compared with a 37% response rate at a dose of 75 mg/m2. A similar dose response relationship exists for ifosfamide and for combination chemotherapy, and the regimens with the best reported results are those using the highest doses.

C. Primary chemotherapy regimen (adjuvant or advanced)

The most effective primary chemotherapy regimens include doxorubicin and ifosfamide (high-dose AI) or doxorubicin and dacarbazine (ADIC), with or without the addition of cyclophosphamide (CyADIC) or ifosfamide and mesna (MAID). The CyADIC regimen is a modification of the standard CyVADIC regimen, which includes vincristine. Because analysis has shown that vincristine makes no significant contribution and produces neurotoxicity, its addition at a dose of 2 mg maximum or 1.4 mg/m2 weekly for 6 weeks and then once

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every 3 to 4 weeks is recommended only for treatment of rhabdomyosarcoma and Ewing's sarcoma.

By giving doxorubicin and dacarbazine by continuous 72- or 96-hour infusion, with the two drugs mixed in the same infusion pump, nausea and vomiting are markedly reduced, and the chemotherapy can be continued until a cumulative doxorubicin dose of 800 mg/m2 is reached, with less cardiac toxicity than with standard doxorubicin administration and a cumulative dose of 450 mg/m2.

  • The high-dose AI regimen is as follows:

    • Doxorubicin by continuous 72-hour infusion at 75 mg/m2 IV (25 mg/m2/day for 3 days), and

    • Ifosfamide 2.5 g/m2 IV over 2 to 3 hours daily for 4 days.

    • Vincristine 2 mg total dose is added on day 1 for small cell tumors such as rhadomyosarcoma, Ewing's sarcoma (high-dose VAI).

    • Mesna 500 mg/m2 is mixed with the first ifosfamide dose, and 1,500 mg/m2 is given as a continuous infusion over 24 hours for 4 days in 2 L of alkaline fluid.

    • Filgrastim (granulocyte colony-stimulating factor) 5 g/kg SC is given on days 5 to 15 or until granulocyte recovery to 1,500/ L. Alternatively, Pegfilgrastim at a dose of 6 mg is given on day 5.

    Repeat cycle every 3 weeks.

  • The continuous-infusion CyADIC regimen is as follows:

    • Cyclophosphamide 600 mg/m2 IV on day 1, and

    • Doxorubicin, by continuous 96-hour infusion at 60 mg/m2 IV (15 mg/m2/day for 4 days), and

    • Dacarbazine by continuous 96-hour infusion at 1,000 mg/m2 IV (250 mg/m2/day for 4 days) mixed in the same bag or pump as the doxorubicin. Doses should be divided into four consecutive 24-hour infusions.

    Repeat cycle every 3 to 4 weeks.

  • The continuous-infusion ADIC regimen is as follows:

    • Doxorubicin by continuous 96-hour infusion at 90 mg/m2 IV (22.5 mg/m2/day for 4 days), and

    • Dacarbazine by continuous 96-hour infusion at 900 mg/m2 IV (225 mg/m2/day for 4 days) mixed in the same bag or pump as the doxorubicin. Doses should be divided into four consecutive 24-hour infusions.

    Repeat cycle every 3 to 4 weeks.

  • The MAID regimen is as follows:

    • Mesna by continuous 96-hour infusion at 8,000 mg/m2 IV (2,000 mg/m2/day for 4 days).

    • Doxorubicin by continuous 72-hour infusion at 60 mg/m2 IV (20 mg/m2/day for 3 days).

    • Ifosfamide by continuous 72-hour infusion at 6,000 mg/m2 IV (2,000 mg/m2/day for 3 days). Doses should be divided into three consecutive 24-hour infusions. (Some investigators prefer to infuse ifosfamide over 2 hours rather than over 24 hours because of higher single-agent activity with the shorter infusions.)

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    • Dacarbazine by continuous 72-hour infusion at 900 mg/m2 IV (300 mg/m2/day for 3 days) mixed in the same bag or pump as the doxorubicin. Doses should be divided into three consecutive 24-hour infusions.

    Repeat cycle every 3 to 4 weeks.

  • Dose modification. Doses of doxorubicin, cyclophosphamide, ifosfamide, and mesna should be increased by 25% and may be decreased by 20% for each course of therapy to achieve a lowest absolute granulocyte count of approximately 500/ L if growth factors are not used. The maximum doxorubicin dose is limited to 600 to 800 mg/m2, depending on the duration (48 96 hours) of infusion, at which point, therapy should be discontinued unless cardiac biopsy specimens indicate that it is safe to continue. With Ewing's sarcoma and rhabdomyosarcoma, therapy may be continued, and dactinomycin 2 mg/m2 in a single dose or 0.5 mg/m2 daily for 5 days may be substituted for the doxorubicin, with continuation of the regimen for a total of 18 months.

  • An alternative regimen for children with rhabdomyosarcoma is an alternating regimen, using ifosfamide and etoposide alternating with the so-called VAdriaC regimen.

    • Vincristine 1.5 mg/m2 is given weekly 3 for the first two cycles of VAdriaC and then on day 1 only.

    • Doxorubicin is given at a dose of 60 to 75 mg/m2 as a 48-hour continuous infusion, and

    • Cyclophosphamide 600 mg/m2 is given daily for 2 days (with mesna).

      After 3 weeks,

    • Ifosfamide is given at a dose of 1,800 mg/m2 daily for 5 days (with mesna), and

    • Etoposide is given at a dose of 100 mg/m2 daily for 5 days.

      Chemotherapy cycles are alternated every 3 weeks for 39 weeks.

  • A less-intensive, older, but still effective regimen for children with good-prognosis rhabdomyosarcoma is the so-called pulse VAC regimen. Dactinomycin is given at a total dose of 2 to 2.5 mg/m2 by divided daily injection over 5 to 7 days (e.g., 0.5 mg/m2 daily for 5 days) repeated every 3 months for a total of five courses. Cyclophosphamide pulses of 275 to 330 mg/m2 daily for 7 days are begun at the same time but are given every 6 weeks with vincristine 2 mg/m2 on days 1 and 8 of each cyclophosphamide cycle. Cyclophosphamide cycles are terminated prematurely if the white blood cell counts fall below 1,500/ L. Chemotherapy continues for 2 years. (The necessity of the 2-year duration of the chemotherapy program is not certain.)

D. Secondary chemotherapy

Secondary chemotherapy for patients with sarcoma is relatively unrewarding, with response rates lower than 10% for almost all conventional drugs or regimens tested. The best commercially available drug is ifosfamide, which, if not used in primary treatment, produces

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a response in approximately 20% of patients. High-dose ifosfamide (12 g/m2 or higher) may produce responses in patients resistant to lower doses in combination. Gemcitabine in our hands has a response rate of 18% and has become our standard drug for salvage therapy. Recent data indicate that the combination of gemcitabine and docetaxel (the Gem-Tax regimen) improves response rate, time to progression, and survival in a randomized comparison with gemcitabine alone.

The Gem-Tax regimen is as follows:

  • Gemcitabine 900 mg/m2 over 90 minutes on days 1 and 8.

  • Docetaxel 100 mg/m2 on day 8 only.

  • Filgrastim (granulocyte colony-stimulating factor) 5 g/kg SC is given on days 9 to 15 or until granulocyte recovery to 1, 500/ L. Alternatively, Pegfilgrastim at a dose of 6 mg is given on day 9.

The duration of gemcitabine infusion is critical, since it can only be converted to its active metabolite, gemcitabine triphosphate, at a rate of 10 mg/m2/minute. Doses are reduced by 25% to 675 mg/m2 and 75 mg/m2, respectively, for patients with extensive prior therapy or pelvic radiation. Dexamethasone 8 mg PO b.i.d. should be given for 3 days starting 1 day before docetaxel.

Methotrexate, with a response rate of approximately 15% regardless of schedule, is the only other active agent. Patients who do not respond to doxorubicin, ifosfamide, or gemcitabinedocetaxel should be entered in a phase II study of a new agent to see if some activity can be established because other reasonably good alternatives do not exist.

E. Complications of chemotherapy

Side effects of sarcoma chemotherapy can be classified into three categories: life threatening, potentially dangerous, and unpleasant.

  • Life-threatening complications of chemotherapy are infection or bleeding. Thrombocytopenia lower than 20,000/ L occurs with this type of chemotherapy when growth factors are used to maintain dose intensity, but bleeding is rare and can be minimized by transfusing platelets at 10,000/ L. Approximately 20% to 40% of patients have documented or suspected infection related to drug-induced neutropenia at some time during their treatment course. These infections are rarely fatal if treated promptly with broad-spectrum, bactericidal antibiotics at the onset of the febrile neutropenia episode.

  • Potentially dangerous side effects of chemotherapy include the following:

    • Mucositis, which occurs in fewer than 25% of patients, may interfere with oral intake or may act as a source of infection.

    • Granulocytopenia predisposes the patient to infection but, because of its brevity, rarely causes infection.

    • Cardiac damage from doxorubicin rarely causes clinical problems at the doses recommended, with usually reversible congestive heart failure occurring in fewer than 5% of patients.

    • d. Renal insufficiency is a rare complication of ifosfamide. Fanconi syndrome, particularly manifested by a

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      significant loss of bicarbonate, is a dose-related complication of ifosfamide, occurring in 10% to 30% of patients at standard ifosfamide doses and in close to 100% of patients with high-dose regimens, the morbidity of which can be minimized by the routine use of alkaline infusions and correction of electrolyte levels with intravenous or oral replacement therapy. Only rarely does the nephrotoxicity progress to renal failure, often precipitated by dehydration or administration of minimally nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs). Patients treated with ifosfamide should be instructed to avoid NSAIDs, even years after chemotherapy!

    • CNS toxicity of ifosfamide is rarely a serious complication. Patients frequently demonstrate minor confusion, disorientation, or difficulty with fine movements. Somnolence and coma are rarely seen in patients without hypoalbuminemia and/or acidosis.

    • Hemorrhagic cystitis, a rare complication of cyclophosphamide therapy, used to be the dose-limiting toxicity of ifosfamide. It can be prevented in most cases by administration of another agent, mesna, before and after each ifosfamide dose, allowing higher doses of ifosfamide to be used.

    • Pulmonary toxicity, manifested by increasing dyspnea, is seen in less than 10% of patients treated with the gemcitabine docetaxel combination, but occurs with about twice the frequency of that seen with gemcitabine alone. Careful attention to the possible occurrence of this problem and prompt treatment with high doses of corticosteroids can be life saving.

  • Unpleasant but rarely serious problems include nausea and vomiting (primarily from dacarbazine, ifosfamide, and docetaxel) and alopecia (from doxorubicin, cyclophosphamide, ifosfamide, and docetaxel). Gemcitabine, and to a greater extent, the gemcitabine docetaxel combination, can cause profound fatigue. Gemcitabine can also cause drug fever and a rash (often confused for cellulitis) that can respond to corticosteroids.

F. Special precautions

  • Ifosfamide. Patients must be kept well hydrated with an alkaline pH to prevent CNS toxicity and minimize nephrotoxicity. Sodium bicarbonate or sodium acetate should be added to IV fluids at an initial concentration of 100 to 150 mEq/L, and fluid administration should be adjusted to produce a urine output of at least 2 L/day and to maintain the serum bicarbonate concentration at 25 mEq/L or higher. Other electrolytes should be adjusted as needed on a daily basis. Serum albumin should be kept within normal limits.

  • Doxorubicin. Avoid extravasation. Continuous infusions must (and short infusions should) be administered through a central venous catheter. Attention to cumulative dose administered (varying according to the schedule of administration) is critical to minimize the risk of cardiac toxicity.

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Handbook of Cancer Chemotherapy
Handbook of Cancer Chemotherapy
ISBN: 0781765315
EAN: 2147483647
Year: 2007
Pages: 37

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