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Chemotherapy of high-grade malignant sarcoma


Medical editor Kirsten Sundby Hall MD
Oncologist
Oslo University Hospital

General

Adult patients with soft tissue sarcoma are increasingly given adjuvant chemotherapy.

There is reason to believe that the effect of chemotherapy is most pronounced in patients with highly malignant tumors and SSG has therefore selected a high-risk group for a study protocol where adjuvant chemotherapy is involved.

Patients in the high-risk group is registered simultaneously prospectively in a phase 2 research study to compare survival results between chemotherapy-treated patients with matched historical controls. The high-risk group is selected according to age, histology, grade of malignancy, tumor size and localization as well as the presence of necrosis, vessel invasion and a diffuse infiltrative growth pattern.

The chemotherapy regimen consist of 6 courses of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2), which are most effective drug treatment for soft tissua sarcoma. Patients ≥ 70: Doxorubicin (50 mg/m2) and ifosfamide (5 g/m2)

Patients with metastases are not appropriate for the research study.

Tumor with the following pathological findings:

  • Infiltration of a blood vessel
  • and/or two out of three of the following criteria:
    •  ≥ 8 cm
    • infiltrating peripheral growth pattern
    • tumor necrosis

Appropriate patients:

  • Age ≥ 18 and ≤ 75 years 
  • No serious internal medical disease
  • Normal heart and lung function
  • All high-grade malignant histological types except for intralesional osteosarcoma and chondrosarcoma, Ewing's, PNET, rhabdomyosarcoma, Kaposi's sarcoma, malignant mesenchynoma, clear cell sarcoma, alveolar soft tissue sarcoma, epithelioid sarcoma
  • No metastases at the time of diagnosis
  • Not treated for other non-metastatic cancer disease in the past five years. Patients with basal cell carcinoma of the skin or cervical cancer in situ may be included.
  • No previous treatment with anthracyclines.

Indications

  • Soft tissue sarcoma in extremity or trunk which fits into group A or B.

Goal

  • Cure the disease

Preparation

Before starting treatment

  • Information about treatment, duration and side effects 
  • Blood tests:
    • Leukocytes, neutrophile granulocytes, thrombocytes
    • Creatinine, ALAT and bilirubin
  • MRI of the tumor is performed before surgery in group A patients and before starting chemotherapy in group B patients.
  • X-ray of thorax 
  • CT thorax
  • Offer sperm banking
  • Information about birth control

Examinations before each course of chemotherapy

  • Weight
  • Blood tests:
      • Leukocytes, neutrophile granulocytes, thrombocytes
      • Creatinine, ALAT and bilirubin
  • After each course of chemotherapy and radiation treatment, acute side effects are registered, if present.

Weekly tests

  • Blood status:
    • Leukocytes, neutrophile granulocytes, thrombocytes

Before 4th course of chemotherapy

  • X-ray of lungs
  • MUGA (left heart ventricle function at rest)
  • GFR (kidney function)

     


    Implementation

    The patient receives six chemotherapy courses with three week intervals. Each course lasts three days. The radiation treatment is given between the 3rd and 4th course, twice daily for 10-12 days.


    Follow-up

    After the last course of chemotherapy

    Follow-up 6 weeks after the last course of chemotherapy. The following examinations are performed:

    • Blood tests 
      • leukocytes, thrombocytes, ALAT, total bilirubin, creatinine
    • Clinical examination of the tumor area
    • MRI of area tumor where the was localized
    • X-ray of lungs 
    • MUGA
    • GFR

    Further follow-up

    All patients who have been included in the treatment are followed up including those who did not complete the entire protocol.

    • 1.– 2. years: every 3. months
    • 3.– 5. years: every 6. months
    • 6.–10. years: annually

    Examinations:

    • Clinical examination of the area where the tumor was localized 
    • MRI when clinical assessment is difficult or suspicious
    • X-ray thorax
    • CT thorax for suspect findings on thoracic X-ray
    • MUGA and GFR are performed 1,5 and 10 years after treatment has ended

    Side effects and delayed effects

    Nutrition

    Nutritional problems occur to a greater or lesser extent for patients undergoing this treatment. This is due to nausea, vomitting, mucositis, diarrhea, dry mouth, pain, constipation, and changes in sense of smell and taste. Many will require intravenous nutrition. Good nutrition guidance is important.

    Mucositis

    Mucositis, both in the mouth and other mucous membranes occur often when blood values are at their lowest. The degree of soreness is individual. Sore mucous membranes in the mouth are not only an entrance for bacteral but it can also be painful. Preventative mouth hygiene is performed during the entire treatment.

    Nausea

    Nausea improves after 1-2 days after concluded treatment. Some patients have lasting problems of multifactorial etiology.

    Alopecia

    Alopecia will occur 2-3 weeks after starting chemotherapy treatment. Hair will usually fall off in tufts. 

    Neutropenia

    Leucopenia and thrombocytopenia occur regularly between courses. Measurement of hemoglobin, leukocytes, and thrombocytes are routinely carried out twice weekly. For febrile neutropenia, use of kiney toxic antibiotics should be avoided due to the fear for additive kidney toxicity in combination with cisplatin and high-dose ifosfamide. This applies for one year after concluded treatment. Transfusion of thrombocytes might be necessary especially at the conclusion of treatment.

    Hemorragic cystitis

    Hemorragic cystitis is due to the large doses of ifosfamide. Despite using a prophylactic with forced hydration and Mesna, some patients still develop hematuria/dysuria/pollakisuria. The symptoms usually appear during or after the first days of the ifosfamide infusion. Certain patients can develop hemorragic cystitis later in the course.

    Cardiomyopathy

    Anthracyclines are cardiotoxic especially by high, cumulative doses. Cardiomyopathy is dose-dependent and may occur long after end of treatment.

    Infertility

    Infertility in men is a regular complication, especially due to the accumulated dose of ifosfamide, cisplatin, and doxorubicin. For age-appropriate patients, freezing of sperm is recommended. Female egg production is also influenced, but freezing of female eggs is currently only in a testing phase in Norway and is not routinely offered.


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