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---Laurence H. Baker, D.O.
NCCN Guidelines
The University of Michigan Comprehensive Cancer Center belongs
to the National Comprehensive Cancer Network (NCCN) —
an organization of leading cancer centers taking a leadership
role in the development of diagnostic and treatment guidelines.
Figures 1-3 are printed with the permission of the NCCN and
describe the guidelines for soft tissue sarcomas of the extremity
(Fig. 1), the retroperitoneum and viscera (Fig. 2), and desmoid
tumors (Fig. 3). These guidelines are based on evidence from
the medical literature, and sometimes when evidence is not
yet available, from a panel of sarcoma experts from the NCCN
organizations. Perhaps no statement is more important to the
evaluation and management of the patient with a sarcoma than,
“patients should be presented to a multidisciplinary
Sarcoma Tumor Board for evaluation prior to initiation of
definitive therapy.” In no other guideline of the NCCN,
which now covers more than 95 percent of cancer patients is
such a statement made.
Every patient presenting to U-M is reviewed at our tumor board
consisting of expert pathologists, radiologists and surgical,
orthopedic, radiation and medical oncologists. This tumor
board meets weekly, following the clinics of Drs. Biermann,
Sondak and Baker.
Surgical Principles
There are other important principles presented in these guidelines.
Sarcoma surgical principles include: (1) providing optimal
margins and oncologic control; (2) providing maximal function;
(3) limb sparing; and (4) consideration of preoperative cytotoxic
therapy (chemotherapy, RT) if a patient cannot be treated
in accordance with these principles of sarcoma surgery. Indeed,
these principles can only be accomplished with a team of physicians
as described above.
Evaluation
The initial evaluation for patients is based upon the staging,
just as the treatment. Thus, for a small, low-grade and superficial
sarcoma, MRIs and CTs are not deemed necessary. Similarly,
a chest CT looking for pulmonary metastases is necessary with
large, high-grade and deep sarcomas, but not necessarily if
some or more of the poor prognostic factors are not present.
Follow-up exams are similar, except that a chest X-ray is
used to routinely survey the lungs, while the CT of the chest
is reserved for times when decisions need to be made.
Chemotherapy
The only chemotherapy specified in these guidelines is the
use of doxorubicin/ifosfamide as primary chemotherapy or adjuvant
chemotherapy. This is done despite the lack of any controlled
clinical trial being published in full form. The Rizzolli
Orthopedic Institute did publish, in abstract form, a clinical
trial that was so positive in favor of the chemotherapy arm
(doxorubicin/ifosfamide) vs. the control that an early stopping
rule was evoked. Second-line chemotherapy is not further specified
in these guidelines, and only supportive care is recommended
after second-line chemotherapy. The guidelines do, however,
recommend the use of metastectomy as an appropriate treatment
for metastasis to a single organ, whether or not the patient
has had prior chemotherapy. However, in the medical management
of extra-abdominal desmoids, several medications are specified
including: tamoxifen, sulindac or other NSAID, methotrexate/vinblastine,
and doxorubicin-based combinations. For the sake of this review,
Tables 1 and 2 provide our understanding of the effectiveness
of chemotherapy in soft tissue sarcomas and bone sarcomas
as single agents (Table 1) and in combination (Table 2).
Response Rates
Remarkably, the chemotherapy sensitivity of the soft tissue
sarcomas and osteogenic sarcomas is similar. Table 1 compares
the published data of single-agent chemotherapy. The single
most active drug in both disease categories is doxorubicin.
The response rate is 26 percent in both sets of patients.
These data are obtained from the published literature of patients
with disseminated sarcoma treated with single agents. High-dose
methotrexate with folinic acid rescue appears more effective
in osteosarcoma patients (25 percent overall response) than
the reported series of patients with soft tissue sarcomas
in which the combined response rate is 13 percent. Ifosfamide,
similar to doxorubicin, has remarkably similar data in the
two groups: 24 percent response in osteogenic sarcoma, and
27 percent in soft tissue sarcoma. Cyclophosphamide is also
similar between the two groups, 14 percent and 12 percent,
and approximately half as effective as its analogue ifosfamide.
Cisplatin seems more effective in osteogenic sarcomas, 18
percent vs. 12 percent. This is probably the reason this drug
is included in adjuvant studies of osteogenic sarcomas while
adjuvant cisplatin was only studied in uterine sarcoma patients.
As would be anticipated from these data, the duration of response,
frequency of complete remission, and overall survival allappear
similar.
The data regarding the treatment of patients with either disseminated
soft tissue sarcoma or osteogenic sarcomas with combination
chemotherapy is shown in Table 2. Once again, there is remarkable
similarity among the two groups. Unfortunately, the most active
combination in the soft tissue category are unstudied in the
osteosarcoma group. The combinations of doxorubicin and ifosfamide
or doxorubicin, ifosfamide, and dacarbazine (DTIC) have reported
response rates of 36 percent to 47 percent.
Investigational Chemotherapy
Only in the category of soft tissue sarcoma is there an extensive
reporting of investigational chemotherapies. Some argue that
these investigational drugs should only be studied within
the context of no prior chemotherapy exposure. Yet all of
the drugs identified as active, and indeed now part of curative
adjuvant strategies, have been uncovered within the setting
of prior chemotherapy treatment.
Evaluation of chemotherapy’s role as an adjunct clearly
shows a much greater effect of chemotherapy in those patients
with osteogenic sarcoma than soft tissue sarcoma. In an evaluation
of soft tissue sarcoma patients, the improvement in overall
survival was 14 percent in patients treated adjunctively with
chemotherapy vs. patients treated with only surgery and perhaps
radiation therapy. The impact of chemotherapy on overall survival
in patients treated adjunctively with chemotherapy for osteogenic
sarcoma is at least a 30 percent improvement.
References
- Benjamin RS, Baker LH, O’Bryan RM, et al. Chemotherapy of metastatic osteosarcoma: Studies by the MD Anderson Hospital and the Southwest Oncology Group. Cancer Treat Rep. 62:237-238, 1978.
- Antman K, Amato D, Pilepich M, et al. Combined modality therapy for disseminated soft tissue sarcoma, phase III: A Southwest Oncology Group study (8024). Proc ASCO. 6:138, 1987 (abstract).
- Baker LH, Frank J, Fine G, et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcoma: A randomized comparative trial—a Phase III Southwest Oncology Group study. J Clin Oncol. 5:851-861, 1987.
- Benjamin RS, Gottleib JA, Baker LH, et al. CYVADIC vs. CYVADACT - A randomized trial of cyclophosphamide, vincristine, and adriamycin plus either
dacarbazine or actinomycin-D in metastatic sarcomas. Proc AACR. 17:256, 1976.
- Loehrer PJ Sr, Sledge GW Jr, Nicaise C, et al. Ifosfamide plus doxorubicin in metastatic adult sarcomas. A mult-institutional phase II trial. J Clin Oncol. 7:1655-1659, 1989.
- Schuette J, et al. Adriamycin and ifosfamide, a new efficient combination in advanced soft tissue sarcoma: Preliminary report of a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Proc European Conf Clin Oncol. 4:232, 1987.
- Zalupski MM, Ryan J, Hussein M, et al. Defining the role of adjuvant chemotherapy for patients with soft tissue sarcomas of the extremities. In: Adjuvant Therapy of Cancer VII, Salmon S (ed), Philadelphia, PA, Lippincott, pp. 385-393, 1993.
- Eckhart JJ. Management of stage IIB osteogenic sarcoma: Experience at the University of California. Los Angeles Cancer Treatment Symposia. 3:117-130, 1985.
- Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 134:1600-1606, 1986.
- Rosen G, Caoparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 49:1221-1230, 1982.
- Biermann JS, Baker LH. The future of sarcoma treatment. Sem Oncol. 24(5): 1-7, 1997.
- NCCN Guidelines Meeting, March, 1997, Fort Lauderdale, FL
Laurence H. Baker, D.O., is a professor of Internal Medicine and deputy director of the U-M Cancer Center.
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