PDQ® Treatment Health Professionals
This treatment information summary on childhood rhabdomyosarcoma is an overview of prognosis, diagnosis, classification, and patient treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists.
Cancer in children and adolescents is rare. A team approach that incorporates the skills of the primary care physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.
Childhood rhabdomyosarcoma, a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of cases of cancer among children 0-14 years and 2% of cases among adolescents and young adults 15-19 years of age.[2,3] It is a curable disease in the majority of children who receive optimal therapy, with more than 60% surviving 5 years after diagnosis.[4,5] The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal, orbit, pharyngeal, etc.), the genitourinary tract, and the extremities.[4,5] Other less common primary sites include the trunk, intrathoracic region, the gastrointestinal tract (including liver and biliary tract), and the perineal/anal region.
The prognosis for a child or adolescent with rhabdomyosarcoma is related to the site of origin, and extent and histopathology of disease.[4,5] There are also preliminary data describing the possible prognostic significance of specific biological characteristics of rhabdomyosarcoma tumor cells. Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below.
b. Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (<5 cm) have improved survival compared to children with larger tumors, while children with metastatic disease at diagnosis have the poorest prognosis.[4,6,8] The prognostic significance of metastatic disease is modified by tumor histology, age at diagnosis, and primary site. Patients with metastatic disease who are less than 10 years of age and whose tumors have embryonal histology have 5-year survival rates greater than 50%, while those over 10 years of age or with alveolar histology have a much poorer outcome. Similarly, patients with metastatic disease and with genitourinary (but non-bladder, non-prostate) primary tumors have a more favorable outcome than patients with metastatic disease and primary tumors at other sites. In addition, patients with otherwise localized disease but with proven regional lymph node involvement have a poorer prognosis than patients without regional nodal involvement.[11,12]
c. The extent of disease following the primary surgical procedure (i.e., the clinical group) is also correlated with outcome. In the Intergroup Rhabdomyosarcoma Study (IRS) III, patients with gross residual disease after initial surgery (Group III) had a 5-year survival rate of approximately 70% compared with a greater than 90% 5-year survival rate for patients with no residual tumor after surgery (Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor following surgery (Group II).
d. Although the alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., older age, extremity primaries, and metastatic disease), it is not clear that alveolar histology predicts poor outcome independent of these clinical features. In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome in patients whose primary site was completely resected (Group I). Statistically significant differences in survival for histopathologic subtype were not, however, noted when all patients with rhabdomyosarcoma were analyzed, nor were differences noted by histologic subtype in a large group of German children with rhabdomyosarcoma. In the IRS-III study, outcome for patients with Group I tumors and alveolar subtype was similar to those of other patients with Group I tumors, but the patients with alveolar subtype received more intensive therapy.
e. Cellular DNA content (ploidy) of rhabdomyosarcoma tumor cells appears to have prognostic significance. Patients with tumor cells that have cellular DNA content that is approximately 1.5-fold higher than normal (termed hyperdiploid) appear to have better outcome than patients whose tumors cells have normal DNA content (termed diploid) or than patients whose tumors have twice the normal DNA content (termed tetraploid).[14,15] Hyperdiploid DNA content is associated with embryonal histology, while tetraploid DNA content is associated with alveolar histology.[14,15]
Rhabdomyosarcoma can be divided into several histologic subsets: embryonal, botryoid subtype of embryonal rhabdomyosarcoma, spindle cell, alveolar, and pleomorphic.[1,2] The embryonal subtype is the most frequently observed histologic subtype in children, accounting for approximately 60%-70% of rhabdomyosarcomas of childhood. Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site. Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, and nares. The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site. Both the botryoid and the spindle cell subtypes are associated with very favorable outcome. Approximately 20% of children with rhabdomyosarcoma have the alveolar subtype, with an increased frequency of this subtype noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perirectal region. Pleomorphic rhabdomyosarcoma occurs predominantly in patients aged 30-50 years and is rarely seen in children.
The embryonal and alveolar histologies have distinctive molecular characteristics which have been used for diagnostic confirmation and which may be useful in the future for monitoring the presence of small numbers of tumor cells after treatment has been initiated.[4-6] Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are characteristic of alveolar rhabdomyosarcoma. Translocations involving the PAX3 gene occur in approximately 70% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 20% of cases. Alveolar cases associated with the PAX7 gene appear to occur at a younger age and may have longer event-free survival rates than cases associated with PAX3 gene rearrangements. Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11.[8,9] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, although a specific gene whose loss is a critical step in the pathogenesis of embryonal rhabdomyosarcoma has not yet been identified.
Alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma also differ in the propensity of their tumor cells to undergo genomic amplification. Genomic amplification is rare in embryonal rhabdomyosarcoma, although gains of whole chromosomes occur commonly. Gene amplification commonly occurs in alveolar rhabdomyosarcoma. Another difference between the two types of rhabdomyosarcoma is in their cellular DNA content (ploidy): alveolar histology tumors are commonly near-tetraploidy (2x normal DNA content), while embryonal tumors are most frequently hyperdiploid (1.1 to 1.8x normal DNA content).[11-13]
As noted previously, prognosis for children with rhabdomyosarcoma is dependent on the extent of disease, primary site, and histologic subtype. Favorable prognostic groups have been identified by previous Intergroup Rhabdomyosarcoma Studies, and treatment plans have been designed based on assignment of patients to different groups based on prognosis. The first three Intergroup Rhabdomyosarcoma Studies (IRS I-III) prescribed treatment plans based on a clinical grouping system with groups defined by the extent of disease and by the extent of initial surgical resection. The definitions of the clinical groups on the IRS I-III studies are given below.[1,2]
Group I has localized disease that is completely resected with no regional nodal involvement. Approximately 13% of all patients are in this group.
Group IIA has grossly resected tumor with microscopic residual disease, but no regional nodal involvement. Group IIB has regional disease with involved nodes, with complete resection and no residual disease. Group IIC has regional disease with involved nodes, grossly resected, but with evidence of microscopic residual and/or histologic involvement of the most distal regional node (from the primary site). Approximately 20% of all patients are in this group.
Group III has incomplete resection (or biopsy only) of the primary site and therefore has gross residual disease. Approximately 48% of all patients are in this group.
Group IV has distant metastatic disease present at the time of diagnosis. Approximately 18% of all patients are in this group.
In addition to clinical group, current Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols base treatment decisions on a TNM-based pretreatment staging system. A patient's stage is determined clinically by primary tumor size and site, by nodal status, and by the presence or absence of metastases.
Stage 1: Favorable localized disease involving the orbit or head and neck
The IRSG assigns patients to treatment protocols using a risk classification scheme that combines the clinical group and stage information described above. Patients are classified for protocol purposes as low risk, intermediate risk, or high risk. General definitions of each of these categories are as follows:
Low risk: patients with embryonal rhabdomyosarcoma occurring in favorable sites (i.e., Stage 1) and embryonal rhabdomyosarcoma with either completely resected disease (i.e., Group I) or microscopic residual disease (i.e., Group II) occurring at unfavorable sites.
Intermediate risk: patients with embryonal rhabdomyosarcoma with gross residual disease (i.e., Group III) occurring at unfavorable sites or metastatic embryonal rhabdomyosarcoma in children less than 10 years of age, and non- metastatic alveolar rhabdomyosarcoma at any site.
High risk: patients with metastatic rhabdomyosarcoma at presentation except embryonal cases in children less than 10 years of age.
All children with rhabdomyosarcoma require multimodality therapy. This entails surgical resection, if possible, followed by chemotherapy, followed by second-look surgery for some patients with initially unresected tumors, and, depending on original extent of disease and extent of resection, radiation therapy. The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing surgery, chemotherapy, and radiation therapy.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Surgical management treatment options:
The basic principle for the initial surgical treatment of children with rhabdomyosarcoma is complete resection of the primary tumor with a surrounding "envelope" of normal tissue, although important exceptions to this rule do exist (e.g., tumors of the orbit and of the genitourinary region).[1-3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but is a reasonable concept if easily accomplished. Patients with "microscopic residual" tumor following their initial excisional procedure appear to have improved prognoses if a second surgical procedure with wider excision of the tumor bed prior to initiation of chemotherapy achieves complete removal of tumor. Because rhabdomyosarcoma can arise at so many primary sites, surgical care must be tailored to the unique aspects of each site. Surgical management of the more common primary sites are given below.
For tumors at the primary sites of the head and neck that are superficial and non-orbital, wide excision is appropriate when feasible, although narrower margins are common because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. However, these techniques at the present time should only be considered in children with recurrent local regional disease and residual disease following chemotherapy and radiation therapy. For patients with head and neck primary tumors that are considered unresectable, chemotherapy and radiation therapy are the mainstay of primary management.[1,5-8] Rhabdomyosarcomas of the orbit do not require orbital exenteration at diagnosis; they require only a biopsy to establish diagnosis. Biopsy is followed by chemotherapy and radiation therapy, with orbital exenteration reserved for the small number of patients with local persistent or recurrent disease.[7,10]
Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, vagina, and uterus. Specific considerations for the surgical management of tumors arising at each of these sites are discussed in the paragraphs below.
Lesions adjacent to the testis or spermatic cord should be removed by orchiectomy and resection of the entire spermatic cord, which requires an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[1,11] Resection of scrotal skin is required when there is tumor fixation or invasion, or when a previous trans-scrotal biopsy has been performed. Paratesticular tumors have been found to have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II studies), and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic computerized tomographic (CT) scans with contrast to evaluate nodal involvement. For patients whose CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, however, a repeat CT scan every 3 months is recommended.[10,13,14] For patients with suggestive or positive CT scans, retroperitoneal lymph node sampling (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[3,11,15] European investigators tend to rely on radiographic rather than surgical assessment of retroperitoneal lymph node involvement. Resection of scrotal skin is required when there is tumor fixation or invasion or when a previous trans-scrotal biopsy has been performed.
Bladder salvage is an important goal of therapy for patients with tumors arising in the prostate and bladder. In rare cases the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and radiation therapy have been used to reduce tumor bulk,[16,17] followed when necessary by a more limited surgical procedure such as partial cystectomy. Early experience with this approach was disappointing, with only 20%-40% of patients with bladder/prostate tumors remaining alive and with functional bladders 3 years following diagnosis (overall 3-year survival 70% in IRS-II studies);[18-20] the more recent experience from IRS-III studies, which used more intensive chemotherapy and radiation therapy, showed 50% of patients alive with functional bladders at 3 years from diagnosis, with overall 3-year survival of 90%.[17,21] Thus, this approach to therapy remains generally accepted with the belief that more effective chemotherapy and radiation therapy will continue to increase the frequency of bladder salvage. The initial surgical procedure in most patients consists of a biopsy, which often can be performed endoscopically, perineally, or suprapubically but rarely requires laparotomy. Subsequently, for patients with biopsy-proven residual tumor following chemotherapy and radiation therapy, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually anterior with preservation of the rectum). One study suggests that residual tumors with histologic evidence of maturation in patients with primary bladder tumors may warrant additional courses of chemotherapy prior to considering cystectomy.
For patients with genitourinary primary tumors of the vagina/vulva/uterus, the initial surgical procedure is usually transvaginal biopsy. The responsiveness of tumors of the vagina and vulva to chemotherapy generally precludes the need for initial radical surgery (e.g., pelvic exenteration). Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation when necessary, appears to result in excellent disease-free survival.[22,23] Because of the small number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision. In one series of 14 patients, good response to chemotherapy, limited surgery, and radiation therapy was observed in all but 1 patient. Unfortunately, 4 of the 14 patients died of sepsis and/or other treatment- related complications. Exenteration is usually not required for primary tumors at these sites, but if needed it may be done with rectal preservation in most cases.
The definitive surgical procedure involves wide local excision with removal en bloc of a cuff of normal tissue.[1,2] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure. Amputation may be indicated for selected patients with extracompartmental lesions involving major neural and/or vascular structures in addition to the muscle of origin. Due to the significant incidence of nodal spread for extremity primary tumors (often without clinical evidence of involvement), and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment for regional nodal involvement is warranted.[12,25,26] The Intergroup Rhabdomyosarcoma Study Group (IRSG) study has recommended axillary node dissection (with preservation of the pectoral muscles, long thoracic nerve, and thoracodorsal nerve) for patients with upper-extremity primary tumors and clinically negative nodes. It also recommends femoral triangle node sampling for patients with lower-extremity primary tumors. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to dissection or sampling of the involved nodal region. Sentinel lymph-node mapping is employed at some centers to identify the regional nodes which are the most likely to be involved.
Primary resection of metastatic disease is rarely indicated except for isolated pulmonary metastases. Persistent metastatic disease in the lung following radiation and chemotherapy should be resected when possible to render patients disease free, provided adequate pulmonary function can be preserved.
Chemotherapy treatment options:
For children with the most favorable prognosis, an important consideration is
maintaining high survival rates (>90%) while minimizing the long-term
consequences of chemotherapy. As discussed in the general information and
staging sections of this summary, favorable prognosis is defined as patients
with embryonal rhabdomyosarcoma occurring in favorable sites (i.e., Stage 1)
and embryonal rhabdomyosarcoma with either completely resected disease (i.e.,
Group I) or microscopic residual disease (i.e., Group II) occurring at
unfavorable sites. Previous IRSG studies have shown that vincristine (VCR)
with dactinomycin (DACT) with or without cyclophosphamide (CYC) is an
effective chemotherapy regimen for these patients with a favorable
One sub-group of the favorable prognosis population has achieved high
survival rates with a chemotherapy regimen using only VCR with
DACT.[29-31] This sub-group is defined by favorable tumor site with
complete resection or microscopic residual disease, unfavorable site with
small tumor and complete resection, or orbital primary site with gross
residual disease (see Stage Information section for details). For patients
with an orbital primary site, the addition of CYC to VCR and DACT may
increase the event-free survival rate, but appears to have no impact on
survival (5-year survival 95%).[31,32] Given the long-term toxic effects
associated with CYC, the currently favored approach in the United States is
to treat these patients with only VCR and DACT and administer radiation using
an appropriate dose and field.
Another sub-group of favorable prognosis population has achieved high
survival rates with a chemotherapy regimen using VCR and DACT combined with
CYC. This sub-group includes patients with favorable site and positive lymph
nodes, patients with favorable site (excluding orbit) and gross residual
disease, and patients with an unfavorable site without gross residual disease
(see Stage Information section for details).
Patients with intermediate prognosis have survival rates ranging from 55%-
70%, including patients with embryonal rhabdomyosarcoma with gross residual
disease (i.e., Group III) occurring at unfavorable sites, or metastatic
embryonal rhabdomyosarcoma in children less than 10 years of age, and non-
metastatic alveolar rhabdomyosarcoma at any site. For patients with
intermediate prognosis, VAC (VCR, DACT, and CYC) is the standard chemotherapy
Patients with metastatic disease at diagnosis (Stage 4) have a poor
prognosis with current therapy, and new approaches to treatment are
needed to improve survival in this group.[31,33,34] The exception are
patients who have embryonal histology and are less than 10 years of age.
These patients appear to have a significantly better prognosis (survival
>50%) than other patients with metastatic disease.
2. Alternating multi-agent regimens:
These regimens combine VAC-like treatment courses including doxorubicin with treatment courses of other drug combinations.[41,42] While these multi-agent regimens have produced good outcomes, there have not been comparative studies showing that they are superior to the use of VAC alone.
3. Dose-intensified VAC:
Previous studies by the IRSG have demonstrated an apparent improvement in outcome for patients with embryonal rhabdomyosarcoma as the dose intensity of CYC increased in successive studies. This observation has provided impetus to investigate whether even higher doses of CYC might further improve outcomes for patients with intermediate and poor risk rhabdomyosarcoma, but data from studies evaluating this strategy are not yet available.
4. Adding topoisomerase-I inhibitors (topotecan or irinotecan) treatment courses to VAC regimens: Topotecan, a topoisomerase-I inhibitor, has demonstrated significant antitumor activity in rhabdomyosarcoma xenograft models. The IRSG has demonstrated that topotecan is an active agent for rhabdomyosarcoma in previously untreated patients, particularly those with alveolar histology. The combination of CYC with topotecan demonstrated high levels of activity in patients with recurrent rhabdomyosarcoma. The topotecan plus CYC combination is being evaluated by the IRSG for children with intermediate prognosis rhabdomyosarcoma. Irinotecan is another topoisomerase-I inhibitor that demonstrated significant antitumor activity in rhabdomyosarcoma xenograft models. Irinotecan produced partial responses in 3 of 4 children with rhabdomyosarcoma treated in a phase I trial, and it is currently being evaluated by the IRSG for children with metastatic rhabdomyosarcoma (excluding patients less than 10 years of age with embryonal tumors).
5. Autologous bone marrow transplant (ABMT):
ABMT has been evaluated in a limited number of patients with rhabdomyosarcoma. This treatment strategy generally uses conventional chemotherapy, radiation therapy, and surgical management for approximately 6 months to achieve significant reduction in tumor burden. Patients then receive one or two courses of myeloablative chemotherapy and subsequent ABMT. There is relatively little experience with ABMT for patients with rhabdomyosarcoma,[49-52] and interpretation of published studies regarding ABMT is complicated by the small numbers of patients, short periods of follow-up, and possible patient selection bias. However, available data indicate that ABMT is of unproven value in the therapy of poor-risk rhabdomyosarcoma and should be performed only as part of controlled clinical trials.
Radiation therapy management treatment options:
The radiation therapy dose depends predominantly on the extent of disease
following the primary surgical resection. In general, patients with
microscopic residual disease (Group II) receive radiation therapy to
approximately 4,100 cGy,[54,55] although doses from 3,000 to 4,000 cGy may
be adequate in patients receiving effective multiagent chemotherapy.
IRS-II patients with gross residual disease (Group III) who received 4,000 to
greater than 5,000 cGy had local/regional relapse rates of over 30%; higher
doses of radiation (>6,000 cGy) have been associated with unacceptable
long-term toxic effects.[57,58] Patients on the IRS-IV standard treatment
arm receive approximately 5,000 cGy.[53,59]
The treated volume should be determined by the extent of tumor at diagnosis
prior to surgical resection and prior to chemotherapy. A margin of 2 cm is
generally used, including clinically involved nodes. While the volume
irradiated may be modified based on guidelines for normal tissue tolerance,
gross residual disease at the time of irradiation should receive full-dose
The timing of radiation therapy generally allows for chemotherapy to be given
for 2-3 months prior to the initiation of radiation therapy, with the
exception of patients with parameningeal disease and evidence of meningeal
extension in whom radiation therapy generally begins at the time of
diagnosis.[30,60] Radiation therapy is usually given for 5-6 weeks (e.g.,
180 cGy per day for 28 treatment days), during which time chemotherapy is
usually modified to avoid radiosensitizing agents such as dactinomycin and
2. Patients with bladder/prostate primary tumors that present with a large pelvic mass resulting from a distended bladder from outlet obstruction receive treatment to a volume defined by imaging studies following initial chemotherapy.
3. Patients with parameningeal disease with intracranial meningeal extension receive whole-brain radiation (2,340-3,060 cGy) in addition to treatment of the primary tumor as outlined above. Patients without intracranial extension and only bone erosion and/or cranial nerve palsy do not require whole-brain radiation, and receive treatment to the site of original disease with a 2 cm margin to include the meninges adjacent to the primary tumor.
4. A 2 cm margin is advised for patients with extremity primary tumors, but care should be taken to avoid circumferential irradiation of all extremity lymphatics and to avoid treating across a joint.
Brachytherapy using either intracavitary or interstitial implants is another
method of local control that is under clinical investigation and has
been used for children with rhabdomyosarcoma, especially those with primary
tumors at vaginal or vulval sites.[62-64] In a small, single-
institution study, this treatment approach was associated with a high
survival rate (85%) and with retention of a functional vagina in the majority
of patients. Other sites, especially head and neck, have been treated
Patients with initial Group III disease who then have microscopic residual
disease after chemotherapy with or without delayed surgery are likely to
achieve local control with radiation at doses of 4,000 cGy or more.
Although a patient with recurrent or progressive rhabdomyosarcoma can sometimes achieve a complete remission with secondary therapy, the long-term prognosis is guarded. Patients whose primary tumor was initially completely resected (Group I) have a higher likelihood of extended survival following relapse than patients initially presenting with Group II-IV tumors; for the latter patients, 3-year survival after relapse is less than 15%. The selection of further treatment depends on many factors, including the site of recurrence and previous treatment, as well as individual patient considerations. The combination of ifosfamide/etoposide has considerable activity in the treatment of children with recurrent rhabdomyosarcoma not previously treated with these agents. Other regimens that have shown activity against recurrent rhabdomyosarcoma include the two-drug combination of carboplatin given with etoposide, and the three-drug combination of ifosfamide given with carboplatin and etoposide.[5,6] Very intensive chemotherapy followed by autologous bone marrow re-infusion is also under investigation for patients with recurrent rhabdomyosarcoma. New agents under clinical evaluation in phase I and phase II trials should be considered for these patients.
Date Last Modified: 11/1999