Radiation Oncology Synopsis

PEDS: Rhabdomyosarcomas

Pediatric rhabdomyosarcoma is a highly malignant sarcoma arising from embryonal mesenchyme with the potential for differentiating into striated muscle. It was first described in 1854 and characterized into four classic forms in 1958,

Rhabdomyosarcoma can arise anywhere in the body , is rapidly invasive and disseminates early. Initially surgery was the only treatment which was highly disfiguring and not available to those who had disseminated disease. Early in the 20th century, high dose radiation therapy was added and increased the potential for local control but it came with its own set of morbidities.

Advances in chemotherapy throughout the 20th century increased control of distant metastases and improved local control, but surgery and radiation continue to play important roles in the treatment of rhabdomyosarcoma. Chemotherapy reduced the need for aggressive survery and large volume radiation therapy. Overall survival rates have increased form 15% - 25% to more than 70%.

The tumor itself is rare with clinical and biological heterogeneity. There have been a number of study groups over the years which have had clinical studies leading to the substantial improvoments in outcomes. The Intergroup Rhabdomyosarcoma groups did three studies:

There is now a database of 4000 children with rhabdomyosarcoma treated on these studies. the COG has assume responsibility for these studies. In Europe, SIOP and UK CSTG are parallel organizations.

Epidemiology and Demographics

RMS is the most common soft tissue sarcoma of childhood representing almost half of the sarcomas in children. 70% occur before the age of 10 and there is a slight male predominance. The peak incidence is 2-5 years. Congenital abnormalities have been identified in as many as 1/3 mostly GI, GU cardiovascular and CNS. The incidence is 4.4 / 1M white and 1.3/1M black.

The majority of cases are sporadic, but a small number are associated with several genetic syndromes:

There are postulates that in-utero exposure to marijuana, cocaine use and radiation may have a role in the development of RMS.

Embryonal and alveolar RMS appear appear to differ in genetics.

Embryonal RMS is often characterized by a loss of heterozygosity of 11p15.5 suggesting the presence of a tumor suppressor gene. In addition gene amplification is rare in embryonal RMS, with whole chromosome gains (Ch 2,8, 12, 13) being common and hyperdiploidy also common.

In contrast, alveolar RMS has common gene amplification and is associated with t(2:13) translocation in 70% and t(1:13) in 20%. There genes are the PAX3 or PAX7 with FHKR.

Mesenchymal fibroblast cells differentiate inot skeletal muscle under the control of the MyoD protein family (actin, myosin, dsmin, myoglobin).

In alveolar RMS, n-myc amplification predicts a fatal outcome. N-myc amplification is uniformly absent in embryonal RMS.

p53 is a G1 checkpoint. Normal p53 in conjunction withmyc drives damaged cells at the G1 checkpoint toward apoptosis.

RMS histologies by prognosis from best to worst:

Histology OS5
botryoid 95%
spindle cell 88%
embryonal 66%
alveolar 54%
undifferentiated 40%
  1. Spindle cell and botryoid
  2. classical embryonal
  3. Alveolar
  4. Undifferentiated

RMS is divided into favorable and unfavorable sites. These favorable sites have a 94% OS3. The favorable sites are:

The non-parameningeal head and neck sites are:

For unfavorable sites, the overall 3 year survival rate is 70%.

The para-meningeal head and neck sites are:

There are a number of sites associated with a high propensity for lymph node metastases. Disease occurences at these sites require lymph node dissection. The following sites are associated with a 20% Lymph node metastases rate:

The IRS-IV study called for routine sampling of LN in the extremity due to a 10% cN+ and a 50% rate of pN+ disease. Of those who were clinically node negative, 17% were pN+.

Non-regional lymph nodes by site are:

Clinical Presentation

RMS can occur in any anatomic site with the presence of skeletal muscle and several additional sites:

RMS commonly presents a mass with poorly defined margins with symptoms related to the primary site: GU may present with obstructions or the mass may protrude from the vagina (botryoid) or cervix or urethra. Grape-like clusters are called botryoid sarcoma. Prostate and bladder RMS may also appear botryoid and may protrude into the bladder lumen. Hematuria, urinary frequency or retention may occur. Less than

Paratesticular RMS presents with a mass and may be mistaken for hydrocele, incarcerated hernia, or testicular torsion. RMS in the extremities may be a palpable mass or cause pain or limit function.

Paratesticular RMS arises from the distal spermatic duct.

Parameningeal sites may present with upper airway obstruction or a palpable mass. It can erode into the base of skull and cause CN palsies. If it penetrates the skull, it can impinge on the brain and cause mass effect with headache, vomiting and diploplia.

Non-parameningeal RMS can cause a palpable mass on the cheek or aerodigestive tract obstruction. Orbital RMS usually presents with proptosis, discoloration or limited extraocular motions. In the trunk, RMS primarily resents as a mass effect.

Diagnostic Evaluation

The workup including H&P should focus on the extent of local disease and the presence of metastases. This is particularly true for those sites that have increased propensity for LN metastases (> 20&) including extremities, nasopharynx, bladder, and paratesticular for age > 10. RMS extends focally and along a fascial plane and into surrounding tissues and may have indistinct margins.

Imaging

Imaging workup includes CT, MRI and plain films. Genitourinary RMS is often initially investigated with ultrasound, voiding cystourethrogram and barium enema, along with cystoscopy or pelvice EUA. CT and surgery are used to evaluate the draining lymphatics of the extremities and GU sites.

Chest CT is optimal for evaluating lung metastases as the most common site of distant metastases. Bone scans may be used to detect bony metastases, but cannot be relied upon for base of skull involvement.

Parameningeal tumors should be imaged with MRI. MRI is also used to determine the spinal cord patency when cord related symptoms are present.

PET/CT is being used with increasing frequency for detecting regional lymph node metastases and distant metastases.

Biopsy

For parameningeal sites, specific additional work up is required: CSF cytology are used to determine if a tumor is parameningeal, and if positive, a neuro-axial MRI should be obtained.

Staging

The AJCC staging is straightforward, but there are multiple staging systems in use. The International Rhabdomyosarcoma Study group (IRS-III) developed a pre-treatment staging system based on tumor, node and metastases, similar to a SIOP staging system. IRS-IV and IRS-V and COG trials now use this TNM staging system.

RMS Staging -- Fav. sites(non-parameningeal H&N, Orbit, non-bladder/prostate GU)
Unfav: PM H&N, bladder/prostate, trunk, extremity,
Stage Site Size Nodes Mets
I favorable N0 or N1 M0
II unfav < 5 cm N0 Mo
III unfav >5 cm or N1 M0
IV M1
IRS/SIOP TNM Staging Criteria
T1a Confined to antatomic site of origin ≤ 5 cm
T1b > 5 cm
T2a extension to or fixed to adjacent tissue ≤ 5 cm
T2b adjacent tissue involvement > 5 cm
N1 Regional LN involvment
M1 Distant mets

The pre-op staging criteria for RMS

Stage Sites Invasiveness Size Nodes Mets
1 FAVORABLE:
  • Orbit
  • Head and Neck
  • Genitourinary
  • Bilary trac
T1 or T2 Any size Any N M0
2 UNFAVORABLE
  • GU: bladder or prostate
  • Parameningeal Head and Neck
  • Paratesticular (age & gt; 10)
  • Trunk
  • Retroperitoneal
  • Extremity
 T1 or T2 < 5 cm N0/Nx M0
3 UNFAVORABLE T1 or T2 < 5 cm N1 M0
UNFAVORABLE T1 or T2 > 5 cm N0 M0
4 All sites T1 or T2 Any size Any N M1

Note: Although tumor invasiveness is included, it does not appear to discriminate in the determination of pre-op stage grouping. IRS-IV, IRS_V and COG trials are using this staging system which incorporates these factors. Stage 1 tumors are in favorable sites, All other stages are unfavorable sites. Stage 2 tumors are small (<5 cm), and are N0, Stage 3 tumors are large or with N+ disease. Stage 4 is distant metastases. This staging system has been validated for outcomes.

There is also an IRS Grouping System which segregates patients into prognostic groups. This grouping system describes the post-surgical disease extent at the time. This group reflects absence of disease, microscopic disease, gross disease or metastatic disease.

Group Description Patient Percentage
I Localized Disease completely resected
  1. Confined to organ or muscle of origin (T1)
  2. Infiltration outside organ or muscle of origin (T2)
 13%
II Gross Total Resection
  1. Microscopic residual disease
  2. Positive Lymph nodes
  3. both
20%
III Subtotal Resection
  1. Biopsy only
  2. After major resection (> 50 residual disease)
48%
IV Metastatic Disease 18%

Most RMS patients present with Group III disease. Group III is essentially an R2 resection or biopsy only. Only 25% of Clinical Group III patients achieve a gross total resection.

The IRS has developed a 3 tier risk grouping as part of the IRS - IV risk group. These groups are segregated as follows:

Low Risk (OS5 90% - 95%) non-metastatic embryonal and
favorable site all groups or
unfavorable site groupts I/II (R0/R1 resection)
Intermediate Risk:
non-metastatic Group III (R2 resection), embryonal histology, any site. (OS5 70-85%)
non-metastatic unfavorable histology and any site. (OS5 5-60%
High Risk includes all metastatic disease: < 10 y.o. embryonal, (OS5 25%-35%)

The primary disease site determines outcomes. The data from IRS-II and IRS-III demonstrate disease site, in part, determines the maximum feasible extent of surgical resection which determines the IRS grouping. Completeness of surgical resection is also determined by the degree of invasiveness. Most orbital lesions are Group III (R2) at around 73.5% as are parameningeal lesions.

Most bladder and prostate lesions are also Group III. Non-bladder/non-prostate GU lesions and most extremity tumors are Group I (R0) or Group II (R1). or are metastatic at diagnosis (Group IV)

Primary site also determines the propensity for lymphatic spread. GU, abdominal, pelvic, and extremity disease commonly involves lymph nodes (≥ 20%). Tumors of the head and neck, trunk and female genitalia rarely involve nodes.

Prognostic Groups

Treatment

Current COG studies stratify into one of 3 risk groups described above. Treatments for RMS in the IRS studies varies based on these risk groups. The general treatment paradigm is: Maximum safe resection or biopsy alone → chemotherapy ± radiation with the timing of CRT based on the risk groups.

Prognostic factors include age with age > 10 being worse (EFS 14% than age younger than 10 (EFS 47%) Other factors portending higher risk include subarachnoid space involvemnt with skull base erosion in parameningeal head and neck disease, CN palsy and intracranial extension. DFS is reduced to 51% from 81% without risk factors.

Chemotherapy agents generally used are VAC (vincristine, actinomycin D and cytoxan. Isfosphamide is also used in some subsets of RMS.

International RMS Studies

The sentinel trial that supported the use of chemotherapy in RMS dates to the 1970's. Hen reported on a study comparing vincristine/actinomycin D with observation after surgery. This study demonstrated an advantage in post-operative use of chemotherapy.

IRS-I Study This study demonstrated that for

  1. Group I/Favorable histology, radiation therapy was not needed.
  2. Group II: Radiation therapy + Vincristine and Actinomycin D but no need for Cytoxan
  3. Group III-IV: RT + VAC x 2 years (no adriamycin needed. Distant metastastes failure more common than local failure
  4. No dose response for RT and no difference with large v. small field radiation therapy.
  5. Parameningeal RMS had increased CNS relapse if certain high risk features were present.

IRS-II This study determined that for:

Both of these studies demonstrated that the prostate was shown to have the highest risk of lymph node involvement at 40%.

IRS-III This study demonstrated that WBRT prophylaxis did not improve outcome or CNS relapse .

IRS III Special Pelvic Sites: IRS-III examined special pelvic sites (ie vagina, bladder dome, and uterus) and (bladder neck/trigone and prostate). Treatment and findings were:

IRS IV focused on improving outcomes for Group III (R2) by adding isfosfamide and etoposide with BID radiation at 1.1 Gy BID to 59.4 Gy.

Prophylactic WBRT was used in IRS I-III to 30 Gy with intrathecal chemotherapy. All started on Day 0. IRS-IV started on day zero but did not treat the whole brain, involved field only in high risk parameningeal sites. IRS-VI (present study) has omitted radiation on day zero in favor of delayed radiation in parameningeal high risk sites with base of skull invasion or CN palsy. Radiation therapy now starts in week 4 except for intracranial extension in intermediate risk and metastatic parameningeal disease.

Wolden Reviewed IRS I-III RT v. No RT in Group I patients (Woldon, 1999, JCO)This analysis showed only a trend to improved Failure Free Survival (FFS) and on overall survival with RT in favorable histology patients. However, in unfavorable histology patients radiation therapy improved FFS and overall survival.

IRS-VI is now underway. Low risk patients on the IRS-VI study are in two subsets:

the major study questions for IRS - VI for intermediate risk patients are type of chemotherapy: VAC vs. VAC alternating with vincristine/irinotecan and the timing of radiation therapy. Should radiation therapy begin at week 4 or week 10?

For high risk (metastatic disease) the IRS - VI study questions are does VAC alternating with IE in dose dense fashion improve local control and does using vincristine/irinotecan with Radiation Therapy improve local control?

Radiation therapy

Timing

IRS-V Radiation therapy timing in IRS V is different for each risk group:

Secondary questions for IRS - VI include radiation dose: Is 36 Gy adequate for N0, R1 and is 45 Gy adequate for orbital RMS? A retrospective review by Mandell in 1990 (JCO) failed to demonstrate a difference between < 40 Gy and > 40 Gy in 32 Group II (R1) patients in local control at MSKCC.

Remember: No RT for favorable histology Group I (R0)!

Nodes

Also remember: Radiation is NEVER omitted in Node Positive disease. Radiation doses in node + patients are 41.4 Gy in R0 (Group I) resections. If gross disease is present or suspect then the dose is carried to 50.4 Gy

All patients with initial nodal involvment, regardless of response to induction therapy or second look surgery must get radiation therapy to 41.4 Gy, if R0/R1 resection (Group I/II). If there is suspected gross disease then treat to 50.4 Gy.

General Techniques and Information -- "Guidelines"

Radiation therapy should be held for ANC< 750, platelets < 75 and for uncontrolled infection or Hb < 10. Radiation may be restarted after these have normalized. If the Hb or platelets are the problem, then chemotherapy should be held or modified until after radiation is completed.

Wolden (2005 IJROBP) reviewed IMRT in head and neck patients. A review of 28 patients with 21 parameningeal sites were treated with IMRT with a 1.5 cm margin, and a median dose of 50.4 Gy. Excellent local control at 95% was noted with IMRT despite reduced margins. Wolden noted comparable acute toxicity.

Delayed Treatment

IRS-V provided for dose modifications if treatment were to be delayed. These modifications are:

Para-aortic node techniques

Treat AP/PA to 36 Gy, then off cord to 50.4 Gy

Extremity Site Techniques

Extremity sites must consider these concerns:

"Special" Sites: Vagina, Cervix, Uterus

If a complete response after induction chemotherapy with a Group III N0 tumor in these sites no radiation therapy is required.

For embryonal (favorable risk histology) Group I Stages I-III no radiation therapy is indicated. For unfavorable histologies and Group I 36 Gy is given.

Orbit and parameningeal disease are not recommended for surgery and are treated with radiation and chemotherapy.

Lymph node dissection is indicated for GU ( paratesticular and bladder) sites, in which pelvic and para-aortic lymph node dissections are recommended, and in the extremities and trunk, where the axillary or inguinal/femoral nodes are dissected.

High Risk Disease (mets)

If a patient is high risk the question arises: should the primary be treated with radiation therapy. At Johns Hopkins, the preferred approach is to treat the primary disase and let the patient complete the chemotherapy course. Then metastases are treated with radiation. A recommendation is to consider treating the metastases if there is limited bone marrow in the treated field.

The entire PTV should be covered by the 95% isodose surface and no more than 10% of the PTV should receive > 110% of the prescription dose.

Dose standards for the COG include the following criteria:

Dose

St Jude (Regine IJROBP 1995) data suggests taht for 24 CG II patients a local control rate of 89% with < 40 Gy was not statistically different from > 40 Gy (100%). An additional study at MSKCC (Mandell 1990 JCO) noted for 32 patients treated with various doses also found that local control for doses < 40 Gy was equivalent to doses ≥ 40 Gy. This is used as a rationale for including a test dose of 36 Gy in the IRS-VI trial.

Specific Sites: Unfavorable

Bladder and Prostate RMS

Bladder and prostate RMS account for about 50% of all GU RMS. Bladder alone (when it can be identified as the source) indicates a more favorable prognosis. Frequently, bladder and prostate sources of origin cannot be identified. RMS of this site tends to occur in the very young (age < 5 years at diagnosis). Signs include: incontinence, retention, dysuria, polyuria. Regional lymph nodes involvement is common (20+%) at this site, particularly for prostate origin. Hypogastric or external iliac nodes are most commonly involved. Only 15% have distant mets at diagnosis.

Goals of Treatment

The treatment of prostate/bladder RMS is to use multimodality therapy with organ preservation (bladder) to cure. Radical surgeries are no longer used. Neoadjuvant chemotherapy ± radiation therapy is used if surgery cannot achieve a complete (Group I/R0) resection up front with bladder preservation.

IRS-I enrolled 64 patients with bladder/prostate disease and initially were managed with pelvic exent/anterior exenteration. Chemotherapy followed for most patients ± radiation therapy. This treatment led to high rates of local control and survival but led to an effort to reduce the morbidity of surgery. IRS-1 bladder preservation rate was 23% and most recurrences were local with pelvic exenteration used for salvage therapy. Lymph node dissection for node and adjuvant radiation therapy in node positive patients did provide a benefit.

IRS-2 attempted to substitute chemotherapy (more intense dosing) for surgery, but the bladder intact 3 year survival rates were the same as the initial IRS-1, despite a high initial rate of complete response due to higher rates of recurrence.

IRS 3 administered RT routinely to all patients at week 6 after induction chemotherapy initiation, execept in those patients where a complete resection was possible. This was an attempt to eliminate the local failure problem of the first two studies. This resulted in a 4 year bladder preservation rate of 60% and survival of 90% for patients presenting with local or regional disease. Heyn et al showed that 54% ultimately retain their bladders.

Paratesticular Sites

Paratesticular sites are less common GU sites than bladder/prostate GU sites accounting for about 1/3 of all GU RMS. Intrascrotal paratesticular disease arises from the distal area of the spermatic cord and may invade the testes or surrounding tissues. Presentation is usually a painless scrotal mass that does not transilluminate. Biopsy should be performed (inguinal so as not to violate the scrotum). Inguinal orchiectomy is preferred with high ligation of the spermatic cord at the level of the inguinal ring. If a trans-scrotal orchiectomy is performed, the patient is considered to be Group II. Resection of the violated scrotal area is then recommended and radiation or hemiscrotectomy is indicated. Paratesticular RMS has a high rate of spread to the lymph nodes, first to the para-aortic lymph nodes, following the spermatic cord into the renal hilar space. Nearly all are embryonal types (favorable histology).

Radiation doses are 50.4 Gy to the PALN if there is gross residual disease (R2/Group III) or 41.4 Gy if R1/Group II if there is pathologic confirmation of tumor response. All patients with node positive disease get radiation.

Outcomes

Most treatment failures are local. Local failures are greater than distant failures. Lymph node positivity is the most important predictor of local failure.

Per the IRS-IV, favorable prognostic indicators include ≤ 2 metastatic sites and embryonal histology. (Breneman 2003, JCO)

Toxicities of Treatment and Organ Dose Constraints

The dose constraint to the whole kidney is 19.8 Gy.

The dose constraint to the whole liver is 23.4 Gy.

The dose limit to the optic chiasm is 46.8 Gy.

The dose limit to the whole heart is 30.6 Gy.

The dose limit to the abdomen and pelvis is 24 Gy at 1.5 Gy/fraction.

These constraints are described in detail and are derived from the IRS-VI studies.

The major side effect of VAC chemotherapy is veno-occlusive disease of the liver.