Rhabdomyosarcoma of the head and neck in children

RHABDOMYOSARCOMA OF HEAD AND NECK IN CHILDREN

Corn bination T r e a t m e n t by Surgery, Irradiation, and Chernotlrcrapy

SARAH S. DONALDSON, MD,* JOSEPH R. CASTRO, MD,+ JORDAN R. W I L B U R , M D , ~

AND RICHARD H. JESSE, J R . , M D ~

Combined systematic therapy offers the best chance of cure for children with rhabdomyosarcoma originating in the head a n d neck. Recommended therapy includes: 1. local excision or biopsy; 2. radiation therapy with doses of 6,000 rads/6 weeks, a n d 3. multi-drug chemotherapy, i.e., vincristine sulfate, actinomycin D, and cyclophosphamide. Severe ocular, dental , soft tissue, a n d possibly bone complications may be encountered. Provision for p rompt medical a n d nursing support must be available for possible associated morbidity. Of 19 patients treated, minimum 2-year survival is 74%, and local control 89%. Late recurrences or complications require fur ther follow-up.

HABDOMYSARCOMA IS A DIAGNOSTIC AND R therapeutic problem in the management of pediatric tumors, representing the most common soft tissue sarcoma of childhood.12 Those tumors originating in the head and neck area may be considered separately from other rhabdomyosarcomas, as they create spe- cific problems and have a distinct prognosis. Children with rhabdomyosarcoma originating in the head and neck can be effectively treated

Presented at the First Joint Meeting of the James Ewine Societv. the Societv of Head and Neck SurEeons. and ;he Arneiican Radi;m Society, Boca Raton, Fla.; May 14-19, 1972.

From the Departments of Radiotherapy, Pediatrics, and Surgery, M.D. Anderson Hospital and Tumor In- stitute, Houston, Tex.

Supported by Grants CA-08122, CA-03713, and CA. 06294, from the National Cancer Institute, National In- stitutes of Health, United States Public Health Service, and the Russell G. Adderley Research Fund.

Fellow, Department of Radiology, Division of Ra- diation Therapy, Stanford University School of Medi- cine, Stanford, Calif.

+ Chief, Department of Radiotherapy, Mt. Zion Hos- pital and Medical Center, San Francisco, Calif.

t Head, Department of Pediatrics, M.D. Anderson Hospital and Tumor Institute, Houston, Tex.

gChief, Head and Neck Service, Department of Sur- gery, M.D. Anderson Hospital and Tumor Institute, Houston, Tex.

Address for reprints: Sarah S. Donaldson, MD, De. partment of Radiology, Division of Radiation Therapy, Stanford University School of Medicine, Stanford, Calif. 94305.

The authors wish to thank Edward Maxwell, MD, Head of Department of Radiology, St. Joseph’s Infir- mary, Louisville, Ky. for the use of the diagnostic radiograph (Fig. 7).

Received for publication September 11, 1972.

by combined surgery, radical radiation therapy, and aggressive chemotherapy.16J8 Our previous experience in the evolution of these treatment techniques has been reported.11 Our purpose here is to update these results in a group of patients treated with systematic combined therapy (surgery, irradiation, and chemotherapy) .

MATERIALS AND METHODS

Twenty-five children with a diagnosis of rhabdomyosarcoma, primary in the head and neck area, presented at the University of Texas, M.D. Anderson Hospital at Houston, between July 1965 and June 1970. Of these 25 pediatric patients (16 years and under), three had initial therapy at other institutions, two were found to have distant metastasis, and one was initially given single drug chemotherapy, rather than combination chemotherapy. T h e responses to combined therapy of the remaining 19 patients form the basis of this report. All were found free of widespread disease and treated with curative intent. A minimum follow-up period of 2 years is available on these patients which previously has been adequate for evaluation of treatment techniques since most primary recurrences and distant metastases occur within this time.ll

The age at diagnosis was 2 to 15 years, with an average age 8x2 years and a median of 7 years. The sex distribution revealed 8 males

26

No. 1 RHABDOMYOSARCOMA OF HEAD AND NECK IN CHILDREN Donaldson et al. 27

TABLE 1. Sites of Primarv Tumor

Nasophary nx

canal Nasal cavity Orbit Cheek (boccinator muscle and masseter

Maxillary antrum Retromolar trigone area Tonsilar area Scalp. Temporal muscle

nasopharynx and/or external auditory

muscle)

TOTAL

5

1 2 2

1 3 1 1 2 1

19

and 11 females. One patient was Negro, the other 18 were Caucasians.

The sites of the primary tumor are listed in Table 1. Eight of 19 tumors originated in the nasopharynx or nasal cavity. In only two cases in this series was the site of origin in the orbit; in six patients, the primary'site was in the cheek or adjacent area, i.e., tonsil, retromolar trigone, or maxillary antrum.

All patients had histologic confirmation of their tumor by the Department of Pathology, M.D. Anderson Hospital. Tumors were cate- gorized according to the Horn and Enterline classification.G Table 2 shows the histoclassi- fication; most patients had embryonal rhabdomyosarcoma.

CLINICAL STAGING

A proposed clinical staging is shown in Table 3, a modification of the American Joint Com- mittee for Cancer Staging, and the U.I.C.C. classification for head and neck tumors. Clini- cal work-up was individualized depending on the site of the primary lesion. Routine studies in all patients included: chest x-ray, complete blood count, platelet count, liver function tests, and bone marrow aspirate. Most patients had, in addition, skeletal survey, skull and sinus films. Selected patients had brain scan, liver scan, bone scan, EEG, lumbar puncture, radiographic tomograms, arteriograms, and lymphangiogram. The importance of complete work-up is reflected in the fact that while some patients had localized disease, 10 were staged as T,3 after extensive evaluation because of the tendency of rhabdomyosarcoma to invade diffusely in soft tissues or bone.

* V.A.C.-vincristine sulfate, actinomycin D, and cyclophosphamide.

TABLE 2. Histology

Embryonal 13 Botryoid 0 Alveolar 4 Unclassified 2 Pleomorphic 0

TOTAL 19

TREATMENT TECHNIQUES

Systematic combined therapy consisted of surgery, radiation therapy, and V.A.C." chemotherapy (Fig. 1).

Surgery A complete excision of the primary was pos-

sible in only 3 of 19 patients. All were staged as TI, although one patient had an orbital primary treated by exenteration; the other two patients had scalp primaries. In two additional cases, incomplete excision was performed initially, because of extensive soft tissue and periosteal invasion. Of the 14 remaining patients, the initial surgical approach was biopsy only.

Three patients had surgical procedures later in the course of their therapy. One patient required an orbital exenteration for radiation keratitis and iritis. An additional patient required an orbital exenteration and later a bi- frontal craniotomy for local control of invasive

TABLE 3.

N-0 N-1 N-2 N-3 Total - T- 1 4 1* - 5

T-2 - 1 1 2 T-3 10 1 1 - 12

14 3 1 1 19

-

Staging+ T- 1

T-2

T-3

N-0 N-1

N-2

N-3

Tumor localized to one region or site, i.e., orbit, scalp. Tumor extension to neighboring structures or two or more sites, i.e., cheek + tonsillar area, nasopharynx, soft palate. Radiographic evidence of bone destruction, or cranial nerve involvement. No clinical evidence of lymph node metastasis. Single clinically positive lymph node less than 3 cm in diameter. Single lymph node over 3 cm in diameter, or multiple ipsilateral palpable nodes. Fixed lymph nodes or bilateral palpable nodes.

* Presented to M.D. Anderson Hospital with lymph

+ Modification of American Joint Committee for node metastasis after excision of primary.

Cancer Staging, and the U.I.C.C. classification.

28 CANCER January 1973 Vol. 31

I

FIG. 1. Schedule for combination therapy: surgery, irradiation, and chemotherapy.

tumor. One patient had a maxillary antro- tomy after 2 years because of the radiographic suspicion of infection vs. tumor.

Radiation Therapy High-dose irradiation was given at tumor

doses of 5,000 rads/5 weeks to 6,500 rads/8 weeks to the primary tumor. Eleven patients were treated with cobalt60 teletherapy, five pa-

tients with electron beam, energies ranging from 6-18 MeV, and three patients with combination of both modalities.

Three patients with primary tumors were treated in planned split course fashion with 3,000-3,500 rads/3-4 weeks, a 2- to 4-week split in therapy followed by 2,000-3,000 rads/3 weeks. Treatment ports and isodose dis- tributions were individualized for each patient. In general, the portals included the primary tumor with wide margins, and the adjacent lymph node stations, ranging in size from 6 x 5 cm to 12 x 9 cm. Wedged fields were fre- quently utilized to localize the high dose area and protect normal structures. Additional shielding was used where possible for protec- tion, such as intra-oral stents to move the tongue out of the radiation field, etc. In select cases, modified weighting of 2: 1 was used for unilateral disease. Prophylatic neck irradiation was not administered in No cases. T h e high neck nodes generally were included in the primary treatment field, with low neck nodes included only if clinically positive nodes were present in the upper neck. When neck treatment was given, doses utilized were 4,000

FIG. 2 (left). Treatment portals in a patient with a T,N, nasopharynx primary. FIG. 3 (right). Radiographic localization films in same patient, T,N, nasopharynx primary.

No. 1 RHABDOMYOSARCOMA OF HEAD AND NECK IN CHILDREN Donaldson et al. 29

rads/4 weeks to 6,000 rads/6 weeks. Only 6 of the 19 patients required neck treatment.

An example of treatment portals and radiographic localization films in a patient with a T3N2 tumor of nasopharynx primary is shown in Figs. 2 and 3.

Radiographs and isodose distribution in a patient with a T,N,, tumor arising in the left maxillary antrum and extending to the floor of the orbit, zygoma, and mandible with bony erosion are shown in Figs. 4 and 5. Two 45" wedged fields were utiliLed to include a gener- ous target volume within 100% isodose curve,

Chemotherapy The same plan of chemotherapy was initi-

ated in each case but was modified individu- ally depending on the patient's tolerance. Early in the study, in some patients with small primary tumors, adequacy of drug therapy was considered at a slightly lower drug dose, if they had complete surgical removal and high- dose postoperative irradiation. The plan of chemotherapy was to achieve maximal drug response, within acceptable limits of toxicity.

Vincristine sulfate: A dose of 2 mg/mz I.V., weekly for 12 weeks (maximum dose 2 mg) was completed by 16 of 19 patients. One patient received only six injections and did not complete the course following hospital discharge, and one patient had only five injections. Selected patients had modified dosages depending on their tolerance. In no patient was vincristine therapy discontinued because of toxicity. One patient has had a supplemen- tal vincristine course consisting of 12 initial injections, followed by every 3 months rein- forcement of every week x 4, repeated for 5 cycles, due to inability to tolerate further actinomycin D.

Actinomycin D: A dose of .075 mg/kg I.V. (maximum 0.5 mg/day) given over 5- to %day period with courses repeated every 3 months x 5. Repeated courses were given depending on the patient's tolerance. Early in the study, in selected cases of Stage I disease, it was not felt necessary to give repeated courses of drug.

Cyclophospharnide: Chemotherapy includes long-term cyclophosphamide treatment given orally for 2 years at doses of 2.5 mg/kg daily. In the first patients with T, tumors treated in this group, cyclophosphamide was omitted it they were felt to be cured by initial treatment. More recently, all patients received cyclophosphamide.

Other agents: Three of 19 patients failed in-

FIG. 4. Localization radiograph in a patient with T,N, tumor of left maxillary antrum, extending to floor of orbit, zygoma, and mandible.

itial chemotherapy and were given trials with a variety of other agents which were unsuc- cessful.

lo I 4 C060 D fUsed 8 xBI 45" Wedge

80 crn SSD

Left

FIG. 5. Isodose distribution in same patient using two 45O wedged fields.

30 CANCER January 1973 Vol. 3 1

KWOl pot,cnrs 4 5 (19) Tunc ycoi-s

FIG. 6. Survival and status.

RESULTS

The results of therapy are depicted in Fig. 6 and Table 4. Of 19 patients studied, 14 (74y0) are living with no evidence of disease between 2 and 7 years, with an average of 2 years 11 months, and a median of 2 years 8 months. Five have died. One patient died of unex- plained renal failure while undergoing chemotherapy. Autopsy showed no local or metastatic disease. The other four patients died with disease. In one case, after the radiation therapy and hospital discharge, the patient failed to receive his planned chemotherapy for an extensive T,N, tumor of the nasopharynx. He died 11 months after diagnosis with clinical findings of recurrent local disease and no ob- vious distant metastases; however, no autopsy was performed. One patient developed a marginal local recurrence shortly after her primary radiation therapy for a T,N, maxillary antrum primary, ultimately succumbing at 2 years to distant metastasis.

Two patients had local control of tumor at the time they died of distant metastases, 1 and 2 years post-treatment. One patient developed pulmonary metastases while undergoing chemotherapy. The remaining patient who was treated early in this series had a clinically suspicious neck node initially, which was not irradiated. The significance of this node became clear as i t began to grow after completion of primary irradiation. Despite a radical neck dissection and further attempts at chemotherapy, the disease progressed and the patient died of widespread tumor involvement.

Thus, only 2 of 19 patients have had local failure with combined therapy, for a local control rate of 89% (minimum follow-up of 2 years). One additional patient had a marginal local failure after irradiaton salvaged locally by surgery and chemotherapy.

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COMPLICATIONS OF TREATMENT

Eye: Seven of the 19 patients had tumor involving the eye or orbit which necessitated therapy to the eye; two had primary orbital tumors, and five had orbital extension from another primary. One of the seven patients was treated by orbital exenteration primarily. Only one of the remaining six patients has required orbital enucleation for radiation keratitis, iritis, and conjunctivitis, 8 months after therapy. However, one patient has an asymp- tomatic radiation-induced cataract occurring 27 months after therapy, and one patient has mild superficial keratitis with early corneal stippling one year post-therapy. Two patients who had the eye included in the radiation field had no ocular difficulties, but one died 11 months after treatment with local control of tumor but widespread metastasis, and the second had a corneal shield utilized through- out the radiation therapy. The sixth patient required exenteration for residual orbital tumor after irradiation. Further ocular complications may be encountered as late anticipated sequelae.

Oral: Fifteen of the 19 patients had tumor involving the oral cavi ty-oropharynx, nasopharynx, or paranasal sinus regions -requiring that the primay irradiation field include a portion of the oral cavity. The addi- tive effect of actinomycin D and irradiation demonstrated the most severe morbidity in terms of mucositis, dysphagia, glossitis, phar- yngitis, esophagitis, gingivitis, and erythema. This reaction correlated with the size and pos- tion of the irradiation field. Mucositis was fre- quently severe and confluent, and, in some patients, necessitated nasogastric tube feeding for adequate nutrition as well as intravenous fluids for hydration. Two patients have developed post-irradiation trismus, a sequela of the large volume of tissue treated. X-rays of one patient show lytic defects suggestive of osteo- radionecrosis of the mandible after 20 months. To date, 2 of the 15 patients have had severe dental problems as a sequelae of irradiation to the teeth and gums. In both, there is dental decay, and, in one, there is also atrophy of the zygoma and an abnormal occlusion within the irradiated field. Xerostomia is an anticipated complication in this group of patients.

Infection: Localized infection has occurred on seven occasions in 5 of the 19 patients. There were three instances of ear infections, one which required simple mastoidectomy

after 2 years of recurrent infections. Cellulitis in the irradiated cheek and facial tissue has occurred in two cases-in one 18 months after irradiation and in one 3 months after irradiation, in association with administration of actinomycin D. T ~ L I S , reactivation of latent radiation effects in irradiated tissues which have returned to normal in appearance is referred to as the recall phenomena.

There have been two episodes of infection after enucleation. One patient developed a Pseudomonas infection in the graft after orbital exenteration; another developed cellulitis around the prosthetic retainer after enucleation.

Skin: T h e anticipated skin changes of irradiation have included erythema, desquama- tion, and tanning. These reactions have been exaggerated by the concomitant use of actinomycin D but have created no long-term effects, to date. Subsequent courses of actinomycin D intensified the erythema, oral ulceration, and mucositis, as recall phenomena.

Drugrelated: Vincristine therapy was associated with alopecia, neurotoxicity, and con- stipation. Peripheral neurotoxicity was often marked, but not severe enough to require cessa- tion of drug. A cyclophosphamide-related hemorrhagic cystitis was observed in 2 of 16 cases, and confirmed at cystoscopy in one patient.

Bone marrow suppression-leukopenia, thrombocytopenia, and anemia-was fre- quently observed related to both actinomycin D and cyclophosphamide. Adjustments in the schedule of cyclophosphamide were made if the total neutrophil count was less than 1,000 cells/mms.

DISCUSSION

There has been no widely accepted staging system for rhabdomyosarcoma, as has been observed for other childhood tumors such as Wilms’ tumor, neuroblastoma, or lymphomas. The proposed staging system (Table 3) dem- onstrates that: 1. rhabdomyosarcoma extending beyond a local region, i.e., beyond TI, is often shown by careful evaluation to be associated with bone destruction or cranial nerve involvement (TR) in 12/14 (86y0) of patients, and 2. the presence of lymph node metastases does not correlate directly with size or extent of primary tumor. Only 5/19 (Zf3yo) patients have clinically apparent nodal disease, which includes only 2/12 (18%) patients with T, neoplasms.

No. 1 RHAUDOMYOSARCOMA OF HEAD A N D NECK I N CHILDREN * Donnldson et al. 33

In other large series including head and neck primaries, the orbit is a frequent primary site and associated with a good prognosis.19-22 Probably this is related to the paucity of lymphatics in the orbit and i t s bony confines, which makes wide invasion of tumor less likely and earlier diagnosis more probable. In coti- trast to the good prognosis of orbital lesions, tumors located in the nasal cavity-nasopliar- ynx and maxillary antrum have previously had a poor prognosis11 presumably because of abundant lymphatics, ease of extension to neighboring structures, and lack of anatomical confines to tlie tumor. Seventy-four per cent of tlie patients in the present series had such lesions: 8/19 (429/0) tumors arose in the nasal cavity-nasopharynx, and 6/19 (32Yu) in the cheek or neighboring area. Yet this group, with a previously poor outlook, had a local control rate of 14/16 (86Yu) with a follow-up period ranging frotn 11-63 months.

Nonembryonal forms of rhabdomyosarcoma, i.e., alveolar or pleomorphic forms; have also been associated with a poor prognosis.”zz T o date, no difference in prog nosis has been noted in our patients with the nonembryonal form of rhabdomyosarcoma.

Early and aggressive therapy is essential in obtaining a cure. Only 1 of the 3 patients with less aggressive treatment elsewhere, referred to tlie M.D. Anderson Hospital after local failure, was salvaged. T w o patients who presented with metastatic disease are dead from disease, local and distant. One patient treated with single agent chemotherapy only, in addition to irradiation, died of widespread metastatic disease, with local control.

A radical surgical approach with exenteration is still recommended by somes.9 as the treatment of choice for obital primaries. How- ever, the sites of origin in head and neck primaries often preclude curative excision, or require a severely mutilating or unacceptably deforming 0pera t ion .4~7~~~ The present series denionstrates that biopsy alone, followed by aggressive irradiation and chemotherapy has been beneficial in treating these primaries. Such an approach offers the child maximum therapy to a wide field and, in a high percent- age of patients, prevents the need for further s u rg i c a 1 procedures .

Rhabdomyosarcoma has been shown to be radiosensitivelOJ5 and radiocurable in select cases.l.19 However, local failure with irradiation alone has led to suggestions for such combinations as preoperative irradiation fol-

lowed by radical excision,13 or irradiation with attempt to potentiation by c l i e m ~ t l i e r a p y . ~ J ~ ~ ~ Our own experience has led us to attempt a systematic, aggressive combination approach to treatment.?l

Altliougli i t has been suggested that bone involvement by tumor is beyond tlie control of irradiation alone,l7 we have seen instances where pretreatment bone destruction healed under the effect of irradiation and cliemotlier- apy. Figures 7 arid 8 exemplify a case of tlocu- merited bony destruction of the mandible and mastoid extending to tlie floor of the orbit from a primary rliabdomyosarcoma of tlie left maxillary antrum. One year following radiation therapy, 6,000 rads/6 weeks and V.A.C. chemotherapy, follow-up x-rays show absence of soft tissue mass and reconstitution of bone.

Adequate radiation therapy requires wide fields and large volumes of tissue to be irradiated. Clinically suspicious lymph node involvement should be surgically confirmed or included in the radiation field. One must be willing to accept sequelae of irradiation, i.e., expected eye complications, arrest in bone growth, and oral problems, if approaching a patient with curative intent. The reactions from irradiation are severe, particularly with addition of actinomycin D.2.23 Split course therapy may be useful in allowing time for subsidence of tissue reactions and possibly re- ducing the volume of tissue to be irradiated in the second course of treatment. Intense local therapy and support including meticulous oral hygiene and nutritional support is required to decrease local reactions. Prompt intensive antibiotic therapy at the first sign of infection is also vital.

Two failures in the T3 group were secondary to inadequate coverage of tlie primary tumor by the initial radiation portals with rapid marginal recurrence and eventual dis- seminated disease. Caution must be taken to ensure wide coverage since rhabdomyosarcoma locally invades widely. In one patient with extensive cranial nerve involvement, i t was necessary to use large fields encompassing the base of the skull.

A review of the literature reveals that the overall survival of rhabdomyosarcoma of head and neck has ranged between 10-3070 in large series. More recently, the use of adjuvant chemotherapy in addition to irradiation and surgery has been suggested as a possible approach to improving survival statistics.20s22 The present series shows an overall survival


FIG. 7. (left). Pretreatment, May 3 , 1969. X-ray documenting bony destruction of mandible and

FIG. 8 (right). One year, August 21, 1970, post-irradiation therapy and V.A.C. chemotherapy, mastoid extending to floor of the orbit from left maxillary antrum primary.

showing absence of soft tissue mass and reconstitution of bone.

of 74% from 2-6 years. Of five patients with TI lesions, all ( l O O ~ o ) show no evidence of disease from 25 to 72 months. Two patients with T, neoplasms show no evidence of disease (100%) at 32 and 33 months. Of the 12 patients with T, neoplasms, 7/12 (5875) are free of disease, from 24 to 57 months.

I t will require longer follow-up to cleter- mine if the occiirrence of distant meta5tases is actually lowered or just delayed by chemotherapy. The question of treating very small TI primaries with less aggressive chemotherapy as

well as irradiation is also unanswered as yet. In the piesetit series there was no mortality secondary to therapy; however, the associated morbidity makes intensive meclical and nursing care essential. In the tnajority of cases, patients required IiospitaliLation during some portion of their therapy, and many were hos- pitalized for long periods of treatment. Suc- cessful therapy demands attentive nursing care, and prompt medical support with trans- fusions, antibiotics, adequate nutrition, and hydration.

REFERENCES

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Rhabdomyosarcoma of the head and neck in children

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