Late Effects of Pelvic Rhabdomyosarcoma and Its Treatment in Female Survivors
http://www.100md.com
《临床肿瘤学》
the Departments of Hematology-Oncology, Biostatistics, and Radiological Sciences (Radiation Oncology Division), St Jude Children's Research Hospital
the Department of Pediatrics, The University of Tennessee College of Medicine, Memphis, TN
ABSTRACT
PURPOSE: To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma.
PATIENTS AND METHODS: We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
RESULTS: The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041).
CONCLUSION: The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.
INTRODUCTION
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, accounting for approximately 3% of malignancies in patients younger than age 20 years.1 During the last several decades, improved treatment has increased the likelihood of long-term disease-free survival from 51% in the first Intergroup Rhabdomyosarcoma Study (1972 to 1978)2 to 70% in the fourth Intergroup Rhabdomyosarcoma Study (1992 to 1997).3,4
Various studies have addressed late effects in survivors of head and neck,5-11 paratesticular,12,13 and bladder/prostate RMS.14,15 The occurrence of secondary cancers after treatment of childhood RMS has also been analyzed.16,17 The genitourinary tract is the second most common primary site of RMS. Although the survival of patients with genitourinary primary tumors has improved in concert with that of other patients,18,19 little is known about the late effects of RMS and its treatment in this group of long-term survivors. To characterize the long-term outcomes of female survivors of pelvic RMS, we reviewed the records of female patients treated for pelvic RMS at our institution who survived free of disease for 5 or more years.
PATIENTS AND METHODS
Patients
Between March 1962 and December 1996, 45 female patients younger than age 21 years were treated at St Jude Children's Research Hospital (Memphis, TN) for RMS of the pelvic region. Of these, 26 were free of disease at 5 years after the initial diagnosis and are the subject of this report. The pelvic region was defined as including the pelvic portions of the genitourinary tract (uterus, cervix, vagina, and bladder) and retroperitoneum, as well as the perineum, perirectal region, and buttock. Although the buttock is considered an extremity site in the Intergroup Rhabdomyosarcoma Study Group staging guidelines, we included patients with buttock tumors in this study because we expected their late effects related to surgery and radiotherapy (RT) to be more like those of patients with pelvic tumors than like those of patients with extremity tumors.
Data Collection
Demographic data abstracted from the patients' records included race, age at the time of diagnosis of RMS, and duration of follow-up. Tumor characteristics that were recorded were the primary site, size, histologic subtype, regional lymph node status (positive or negative), and distant disease extent (metastatic or nonmetastatic). The Intergroup Rhabdomyosarcoma Study Group guidelines were used to establish each patient's disease stage and clinical group. Tanner stage and menarchal status (pre- or postmenarchal) at initial presentation were obtained from the patient records, as were details of initial therapy and treatment of recurrent disease. All surgical interventions, chemotherapy regimens, and RT (including dose and field) were recorded.
Late adverse effects were defined as abnormalities or adverse events that occurred or persisted 5 or more years after the initial diagnosis and that could be related to the disease or its treatment. Events that occurred after systemic therapy for a secondary malignancy were excluded. Late effects were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Surgical absence of the uterus, both ovaries, or the urinary bladder was coded as a grade 3/4 late effect. Abnormalities or events that could not be categorized adequately or graded using the CTCAE system are described in narrative fashion. Reported secondary malignancies were confirmed by obtaining the operative note and pathology report for the procedure that established the diagnosis. Because the patients in this study were treated over an extended period of time during which there were many changes in treatment, we also compared the incidence of late effects in two treatment eras (diagnosis of RMS before v after 1984).
Statistical Methods
The total number of late effects (grade 1/2 and/or grade 3/4) for each patient was calculated. The median number of late effects was then determined using standard methods. The exact Wilcoxon rank sum test was used to compare the numbers of late effects according to treatment era and administration of RT. The association between age at diagnosis of RMS and the number of late effects was investigated using a Spearman correlation coefficient. The cumulative incidence of secondary cancer was estimated using the methods of Kalbfleisch and Prentice.20 Competing events included recurrent or progressive disease before second cancer or death before second cancer.
RESULTS
Patients
Of the 26 patients studied, 23 were alive at the time of this analysis on July 1, 2004. Twenty of the 23 survivors had been seen or contacted within the previous 2 years. The presenting features of the patient cohort are listed in Table 1. The median age at the time of diagnosis of RMS was 3.4 years (range, 0.2 to 17.2 years), and only six patients had undergone menarche. The most common primary tumor sites were vagina (n = 7), retroperitoneum/pelvis (n = 6), and bladder (n = 4). The histologic subtype of RMS was favorable (embryonal or botryoid) in 22 patients (85%). A majority of the tumors (62%) were more than 5 cm in maximal diameter. Five patients had regional lymph node involvement, and three patients had distant metastatic disease.
Treatment of RMS (Table 2) depended on the extent of disease and year of diagnosis. All patients received chemotherapy that included vincristine and dactinomycin, with or without other agents. Most (88%) received an alkylating agent, and almost two thirds (62%) received doxorubicin (median cumulative dose, 242 mg/m2; range, 161 to 351 mg/m2). One patient underwent autologous peripheral-blood stem-cell transplantation after receiving a cyclophosphamide/topotecan preparative regimen. Twenty-three of the 26 patients underwent some type of tumor resection, either at the time of initial presentation or during treatment. The surgical procedure included a hysterectomy in 10 patients, complete or partial vaginectomy in nine patients, complete cystectomy in three patients, partial cystectomy in one patient, bilateral oophorectomy in one patient, and unilateral oophorectomy in three patients.
RT was administered to the primary site in 22 of the 26 patients. Five of these patients also received additional RT to regional lymph nodes (n = 3), whole pelvis (n = 2), whole abdomen (n = 1), whole lungs (n = 1), and T10 through S1 paraspinal tumor mass (n = 1). Nineteen patients received external-beam RT to the primary tumor (median cumulative dose, 42 Gy; range, 16 to 60.5 Gy); one of these patients who had received a dose of 48 Gy also received a radium vaginal implant with a dose of 84 Gy at the vagina. The remaining three patients received 50 Gy of brachytherapy alone. Two patients experienced tumor recurrence (one local, one distant); their treatment is included in the therapy summary provided earlier.
At the time of this analysis, the median age of the 23 surviving patients was 25.3 years (range, 10.8 to 51.1 years) and median follow-up was 20.3 years (range, 7.2 to 39.6 years) from the date of RMS diagnosis.
Summary of Late Effects
We identified a total of 235 late effects, of which 98 (42%) were grade 3/4 and 137 (58%) were grade 1/2. Only two patients, neither of whom had received RT, were free of late effects. Twenty-three of the 24 affected patients had grade 3/4 late effects; the remaining patient, who had not received RT, had only grade 1/2 late effects. The median number of grade 3/4 late effects per patient was three (range, zero to 14) and the median number of grade 1/2 late effects per patient was 4.5 (range, zero to 14). Fourteen patients (54%) required surgical treatment of late complications (Table 3). The most common surgical procedures were vaginal dilation/reconstruction to correct stenosis (n = 7), procedures to relieve ureteral obstruction (n = 6), intestinal stricture dilation or repair (n = 5), and fistula repair (n = 4).
There was a median of 9.5 (range, two to 28) late effects per patient among the 22 patients who had received RT. This number was significantly lower in the four patients who had not received RT (median, one; range, zero to 5; P = .002). Grade 3/4 late effects were significantly more common in patients who had received RT (median three v zero; P = .002), as were grade 1/2 late effects (median 5.5 v one; P = .011).
Late Effects by Organ System
The endocrine system was most frequently affected (Table 3). Twenty of the 26 patients experienced endocrine late effects, and 15 had grade 3/4 late effects. Eleven of 23 patients who had not undergone bilateral oophorectomies experienced failure of ovarian hormone production; all had received pelvic RT. Eight patients had short stature; two of these had central growth hormone deficiency and two had central hypothyroidism documented by provocative testing (one patient had both growth hormone deficiency and central hypothyroidism). Two additional patients with short stature had low levels of insulin growth factor 1 but did not undergo provocative testing to confirm hypothalamic-pituitary dysfunction. Three patients with short stature who did not undergo provocative thyroid testing received thyroid hormone replacement therapy because of clinical evidence of hypothyroidism; these patients had normal thyroid function studies (n = 1), a low-normal free T4 level (n = 1), or autoimmune hypothyroidism demonstrated by serologic testing (n = 1).
Forty-one GI late effects were identified in 18 patients, eight of whom had grade 3/4 late effects. Intestinal complications (strictures, obstruction, perforation, and chronic enteritis) were the most common grade 3/4 late effects, whereas others affected the stomach (gastritis), liver (hepatitis C, cholecystitis), and anus (incontinence). The most common grade 1/2 late effects were chronic constipation and dental caries.
Gynecologic late effects were noted in 15 patients, all of whom had grade 3/4 late effects. Ten patients had undergone total hysterectomy during treatment for RMS (one had also undergone bilateral salpingo-oophorectomy). An additional two patients underwent total hysterectomy and bilateral salpingo-oophorectomy for treatment of cervical carcinoma-in-situ (n = 1) and during anterior pelvic exenteration for treatment of rectovaginal/vesicovaginal fistulas (n = 1). Four patients experienced fistulas involving the vagina (n = 4) and/or uterus (n = 1). Multiple sites were involved in three of the four patients, including the bladder, urethra, GI tract, and peritoneal cavity. All four patients with fistulas had received RT. In two of the four patients, the fistulas developed spontaneously; in the other two patients, the fistulas developed after a surgical procedure to address vaginal stenosis. Vaginal dilation was performed to correct vaginal stenosis in four patients. Three patients underwent vaginal reconstructive procedures, all of which were associated with significant complications (rectal perforation and persistent vaginal stenosis requiring dilation, postoperative cellulitis and residual pelvic floor disorder, and rectovaginal fistula requiring permanent colostomy). Twenty of the patients in this study were incapable of bearing children because of surgical removal of the uterus (n = 12) and/or ovarian hormonal failure (n = 11). One of the remaining six patients had given birth to a child. She was one of the four who had not received RT.
Fourteen patients experienced a total of 58 renal late effects. Ten patients had grade 3/4 late effects, most commonly acute pyelonephritis, ureteral obstruction, cystectomy requiring ileal conduit, neurogenic bladder, and urethral stenosis requiring surgical intervention.
Eighteen patients experienced musculoskeletal late effects, 84% of which were grade 1/2. Five patients had grade 3/4 late effects. Musculoskeletal hypoplasia, deep connective tissue fibrosis, and scoliosis were the most common musculoskeletal late effects.
Ten patients had psychological late effects. Three patients had grade 3/4 depression and/or anxiety; the remaining seven had grade 1/2 depression, anxiety, or insomnia. Eight patients reported academic difficulties, and four of these failed to complete high school. One patient abused alcohol, and a second experienced long-term narcotic dependence.
Neurologic late effects were noted in two patients. The only grade 3/4 late effect was a cerebrovascular accident that caused paresthesias 11 years after the diagnosis of RMS. Imaging revealed a small lacunar infarct in the left temporal region and encephalomalacia in the right centrum semiovale.
Two cardiovascular late effects were identified, both of which were grade 3/4. One patient with pre-existing tricuspid regurgitation developed doxorubicin-induced (cumulative dose, 340 mg/m2) cardiomyopathy that necessitated cardiac transplantation. She ultimately died as a result of cardiac complications. Another patient experienced a hypertensive crisis of uncertain cause that required long-term antihypertensive management.
Secondary Cancers
Three patients had confirmed secondary cancers. The cumulative incidence was 13.5% ± 7.4% at 20 years. An additional patient who had received whole-pelvis RT for treatment of RMS of the bladder was reported to have developed cervical carcinoma, but the details were not available. One patient developed metastatic osteosarcoma of the right iliac crest 10.2 years after the diagnosis of retroperitoneal RMS. This tumor arose within the RT field and ultimately proved fatal. A second patient developed multifocal squamous cell carcinoma-in-situ of the cervix 10.2 years after treatment (including RT) for retroperitoneal RMS. Review of the RT port films suggested that this tumor arose within the radiation field. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for treatment of the secondary malignancy and was alive and disease-free at the time of this report, 17.6 years after the second diagnosis. The third patient had received RT for RMS of the bladder and developed adenocarcinoma in situ of the colon within the RT field, 9.2 years after the diagnosis of RMS. She had undergone endoscopic removal of adenomatous polyps of the sigmoid colon and rectum 10 months previously. Approximately 6 months after the diagnosis of adenocarcinoma in situ, the patient underwent left hemicolectomy. Pathologic examination revealed moderately differentiated Duke's stage B adenocarcinoma, apparently also arising within the RT field, and no adjuvant therapy was administered. Six months later, the patient died as a result of complications of a heart transplant necessitated by doxorubicin-induced cardiomyopathy. Review of her family history suggested the possibility of Li-Fraumeni syndrome.21 Her father had died of a malignant brain tumor at 28 years of age and several other family members on the paternal side were noted to have had cancer, though the specific tumor types were not noted. The family histories of the other two patients with second malignant neoplasms did not suggest the presence of Li-Fraumeni syndrome or another familial cancer syndrome.
Late Effects by Age at Diagnosis
Because young children are known to be at higher risk than older children and adults for certain late effects, we evaluated the association between age at diagnosis of RMS and the incidence of late effects. Among all 26 patients, there was no evidence of an association between the age at diagnosis of RMS and the number of late effects (P = .74 for grade 3/4 late effects; P = .94 for grade 1/2 late effects; P = .78 for all late effects). The 11 patients younger than 3 years of age experienced no more grade 3/4 late effects (median, three per patient; range, zero to nine) than the 15 patients older than 3 years of age (median, two per patient; range, zero to 14; P = .65). In the subset of patients who received RT (n = 22), the median number of grade 3/4 late effects per patient was five (range, one to nine) for the nine patients younger than 3 years of age compared with a median of three (range, one to 14) for the 13 patients older than 3 years of age (P = .31).
Late Effects by Treatment Era
We investigated the association between treatment era and the incidence of late effects to evaluate whether improvement of therapy over time significantly affected the likelihood of long-term sequelae. Recognizing that therapy improved continuously during the decades encompassed by this study, we somewhat arbitrarily selected 1984 as the cut point for this analysis because approximately half of the patients were diagnosed before and half were diagnosed after this date. The 12 patients whose RMS was diagnosed in 1984 or later had a higher median number of late effects than the 14 patients diagnosed earlier (12.5 v 6.5; P = .041). However, only grade 1/2 late effects were increased in the later treatment era (median seven v three; P = .063). The incidence of grade 3/4 late effects did not differ substantially by treatment era (median three v 2.5; P = .39).
DISCUSSION
Our review suggests that virtually all female long-term survivors of pelvic RMS experience significant, and in many cases debilitating, late sequelae of the disease and its treatment. Most survivors (88%) had at least one grade 3/4 late effect documented more than 5 years after the initial diagnosis. Furthermore, most patients had multiple grade 3/4 (median, three) and grade 1/2 (median 4.5) late effects. More than half of the patients required surgical intervention for the long-term sequelae of treatment. Although not all late effects were related to RT, RT was strongly associated with late effects: the median number of late effects was 9.5 per patient who received RT and only one per patient who did not receive RT (P = .002). The burden of late effects in this pediatric population seems to be significantly greater than that seen in adults treated with similar RT doses. A recent analysis of adjuvant RT for endometrial carcinoma in adults showed that 51% of patients experienced late effects, and only 11% of patients had severe late effects.22
Endocrine late effects were evident in 77% of our study group, and three fourths of the affected patients had grade 3/4 late effects. Forty-eight percent of the patients with at least one remaining ovary, all of whom had received pelvic RT, experienced ovarian hormonal failure. This figure likely underestimates the true incidence, because some patients were prepubertal at the time of the analysis, and menstrual function was not well documented for several patients treated during the early era. Nearly one third of the patients in this series had short stature. The cause of this finding is unclear, although three patients had documented central growth hormone and/or thyroid hormone deficiency. These complications are usually seen after irradiation of the hypothalamic-pituitary axis, which none of our patients underwent. However, both central growth hormone deficiency and hypothyroidism have been reported after chemotherapy alone.23,24 Nutritional impairment because of chronic radiation enteritis also may have contributed to short stature in this patient group. Previous studies have shown that nutritional deficiencies may influence the growth hormone–insulin-like growth factor axis.25 However, the lack of routine nutritional screening in this cohort precluded assessment of the contribution of nutritional deficiency to the observed growth impairment.
The GI late effects we noted were varied and significant. Most grade 3/4 GI late effects were intestinal complications, which included strictures, obstructions, perforations, and chronic enteritis. Other late effects included gastritis, chronic hepatitis C, cholecystitis, and bowel incontinence. Four patients had fistulas. These involved both the GI and genitourinary tracts and occurred after surgical procedures in half of the patients. All of the patients with documented fistulas had received pelvic RT. Previous studies suggest that fistulas are a common consequence of RT for pelvic tumors.26-28 As our institution has previously reported, hepatitis C infection is documented in approximately 7% of patients treated for childhood cancer who received blood product transfusions before 1992.29
Gynecologic sequelae were common and, in many cases, severe. Most notably, about three fourths of the survivors were incapable of bearing children because of surgical removal of the uterus and/or because of ovarian hormonal failure. Of the remaining patients, only one gave birth. Sexual dysfunction also seemed to be a significant problem in this population. Although many of the patients were not yet sexually active and sexual activity was often not documented, there was considerable evidence of disturbed sexual function. One fourth of the patients had undergone vaginal dilation or reconstruction procedures. Vaginal reconstruction resulted in severe complications in all patients, including the formation of fistulas. Other reported gynecologic late effects included chronic pelvic pain, pelvic floor disorder, and vaginal dryness. To our knowledge, no studies have evaluated sexual function after treatment for childhood cancer. However, studies in adults treated for gynecologic tumors suggest that treatment-induced anatomic and physiologic abnormalities may significantly impair quality of life, sexual function, and sexual satisfaction.30-32
More than half of the patients in this study experienced urinary tract late effects. The frequency of kidney and bladder late effects was similar. Grade 1/2 late effects predominated; however, it is important to note that these low-grade late effects had a significant impact on the survivors' quality of life. Eight patients had urinary incontinence, and three reported persistent symptoms of urinary frequency and urgency. Long-term infectious complications occurred frequently; nine patients experienced recurrent urinary tract infections, and six of these had acute pyelonephritis.
Second cancers were also a significant problem, occurring in 11% of our patients. At the time of our review, the details of reported cervical carcinoma in an additional patient had not been confirmed. All of the documented second malignancies developed within the RT field used to treat the RMS. Previous studies of survivors of RMS have documented a 1.7% to 3.4% cumulative incidence of secondary malignancy at 10 to 20 years of follow-up.16,17 The higher rate of secondary cancer in our population may reflect the longer follow-up in our study (20 years), compared with that in previous studies (8 to 9 years). The nearly universal use of RT in our patient population may also have contributed to this result. However, it is also possible that the rate of second cancers in our study is artificially elevated by chance because of the small number of patients in the study population.
We found that 10 patients (approximately 38%) experienced some type of psychological late effect, including depression, anxiety, or insomnia. We believe that our study greatly underestimates the psychosocial late effects experienced by these patients because such sequelae were not formally assessed as part of their follow-up. Because the CTCAE grading system does not include a specific category for school difficulties or academic underachievement, it was not possible for us to grade these findings and include them in our analysis. However, we noted that several patients had experienced academic difficulty or failed to complete high school. Several studies suggest that long-term survivors of childhood cancer report adverse effects on mental health, including depression, somatization, anxiety, and post-traumatic stress disorder.33,34 Both school underachievement and psychological disorders can significantly alter quality of life. More studies are needed to address the quality of life of this patient population.
Interestingly, we found no evidence that the incidence of late effects had declined in the recent treatment era. Patients treated during the last two decades had a slightly higher median incidence of late effects than those treated previously (P = .041). It is possible that late effects were documented more carefully in the later era than in the earlier era. This hypothesis is supported by the observation that the incidence of grade 3/4 late effects, which generally are well documented in the medical record, was similar in the two treatment eras, whereas a greater incidence of the more subtle grade 1/2 late effects was noted in the later era. Our results suggest, however, that efforts to minimize the late effects of therapy have had little impact on the long-term complications of treatment.
We also found that younger children did not experience more late effects than older children, nor did they experience more grade 3/4 late effects. Although somewhat unexpected, this finding may simply reflect the small study population. However, it is also possible that many of the late effects observed in this study are independent of age at the time of treatment and only a few are age-dependent. Additional studies are needed to clarify the impact of age at the time of treatment on long-term outcomes.
Our study has several limitations that should be considered in the interpretation of our findings. The study cohort is small, but their outcomes are likely to be representative of the broader population of survivors who have received intensive multimodal therapy during childhood. We obtained data through retrospective review of medical records and, therefore, were limited by the clinician's expertise in identifying late effects and documenting these findings in the medical record. The recent publication of risk-based late effects screening guidelines for survivors of childhood cancer may ameliorate the identification of late effects in these patients.35 Undoubtedly, prospective evaluation based on therapeutic exposure would provide a more accurate assessment of long-term treatment morbidity. Finally, the pediatric setting did not facilitate the evaluation of some toxic effects (eg, sexual dysfunction) that are more routinely addressed in adult health care settings.
Although it is well known that female survivors of pelvic RMS are at risk for a number of long-term sequelae, our study shows that late effects in this population are both common and severe. Our findings also suggest that even many years after pelvic RT for childhood RMS, surgery is associated with a considerable risk of serious and potentially long-term complications. Thus, pelvic late effects after RT should be managed conservatively whenever possible, with surgery reserved for complications mandating its use.
The significant burden of late effects in this patient population is certain to reduce the quality of life and the functional capacity of these patients, and illuminates the need for long-term medical and psychosocial follow-up. More interventions are needed to address altered quality of life and to assist these women in coping with the long-term sequelae of their treatment. Prospective studies that evaluate the complex relationship between specific treatment exposures and the resulting late effects are needed to help guide future treatment approaches for childhood RMS. Future therapeutic studies for children with RMS must focus not only on the quantity, but also on the quality of survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Sharon Naron, ELS, for editorial assistance.
NOTES
Supported by Grants No. CA 23099 and P30 CA 21765 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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the Department of Pediatrics, The University of Tennessee College of Medicine, Memphis, TN
ABSTRACT
PURPOSE: To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma.
PATIENTS AND METHODS: We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
RESULTS: The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041).
CONCLUSION: The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.
INTRODUCTION
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, accounting for approximately 3% of malignancies in patients younger than age 20 years.1 During the last several decades, improved treatment has increased the likelihood of long-term disease-free survival from 51% in the first Intergroup Rhabdomyosarcoma Study (1972 to 1978)2 to 70% in the fourth Intergroup Rhabdomyosarcoma Study (1992 to 1997).3,4
Various studies have addressed late effects in survivors of head and neck,5-11 paratesticular,12,13 and bladder/prostate RMS.14,15 The occurrence of secondary cancers after treatment of childhood RMS has also been analyzed.16,17 The genitourinary tract is the second most common primary site of RMS. Although the survival of patients with genitourinary primary tumors has improved in concert with that of other patients,18,19 little is known about the late effects of RMS and its treatment in this group of long-term survivors. To characterize the long-term outcomes of female survivors of pelvic RMS, we reviewed the records of female patients treated for pelvic RMS at our institution who survived free of disease for 5 or more years.
PATIENTS AND METHODS
Patients
Between March 1962 and December 1996, 45 female patients younger than age 21 years were treated at St Jude Children's Research Hospital (Memphis, TN) for RMS of the pelvic region. Of these, 26 were free of disease at 5 years after the initial diagnosis and are the subject of this report. The pelvic region was defined as including the pelvic portions of the genitourinary tract (uterus, cervix, vagina, and bladder) and retroperitoneum, as well as the perineum, perirectal region, and buttock. Although the buttock is considered an extremity site in the Intergroup Rhabdomyosarcoma Study Group staging guidelines, we included patients with buttock tumors in this study because we expected their late effects related to surgery and radiotherapy (RT) to be more like those of patients with pelvic tumors than like those of patients with extremity tumors.
Data Collection
Demographic data abstracted from the patients' records included race, age at the time of diagnosis of RMS, and duration of follow-up. Tumor characteristics that were recorded were the primary site, size, histologic subtype, regional lymph node status (positive or negative), and distant disease extent (metastatic or nonmetastatic). The Intergroup Rhabdomyosarcoma Study Group guidelines were used to establish each patient's disease stage and clinical group. Tanner stage and menarchal status (pre- or postmenarchal) at initial presentation were obtained from the patient records, as were details of initial therapy and treatment of recurrent disease. All surgical interventions, chemotherapy regimens, and RT (including dose and field) were recorded.
Late adverse effects were defined as abnormalities or adverse events that occurred or persisted 5 or more years after the initial diagnosis and that could be related to the disease or its treatment. Events that occurred after systemic therapy for a secondary malignancy were excluded. Late effects were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Surgical absence of the uterus, both ovaries, or the urinary bladder was coded as a grade 3/4 late effect. Abnormalities or events that could not be categorized adequately or graded using the CTCAE system are described in narrative fashion. Reported secondary malignancies were confirmed by obtaining the operative note and pathology report for the procedure that established the diagnosis. Because the patients in this study were treated over an extended period of time during which there were many changes in treatment, we also compared the incidence of late effects in two treatment eras (diagnosis of RMS before v after 1984).
Statistical Methods
The total number of late effects (grade 1/2 and/or grade 3/4) for each patient was calculated. The median number of late effects was then determined using standard methods. The exact Wilcoxon rank sum test was used to compare the numbers of late effects according to treatment era and administration of RT. The association between age at diagnosis of RMS and the number of late effects was investigated using a Spearman correlation coefficient. The cumulative incidence of secondary cancer was estimated using the methods of Kalbfleisch and Prentice.20 Competing events included recurrent or progressive disease before second cancer or death before second cancer.
RESULTS
Patients
Of the 26 patients studied, 23 were alive at the time of this analysis on July 1, 2004. Twenty of the 23 survivors had been seen or contacted within the previous 2 years. The presenting features of the patient cohort are listed in Table 1. The median age at the time of diagnosis of RMS was 3.4 years (range, 0.2 to 17.2 years), and only six patients had undergone menarche. The most common primary tumor sites were vagina (n = 7), retroperitoneum/pelvis (n = 6), and bladder (n = 4). The histologic subtype of RMS was favorable (embryonal or botryoid) in 22 patients (85%). A majority of the tumors (62%) were more than 5 cm in maximal diameter. Five patients had regional lymph node involvement, and three patients had distant metastatic disease.
Treatment of RMS (Table 2) depended on the extent of disease and year of diagnosis. All patients received chemotherapy that included vincristine and dactinomycin, with or without other agents. Most (88%) received an alkylating agent, and almost two thirds (62%) received doxorubicin (median cumulative dose, 242 mg/m2; range, 161 to 351 mg/m2). One patient underwent autologous peripheral-blood stem-cell transplantation after receiving a cyclophosphamide/topotecan preparative regimen. Twenty-three of the 26 patients underwent some type of tumor resection, either at the time of initial presentation or during treatment. The surgical procedure included a hysterectomy in 10 patients, complete or partial vaginectomy in nine patients, complete cystectomy in three patients, partial cystectomy in one patient, bilateral oophorectomy in one patient, and unilateral oophorectomy in three patients.
RT was administered to the primary site in 22 of the 26 patients. Five of these patients also received additional RT to regional lymph nodes (n = 3), whole pelvis (n = 2), whole abdomen (n = 1), whole lungs (n = 1), and T10 through S1 paraspinal tumor mass (n = 1). Nineteen patients received external-beam RT to the primary tumor (median cumulative dose, 42 Gy; range, 16 to 60.5 Gy); one of these patients who had received a dose of 48 Gy also received a radium vaginal implant with a dose of 84 Gy at the vagina. The remaining three patients received 50 Gy of brachytherapy alone. Two patients experienced tumor recurrence (one local, one distant); their treatment is included in the therapy summary provided earlier.
At the time of this analysis, the median age of the 23 surviving patients was 25.3 years (range, 10.8 to 51.1 years) and median follow-up was 20.3 years (range, 7.2 to 39.6 years) from the date of RMS diagnosis.
Summary of Late Effects
We identified a total of 235 late effects, of which 98 (42%) were grade 3/4 and 137 (58%) were grade 1/2. Only two patients, neither of whom had received RT, were free of late effects. Twenty-three of the 24 affected patients had grade 3/4 late effects; the remaining patient, who had not received RT, had only grade 1/2 late effects. The median number of grade 3/4 late effects per patient was three (range, zero to 14) and the median number of grade 1/2 late effects per patient was 4.5 (range, zero to 14). Fourteen patients (54%) required surgical treatment of late complications (Table 3). The most common surgical procedures were vaginal dilation/reconstruction to correct stenosis (n = 7), procedures to relieve ureteral obstruction (n = 6), intestinal stricture dilation or repair (n = 5), and fistula repair (n = 4).
There was a median of 9.5 (range, two to 28) late effects per patient among the 22 patients who had received RT. This number was significantly lower in the four patients who had not received RT (median, one; range, zero to 5; P = .002). Grade 3/4 late effects were significantly more common in patients who had received RT (median three v zero; P = .002), as were grade 1/2 late effects (median 5.5 v one; P = .011).
Late Effects by Organ System
The endocrine system was most frequently affected (Table 3). Twenty of the 26 patients experienced endocrine late effects, and 15 had grade 3/4 late effects. Eleven of 23 patients who had not undergone bilateral oophorectomies experienced failure of ovarian hormone production; all had received pelvic RT. Eight patients had short stature; two of these had central growth hormone deficiency and two had central hypothyroidism documented by provocative testing (one patient had both growth hormone deficiency and central hypothyroidism). Two additional patients with short stature had low levels of insulin growth factor 1 but did not undergo provocative testing to confirm hypothalamic-pituitary dysfunction. Three patients with short stature who did not undergo provocative thyroid testing received thyroid hormone replacement therapy because of clinical evidence of hypothyroidism; these patients had normal thyroid function studies (n = 1), a low-normal free T4 level (n = 1), or autoimmune hypothyroidism demonstrated by serologic testing (n = 1).
Forty-one GI late effects were identified in 18 patients, eight of whom had grade 3/4 late effects. Intestinal complications (strictures, obstruction, perforation, and chronic enteritis) were the most common grade 3/4 late effects, whereas others affected the stomach (gastritis), liver (hepatitis C, cholecystitis), and anus (incontinence). The most common grade 1/2 late effects were chronic constipation and dental caries.
Gynecologic late effects were noted in 15 patients, all of whom had grade 3/4 late effects. Ten patients had undergone total hysterectomy during treatment for RMS (one had also undergone bilateral salpingo-oophorectomy). An additional two patients underwent total hysterectomy and bilateral salpingo-oophorectomy for treatment of cervical carcinoma-in-situ (n = 1) and during anterior pelvic exenteration for treatment of rectovaginal/vesicovaginal fistulas (n = 1). Four patients experienced fistulas involving the vagina (n = 4) and/or uterus (n = 1). Multiple sites were involved in three of the four patients, including the bladder, urethra, GI tract, and peritoneal cavity. All four patients with fistulas had received RT. In two of the four patients, the fistulas developed spontaneously; in the other two patients, the fistulas developed after a surgical procedure to address vaginal stenosis. Vaginal dilation was performed to correct vaginal stenosis in four patients. Three patients underwent vaginal reconstructive procedures, all of which were associated with significant complications (rectal perforation and persistent vaginal stenosis requiring dilation, postoperative cellulitis and residual pelvic floor disorder, and rectovaginal fistula requiring permanent colostomy). Twenty of the patients in this study were incapable of bearing children because of surgical removal of the uterus (n = 12) and/or ovarian hormonal failure (n = 11). One of the remaining six patients had given birth to a child. She was one of the four who had not received RT.
Fourteen patients experienced a total of 58 renal late effects. Ten patients had grade 3/4 late effects, most commonly acute pyelonephritis, ureteral obstruction, cystectomy requiring ileal conduit, neurogenic bladder, and urethral stenosis requiring surgical intervention.
Eighteen patients experienced musculoskeletal late effects, 84% of which were grade 1/2. Five patients had grade 3/4 late effects. Musculoskeletal hypoplasia, deep connective tissue fibrosis, and scoliosis were the most common musculoskeletal late effects.
Ten patients had psychological late effects. Three patients had grade 3/4 depression and/or anxiety; the remaining seven had grade 1/2 depression, anxiety, or insomnia. Eight patients reported academic difficulties, and four of these failed to complete high school. One patient abused alcohol, and a second experienced long-term narcotic dependence.
Neurologic late effects were noted in two patients. The only grade 3/4 late effect was a cerebrovascular accident that caused paresthesias 11 years after the diagnosis of RMS. Imaging revealed a small lacunar infarct in the left temporal region and encephalomalacia in the right centrum semiovale.
Two cardiovascular late effects were identified, both of which were grade 3/4. One patient with pre-existing tricuspid regurgitation developed doxorubicin-induced (cumulative dose, 340 mg/m2) cardiomyopathy that necessitated cardiac transplantation. She ultimately died as a result of cardiac complications. Another patient experienced a hypertensive crisis of uncertain cause that required long-term antihypertensive management.
Secondary Cancers
Three patients had confirmed secondary cancers. The cumulative incidence was 13.5% ± 7.4% at 20 years. An additional patient who had received whole-pelvis RT for treatment of RMS of the bladder was reported to have developed cervical carcinoma, but the details were not available. One patient developed metastatic osteosarcoma of the right iliac crest 10.2 years after the diagnosis of retroperitoneal RMS. This tumor arose within the RT field and ultimately proved fatal. A second patient developed multifocal squamous cell carcinoma-in-situ of the cervix 10.2 years after treatment (including RT) for retroperitoneal RMS. Review of the RT port films suggested that this tumor arose within the radiation field. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for treatment of the secondary malignancy and was alive and disease-free at the time of this report, 17.6 years after the second diagnosis. The third patient had received RT for RMS of the bladder and developed adenocarcinoma in situ of the colon within the RT field, 9.2 years after the diagnosis of RMS. She had undergone endoscopic removal of adenomatous polyps of the sigmoid colon and rectum 10 months previously. Approximately 6 months after the diagnosis of adenocarcinoma in situ, the patient underwent left hemicolectomy. Pathologic examination revealed moderately differentiated Duke's stage B adenocarcinoma, apparently also arising within the RT field, and no adjuvant therapy was administered. Six months later, the patient died as a result of complications of a heart transplant necessitated by doxorubicin-induced cardiomyopathy. Review of her family history suggested the possibility of Li-Fraumeni syndrome.21 Her father had died of a malignant brain tumor at 28 years of age and several other family members on the paternal side were noted to have had cancer, though the specific tumor types were not noted. The family histories of the other two patients with second malignant neoplasms did not suggest the presence of Li-Fraumeni syndrome or another familial cancer syndrome.
Late Effects by Age at Diagnosis
Because young children are known to be at higher risk than older children and adults for certain late effects, we evaluated the association between age at diagnosis of RMS and the incidence of late effects. Among all 26 patients, there was no evidence of an association between the age at diagnosis of RMS and the number of late effects (P = .74 for grade 3/4 late effects; P = .94 for grade 1/2 late effects; P = .78 for all late effects). The 11 patients younger than 3 years of age experienced no more grade 3/4 late effects (median, three per patient; range, zero to nine) than the 15 patients older than 3 years of age (median, two per patient; range, zero to 14; P = .65). In the subset of patients who received RT (n = 22), the median number of grade 3/4 late effects per patient was five (range, one to nine) for the nine patients younger than 3 years of age compared with a median of three (range, one to 14) for the 13 patients older than 3 years of age (P = .31).
Late Effects by Treatment Era
We investigated the association between treatment era and the incidence of late effects to evaluate whether improvement of therapy over time significantly affected the likelihood of long-term sequelae. Recognizing that therapy improved continuously during the decades encompassed by this study, we somewhat arbitrarily selected 1984 as the cut point for this analysis because approximately half of the patients were diagnosed before and half were diagnosed after this date. The 12 patients whose RMS was diagnosed in 1984 or later had a higher median number of late effects than the 14 patients diagnosed earlier (12.5 v 6.5; P = .041). However, only grade 1/2 late effects were increased in the later treatment era (median seven v three; P = .063). The incidence of grade 3/4 late effects did not differ substantially by treatment era (median three v 2.5; P = .39).
DISCUSSION
Our review suggests that virtually all female long-term survivors of pelvic RMS experience significant, and in many cases debilitating, late sequelae of the disease and its treatment. Most survivors (88%) had at least one grade 3/4 late effect documented more than 5 years after the initial diagnosis. Furthermore, most patients had multiple grade 3/4 (median, three) and grade 1/2 (median 4.5) late effects. More than half of the patients required surgical intervention for the long-term sequelae of treatment. Although not all late effects were related to RT, RT was strongly associated with late effects: the median number of late effects was 9.5 per patient who received RT and only one per patient who did not receive RT (P = .002). The burden of late effects in this pediatric population seems to be significantly greater than that seen in adults treated with similar RT doses. A recent analysis of adjuvant RT for endometrial carcinoma in adults showed that 51% of patients experienced late effects, and only 11% of patients had severe late effects.22
Endocrine late effects were evident in 77% of our study group, and three fourths of the affected patients had grade 3/4 late effects. Forty-eight percent of the patients with at least one remaining ovary, all of whom had received pelvic RT, experienced ovarian hormonal failure. This figure likely underestimates the true incidence, because some patients were prepubertal at the time of the analysis, and menstrual function was not well documented for several patients treated during the early era. Nearly one third of the patients in this series had short stature. The cause of this finding is unclear, although three patients had documented central growth hormone and/or thyroid hormone deficiency. These complications are usually seen after irradiation of the hypothalamic-pituitary axis, which none of our patients underwent. However, both central growth hormone deficiency and hypothyroidism have been reported after chemotherapy alone.23,24 Nutritional impairment because of chronic radiation enteritis also may have contributed to short stature in this patient group. Previous studies have shown that nutritional deficiencies may influence the growth hormone–insulin-like growth factor axis.25 However, the lack of routine nutritional screening in this cohort precluded assessment of the contribution of nutritional deficiency to the observed growth impairment.
The GI late effects we noted were varied and significant. Most grade 3/4 GI late effects were intestinal complications, which included strictures, obstructions, perforations, and chronic enteritis. Other late effects included gastritis, chronic hepatitis C, cholecystitis, and bowel incontinence. Four patients had fistulas. These involved both the GI and genitourinary tracts and occurred after surgical procedures in half of the patients. All of the patients with documented fistulas had received pelvic RT. Previous studies suggest that fistulas are a common consequence of RT for pelvic tumors.26-28 As our institution has previously reported, hepatitis C infection is documented in approximately 7% of patients treated for childhood cancer who received blood product transfusions before 1992.29
Gynecologic sequelae were common and, in many cases, severe. Most notably, about three fourths of the survivors were incapable of bearing children because of surgical removal of the uterus and/or because of ovarian hormonal failure. Of the remaining patients, only one gave birth. Sexual dysfunction also seemed to be a significant problem in this population. Although many of the patients were not yet sexually active and sexual activity was often not documented, there was considerable evidence of disturbed sexual function. One fourth of the patients had undergone vaginal dilation or reconstruction procedures. Vaginal reconstruction resulted in severe complications in all patients, including the formation of fistulas. Other reported gynecologic late effects included chronic pelvic pain, pelvic floor disorder, and vaginal dryness. To our knowledge, no studies have evaluated sexual function after treatment for childhood cancer. However, studies in adults treated for gynecologic tumors suggest that treatment-induced anatomic and physiologic abnormalities may significantly impair quality of life, sexual function, and sexual satisfaction.30-32
More than half of the patients in this study experienced urinary tract late effects. The frequency of kidney and bladder late effects was similar. Grade 1/2 late effects predominated; however, it is important to note that these low-grade late effects had a significant impact on the survivors' quality of life. Eight patients had urinary incontinence, and three reported persistent symptoms of urinary frequency and urgency. Long-term infectious complications occurred frequently; nine patients experienced recurrent urinary tract infections, and six of these had acute pyelonephritis.
Second cancers were also a significant problem, occurring in 11% of our patients. At the time of our review, the details of reported cervical carcinoma in an additional patient had not been confirmed. All of the documented second malignancies developed within the RT field used to treat the RMS. Previous studies of survivors of RMS have documented a 1.7% to 3.4% cumulative incidence of secondary malignancy at 10 to 20 years of follow-up.16,17 The higher rate of secondary cancer in our population may reflect the longer follow-up in our study (20 years), compared with that in previous studies (8 to 9 years). The nearly universal use of RT in our patient population may also have contributed to this result. However, it is also possible that the rate of second cancers in our study is artificially elevated by chance because of the small number of patients in the study population.
We found that 10 patients (approximately 38%) experienced some type of psychological late effect, including depression, anxiety, or insomnia. We believe that our study greatly underestimates the psychosocial late effects experienced by these patients because such sequelae were not formally assessed as part of their follow-up. Because the CTCAE grading system does not include a specific category for school difficulties or academic underachievement, it was not possible for us to grade these findings and include them in our analysis. However, we noted that several patients had experienced academic difficulty or failed to complete high school. Several studies suggest that long-term survivors of childhood cancer report adverse effects on mental health, including depression, somatization, anxiety, and post-traumatic stress disorder.33,34 Both school underachievement and psychological disorders can significantly alter quality of life. More studies are needed to address the quality of life of this patient population.
Interestingly, we found no evidence that the incidence of late effects had declined in the recent treatment era. Patients treated during the last two decades had a slightly higher median incidence of late effects than those treated previously (P = .041). It is possible that late effects were documented more carefully in the later era than in the earlier era. This hypothesis is supported by the observation that the incidence of grade 3/4 late effects, which generally are well documented in the medical record, was similar in the two treatment eras, whereas a greater incidence of the more subtle grade 1/2 late effects was noted in the later era. Our results suggest, however, that efforts to minimize the late effects of therapy have had little impact on the long-term complications of treatment.
We also found that younger children did not experience more late effects than older children, nor did they experience more grade 3/4 late effects. Although somewhat unexpected, this finding may simply reflect the small study population. However, it is also possible that many of the late effects observed in this study are independent of age at the time of treatment and only a few are age-dependent. Additional studies are needed to clarify the impact of age at the time of treatment on long-term outcomes.
Our study has several limitations that should be considered in the interpretation of our findings. The study cohort is small, but their outcomes are likely to be representative of the broader population of survivors who have received intensive multimodal therapy during childhood. We obtained data through retrospective review of medical records and, therefore, were limited by the clinician's expertise in identifying late effects and documenting these findings in the medical record. The recent publication of risk-based late effects screening guidelines for survivors of childhood cancer may ameliorate the identification of late effects in these patients.35 Undoubtedly, prospective evaluation based on therapeutic exposure would provide a more accurate assessment of long-term treatment morbidity. Finally, the pediatric setting did not facilitate the evaluation of some toxic effects (eg, sexual dysfunction) that are more routinely addressed in adult health care settings.
Although it is well known that female survivors of pelvic RMS are at risk for a number of long-term sequelae, our study shows that late effects in this population are both common and severe. Our findings also suggest that even many years after pelvic RT for childhood RMS, surgery is associated with a considerable risk of serious and potentially long-term complications. Thus, pelvic late effects after RT should be managed conservatively whenever possible, with surgery reserved for complications mandating its use.
The significant burden of late effects in this patient population is certain to reduce the quality of life and the functional capacity of these patients, and illuminates the need for long-term medical and psychosocial follow-up. More interventions are needed to address altered quality of life and to assist these women in coping with the long-term sequelae of their treatment. Prospective studies that evaluate the complex relationship between specific treatment exposures and the resulting late effects are needed to help guide future treatment approaches for childhood RMS. Future therapeutic studies for children with RMS must focus not only on the quantity, but also on the quality of survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Sharon Naron, ELS, for editorial assistance.
NOTES
Supported by Grants No. CA 23099 and P30 CA 21765 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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