66_04 sequele

Sequelae of Treatment

Irradiation Alone

Acute Sequelae

Descriptions of sequelae vary among institutions because toxicity grading scales are not uniform and the scoring system for complications is not clearly stated in all reports.

Dusenbery et al. (132) reported 21 (6.4%) life-threatening complications in 327/462 patient implants.

Lanciano et al. (348), in 95 tandem and ovoid insertions for cervical cancer in 91 patients and for endometrial cancer in four, observed two uterine perforations and a vaginal laceration in two patients. Twenty-four percent of implants in 16 patients were associated with temperatures higher than 100.5°F. Five implants (5%) were removed because of presumed sepsis, pulmonary disease, arterial hypotension, change in mental status, and myocardial infarction.

Jhingran and Eifel (282), in 4,043 patients with carcinoma of the cervix who had undergone 7,662 intracavitary procedures, observed 11 (0.3%) documented or suspected thromboembolism, resulting in four deaths; the incidence of postimplant thromboembolism did not decrease significantly with the routine use of minidose heparin prophylaxis. Other life-threatening perioperative complications included myocardial infarction (one death in five patients), cerebrovascular accident (two patients), congestive heart failure (three patients), and halothane liver toxicity (two deaths). Intraoperative complications included uterine perforation (2.8%) and vaginal laceration (0.3%), which occurred more frequently in patients 60 years of age or older (p <0.01).

Wollschlaeger et al. (659) reported morbidity during hospitalization in 128 patients with cervical carcinoma undergoing 110 LDR intracavitary brachytherapy insertions. Forty-two implants (24.7%) were associated with acute problems; the most common were fever/infection (14.1%) or gastrointestinal problems (5.9%).

Acute gastrointestinal side effects of pelvic irradiation include diarrhea, abdominal cramping, rectal discomfort, and occasionally rectal bleeding, which may be caused by transient enteroproctitis. Patients with hemorrhoids may experience discomfort earlier than other patients. Diarrhea and abdominal cramping can be controlled with the oral administration of diphenoxylate hydrochloride, with loperamide, atropine sulfate, or opium preparations or emollients such as kaolin and pectin. Proctitis and rectal discomfort can be alleviated by small enemas with hydrocortisone and anti-inflammatory suppositories containing bismuth, benzyl benzoate, zinc oxide, or Peruvian balsam. Some suppositories contain cortisone. Small enemas with cod liver oil are also effective. A low-residue diet with no grease or spices and increased fiber in the stool (psyllium, polycarbophil) usually help to decrease gastrointestinal symptoms.

Genitourinary symptoms, secondary to cystourethritis, are dysuria, frequency, and nocturia. The urine is usually clear, although there may be microscopic or even gross hematuria. Methenamine mandelate and antispasmodics such as phenazopyridine hydrochloride or a smooth muscle antispasmodic such as flavoxate hydrochloride, hyoscyamine sulfate, oxybutynin chloride, or tolterodine tartrate can relieve symptoms. Fluid intake should be at least 2,000 to 2,500 mL daily. Urinary tract infections may occur; diagnosis should be established with appropriate urine culture studies, including sensitivity to sulfonamides and antibiotics. Therapy should be promptly instituted.

Erythema and dry or moist desquamation may develop in the perineum or intergluteal fold. Proper skin hygiene and topical application of petroleum jelly, petrolatum, or lanolin should relieve these symptoms. U.S.P. zinc oxide ointment and intensive skin care may be needed for severe cases.

Management of acute radiation vaginitis includes douching every day or at least three times weekly with a mixture of 1:5 hydrogen peroxide and water. Douching should be continued on a weekly basis until the mucositis has resolved or for 2 or 3 months as necessary. Superficial ulceration of the vagina responds to topical (intravaginal) estrogen creams, which stimulate epithelial regeneration within 3 months after irradiation. Use of vaginal dilators several times daily, started during the course of treatment, prevents vaginal stenosis.

Psychoeducational intervention and motivation improve the compliance in use of dilators (278). More severe necrosis may require debridement on a weekly basis until healing takes place. Judicious use of biopsies is recommended to rule out persistent or recurrent cancer.

Late Sequelae

The incidence of major late sequelae of radiation therapy for stage I and IIA carcinoma of the cervix ranges from 3% to 5%, and for stage IIB and III, between 10% and 15%. The most frequent major sequelae for the various stages are listed in Tables 66.25 and 66.26.

Injury to the gastrointestinal tract usually appears within the first 2 years after radiation therapy, whereas complications of the urinary tract are seen more frequently 3 to 5 years after treatment (327,469).

Pedersen et al. (467), in a review of morbidity of radiation therapy in 442 patients with cervical cancer stages IIB, III, and IVA, recommended that actuarial estimates rather than frequency of sequelae be reported to avoid underestimation of risks of late morbidity after radiation therapy in long-term survivors.

In fact, Eifel et al. (140), in 1,784 patients with stage IB carcinoma of the cervix, noted that the greatest risk of sequelae is in the first 3 years after therapy. The risk of rectal complications declined after the first 2 years of follow-up to 0.6% per year, whereas the risk of major urinary tract complications for survivors continued at 0.3% per year, with a 20-year actuarial risk of major complications of 14.4%.

Montana et al. (417), Perez et al. (475), and Pourquier et al. (500) noted a greater incidence of complications with higher doses of irradiation.

Perez et al. (469) and Pourquier et al. (500)

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reported that with doses below 75 to 80 Gy delivered to limited volumes, grade 2 and 3 complications in the urinary tract and rectosigmoid were approximately 5%. However, the incidence increased to over 10% with higher doses of irradiation to these organs (Fig. 66.32). Doses higher than 60 Gy were also correlated with a greater incidence of small bowel injury (Fig. 66.33).

The same analysis showed that patients who experienced sequelae of therapy had slightly better survival rates than patients without any complications. This was related to improved tumor control with higher doses of irradiation (469).

Perez et al. (475) quantitated the impact of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in 1,456 patients treated for cervical cancer with external-beam irradiation plus two LDR intracavitary insertions to deliver 70 to 90 Gy to point A. Median follow-up was 11 years. In stage IB, the frequency of grade 2 morbidity was 9%, and grade 3, 5%; in stages IIA, IIB, III, and IVA, the frequency of grade 2 morbidity was 10% to 12%, and of grade 3, 10%. The most frequent grade 2 urinary/rectal sequelae were cystitis and proctitis (0.7% to 3%). The most common grade 3 sequelae were vesicovaginal fistula (0.6% to 2% in patients with stage I to III tumors), rectovaginal fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In the bladder, doses below 80 Gy correlated with a <3% incidence of morbidity and 5% with higher doses (p = 0.31). In the rectosigmoid, the incidence of significant morbidity was <4% with doses below 75 Gy and increased to 9% with higher doses. For the small intestine, the incidence of morbidity was <1% with 50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall (p = 0.04). Multivariate analysis showed that dose to the rectal point was the only factor influencing rectosigmoid sequelae, and dose to the bladder point affected bladder morbidity (Table 66.25).

In a review of the Patterns of Care Study, Lanciano et al. (349) observed a 5-year actuarial rate of 14% for major late complications in 1,558 patients treated with irradiation for invasive carcinoma of the cervix. Women younger than 40 years of age or with a history of prior surgery or laparotomy for staging had a greater incidence of significant morbidity (15% to 18% vs. 8% to 9%). Also, EBRT dose per fraction >2 Gy, paracentral doses of 85 Gy or greater, and lateral parametrial doses higher than 60 Gy were independently associated with a higher complication rate.

Lee et al. (369), using 3 Gy fractions with EBRT, calculated the rectal point dose in the anterior wall at the level of the cervical os and noted that total higher BED (142.7 Gy) were associated with rectal sequelae compared with BED <131 Gy.

Mitchell et al. (413) evaluated 398 patients with stage I to III cervical carcinoma treated with radiation therapy. Patients were divided into nonelderly (35 to 69 years of age; n = 338) and elderly (≥70 years of age; n = 60) groups. The frequency and severity of acute and chronic sequelae were equivalent in both groups.

When late radiation proctitis occurs, initial treatment is the same as for acute proctitis. If the symptoms and rectal bleeding persist, laser treatment of rectal telangiectasis or ulcers is frequently beneficial.

Roche et al. (515) treated six patients with hemorrhagic radiation-induced proctitis using outpatient intrarectal application of formaldehyde 4%. In four cases the bleeding ceased after the first formaldehyde application; two patients continued to bleed, but another application 3 weeks later definitively controlled the hemorrhage. There were no complications, such as burns or late stenosis of the deep layers of the rectum, and this technique was well tolerated.

Rubinstein et al. (531) and Seow-Choen et al. (550) also reported

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treatment of radiation proctitis with a similar technique. Patients are sedated, a local anesthetic block is administered, and a sponge moistened with 4% formalin is applied for 4 minutes to each bleeding area of the rectum. Care is taken to protect the perianal skin from any caustic effects of the formalin.

Occasionally, a colostomy is necessary if conservation management fails. The importance of performing colonoscopy in patients with rectal bleeding, to exclude other lesions in the colon, including polyps or cancer, is emphasized.

Anal incontinence is occasionally observed. This sequela must be assessed in light of a report by Nelson et al. (438), who in a survey of 6,959 nonirradiated patients identified 153 (2.2%) who reported anal incontinence, without specific etiology. Thirty percent of incontinent subjects were older than 65 years of age, and 63% were women. Of those with anal incontinence, 36% were incontinent to solid feces, 54% to liquid feces, and 60% to gas.

Kim et al. (317) investigated the effects of radiation on anorectal function using manometry in 24 patients with carcinoma of the uterine cervix who had late radiation proctitis. These data were compared with those from 24 age-matched nonirradiated female volunteers. Regardless of the severity of proctitis symptoms, 75% of irradiated patients exhibited abnormal manometric parameters for sensory or motor functions. Radiation damage to nerves and to the external sphincter muscle were considered to be an important cause of motor dysfunction.

Quilty (504) noted a greater incidence of pelvic complications in patients treated with higher doses to the whole pelvis (40 to 50 Gy). The author commented that the intracavitary radium dose was not correlated with severe complications.

Similar observations were made by Stryker et al. (584) in 132 patients, who recorded a 9% incidence of fistulas and a 14% incidence of grade 2 and 3 complications after delivery of 50 Gy or higher to the whole pelvis (1.8-Gy daily dose) combined with intracavitary insertion. They recommended that the whole pelvis dose should not exceed 40 to 45 Gy when doses of approximately 40 Gy are delivered to point A with LDR intracavitary insertions.

Kuske et al. (344), comparing results of therapy in 99 patients with carcinoma of the cervix on whom minicolpostats were used, noted a 15% higher incidence of grade 2 and 3 complications, which was higher than the 8% incidence noted in a similar group of patients treated with regular colpostats during the same period (p = 0.08).

Perez et al. (469) reported that the incidence and type of complications with interstitial therapy at Washington University were approximately the same as in patients treated with intracavitary technique only.

On the contrary, Kashibhatla et al. (300) noted 6% small bowel obstruction in 36 women with gynecological cancer treated with EBRT and interstitial brachytherapy, which was aggravated by previous abdominopelvic surgery. The 3-year risk of rectovaginal fistula was 18%, and it was significantly higher in patients who received total doses >76 Gy (100% vs. 7%; p = 0.009).

Irradiation of the para-aortic lymph nodes has been reported to cause increased morbidity, particularly if it is done after transperitoneal staging para-aortic lymphadenectomy.

In a randomized study reported by Rotman et al. (527), a somewhat higher incidence of grade 2 and 3 complications was reported in 170 patients (10 complications) given 45 Gy to the para-aortic area in addition to standard pelvic irradiation, compared with five complications in 167 patients treated by pelvic irradiation only. The incidence of fatal (grade 5) complications was four and one, respectively. In a similar randomized

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study by Haie et al. and the EORTC (219), the incidence of grade 3 small bowel injury was 2.3% in the para-aortic irradiation group and 0.9% in the pelvic irradiation–only group. The overall incidences of severe complications were 9% and 4.8%, respectively.

Although it is common knowledge in the radiation oncology community, only a few sketchy reports have been published on the possible intolerance to pelvic irradiation in patients with inflammatory bowel disease (134,252).

Willett et al. (655) reported on 28 patients with inflammatory bowel disease (10 with Crohn's disease, 18 with ulcerative colitis) who underwent external-beam abdominal or pelvic irradiation. Patients were treated either by specialized techniques (16 patients) to minimize small and large bowel irradiation or by conventional approaches (12 patients). The overall incidence of severe toxicity was 46% (13/28 patients), and six (21%) experienced severe acute toxicity necessitating cessation of radiation therapy. Late toxicity requiring hospitalization or surgical intervention was observed in 8/28 patients (29%). For patients treated with conventional approaches, the 5-year actuarial rate of late toxicity was 73% versus 23% for patients treated by specialized techniques (p = 0.02). In patients with inflammatory bowel disease undergoing abdominal or pelvic irradiation, judicious use of this modality must be observed.

On the contrary, Song et al. (567), in a review of 24 patients with a history of inflammatory bowel disease who received RT (median dose of 45 Gy in 1.8 to 3 Gy fractions) to fields encompassing some portion of the gastrointestinal tract, noted that five patients (21%) experienced acute intestinal toxicity of grade 3 or greater and two (8%) had grade 3 or greater late intestinal toxicity. Fifteen patients also received concurrent chemotherapy. The authors believed that the gastrointestinal toxicity in these patients was more modest than generally perceived.

Also, Tiersten and Saltz (612) noted that five patients with inflammatory bowel disease and gastrointestinal malignancy completed planned radiation therapy (30 to 54 Gy), usually with concurrent 5FU, without difficulty.

Salama et al. (542) reported preliminary observations on acute toxicity with extended field IMRT in 13 patients with gynecological cancer. With median follow-up of 11 months, two patients treated with chemoradiation experienced grade 3 or higher morbidity and one (with history of previous surgeries) developed small bowel obstruction.

Levenback et al. (374) identified 116/1,784 patients (6.5%) with stage IB carcinoma of the cervix treated with irradiation in whom hemorrhagic cystitis developed, 23% grade 2 (repeated minor bleeding), and 18% grade 3 (hospitalization required for medical management). The median interval to onset of hematuria was 35.5 months. The risk of severe hematuria requiring surgical intervention was 1.4% at 10 years and 2.3% at 20 years. Minor episodes of hematuria are managed by antibiotic therapy. Cystoscopic, laser, or cautery treatment of bleeding points is indicated. Clot evacuation and continuous bladder irrigation are important elements in the acute management of patients with heavy bleeding. Occasionally, a urinary diversion is required for intractable severe hematuria.

In 13 patients with hemorrhagic cystitis treated with hyperbaric oxygen, all but one experienced durable cessation of hematuria (647).

Lee et al. (364) also noted that, in 16/20 patients (80%) with hemorrhagic radiation cystitis, significant improvement was observed after treatment with hyperbaric oxygen at 2.5 atm (44 sessions).

Ureteral stricture at 20 years was observed in 2.5% of 1,784 patients with stage IB carcinoma of the cervix treated with irradiation (274 followed for up to 20 years or longer) (406). The most common presenting symptoms were flank pain and urinary tract infection. In five patients, ureteral stricture was complicated by a vesicovaginal fistula. Seven of 43 patients who had no evidence of cancer and hydroureter or hydronephrosis died of radiation complications. Treatment of ureteral stenosis may consist of stenting or resection of the fibrotic segment and reimplantation of the ureter either with a ureteroneocystostomy or ureteroileocystostomy. In approximately half of the patients, diversion of urinary stream and ileal conduits are necessary. Occasionally, a nephrectomy is performed for removal of a nonfunctional kidney.

Buglione et al. (60) reported a 10% incidence of late urinary morbidity and 1% ureteral fibrosis grade III or IV in 191 patients. They postulated the role of TGF-β1 factor in the activation of fibroblasts and remodeling of extracellular matrix, which may be important in the induction of these sequelae.

Patients with gynecologic malignancies, including those receiving radiation therapy, are prone to development of urinary tract infections.

Prasad et al. (501) collected 216 urine samples from 36 patients receiving pelvic irradiation, 12 of whom had urinary tract infection. The most common organisms isolated were Escherichia coli, followed by Enterococcus species. Appropriate urine bacterial studies and cultures are indicated in patients suspected of having superimposed urinary tract infection during the course of radiation therapy.

Parkin et al. (462) reported a 26% incidence of severe urinary symptoms (urgency, incontinence, and frequency) in patients treated with irradiation alone for cervical carcinoma. They carried out urodynamic studies in 42 women and compared them with 28 women having urodynamic evaluations before and after treatment. There was no difference in the mean maximum flow rate or mean residual volume in the two groups. However, mean volume of full bladder sensation was significantly lower in the postirradiation group than in the pretreatment group, as was the mean maximum cystometric capacity.

This same dysfunction may be noted in approximately 10% of the general female population, and the incidence increases in older women (478).

Ureteroarterial fistula is a rare occurrence, and it is associated with a high mortality rate. When profuse urinary tract bleeding occurs in patients previously diagnosed with a gynecologic malignancy and treated with radiation therapy and extensive surgery, ureteroarterial fistula should be considered in the differential diagnoses (118).

Although extremely rare, lumbosacral plexopathy has been occasionally reported in patients treated for pelvic tumors with doses of 60 to 67.5 Gy. At Washington University, this syndrome was observed in four of 2,410 patients with cervical or endometrial carcinoma receiving 45 Gy to the para-aortic lymph nodes (without spinal cord shielding) or external pelvic irradiation (60 Gy to the parametria) and brachytherapy, with the lumbosacral plexus receiving total doses of 70 to 79 Gy (176).

Lower extremity paralysis secondary to lumbosacral plexopathy was reported in one patient after standard radiation therapy for cervical cancer (3).

Patients previously reported as having radiation myelopathy to the lumbar spine may have suffered a lumbar and sacral nerve plexopathy instead of or in addition to the spinal cord injury. The differential diagnosis of plexopathy with recurrent tumors is sometimes difficult. In a comparison of 20 patients with lumbosacral plexopathy after irradiation and 30 patients with plexus damage from pelvic malignancy,

Thomas et al. (610) noted that indolent leg weakness occurred early in radiation-induced plexopathy (pain occurred initially in 10% of patients, although ultimately it was present in 50%), whereas pain was most frequently associated with tumor plexopathy. Muscular weakness, numbness, and paresthesia are common in both groups. Electromyography showed abnormal myokymic discharges in 57% of patients, whereas this finding was very unusual in tumor-induced plexopathy. CT is extremely helpful in the detection of pelvic masses or bone destruction caused by tumor. The authors also reported extensive retroperitoneal fibrosis of the lumbosacral plexus in two patients and femoral nerve fibrosis with plexopathy in one patient. Although cystometrograms have demonstrated bladder atonicity in some cases,

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several authors have failed to observe bladder or rectal sphincter disturbances. Unfortunately, as in radiation myelopathy, the neurologic deficit is irreversible, and no effective therapy other supportive care has been found.

Other types of less severe, but still clinically significant sequelae have been described.

Bruner et al. (57), in 90 patients treated with intracavitary irradiation for either carcinoma of the cervix (42 patients) or endometrial carcinoma (48 patients), 78 of whom also received external pelvic irradiation (44.5-Gy mean dose), noted that vaginal length decreased in most patients (at 24 months, in endometrial carcinoma from 8.8 cm to 7.8 cm, and in cervical carcinoma from 7.6 cm to 6.2 cm). Pretreatment sexual activity was reported by 31% of women in comparison with 43% after treatment. However, 22% of women reported a decrease in sexual frequency, and 37% a decrease in sexual satisfaction. This was correlated with increased dyspareunia, which was noted in 31% of women treated for carcinoma of the cervix and 44% of those treated for endometrial carcinoma.

Grigsby et al. (204) described complex problems with sexual adjustment in women with gynecologic tumors treated with radiation therapy, with decreased frequency of sexual intercourse, desire, orgasm, and enjoyment of intercourse in 16% to 47% of patients.

Regular vaginal dilation is widely recommended to maintain vaginal health and sexual functioning; however, the compliance rate with this recommendation is not consistent.

In a study to test the effectiveness of an “information-motivation-behavior skills” model, 32 women compliance was significantly improved (278,514).

There was no evidence that the experimental intervention improved global sexual health. Jensen et al. (281) described persistent sexual dysfunction throughout 2 years after RT in 118 women; 85% had low or no sexual interest, 35% lack of vaginal lubrication, and 55% mild to severe dyspareunia. However, 63% of the sexually active patients before RT remained active, although with decreased frequency.

Grigsby et al. (203), in 1,313 patients with gynecologic tumors treated with radiation therapy, identified 207 who received pelvic irradiation to the inguinal areas, including the hips. Femoral neck fractures developed in 10 patients (4.8%); four were bilateral. The cumulative actuarial incidence of fracture was 11% at 5 years and 15% at 10 years. Most of the fractures occurred in patients receiving 45 to 63 Gy, and although radiation dose could not be correlated with the occurrence of fracture, no fractures were noted in patients receiving <42 Gy. Cigarette smoking and osteoporosis were significant prognostic factors for increased risk of fracture.

Blomlie et al. (40) described radiation-induced insufficiency fractures of the pelvis on MRI (characterized by edema on T1-weighted images) in 16/18 women (nine premenopausal and nine postmenopausal) with advanced cervical carcinoma. During the study, the fractures associated with edema subsided without treatment in 41/52 (79%) lesions in 15/16 (94%) patients.

Moreno et al. (420) also described eight patients with pelvic cancer who developed insufficiency fractures after pelvic irradiation. The bone and CT scan showed abnormalities in the sacroiliac joint in all cases, and in the pubis in three cases. In five patients, the initial diagnosis was bone metastases, which was incorrect. Treatment, consisting of nonsteroidal anti-inflammatory drugs and rest, led to symptomatic relief in all cases.

These data should be evaluated in light of a report by Cummings et al. (103) of 9,516 women, 192 of whom sustained hip fractures not due to motor vehicle accidents. The incidence of hip fracture ranged from 1.1 per 1,000 woman-years when no risk factors were present to 27 per 1,000 woman-years in women with risk factors and low bone density.

Bye et al. (65) assessed health-related quality of life (HRQOL) 3 to 4 years after pelvic radiation therapy for carcinoma of the endometrium and cervix in 94 survivors, 79 (84%) of whom answered a survey. The treated women scored lower than the general population on role functioning (81.5 vs. 90.6; p <0.01) and higher on diarrhea (23.8 vs. 9.5; p <0.01). Compared with pretreatment conditions, an increase in cases with pain in the lower back, hips, and thighs was seen and was associated with deterioration in HRQOL.

Sequelae of High–Dose-Rate Brachytherapy

Petereit et al. (481) reported 16 acute events (9.5%) in 169 patients treated with HDR brachytherapy (128 with cervical cancer, also receiving external irradiation, and 41 medically inoperable endometrial carcinomas). The overall 30-day morbidity rate for the patients with cervical cancer was 5.5%, and the 30-day mortality rate was 1.6% (two patients, one died of pulmonary edema 12 days after first HDR insertion and the other had enteritis and died in a nursing home).

The complication rates for HDR and LDR techniques are usually equivalent (165,455).

Petereit et al. (482) observed equivalent morbidity with LDR or HDR brachytherapy (Table 66.27).

However, in the series by Cikaric (87), the rectal complication rate was significantly higher in the LDR group. Bladder complication rates reported, in general, are lower than rectal complication rates; again, except for the series by Cikaric (87) showing a higher complication rate with the LDR technique, there were no significant differences with the two techniques.

Ogino et al. (450), in 253 patients with invasive carcinoma of the cervix treated with HDR brachytherapy, noted that grade 4 rectal complications were not observed in patients with a time–dose factor below 130 or biologic equivalent dose lower than 147, assuming an α/β ratio of 3 Gy for late reactions.

Spontaneous intraperitoneal rupture of the urinary bladder, an extremely rare event, was reported by Fujikawa et al. (166) after radiation therapy for cervical cancer in 6/148 patients treated with HDR intracavitary brachytherapy combined with EBRT. All six patients underwent laparotomy and repair of the perforation; however, rerupture of the bladder occurred in three of these patients.

Clark et al. (88) reported on 43 patients treated with pelvic EBRT (46 Gy) and three HDR intracavitary treatments given weekly combined with concomitant chemotherapy (cisplatin, 30 mg/m2 weekly) for advanced carcinoma of the cervix. At 40 months after treatment, 9/13 patients who received a dose to the rectal reference point greater than the prescribed point A

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dose had a 46% actuarial rate of serious (grade 3 and 4) rectal complications, compared with 14% in the remainder. A strong dose response was observed with a threshold for complications at a brachytherapy dose of 8 Gy per fraction.

Surgery

With improved anesthesia, surgical techniques, and antibiotic therapy, the mortality rate for radical hysterectomy with pelvic lymphadenectomy has decreased to 1% or less. The most frequent sequela after radical hysterectomy is urinary dysfunction, as a result of partial denervation of the detrusor muscle. Patients may have various degrees of loss of bladder sensation, inability to initiate voiding, residual urine retention, and incontinence.

Magrina et al. (392), in 375 patients treated with a modified radical hysterectomy for various gynecologic disorders, observed some form of postoperative (within 42 days of surgery) complications in 89 patients (24%). Patients who had a pelvic lymphadenectomy experienced a greater incidence of lower extremity lymphedema than those who did not undergo this procedure. Preoperative or postoperative pelvic irradiation was a significant predisposing factor for urinary tract infection, lymphedema, and bowel obstruction in these patients compared with those who did not receive pelvic irradiation.

Some loss of defecatory urge associated with chronic rectal dysfunction was observed by Barnes et al. (29) after radical hysterectomy. Manometric studies suggest a disruption of the spinal arcs controlling defecation.

Other complications include ureterovaginal fistula (the incidence of which has decreased to <3%), hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas. Postsurgical complications are usually more amenable to correction than are late complications after irradiation.

Combined Irradiation and Surgery

When irradiation is combined with surgery, the complication rate tends to be somewhat higher, particularly because of injury to the ureter or the bladder (ureteral stricture or ureterovaginal or vesicovaginal fistula) (140). The dose of irradiation, technique, and the type of surgical procedure performed are important in determining the morbidity of combined therapy.

Jacobs et al. (276), in 102 patients with invasive cervical carcinoma treated with low-dose preoperative irradiation and a radical hysterectomy with lymphadenectomy or high-dose preoperative irradiation and a conservative extrafascial hysterectomy, noted a major complication rate of 5%.

As discussed previously, a significant number of complications are associated with pretherapy staging laparotomy, particularly if irradiation (over 55 Gy) is given to metastatic para-aortic lymph nodes. The incidence of complications is between 5% and 20%, depending on the extent of the para-aortic lymph node dissection, use of transperitoneal or retroperitoneal approach for the operation, and dose of irradiation given (651).

Postoperative Irradiation

When postoperative radiation therapy is given to selected patients, further complications of the additional therapy are expected because of intestinal adhesions to denuded surfaces in the pelvis. Enteric complications, such as obstruction, fistula, or dysfunction, were observed in 24% of patients reported by Fiorica et al. (158). Other investigators, however, have reported no increase in the incidence of severe complications in patients treated with postoperative irradiation (355,563).

Montz et al. (419) evaluated bowel obstruction in 98 patients undergoing radical hysterectomy for a nonadnexal gynecologic malignancy. The incidence of small bowel obstruction was significantly higher (p <0.05) in patients who received concomitant radiation therapy (20%). None of these patients had recurrent disease at the time of small bowel obstruction. Findings at surgery consisted of minimal incisional adhesions but extensive matted small bowel adherent to the pelvic operative sites.

After combined treatment, some degree of lymphedema is frequently observed (30% to 40%).

Hormonal Replacement after Treatment of Cervical Cancer

After pelvic irradiation or bilateral salpingo-oophorectomy, usually carried out with a radical hysterectomy in patients treated for carcinoma of the uterine cervix, symptoms of menopause may occur. They can be treated with replacement hormones, although some gynecologists have expressed reservations. During the past 25 years, hormonal replacement therapy has been shown to reduce the risk of cardiovascular diseases, osteoporotic fractures, and colon carcinoma. On the other hand, there is a significant increase of the risk in breast cancer with prolonged use longer than 5 years.

Burger et al. (61) concluded that squamous-cell cancers of the cervix, vulva, and vagina are unlikely to be influenced by hormonal replacement therapy. In a study of women with ovarian cancer, 50 years of age or younger, estrogen replacement therapy did not have a negative influence on disease-free survival. Long-term hormonal replacement therapy in women treated for a gynecologic cancer must be based on the medical history of and discussion of risk with the individual patient (and her family when warranted). Usually, 0.625 to 1.25 mg of coagulated estrogen daily is sufficient (491,538,619).

Palliative Irradiation

Frequently, the radiation oncologist is faced with the challenge of treating a patient with stage IVB or recurrent carcinoma who requires palliation of pelvic pain or bleeding. If vaginal bleeding is the main concern, a single LDR intracavitary insertion with tandem and colpostats for approximately 6,000 mgh (55 Gy to point A) suffices. If irradiation was delivered previously, lower intracavitary doses should be prescribed (4,000 to 5,000 mgh). Grigsby et al. (202) used two fractions of HDR brachytherapy with a ring applicator (once weekly) with control of bleeding in 14/15 patients.

Several high-dose fractionation schedules with external-beam radiation have been used.

Spanos et al. (576) reported on a phase II study of daily multifractionated split-course irradiation in 142 patients with recurrent or metastatic disease in the pelvis. Irradiation consisted of 3.7 Gy per fraction given twice daily for 2 consecutive days, repeated at 3- to 6-week intervals for a total of three courses, aiming to a total tumor dose of 44.4 Gy. Occasionally, this regimen was combined with an LDR intracavitary insertion (4,500 mgh), blocking the midline for the last 14.4-Gy external dose. Twenty-seven patients survived more than 1 year. There were only two recorded cases of grade 3 toxicity (lower gastrointestinal tract).

This study was expanded to a phase III protocol randomizing 136 patients between a short (2-week) or a longer (4-week) rest period between the split courses of irradiation (577). There was a trend toward increased acute toxicity in patients with shorter rest periods (5/58 vs. 0/68; p = 0.07). Late toxicity was not significantly different in the two groups. Pelvic tumor response was comparable in both groups (34% vs. 26%).

Spanos et al. (575) reported a 6% complication rate in 290 patients treated in RTOG Protocol 85-02. No patient receiving <30 Gy experienced late toxicity. There was no significant difference in the incidence of complications for patients with a 2- or 4-week rest (p = 0.47).