Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions

PURPOSE: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placement of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. RESULTS: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received >or=65 Gy and >or=70 Gy to >or=1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). CONCLUSION: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.     

Osteoradionecrosis: causes and prevention

Osteoradionecrosis (ORN) is one of the most serious complications arising from head and neck radiation therapy. Current research has shown that ORN represents nonhealing, dead bone and is not a state of infection. ORN is the result of functional and structural bony changes that may not be expressed for months or years. ORN may occur spontaneously or in response to wounding. Predisposing factors include absorbed radiation dose, fractionation, delivery modality, and dental status. Timing of dental extractions and other factors have also been shown to affect incidence. ORN may be reduced through early intraoral evaluation, treatment, and adequate healing time prior to beginning RT. Hyperbaric oxygen (HBO) therapy has been beneficial in the prevention and treatment of ORN. It is of paramount importance for the medical community to recognize the factors that may reduce ORN incidence, endorse oral care protocols, and acknowledge the value of HBO therapy in the prevention and treatment of this disease.     

Radiotherapy-induced mandibular bone complications

The mandible is among the bones most frequently affected by irradiation. The most severe post-radiation injury of the mandible is osteoradionecrosis (ORN). Conflicting data have been reported on the incidence of this complication, its aetiology and management. The incidence of mandibular ORN in head and neck cancer patients managed with radical or postoperative irradiation, has varied widely in the literature from 0.4% to 56%. The interpretation of data derived from particular series are difficult due to the different scoring methods and classification systems used for the evaluation of post-radiation bone damage. Although ORN occurs typically in the first three years after radiotherapy, patients probably remain at indefinite risk. The diagnosis of ORN is principally based on the clinical picture of chronically exposed bone. Radiological symptoms include decreased bone density with fractures, cortical destruction and loss of spongiosa trabeculation. Numerous factors that may be associated with the risk of ORN include treatment-related variables (for example, total radiotherapy dose, biologically effective dose, photon energy, brachytherapy dose rate, combination of external beam irradiation and interstitial brachytherapy, field size, fraction size, volume of the mandible irradiated with a high dose), patient-related variables (like deep parodontitis, pre-irradiation bone surgery, bad oral hygiene, alcohol and tobacco abuse, bone inflammation, dental extraction after radiotherapy) and tumour-related factors (tumour size or stage, proximity of the tumour to bone, anatomic tumour site). Primary management of post-radiation bone lesions include conservative modalities such as saline irrigations, antibiotics during infectious episodes, topically applied antiseptics, gentle sequestrectomy and removal of visibly loosened bone elements as well as treatment with hyperbaric oxygen (HBO). Surgery is reserved for persistent ORN and includes radical resection of the lesion(sequestrectomy, hemimandibulectomy etc.) with reconstruction. In recent years the introduction of preventive oral hygiene measures and meticulous dental evaluations before and after irradiation, improvement in radiotherapy techniques and the development of reliable diagnostic and therapeutic procedures have resulted in a decreased incidence of ORN. Nevertheless, given the severe impact of ORN on patient quality of life, research should be continued to further ameliorate this problem.     

Radiation-induced cognitive dysfunction: the protective effect of ethyol in young rats

PURPOSE: To evaluate the protective learning and memory effect of Ethyol in irradiated young rats. METHODS AND MATERIALS: One hundred twenty-eight 45-day-old Wistar rats received whole brain fractionated radiation (30 Gy), whereas 48 rats received sham irradiation. Four irradiated subgroups were defined: saline, 37.5 mg/kg, 75 mg/kg, and 150 mg/kg Ethyol. Sequential behavioral studies including one-way and two-way avoidance tasks were undertaken before and after radiation. RESULTS: Before radiation, the performances of all groups were similar. For the one-way avoidance task, at 1, 3, and 6 months postradiation, saline-irradiated rats had a lower percentage of avoidance than sham- or Ethyol- (75 or 150 mg/kg) irradiated rats (p 相似文献   

The value of postexcision preradiation mammography in patients with early-stage breast cancer

The purpose of this study was to evaluate the benefit of postexcision preradiation mammography for patients with early-stage breast cancer. The records of 101 patients (103 breasts) with either ductal carcinoma in situ (DCIS) or early invasive breast cancer diagnosed based on microcalcifications on a mammogram between January 1999 and December 2001 at our institution were reviewed. Sixty-one patients had a postexcision preradiation mammogram, and 42 patients did not have a mammogram until the completion of radiation. Of the 61 patients who had a preradiation mammogram, 1 patient (2%) was found to have residual microcalcifications after the completion of chemotherapy. A core biopsy revealed DCIS, and a wide excision revealed no additional abnormalities. Of the 42 patients who underwent a postradiation mammogram, 1 patient had calcifications in the same quadrant as her original biopsy. A wide excision revealed only sclerosing adenosis. For women who receive chemotherapy before the initiation of radiation, a preradiation mammogram ought to be considered because there will frequently be a 6-month interval from the patient's lumpectomy to the initiation of radiation. However, for women scheduled to start radiation within an interval of 4 months or less, our data do not support the routine use of postexcision preradiation mammography. Although we recognize that our data may not be representative of the community at large, our observations do not support the routine use of postexcision preradiation mammography in women with small breast cancers.     

Radiation necrosis of the mandible: A 10 year study. Part I. Factors influencing the onset of necrosis

Of 404 patients who were irradiated for cancer in the oral region between 1971 and 1975, 19.1 % developed radiation necrosis of the mandible. Three main effects, anatomic tumor site, tumor dose, and dental status, were found to have a statistically significant effect on incidence of necrosis. Necrosis was also found to occur more frequently in association with an implant than with treatment administered by an external radiation source alone. The T-stage of the tumor did not appear to affect the incidence of necrosis. Necrosis incidence was also studied over two time periods- 1966-1%9 (study I) and 1971–1975 (study II). Differences between the two periods were found in the primary etiological groupings. Necrosis attributed to spontaneous or unknown cause increased in the second study, while that associated with dental extractions before irradiation decreased. Fewer teeth were extracted before radiation therapy in study If than in study 1. Less necrosis followed mandibular surgery for recurrent disease in study II than study 1.     

Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model

Background

The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy.

Methods

Fourteen U87 tumor–bearing rats were irradiated using a small-animal radiation research platform (40 or 20 Gy), and 6 rats were used as controls. MRI was performed on a 4.7 T animal scanner, preradiation treatment, as well as at 3, 6, 9, and 14 days postradiation. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared.

Results

Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient (ADC) values of tumors increased significantly postradiation (40 and 20 Gy), except at day 3 postradiation, compared with preradiation. The tumor blood flow decreased significantly postradiation (40 and 20 Gy), but the relative blood flow (tumor vs contralateral) did not show a significant change at most time points postradiation. The amide proton transfer weighted (APTw) signals of the tumor decreased significantly at all time points postradiation (40 Gy), and also at day 9 postradiation (20 Gy). The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T₁-weighted images.

Conclusions

Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model.     

Prophylactic hyperbaric oxygen treatment and rat spinal cord re-irradiation

Normal tissue injury may lead to severe, life threatening, late side effects after therapeutic use of irradiation. Neurological complications caused by radiation of the spinal cord are ascribed to progressive, irreversible damage to the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in irradiated tissue and has been proven to reduce late radiation injury in several normal tissues when applied during the latent period before complications become manifest. In the present study: (1). the prophylactic potential of HBO; (2). optimal timing of HBO therapy after spinal cord irradiation, i.e. during the latent period; and (3). effect of HBO on the re-irradiation tolerance of the spinal cord were investigated. The rat cervical spinal cord was locally X-ray irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10) included: irradiation alone and irradiation followed by 30 HBO treatments (100% oxygen at 240 kPa for 90 min) during latency, with HBO starting either immediately, 5, 10 or 15 weeks after the primary irradiation course. One year after the primary treatment, the same spinal cord volume was re-irradiated with 20 Gy single dose. During life span, the animals were observed on the incidence of myelitis and the duration of the latent period. The actuarial analysis revealed no significant difference in neurological complications free survival between the irradiation alone and the irradiation+HBO treatment groups. A tendency towards radiosensitization was found in the group in which the primary irradiation course was immediately followed by the HBO treatment course. The data show that HBO applied during the latent period of progressively developing irradiation damage to the spinal cord does not increase the re-irradiation tolerance of this tissue.     

Radiation necrosis of the mandible: A 10 year study. Part II. Dental factors; onset,duration and management of necrosis

In a review of patients receiving radiation for cancer in the oral region the rate of radiation necrosis of the mandible was found to be similar for patients who had dental extractions before radiation therapy and for the remainder of the dentate population. It was suggested that diseased teeth should be removed prior to irradiation and sufficient healing time should be allowed. Teeth should not be extracted after irradiation. Dental prostheses can be provided for most irradiated patients if adequate care is exercised. The probability of necrosis commencing was highest three to twelve months after the start of therapy, it diminished gradually after that period. The duration of necrosis was depicted as an exponential curve with a constant probability of necrosis termination at each time point after onset. In 46.8 % of the patients in study II (1971–19751, the necrosis was healed by conservative means. This was a significant increase over study I (1966–1969), and a complementary reduction in the necessity for surgical intervention was also found.     

Dental preservation in patients irradiated for head and neck tumours: A 10-year experience with topical fluoride and a randomized trial between two fluoridation methods

Since 1972, the dentures of 935 patients irradiated for head and neck carcinoma have been preserved after careful selection and according to well-defined criteria, using a prospective programme of daily applications of topical sodium fluoride gel. The results of 1-10 years follow-up are given. Four percent of the patients developed a diffuse dental decay and 1% a bone necrosis which can be related to the dental preservation. None of these complications occurred with careful patient selections nor when programme compliance was maintained. Post-irradiation dental extractions were performed in 29 cases with subsequent healing in all cases but one. The surgical technique of such extractions is described. In March 1980, a randomized protocol was activated to compare the use of the sodium fluoride gel to high content fluoride toothpaste (1350 ppm F-). Two hundred and twenty patients were entered. At 12-36 months follow-up, dental caries were observed in 3% of the patients receiving the fluoride gel as compared to 11% receiving the toothpaste (p = 0.1). However, none of the patients adhering to the programme instructions failed in either arm. Currently, it seems reasonable to state that preservation of teeth in irradiated patients should be the rule and not the exception, given good dental condition prior to treatment and patient cooperation. The 5 min daily application of fluoride gel is the most reliable method for prevention of post-irradiation dental caries. The twice daily use of high content fluoride toothpaste is a good alternative provided its limitations are well understood by the clinician and patient.     

Oral complications of cancer therapies. Chronic dental complications

Radiation therapy (RT) and chemotherapy have increased long-term survival with certain cancers. The use of dental investigation and treatment of chronic or delayed oral complications is developing. Altered dental root development, enamel opacities, hypocalcifications, periodontal problems, and a higher caries rate are seen in children treated with chemotherapy. The psychosocial implications of long-term survival on routine dental care are important. Prevention and treatment of long-term oral complications of radiation therapy are changing. Osteoradionecrosis remains complicated and devastating. Strategies that avoid post-RT extractions include caries prevention, oral hygiene measures, meticulous restorative dentistry, overdentures, and improved posts for endodontically treated teeth. Guidelines for post-RT extractions vary greatly. Pediatric patients who receive head and neck irradiation may have total arrest of tooth and jaw development within the portal. The dentist must be able to diagnose and treat the variety of alterations already identified and should engage in scholarly research to answer the questions that remain.     

A clinical staging system and treatment guidelines for maxillary osteoradionecrosis in irradiated nasopharyngeal carcinoma patients

PURPOSE: To develop a clinical staging system for maxillary osteoradionecrosis (ORN) in irradiated nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: The data of maxillary ORN cases among 1,758 irradiated NPC patients were analyzed. A staging system based on the degrees of bone exposure (E), infection (I), and bleeding (B) was developed. Correlations between various clinical parameters and stages of maxillary ORN and relationships between treatment modalities and outcomes at each stage were evaluated. Cumulative success of treatment and risk factors that affect treatment outcomes were analyzed. RESULTS: The incidence of maxillary ORN was 2.7% (48/1,758). TNM stage of NPC (p < 0.001), radiation dose (p = 0.029), and tooth extraction (p < 0.001) appeared to have significant influences on disease severity. Success rates between conservative therapy and surgical treatment were not significantly different for Stage I ORN but differed significantly for Stage II (p = 0.013) and Stage III (p = 0.008) lesions. Grade 3 infection and bleeding significantly jeopardized treatment success (p = 0.043 and 0.015, respectively). The risk ratios of treatment failure for Grade 3 infection and bleeding were 2.523 (p = 0.034) and 3.141 (p = 0.027), respectively. CONCLUSIONS: More serious maxillary ORN tended to occur in cases with more advanced NPC, higher radiation dose, and history of tooth extraction. Surgical treatment was usually required in Stage II and III ORN. The grades of infection and bleeding are important factors in guidance of treatment and prediction of outcomes.     

Effects of sucking acidic candies on saliva in unilaterally irradiated pharyngeal cancer patients

Patients who have received radiation therapy on the head and neck area often use acidic candies to relieve symptoms of dry mouth. Therefore, the aim of this study was to determine the erosive potential in relation to teeth of an acidic candy in 10 such patients. The patients sucked the candy while their whole saliva was collected into a closed system at different times: baseline, candy-stimulated, and post-stimulated. The erosive potential of the candy was evaluated from candy-induced changes in saliva degree of saturation with respect to hydroxyapatite (HAp). Previously published normative values were used for comparison. The results showed that saliva became significantly more undersaturated with respect to HAp in irradiated patients, and failed to return to baseline values during the post-stimulatory period, which it normally does in healthy individuals. Thus, prevention of dental breakdown in these patients should involve counseling regarding choice of stimulant for dry mouth relief.     

Dent et irradiation : prévention et traitement des complications dentaires de la radiothérapie y compris l’ostéoradionécrose

Pre-irradiation dental care depends on teeth health, fields and dose of irradiation, compliance to fluorides, cessation of tobacco and psychosocial cofactors. Dental care aims at preventing complications and preserving the quality of life (eating, speech, and aesthetics). The role of hyperbaric oxygenotherapy for the prevention of osteoradionecrosis after teeth removal on the mandibula in areas receiving 50 Gy or more is still controversial. Medical treatments may be sufficient for early stages of osteoradionecrosis (antibiotics, pain killers, non-steroidal anti-inflammatory drugs as well as clodronate, vitamin E, pentoxifyllin). However, reconstructive surgery should not be delayed in advanced stages of osteoradionecrosis. New irradiation techniques are changing dose distributions and therefore require close collaboration between odonto-stomatologists and radiation oncologists to define the best dental care.     

Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy.

BACKGROUND: Radiation-induced carotid stenosis in patients with head and neck tumors can cause significant mortality and morbidity. This study examined the incidence of stenosis in the extracranial carotid arteries of nasopharyngeal carcinoma patients after radiotherapy. METHODS: The extracranial carotid arteries of 71 (53 male and 18 female; mean age of 53.6 years) postradiation patients with nasopharyngeal carcinoma were examined with color Doppler ultrasound. The distribution of the arterial stenosis and the degree of stenosis were documented. The results were compared with the control group, which comprised 51 newly diagnosed nasopharyngeal carcinoma patients (35 male and 16 female, mean age of 48.8 years) before radiotherapy. Incidences of risk factors for arterial stenosis such as hypertension, smoking, and hypercholesterolemia also were studied in these two groups. RESULTS: There was no significant difference in the incidence of risk factors between the two groups. Arterial stenosis was, however, more common in the postradiation group than the preradiation group (56 of 71 vs. 11 of 51). The common/internal carotid arteries (CCA/ICA) were most commonly involved (55 of 71 vs. 11 of 51; P < 0.01), followed by the external carotid artery (ECA) (32 of 71 vs. 1 of 51; P < 0.01) and vertebral artery (VA; 5 of 71 vs. 0; P = 0.069). Significant stenosis (> 50% reduction of luminal diameter) was only found in the postradiation group (21 of 71 in CCA/ICA, 11 of 71 in ECA, 4 of 71 in VA). CONCLUSIONS: This study showed that radiation could cause significant carotid stenosis. Ultrasound examinations for these patients therefore are necessary for early detection and possible intervention of this late radiation-induced complication.     

Effect of prophylactic hyperbaric oxygen treatment for radiation-induced brain injury after stereotactic radiosurgery of brain metastases

PURPOSE: The purpose of the present study was to evaluate the prophylactic effect of hyperbaric oxygen (HBO) therapy for radiation-induced brain injury in patients with brain metastasis treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: The data of 78 patients presenting with 101 brain metastases treated with SRS between October 1994 and September 2003 were retrospectively analyzed. A total of 32 patients with 47 brain metastases were treated with prophylactic HBO (HBO group), which included all 21 patients who underwent subsequent or prior radiotherapy and 11 patients with common predictors of longer survival, such as inactive extracranial tumors and younger age. The other 46 patients with 54 brain metastases did not undergo HBO (non-HBO group). The radiation-induced brain injuries were divided into two categories, white matter injury (WMI) and radiation necrosis (RN), on the basis of imaging findings. RESULTS: The radiation-induced brain injury occurred in 5 lesions (11%) in the HBO group (2 WMIs and 3 RNs) and in 11 (20%) in the non-HBO group (9 WMIs and 2 RNs). The WMI was less frequent for the HBO group than for the non-HBO group (p = 0.05), although multivariate analysis by logistic regression showed that WMI was not significantly correlated with HBO (p = 0.07). The 1-year actuarial probability of WMI was significantly better for the HBO group (2%) than for the non-HBO group (36%) (p < 0.05). CONCLUSIONS: The present study showed a potential value of prophylactic HBO for the radiation-induced WMIs, which justifies further evaluation to confirm its definite benefit.     

Chemotherapy-induced neutropenia in lung cancer patients: the role of antibiotic prophylaxis

Chemotherapy-induced neutropenia can cause fatal bacterial infections. Colony-stimulating factors (CSFs) are usually recommended as prophylaxis, while routine use of prophylactic antibiotics remains controversial. Based on our literature search in PubMed, quinolones and trimethoprim/sulfamethoxazole were the most frequently used prophylaxis, while CSFs were administered in 22.1% of patients. Lung cancer patients who received prophylactic antibiotics exhibited significantly fewer episodes of febrile neutropenia, fewer documented infections as well as shorter duration of related hospitalisations. Prophylactic use of wide spectrum antibiotics seems effective and should be considered as an alternative strategy in the prevention of chemotherapy-induced neutropenia in lung cancer patients.     

Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923).

BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.     

The acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous flap used in immediate breast reconstruction

Purpose: To analyze the acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous (TRAM) flap reconstruction following modified radical mastectomy for breast cancer.

Methods and Materials: Twenty-five consecutive patients were treated with postoperative radiation therapy after TRAM flap reconstruction between 1985 and 1999. The radiation records for these patients were retrospectively reviewed. Information regarding treatment techniques, timing, and dose was obtained and correlated with the extent of erythema, desquamation, and the need for treatment break.

Results: The median age was 48 years. The median dose of chest wall radiation was 5040 cGy. Additional boost doses were delivered in 13 patients. Twelve patients (48%) developed mild erythema in the treatment field during the course of treatment and 13 patients (52%) developed moderate (40%) or brisk (12%) erythema. Only 10 patients (40%) developed any kind of desquamation; 5 patients (20%) developed dry desquamation and another 5 patients (20%) developed moist desquamation. No patients required a break in the course of treatment because of acute side effects. None of the parameters evaluated (the use of chemotherapy prior to radiation, the interval between surgery and radiation, smoking, prior incidence of fat necrosis, the use of bolus during radiation, and the use of a boost) were predictive of an increased incidence of either the extent of erythema or the development of desquamation in the treatment field.

Conclusion: Postmastectomy radiation for TRAM flap reconstruction is well tolerated and is not associated with an increased incidence of acute side effects. Radiation technique and the use of preradiation chemotherapy do not appear to be correlated with an increased incidence of acute side effects.