Search for residual prostate cancer on pT0 radical prostatectomy after positive biopsy

Reported incidence of no residual prostate cancer (i.e. pathological stage pT0) on radical prostatectomy ranges from 0.07 to 4.2%. The incidence is higher after neoadjuvant endocrine treatment. The aim of this study was to search for residual cancer on radical prostatectomy (RP) specimens when an initial sampling failed to find the cancer in patients with positive biopsy. Our database of 1,328 consecutive patients whose biopsies and RP specimen were both examined at the Polytechnic University-United Hospitals of the Marche Region between March 1995 and June 2006 was reviewed. The radical prostatectomies were grossly completely sampled and examined with the whole mount technique. We identified eight patients (i.e. 0.6%; three untreated and five hormonally treated preoperatively, i.e. 0.3 and 0.8%, respectively, of the total number of RPs included in the study) with positive biopsy and with no residual cancer in the initial routine histological examination of the RP. The RP of this group of eight was subjected to additional sectioning and evaluation of the paraffin blocks of the prostatectomy, also after block-flipping, immunostaining with an antibody against CAM 5.2, p63, PSA, and alpha-methylacyl-CoA racemase, and DNA specimen identity analysis. There were no cases with a false positive biopsy diagnosis, and cancer was not overlooked or missed in the initial routine histological examination of any of the 8 pT0 RPs. A minute focus of cancer (the diameter was always below 2.0 mm) was found on the additional sections in five. In particular, cancer was found after block-flipping in one of them. In an additional case, cancer was eventually discovered after immunostaining tissue sections for cytokeratin CAM 5.2, for p63 and PSA. In the remaining two cases (one untreated and the other hormonally treated), cancer was not found (0.15% of the 1,328 RPs included in the study); the review of the description of the macroscopic appearance of the RP and of its slides revealed that part of the peripheral zone corresponding to the site of the positive biopsy was missing, i.e. not removed from the patient at the time of the operation at least in one of the two. DNA specimen analysis confirmed the identity of the biopsy and prostatectomy in both. An extensive search for residual cancer reduces the number of pT0 RPs after a positive biopsy from 0.6 to 0.15%. It is recommended to have the needle biopsy reviewed, carefully look again at the radical prostatectomy, do deeper sections and then flip certain paraffin blocks. In addition, atypical foci should be stained for basal cell markers and often AMACR, especially in hormone-treated cases. If a block is missing part of the peripheral zone (capsular incision), this should be commented on. DNA analysis for tissue identity should be performed when the other steps have been taken without finding cancer.
Introduction
In 1995, Goldstein et al. [9] introduced the term vanishing cancer phenomenon referring to cases with minute or no cancer on radical prostatectomy after a positive biopsy. They reported 13 patients with minimal (11 patients) or no (two patients) cancer in prostatectomy specimens. In two cases with no residual cancer on RP, they confirmed the identity of the biopsy and the prostatectomy tissue by DNA matching.
The Johns Hopkins Hospital group documented a fivefold increase in the incidence of no residual cancer on prostatectomy in patients in whom both biopsies and prostatectomies were performed at that institution between 1997 and 2005 (0.07% in 1997, 0.13% in 2004 and 0.34% in 2005) [5, 7, 30]. In their first study, they also documented two cases, one in which the biopsy review revealed only high-grade PIN and in which a diagnosis of cancer had been established in another institution, and a second case in which the possibility of specimen switching could not be ruled out due to DNA mismatch between the biopsy and the prostatectomy. Most recently, they have reported a series of 46 patients, 11 with no residual cancer on prostatectomy and 35 with minute cancer, and in 40 cases, they documented specimen identity [5]. In five of the six remaining cases, the results could not be interpreted due to technical problems, and in one case, the tissue from the biopsy with cancer did not match the tissue from the radical prostatectomy.
Bostwick and Bostwick [4] found that 38 patients with no cancer on prostatectomy, identified among 6,843 radical prostatectomies performed at Mayo Clinic during a 30-year period, showed no disease recurrence or progression after a mean follow-up of 10 years. In their experience, the incidence of vanishing cancer declined tenfold, comparing prostatectomies performed before 1980 (2.1% incidence) to a more recent time interval from 1993 to 1995 (0.2% incidence). They have estimated the current incidence of vanishing cancer at 2 per 1,000 radical prostatectomies [4].
Recently, Trpkov et al. [28] found an incidence of no residual cancer on prostatectomy of 0.67% after ten-core positive biopsy. They concluded that in most cases, finding no residual cancer on prostatectomy after additional sectioning and evaluation may indicate minimal patient disease. Very recently Zynger et al. [32] reported that their frequency of finding no residual cancer in RP specimens has increased from 0% in 2002 to 4.2% in 2006. In Canada, Srigley [25] has estimated the incidence of no residual cancer after positive biopsy in his practice at less than 0.5%.
In Germany, the incidence of pT0 in patients with prostate cancer without neoadjuvant treatment was analysed by Herkommer et al. [13]. Based on a database of 3,609 patients, no residual prostate cancer was found in 0.8% after RP. Most men in this pT0 series had previous TURP or open prostatectomy, which may have eliminated prostate cancer, whereas in two patients, cytology was used for primary diagnosis. Only in 0.3% of men with positive prostate needle biopsies was no residual tumour detected in the prostatectomy specimen [13]. The incidence of pT0 patients in a very recent French study was reported to be 0.5% [6].
No residual cancer may also result from preoperative endocrine therapy [11, 12, 15, 16, 19, 24, 26]. The incidence of pT0 after neoadjuvant endocrine therapy for prostate cancer is reported to be higher than in untreated patients [11]. Kollermann et al. [16] analysed a group of 174 men who underwent prolonged androgen deprivation therapy and observed a pT0 in 36 of 174 men (21%).
Several questions are addressed to explain why cancer is not present in a small proportions of prostatectomies. Cancer is missed during the examination of the RP, all prostatectomy tissue is not sampled, and the cancer is overdiagnosed in the biopsy. Pathologists face additional challenges in eliminating the possibility of laboratory error resulting in specimen (blocks, slides) mislabelling or switching and excluding an information system error resulting in specimen mix-up [28].
The aim of this paper was to report the results of a search for residual cancer on RP after an initial stage pT0 evaluation in eight patients with positive biopsy.
Materials and methods
We reviewed our database of 1,328 consecutive patients whose biopsies and RP specimen were examined between March 1995 and June 2006 at the five Pathological Anatomy Services associated with the Polytechnic University-United Hospitals of the Marche Region, Ancona, Italy. Most of the biopsies and all the RPs of this series of 1,328 patients were reported by the same pathologist (RM). Seven hundred patients were untreated before the operation, whereas 628 had received neoadjuvant endocrine treatment for approximately 3 to 6 months.
The biopsies and RPs were routinely processed as follows. The core biopsies from each site were submitted in separate containers. In brief, during biopsy processing, no more than two biopsy cores were embedded in paraffin blocks, and all blocks were sectioned at 3 μm and were stained with haematoxylin–eosin (HE). All cores were sectioned in two separate levels represented on separate slides, with each slide containing three additional sections [28].
All radical prostatectomy specimens (tissue was not harvested for research) were fixed en bloc in 10% buffered formalin for at least 24 h and were grossly completely sampled using a standard protocol [17, 18, 28]. In particular, each specimen was painted over the surface with India ink. The seminal vesicles were amputated at the prostate junction and were grossly completely sampled. The remainder of the specimen was serially cut with a domestic electric food slicer calibrated and set to deliver slices which are 3–4 mm in thickness, representing transverse planes parallel to the initial apical and basal sections. Each prostate slide was processed into complete whole mount section, and one HE slide was routinely sectioned per block. The apical and basal transverse 2- to 3-mm margins were sectioned perpendicularly to assess the prostatic apical and basal margins. Prostatectomies were grossly sectioned in 8.5 slices (mean; range, 6–16), and 15.3 slides (mean; range, 10 to 20) were generated per prostatectomy. Slides from pelvic lymph nodes were not included in the reported number of examined slides.
We identified eight patients with positive 6- to 12-core biopsy and with no residual cancer (pathological stage pT0) in the initial routine histological examination of the RP and successively subjected to additional sectioning and evaluation.
Search for residual cancer
Since 1995, a special cancer searching protocol has been applied to those RPs in which an initial routine-based examination does not show residual cancer [18]. As mentioned earlier, this is basically done in those cases whose biopsies and RP specimen are both examined at the Ancona institution.
The following successive steps were undertaken by two pathologists (RM and RMa). The procedure was usually stopped at the step where cancer is found.
The diagnostic needle biopsies were reviewed to exclude the possibility of a false positive biopsy diagnosis and to assess the approximate location of the biopsy with tumour, such as apex, mid-zone and base, both left and right.The slides of the surgical specimens were reviewed for residual cancer that was initially overlooked or missed.If the prostate was not totally embedded, the remaining prostate tissue was processed in toto. If the prostate was completely sampled, then this step was skipped. This type of information was usually contained in the pathology form where the all the steps of the processing procedure were recorded. The information was further confirmed by searching the specimen’s container for residual pieces. As we routinely sample completely all prostatectomies, this step was skipped.Additional deeper sections (i.e. three to five sections) of the prostatectomy area (paraffin block) corresponding to the location of the core with cancer were re-cut. Further sections were also obtained from all the other paraffin blocks.Additional deeper sections (i.e. three to five sections) of the area corresponding to the location of the positive core as well as of all the remaining blocks were re-cut after block-flipping.Immunostains for p63 and alpha-methylacyl-CoA racemase (AMACR) were performed to evaluate suspicious foci (When these two were not yet available, we used 34betaE12 immunostaining).Immunostain for cytokeratin CAM 5.2, for p63 and for PSA (prostate specific antigen) was performed to identify the so-called “minimal residual cancer” especially in patients receiving neoadjuvant hormonal therapy [17].Review the description of the macroscopic appearance of external and cut surfaces of the surgical specimen as well as inspect the contour of the tissue sections on the slides for hint or clues that might indicate that part of the tissue was missing either due to the surgical procedure or for technical reasons.DNA specimen analysis was performed on formalin-fixed tissue to confirm the identity of the biopsies and prostatectomies whenever necessary.
DNA specimen identity analysis
Tested samples in an individual case included the biopsy core with cancer and a random block for the corresponding RP. The tissue was obtained as a direct section from formalin-fixed and paraffin-embedded blocks. DNA was extracted from paraffin-embedded tissue using the QIAmp DNA mini kit (Qiagen) according to manufacturer’s protocol (Promega, Madison, WI, USA). Fifteen microsatellites and amelogenin locus were co-amplified by the AmpFlSTR identifiler kit (Applied Biosystems, Foster City, CA), and the amplified fragments were electrophorized on an ABIPrism3130 genetic analyzer (Applied Biosystems). Fragment sizing and allele designation were established by GeneMapperID v3.2 software (Applied Biosystems), and genetic profiles from both biopsy and prostatectomy samples were compared.
Results
Residual cancer was not found in eight RPs after an initial routine examination. They represent 0.6% of the 1,328 consecutive patients. Three (0.2%) of them were from the group of untreated patients, whereas five (0.4%) were from those who had received neoadjuvant treatment. The latter figure represents 0.8% of the treated patients.
Patients’ clinical data are summarised in Table 1. The mean age of the patients was 65 years (range, 58–71 years). Mean serum PSA pre-biopsy was 5.1 ng/ml (range, 1.25–9.0 ng/ml). Mean gland volume was 43.9 ml (range, 28.1–93.5 ml). Digital rectal examination was abnormal in 37% of patients, and 25% of patients had abnormal transrectal ultrasound.
Table 1Patients’ clinical dataPatient no.Age (years)PSA Prebiopsy (ng/ml)Digital rectal examinationTRUSGland volume (cc)1689.0AbnormalNormal47.92715.4NormalAbnormal31.43646.1NormalNormal28.14671.25AbnormalNormal93.55605.9NormalNormal36.66663.0AbnormalNormal47.97583.9NormalAbnormal29.38666.5NormalNormal36.6Mean (range)65 (58–71)5.1 (1.25–9.0)43.9 (28.1–93.5)PSA Prostate-specific antigen; TRUS transrectal ultrasound
Patients’ biopsy findings are shown in Table 2. In all patients, carcinoma was found in one core. Seven patients demonstrated biopsy Gleason score of 6 (3 + 3), whereas in one, it was 7 (3 + 4). Cancer occupied approximately 5% of the core length (Fig. 1) in 6 and 10% of the core in two. The positive biopsy location was variable, and there was no side predilection.
Table 2Biopsy findingsPatient no.No. of positive coresGleason scoreCancer length (% of involvement)Positive core location11/123 + 3 = 65Right apex21/103 + 4 = 710Right apex31/63 + 3 = 65Left mid-zone41/63 + 3 = 65Right mid-zone51/63 + 3 = 65Right mid-zone61/123 + 3 = 610Left mid-zone71/103 + 3 = 65Right mid-zone81/123 + 3 = 65Left baseFig. 1Biopsy finding of a small groups of atypical acini (a) devoid of basal cells (b). Section immunostained for p63 (case no. 5). The diagnosis is acinar adenocarcinoma, Gleason score 3 + 3 = 6. (The prostatectomy findings are those seen in Fig. 2)
Search for residual cancer
There were no cases with a false positive biopsy diagnosis (step 1). Cancer was not overlooked or missed in any of the eight prostatectomies (step 2). Each prostate had been totally embedded (step 3).
Cancer was found on deeper sections (steps 4 and 5) in five cases. Cancer was in the right and left apex, respectively, in two of them. Cancer was in the mid-zone in another two, one in the left and the other in the right. The fifth was in the left base. In particular, the cancer found in the right apex was discovered after block-flipping (i.e. step 5; Fig. 2). The location corresponded to site of the positive biopsy in four cases. Two out of five cases were from the untreated group and showed a Gleason score of 3 + 3 = 6. Three cases had the morphologic appearance of cancer with evident regressive changes due to endocrine therapy. The diameter of the tumour, measured on the slides, was always below 2.0 mm. In one of the three treated cases, an additional focus of cancer was seen at a distance from to that of the positive biopsy.
Fig. 2Paraffin blocks, original sections and additional sections before and after block-flipping in case no. 1. a Is the right apex. b Is the left apex. c Includes the whole mount sections of the body of the prostate. d Is the right and left base. e Includes the seminal vesicles and deferens. A1 is the paraffin block. A2 is the original H-E-stained section. A3 includes the additional sections before block-flipping. A4 refers to the additional sections after block-flipping (Block-flipping was done only for a and b). The dotted area (see also the red arrow) on the A4 slides is that of the cancer. It corresponds to the lesion of the biopsy seen in Fig. 1. The same identification procedure applies to b. Concerning c and d the paraffin blocks, the original sections and the additional sections (block-flipping was not done) are shown. For e the paraffin blocks and the original sections are shown. (Other slides contain some annotations and abbreviations to indicate additional findings, slide orientation, and section order, etc.)
The definitive diagnosis was established on steps 6 and 7 in an additional case (the patient was hormonally treated before RP) where cancer was not seen in the additional sections even after block-flipping. Immunohistochemistry for p63 and AMACR was applied to a small suspicious focus of crowded acini. There were a few scattered p63 positive (basal) cells, whereas AMACR was negative. The focus was considered to be benign (i.e. atrophy). Cancer was discovered after immunostaining for cytokeratin CAM 5.2, for p63 and PSA. It was represented by scattered isolated cells positively immunostained with the antibody against CAM 5.2 (Fig. 3) and with PSA and negative for p63 (Fig. 3). The diameter of the focus was 1.0 mm. The block selected for immunohistochemistry corresponded to an H&E-stained slide with hypercellular stroma. There was no exact correspondence with the site of the positive biopsy.
Fig. 3Cancer is discovered after immunostaining for cytokeratin CAM 5.2 (case no. 6). It is represented by scattered isolated cells. The same cells are negative for the basal cell marker p63 and positive for PSA. Part of an atrophic duct is also present
In the remaining two cases (one untreated and the other treated preoperatively), cancer was not found on steps 4 through 7. The review of the description of the macroscopic appearance and the inspection of the contour of the tissue sections on the slides revealed that part of the peripheral zone of the prostate was missing (Fig. 4). This corresponded to the location of the positive biopsy (step 8). DNA specimen analysis confirmed the identity of the biopsy and prostatectomy in both cases (step 9; Table 3). Incidentally, prostate tissue was documented clinically in one of the two patients (patient no. 7, hormonally treated before operation; the same patient whose prostate is shown in Fig. 4). In particular, a biopsy of the residual fragment showed normal prostate tissue and adenocarcinoma with features identical to those seen in the preoperative biopsy.
Fig. 4Whole mount section (case no 7). Part of the peripheral zone, posteriorly, is missingTable 3Results of the search for residual cancerPatient no.Neoadjuvant treatmentCancer foundID test done1NoIn recutNo2NoIn recutNo3YesIn recutNo4YesIn recutNo5YesIn recut after block-flippingNo6YesAfter cytokeratin stainNo7YesNot in RPaYes, identical8NoNoYes, identicalaA post-operative biopsy of the residual prostate fragment in the patient showed normal prostate tissue and adenocarcinoma with features identical to those seen in the preoperative biopsy.
Discussion
Reported incidence of no residual cancer on RPs ranges from 0.07 to 4.2% (1–11, 20). It is higher after neoadjuvant hormonal treatment [16].
There are multiple reasons why cancer may not be found on RP after a positive biopsy. In some cases, the cancer may be minute and completely removed by the initial procedure, either needle biopsy or transurethral resection of prostate. Small cancers may be removed from the RP during the technical preparation of the specimen, such as leveling of the paraffin blocks. Small cancer foci can also be completely obscured if the patient has undergone antiandrogen therapy or the RP shows extensive inflammation or granulomatous inflammation. Other reasons include false-positive diagnosis on the initial biopsy, resulting in cancer overdiagnosis, or false-negative diagnosis rendered on the RP. Review of the material by a second pathologist or a specialist in urological pathology can often resolve the latter scenario. Lastly, errors may occur either before a specimen is submitted for pathological assessment or in the pathology laboratory. These errors include switching of patients’ requisitions, mislabelling or switching of specimen containers, mislabelling or switching slides or blocks and information system errors (e.g. incorrect case entry in the information system or mixed accession numbers) [28].
In our study, the incidence of RPs with no residual cancer after an initial routine examination of the 1,328 specimens was 0.6%. This figure includes both untreated and hormonally treated patients. The incidence was 0.2 and 0.4%, respectively, of the total number of RPs included in the study, or 0.4% (3 out 700 untreated patients) and 0.8% (5 out 628 treated patients) when the two groups were considered separately. The former is well in the range of values reported in the literature for untreated patients and very close to the figure published by Herkommer et al. [11, 13]. The latter value seen in our treated patients is much lower than that observed by Kollermann et al. [16].
Additional sectioning and evaluation of the cases can reduce the number of pT0 RPs after a positive biopsy. In particular, the current study showed that the final incidence was 0.15% and included only two RPs with missing parts, probably due to incomplete removal of the prostate. One of these two patients was hormonally treated preoperatively.
Our findings on the role of immunohistochemistry to detect residual PCa cells are in agreement with previous studies. Gleave et al. [8] found that 50% of the cases that exhibited no residual cancer on routine pathologic assessment had remaining foci of cancer discovered by immunostaining. Without the aid of additional step sections and immunostaining for cytokeratin, these cases would have been reported as being stage pT0 [2].
DNA identity on formalin-fixed tissue from the paraffin blocks is a useful test to establish specimen identity and to exclude the possibility of laboratory error when no residual cancer is found on RP after a positive biopsy. In particular, DNA analysis is a useful test that eliminates the possibility of specimen mishandling or switching by establishing the identity of the tissue from the positive biopsy and the RP. It can be performed in the formalin-fixed tissue from the paraffin blocks. Different methods are used to investigate tissue specimen identity. These include immunolabeling of blood group antigens [22], sex chromosome targeting using fluorescence in situ hybridization [21] and microsatellite analysis. According to some authors, microsatellite analysis is the gold standard for investigating tissue identity [1, 10, 23, 28, 31].
In our study, the clinical and the biopsy data in patients with no initial residual cancer on radical prostatectomy after positive biopsy are similar to the findings from a recent study in patients with single-core positive biopsies and minimal cancer on biopsy [28, 29]. The majority of patients with no residual cancer on prostatectomy demonstrated minute cancer foci in one or two biopsy cores with Gleason score of 6, which, in many cases, may reflect minimal disease [28]. Rare small-volume cancers of higher grade may also be encountered [28]. Follow-up investigations have, in general, shown that no pT0 patient has clinical or biologic evidence of prostate cancer recurrence or progression [6, 14, 20, 27].
There are four aspects that we have not explored in our study. One is that the carcinoma could be lost in facing off of the paraffin blocks. We are fully aware of this potential problem. Our technicians are instructed so that they have to collect tissue sections and not waste material when the paraffin blocks are levelled off. The second is whether the time, effort and expense of the sampling described in this paper are warranted on a routine basis for all pT0 cases. We have not done any analysis in these respects due to the fact that the number of cases is very small and that time and expense do not represent an issue of concern in our institution. The third is what degree of sampling would be necessary to serially section through the entire prostate. Probably thousands of sections would be required, and we were prepared to cut as many sections as needed to find cancer. The fourth is whether there is an outcome difference when the initial pT0 carcinomas are detected after more thorough sampling vs pT0 cases without additional sampling. This was not addressed in our study because the basic aim was to avoid that a pT0 report is rendered to the clinician and to the patient, thus triggering a potential legal issue with all the problems related to it.
There are few observations in the literature on pT0 cases and preoperative diagnosis of cancer made in TURP specimens. The real incidence of no residual cancer after cancer detected by TURP material is not known and is reported to be seen in 6 to 39% of cases [9], presumably due to tumour ablation during the initial resection. However, studies of this phenomenon are limited by variations in the number of tissue sections submitted for histological evaluation and by the small number of cases [3].
Conclusions and recommendations
The current study showed that an extensive search for residual cancer reduces the number of pT0 RPs after a positive biopsy. To achieve this, it is recommended to have the needle biopsy reviewed, carefully look again at the radical prostatectomy, do deeper sections and then flip certain paraffin blocks. In addition, atypical foci should be stained for basal cell markers and often AMACR, especially in hormone-treated cases. If a block is missing part of the peripheral zone (capsular incision), this should be commented on. DNA analysis for tissue identity should be performed when the other steps have been taken without finding cancer.

residual prostate cancer
prostate cancer
vanishing cancer


Safety of aromatase inhibitors in the adjuvant setting

The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life.
Introduction
Tamoxifen became the standard adjuvant therapy for women with early breast cancer following the first demonstration of efficacy more than 20 years ago [1]. Administration of tamoxifen for 5 years has been shown to reduce breast cancer recurrence by 41% and mortality by 34% in women with hormone-responsive tumors [2]. Nevertheless, many limitations of tamoxifen have emerged with widespread use. In the landmark National Surgical Adjuvant Breast and Bowel Project B-14 trial, 66% of tamoxifen-treated patients experienced side effects compared with 58% of patients given placebo [3]. Severe, potentially life-threatening events such as thrombosis were more likely to occur in patients aged >60 years [3]. Long-term adverse effects associated with 5 years’ adjuvant tamoxifen include venous thromboembolic events, vaginal bleeding, vaginal discharge, ischemic cerebrovascular events, endometrial and uterine cancer, and hysterectomy [3, 4]. Experiencing side effects significantly increases the likelihood of patients discontinuing tamoxifen therapy (odds ratio 4.0; 95% confidence interval [CI] 1.1, 13.9 in women aged ≥ 55 years) [5]. Over time, resistance to tamoxifen may develop [6], and therapy beyond 5 years is not recommended because neither further disease-free survival nor survival benefit is gained [7].
The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are rapidly replacing tamoxifen as initial adjuvant therapy [8, 9] or sequential adjuvant therapy after 2–5 years of tamoxifen [10–13]. By potently inhibiting the aromatase enzyme, which converts androgens to estrogen [14, 15], AIs achieve almost total suppression of total body aromatization and dramatic reductions in estrogen concentrations in postmenopausal women [16–18]. AIs are now recommended in international guidelines for the management of breast cancer [19–21]. In addition, guidance is being developed for the management of common co-morbidities such as osteoporosis in postmenopausal women with hormone-sensitive breast cancer receiving AIs [20, 22]. This review examines the safety of AIs and assesses their advantages and disadvantages compared with tamoxifen. It also considers the impact of treatment on co-morbidities commonly encountered in this population.
Possible impact of treatment on common co-morbidities
Adjuvant therapy should be individualized on the basis of clinical and biologic risk factors [21], including the presence of co-morbidities [23–26]. The most prevalent co-morbidities in the postmenopausal patient population are hypertension, arthritis, heart disease, diabetes, chronic obstructive pulmonary disease, eye problems, anemia, depression, fractures, hearing problems, osteoporosis, Parkinson’s disease, renal failure, and urinary tract problems [25]. Understanding the long-term effects of aromatase inhibition on bone and cardiovascular health are particularly important to consider because of the potential effects of altering estrogen concentrations.
Bone disease
Bone health typically may deteriorate as women age, particularly after reaching menopause [27, 28]. A decline in estrogen concentrations accelerates postmenopausal bone loss [29–31] while vitamin D deficiency also increases bone turnover and the risk of fracture [32, 33]. It is important to note that bone health is compromised in women with breast cancer compared with the general population [34]. In the Women’s Health Initiative Observational Study, breast cancer survivors had significantly lower total body bone mineral density (BMD) and total hip BMD [34] and a significantly higher risk of clinical fractures [35]. Of concern, osteoporosis was undiagnosed in more than three quarters of breast cancer survivors and the reference population [34]. Multiple factors contribute to the increased risk of osteoporosis and fractures in postmenopausal women with breast cancer [34]. Furthermore, tumor cells can have a direct effect on bone remodeling [36], and breast cancer therapy can lead to cancer treatment-induced bone loss (CTIBL) [37–39]. In a large cohort study, patients with early breast cancer who received anticancer therapy had a 30% higher risk for osteoporosis/osteopenia (odds ratio 1.29; 95% CI 1.13, 1.46) [38]. The study also showed that other factors such as poor health status, history of smoking, and alcohol abuse can contribute to CTIBL. The most serious consequence of CTIBL is an increased risk of fractures (Fig. 1) [35], which increase morbidity and healthcare costs [40]. The presence of bone metastases can contribute to CTIBL and lead to serious complications, including fractures, spinal compression, bone pain, and hypercalcemia of malignancy [41].
Fig. 1Age-standardized fracture incident rates by survivor status. Standardized rates were calculated using the age distribution of the entire Women’s Health Initiative Observational Study cohort. Excess numbers of fractures per 10,000 person-years are above each set of bars [35]. ©2005 American Medical Association. Reproduced with permission
Aromatase inhibitors and bone disease
In a recent study, the bone health of 1,354 patients with breast cancer receiving an AI (anastrozole, exemestane, or letrozole) was compared with 11,014 controls [39]. Treatment with an AI increased the risk of bone loss (relative risk 1.3; 95% CI 1.1, 1.6; P = 0.01) and bone fracture (relative risk 1.4; 95% CI 1.2, 1.6; P = 0.001). The risks remained significantly higher for AI therapy after adjustment for age and co-morbidities [39]. An increase in the incidence of arthralgia is noted with all three AIs, when compared with tamoxifen.
Anastrozole
Howell and colleagues reported fracture rates after a median follow-up of 68 months in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial [42]. Fractures were reported in 577 (9.3%) of the 6,186 patients and were more common with anastrozole than with tamoxifen (11 vs. 8%, respectively; P < 0.0001). The incidence of hip fractures was 1% in both groups. The rate of fractures was low at approximately 2% per year and decreased to baseline levels after completion of 5 years of treatment. The effects of anastrozole and tamoxifen on BMD were assessed in a sub-analysis of 167 patients from the ATAC trial [43]. Anastrozole-treated patients had significant decreases in lumbar spine BMD (−8.1%; 95% CI −10.1, −6.1; P < 0.0001) and total hip BMD (−7.4%; 95% CI −9.6, −5.3; P < 0.0001) relative to tamoxifen-treated patients, in whom small increases were observed. Bone loss was greatest in the first 2 years of anastrozole treatment, as reported previously [44], but the rate of loss appeared to slow down from years 2 to 5. In the updated analysis after a median follow-up of 68 months, osteopenia or osteoporosis was reported in 11% of patients receiving anastrozole compared with 7% receiving tamoxifen (P < 0.0001) [42, 45]. Another sub-analysis of the ATAC trial showed that the majority of joint symptoms occur within 24 months of initiating treatment [46]. After 68 months’ median follow-up, joint symptoms were reported in 35.6 and 29.4% of patients in the anastrozole and tamoxifen arms, respectively. Most symptoms were mild in intensity, and 46% were reported as an exacerbation of a pre-existing condition. The incidence of serious joint symptoms was similar for anastrozole and tamoxifen (10.6 vs. 10.4%, respectively) and only 2.1 and 0.9%, respectively, discontinued treatment because of joint symptoms. After a median follow-up of 68 months, muscle cramps were less common with anastrozole than tamoxifen (4 vs. 8%, respectively; P < 0.0001), whereas carpal-tunnel syndrome was more common with anastrozole (3 vs. 1%, respectively; P < 0.0001) [42].
These updated results from the ATAC trial confirm that AIs are a well-tolerated initial treatment option in terms of bone health [43, 45, 46]. Although anastrozole is associated with BMD loss, no patient with normal bone at baseline became osteoporotic after 5 years of treatment, and the rate of bone loss in the lumbar spine region slowed down in years 2–5.
The ARNO/ABCSG8 trials investigated the efficacy and safety of switching to anastrozole after 2 years of tamoxifen [12]. Although there were significantly more fractures in patients switching to anastrozole (2.1%) than in those continuing on tamoxifen (1.0%) [12], the rate was lower than that seen at a similar point in the ATAC trial [12]. In the Italian Tamoxifen Anastrozole (ITA) trial, switching to anastrozole after 2–3 years of tamoxifen was not associated with an increase in fracture rate, although differences may emerge with longer follow-up [13].
Letrozole
In the Breast International Group (BIG) 1–98 trial of initial adjuvant therapy, there was a slight yet significant difference in the incidence of fractures (5.7% with letrozole vs. 4.0% with tamoxifen; P < 0.001) [8]. The MA.17 trial of extended adjuvant therapy showed that when compared with placebo, letrozole had no significant impact on fractures [10]. There was a small but significant difference in patient-reported diagnoses of new-onset osteoporosis (8% letrozole vs. 6% placebo, P = 0.003), and arthralgia and myalgia were significantly more common with letrozole than placebo [10]. A companion study to MA.17 demonstrated a significant decrease in lumbar spine BMD (−5.35 vs. −0.70%; P = 0.008) and total hip BMD (−3.6 vs. −0.71%; P = 0.044) over 2 years in patients treated with letrozole compared with placebo, although no patient went below the threshold for osteoporosis in total hip BMD [47]. Data from this companion study suggest that women with a BMD score of −1.0 or greater when starting letrozole after tamoxifen are less vulnerable to enhanced bone resorption and may not require prophylactic bisphosphonate therapy.
Exemestane
In a model of ovariectomized rats, the steroidal AI exemestane was shown to prevent bone loss, presumably via its androgenic properties (both exemestane and its metabolite 17-hydro-exemestane demonstrate affinity for the androgen receptor) [48]. However, a randomized study to compare the effects of progestins and AIs on bone remodeling markers in patients with metastatic breast cancer found that exemestane increased osteoclast activity [49]. In the adjuvant treatment setting, a randomized trial involving 147 patients with early breast cancer demonstrated a non-significant effect of exemestane compared with placebo on the annual rate of BMD loss in the lumbar spine (2.17 vs. 1.84%; P = 0.568) and a small but significant effect in the femoral neck (2.72 vs. 1.48%; P = 0.024) [50]. Of note was the finding that BMD may rapidly improve following AI discontinuation: this trial showed that bone resorption markers returned to or below baseline values, and bone formation markers remained moderately increased within 6 months of stopping exemestane [51].
In the Intergroup Exemestane Study (IES) of exemestane following 2–3 years of tamoxifen, fractures were reported more frequently with exemestane than with tamoxifen after a median follow-up of 30.6 months, although this difference was not statistically significant (3.1 vs. 2.3%; P = 0.08) [52]. However, the difference in incidence of fractures was statistically significant (7.0% with exemestane vs. 4.9% with tamoxifen; P = 0.003) after a median follow-up of 55.7 months [11]. The incidence of osteoporosis was also significantly higher with exemestane than with tamoxifen (9.2 vs. 7.2%, respectively; P = 0.01). Recent results from a 1-year sub-study revealed that patients on exemestane experienced a significant decrease in hip BMD, while patients on tamoxifen did not [53]. These results were confirmed by another recent study, which evaluated the effects of exemestane on bone turnover markers and BMD in 70 postmenopausal women (62.0 ± 8.9 years) with early breast cancer who were switched to exemestane after 2–3 years on tamoxifen [54]. Patients in the exemestane group had a significant decrease in BMD and early parathyroid hormone (at month 6) and an increase in bone alkaline phosphatase (B-ALP) and the carboxy-terminal telopeptide of type I collagen after 24 months. These studies suggest that switching postmenopausal women from tamoxifen to exemestane causes a marked increase in bone turnover markers with a consequent reduction in BMD.
Arthralgia was also significantly more common with exemestane than with tamoxifen (5.4 vs. 3.6%, P = 0.01) in the IES [52]. A study by Lønning et al. discovered a high prevalence of vitamin D deficiency in postmenopausal women treated with exemestane (52 of 59 patients) or placebo (56 of 62 patients), and this could be the most important factor causing bone loss in both groups [55]. Vitamin D substitution is therefore recommended for postmenopausal women, particularly those with breast cancer receiving an AI. The incidence of carpal-tunnel syndrome in the IES was higher in the exemestane arm (2.8%) than in the tamoxifen arm (0.4%; P < 0.001) [11].
Comparative studies of aromatase inhibitors
A randomized trial (Letrozole, Exemestane, and Anastrozole Pharmacodynamics [LEAP]) of healthy volunteers demonstrated that letrozole, exemestane, and anastrozole have similar effects on bone biochemical measurements and all result in increases in bone turnover [56]. There were no statistically significant differences between the AIs in changes from baseline to 24 weeks for B-ALP, serum C-telopeptide crosslinks, and propeptide of type I procollagen. The only difference in the bone remodeling markers was a greater decrease in parathyroid hormone with exemestane than with anastrozole (P = 0.04).
Thus, all AIs seem to have similar effects on bone health. The ATAC bone sub-study results are reassuring for the entire AI class, and women with breast cancer who have normal BMD measurements at the onset of AI treatment may be able to undergo 5 years of therapy without the risk of developing osteoporosis. Patients at risk of clinically relevant BMD loss during treatment should be identified and managed according to evolving clinical guidelines [20, 57].
Bisphosphonates
In the American Society of Clinical Oncology (ASCO) guidelines postmenopausal patients with breast cancer who receive AIs are identified as being at high risk for osteoporosis, and it is recommended that they have baseline BMD evaluation and regular monitoring to guide subsequent therapeutic interventions such as bisphosphonates [20, 58]. Preliminary results have been reported from a small number of clinical trials of bisphosphonates in women receiving adjuvant AI therapy. In one trial, premenopausal breast cancer patients receiving goserelin plus anastrozole or goserelin plus tamoxifen were randomly assigned to the bisphosphonate zoledronic acid (ZA) (4 mg IV every 6 months) or placebo. After 36 months, it was shown that ZA given every 6 months helped prevent bone loss in these premenopausal patients in both the lumbar spine and hip regardless of endocrine therapy [59]. Two randomized trials have shown that bisphosphonates may be beneficial in postmenopausal patients at a higher risk of osteoporosis [60, 61]. In the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) (North American) trial, 602 postmenopausal women with hormone-responsive breast cancer starting adjuvant therapy with letrozole were randomized to receive upfront ZA (4 mg IV infusion every 6 months) or delayed ZA when indicated (either post-baseline T-score decreases < −2 SD or occurrence of fracture) [60, 62]. Preliminary results after 12 months’ follow-up indicate that initial treatment with ZA may be used to prevent CTIBL, and results at 24 months confirm these initial findings [62, 63] although the rate of clinical fractures was not changed. In addition, the small proportion of patients (8%) requiring ZA in the first year highlights the short-term bone tolerability of letrozole [62]. Results from the similarly designed ZO-FAST (European; N = 1,065) trial also support the use of ZA to potentially manage CTIBL in postmenopausal women with early breast cancer receiving adjuvant letrozole [61].
Lipid metabolism: A cohort study demonstrated that total and low-density lipoprotein (LDL) cholesterol concentrations are positively correlated with years since diagnosis of breast cancer [64]. In addition, during menopause, women experience adverse changes in cardiovascular risk factors, including declines in concentrations of high-density lipoprotein (HDL) cholesterol and increases in concentrations of total cholesterol, LDL cholesterol, HDL3 cholesterol, and triglycerides [65, 66]. These changes are independent of age and body mass index.
Assessing the impact of AIs on lipid profiles is difficult in trials where tamoxifen is the comparator. The selective estrogen-receptor modulators (SERMs) such as tamoxifen are known to have lipid-lowering properties [67, 68]. What is clear is that the studies comparing AIs with tamoxifen indicate only that the AIs lack the lipid-lowering effects of tamoxifen.
Aromatase inhibitors and lipid metabolism
Anastrozole
In the ATAC trial, the incidence of hypercholesterolemia was higher in patients receiving anastrozole than tamoxifen (9 vs. 3%, respectively; P < 0.0001) [42]. In the ITA trial, lipid metabolism disorders were reported in 9.3% of patients treated with anastrozole and 4.0% receiving tamoxifen (P = 0.04) [13].
A recent multicenter study in patients with estrogen-receptor positive breast cancer investigated the effects of adjuvant anastrozole and toremifene, a SERM, on serum lipids [68]. Results showed that only toremifene had a beneficial effect on lipid profile, indicated by a decrease in total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, and an increase in HDL cholesterol and apolipoprotein A1. Changes in total cholesterol, HDL, LDL, and apolipoproteins were significantly different between toremifene and anastrozole at 6 and 12 months (P < 0.05).
Letrozole
In the BIG 1–98 trial, according to the protocol, cholesterol concentrations (fasting or non-fasting) were collected systematically in the case-report forms every 6 months and even patients with only a single measurement above the upper limit of normal were defined as hypercholesterolemic [8]. Hypercholesterolemia was reported in 5.4% of the letrozole arm compared with 1.2% of the tamoxifen arm in patients with baseline values within normal limits, who then had an increase of 1.5 times the upper limit of normal [69]. Hypercholesterolemia was typically a single event and in the majority of these patients (80%) occurred at only grade 1 intensity (meaning a slight numerical increase above normal, not requiring medications). Moreover, the majority of cases were single measurements collected in non-fasting patients. Furthermore, when looking at total serum cholesterol levels, there was a 12% median decrease from baseline in total cholesterol in the tamoxifen arm after 6 months, consistent with previous reports demonstrating the lipid-lowering effect of tamoxifen [67], while in the letrozole group total cholesterol values remained stable [8]. Hypercholesterolemia was not predefined as an adverse event in the ATAC trial, and lipid concentrations were not routinely assessed [42].
Exemestane
Hypercholesterolemia was not reported in the IES trial of sequential exemestane after tamoxifen [11, 52].
Another study examined the longitudinal changes in body composition and lipid profiles in 55 postmenopausal women with early breast cancer switched to exemestane after at least 2 years of tamoxifen treatment [70]. Fat mass significantly decreased (P < 0.01) while the fat-free mass to fat mass ratio significantly increased (P < 0.05) by month 12 in the exemestane but not in the tamoxifen group. In addition, triglycerides and HDL cholesterol significantly decreased (P < 0.01 and P < 0.05, respectively) in the exemestane group, while LDL cholesterol significantly increased (P < 0.01) at the end of the 1-year study period.
Aromatase inhibitors versus placebo
When compared with placebo (the most accurate way to assess the true impact of AIs on serum lipids), the final analysis of the MA.17 trial demonstrated the incidence of hypercholesterolemia was 16% in the letrozole and the placebo arms [10]. Results from an MA.17 lipid sub-study showed that in 347 postmenopausal women with primary breast cancer treated for up to 36 months, letrozole (n = 183) does not significantly alter lipid profile (samples drawn under fasting conditions) compared with placebo (n = 164) [71]. In a placebo-controlled study involving 147 postmenopausal women with early breast cancer, exemestane had no major effect on lipid profile except for a modest but significant decrease from baseline in HDL cholesterol (P < 0.001) and apolipoprotein A1 (P = 0.004) [50]. On the basis of these results, it is clear that when compared with placebo, AIs do not have a detrimental effect on lipid profile. However, it should be noted that there have been no placebo-controlled trials of adjuvant anastrozole in women with breast cancer.
Comparative studies of aromatase inhibitors
The LEAP trial directly compared safety parameters between the steroidal AI exemestane and the non-steroidal AIs anastrozole and letrozole in 90 healthy postmenopausal women (Table 1) [72]. Initial results from the trial showed that there were no significant differences between anastrozole and letrozole in effects on LDL:HDL ratios, triglyceride concentrations, and non-HDL concentrations. Exemestane was associated with an increase in LDL:HDL ratio (+17) (P = 0.047) compared with anastrozole. There was no median change from baseline in total serum cholesterol for letrozole, a slight increase for anastrozole (+0.4), and a non-significant decrease for exemestane (−3.9) (P = 0.164 vs. anastrozole) [72].
Table 1Comparative effects of third-generation aromatase inhibitors on lipids [72]Percentage change from baselineAnastrozole (n = 29)Letrozole (n = 29)P value vs. anastrozoleExemestane (n = 32)P value vs. anastrozoleTotal cholesterol Week 12−2.3−3.80.617−5.50.262 Week 24+0.4−0.00.900−3.90.164 Triglycerides Week 12−2.9+9.60.037−7.70.417 Week 24+0.3+5.40.550+2.10.827Ratio of LDL-C:HDL-C Week 12−0.0−3.10.486+8.80.048 Week 24+4.6+3.40.847+17.00.047 Non-HDL-C Week 12−2.7−4.20.667−3.50.820 Week 24+1.3+1.20.975−0.60.630Ratio of apo B:apo A1 Week 12−1.0−3.30.452+4.40.069 Week 24+0.0−0.80.842+9.00.023LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein, apo B apolipoprotein B, apo A1 apolipoprotein A1
Cardiovascular disease
Cardiovascular risk increases substantially and progressively in women aged ≥65 years [73–77]. Isolated systolic hypertension, associated with arterial stiffening, is predominant in middle- and older-aged hypertensives [75] and predisposes individuals to coronary heart disease, heart failure, stroke, vascular dementia, and chronic kidney disease [73]. The risk of cardiac disease is also influenced by ethnicity, smoking, obesity, physical inactivity, alcohol abuse, and the presence of co-morbid diseases such as diabetes.
In patients with breast cancer the presence of co-morbidities, including cardiovascular disease and diabetes, is associated with a poorer prognosis than when co-morbid disease is absent [78] and may explain disparities in outcome between different ethnic groups [79]. There is also evidence that breast cancer is associated with a higher prevalence of hypertension compared with other tumor types [80] and a significantly increased risk of stroke compared with the general population (relative risk 1.12; 95% CI 1.07, 1.17) [81]. Many breast cancer therapies increase the risk of cardiovascular events [82–88]; tamoxifen, however, may have some cardio-protective effects [89, 90].
Tamoxifen and cardiovascular disease
Several studies have demonstrated the potential cardioprotective properties of tamoxifen, including a reduction in hospital admissions due to cardiac disease [89–91] and decreased mortality from cardiac disease [92]. In a meta-analysis, tamoxifen was associated with a significantly decreased incidence of myocardial infarction (relative risk 0.90) and death from myocardial infarction (relative risk 0.62) [93]. This finding is consistent with results from an earlier cohort study [94] and the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis, which demonstrated decreases in the risk of cardiac death and overall mortality from vascular disease in patients receiving tamoxifen compared with those receiving placebo [2].
Aromatase inhibitors and cardiovascular disease
Assessing the impact of different AIs on cardiovascular disease in postmenopausal women with breast cancer is difficult and inter-trial comparisons are confounded by differences in data collection and end points; for example, in the BIG 1–98 trial all potential adverse events were predefined in the case-report forms whereas the ATAC trial used non-specific case-report forms to report adverse events [8, 95]. Furthermore, comparisons with tamoxifen are complicated by its cardioprotective properties. Placebo-controlled trials thus provide the best source of data to delineate the effects of AIs in a patient population with an inherently elevated risk of cardiac events.
Anastrozole
The ATAC trial provided data on the cardiovascular effects of anastrozole as initial adjuvant therapy compared with tamoxifen. The incidence of ischemic cardiovascular disease was higher (but not significantly) with anastrozole than placebo (127/3092, 4.1% vs. 104/3094, 3.4%; P = 0.1). The incidence of angina was also higher with anastrozole (71/3092, 2.3% vs. 51/3094, 1.6%; P = 0.07), while myocardial infarction occurred with similar frequency (37/3092, 1.2% vs. 34/3094, 1.1%; P = 0.7 [42]. Hypertension was statistically significantly more common with anastrozole than with tamoxifen (13 vs. 11%, respectively; P = 0.04) [42]. In the ARNO95 trial vascular events, including hot flashes, ischemic cardiovascular events, deep vein thrombosis, and ischemic cerebrovascular events, occurred in 9.2% of the anastrozole arm compared with 8.8% of the tamoxifen arm [96].
Letrozole
The BIG 1–98 trial demonstrated a similar incidence of cardiac events in the letrozole and tamoxifen groups (4.1 vs. 3.8%, respectively; not significant). However, more women in the letrozole group had grade 3, 4, or 5 cardiac events (2.1 vs. 1.1%, respectively; P < 0.001), but these events remain rare [8]. Of note, a recent update of the monotherapy arms of BIG 1–98 after a longer median follow-up of 51 months showed that the overall incidence of cardiac events was comparable in the two groups (134 events [5.5%] in the letrozole group vs. 122 [5.0%] in the tamoxifen arm), thus confirming the safe cardiac profile of letrozole reported at 26 months [97].
Exemestane
In the IES, there was no significant difference between exemestane and tamoxifen in the incidence of combined cardiovascular disease/thromboembolic events (22.1 vs. 20.9%, respectively; P = 0.34) after a median follow-up of 55.7 months [11]. The incidence of myocardial infarction was higher with exemestane than with tamoxifen, although the difference between treatment groups was not significant (1.3 vs. 0.8%, respectively; P = 0.08) [11].
Overall, the rate of cardiovascular events in patients treated with AIs is well within the range seen in age-matched, non-breast-cancer populations; for example, for women 57–65 years of age, the rates of fatal myocardial infarction and other fatal coronary artery disease are 1.1 and 0.81 per 1,000 patient-years, respectively [98]. Similar rates were recorded in the UK General Practice Research Database and Swedish MI register [99]. Currently, there is insufficient information to fully determine the effect of AIs on cardiovascular disease, especially coronary heart disease.
Aromatase inhibitors versus placebo
Cardiovascular events occurred with similar frequency in the letrozole and placebo arms in the MA.17 trial (5.8 vs. 5.6%, respectively; P = 0.76) [10]. Similar incidences were reported in the letrozole and placebo arms for stroke/transient ischemic attack (0.7 vs. 0.6%, respectively), myocardial infarction (0.3 vs. 0.4%, respectively), new or worsening angina (1.2 vs. 0.9%), angina requiring coronary artery bypass graft (0.2 vs. 0.5%), and thromboembolic events (0.4 vs. 0.2%, respectively) [10]. These results clearly indicate that when compared with placebo, AIs do not have a detrimental effect on cardiovascular safety.
Gynecologic health
The onset of menopause is characterized by numerous adverse events associated with a decline in estrogen concentrations [100–102]. Early symptoms include abnormal vaginal bleeding, hot flashes, and mood changes, while vaginal dryness and irritation, osteoporosis, and heart disease are late symptoms [29, 103, 104]. Vasomotor symptoms, particularly hot flashes, are common during transition to menopause [105–109] and may lead to disturbed sleep, depressive symptoms, and significant reductions in quality of life [110–115]. Cigarette smoking may be associated with increased risk of hot flashes in menopausal women [116]. Sexual dysfunction is also prevalent in menopausal women and is associated with vaginal atrophy, vaginal/genital dryness, dyspareunia (pain during sexual intercourse), vaginitis, cystitis, and urinary tract infections [117].
Aromatase inhibitors and gynecologic health
Anastrozole
In the ATAC trial, the incidence of hot flashes was significantly lower with anastrozole than with tamoxifen (36 vs. 41%; P < 0.0001) [9]. In the latest analysis, anastrozole was associated with a significantly lower incidence of gynecologic events (endometrial hyperplasia, endometrial neoplasia, cervical neoplasm, and enlarged uterine fibroids: 3 vs. 10% with tamoxifen; P < 0.0001) [42]. A quality-of-life (QOL) analysis confirmed that vaginal discharge, vaginal itching/irritation, and vaginal bleeding were less common with anastrozole but found that vaginal dryness, pain during intercourse, and loss of interest in sex were more common [118]. After 2 years of treatment there was a non-significant trend towards a lower incidence of endometrial abnormalities with anastrozole than tamoxifen (odds ratio 0.44; 95% CI 0.146, 1.314; P = 0.14) [119]. The latest update of the ATAC trial revealed reduced libido in significantly more patients receiving anastrozole (1%) than tamoxifen (<1%; P = 0.0001) [42]. Patients receiving anastrozole also experienced a significantly higher incidence of dyspareunia than those receiving tamoxifen (1 vs. < 1%, respectively; P = 0.002), whereas urinary incontinence and urinary tract infection were significantly less common among patients receiving anastrozole (urinary incontinence: 2 vs. 4%, respectively, P < 0.0001; urinary tract infection: 8 vs. 10%, respectively, P = 0.002).
In a randomized study of postmenopausal women in whom abnormal vaginal bleeding and/or asymptomatic endometrial thickening occurred during treatment with tamoxifen, switching to anastrozole was associated with a significant reduction in mean endometrial thickness compared with continuation of tamoxifen (P < 0.0001) [120]. Significantly fewer anastrozole patients required a repeat hysteroscopy and dilation and curettage compared with those taking tamoxifen (4.8 vs. 33.0%, respectively; P < 0.0001).
Letrozole
In the BIG 1–98 trial [8], endometrial biopsies were significantly less common in patients receiving letrozole than tamoxifen (2.3 vs. 9.1%, respectively; P < 0.001), and there was a trend towards fewer invasive endometrial cancers (0.1 vs. 0.3%, respectively; not significant). There was a significantly lower incidence of vaginal bleeding with letrozole than with tamoxifen (3.3 vs. 6.6%, respectively; P < 0.001), and the incidence of hot flashes was also significantly lower (33.5 vs. 38.0%, respectively; P < 0.001). In another study in patients intolerant of tamoxifen, switching to letrozole for 6 weeks was associated with a 53.7% decrease in hot flashes (hot-flash score 97.0–52.1; P = 0.001) [121]. In the MA.17 trial, letrozole was associated with less vaginal bleeding than placebo (6 vs. 8%, respectively; P = 0.005) but a greater incidence of hot flashes (58 vs. 54%, respectively; P = 0.003) [10]. There was no significant difference in the incidence of vaginal dryness between letrozole and placebo.
Exemestane
In the IES, there were no significant differences between the exemestane and tamoxifen treatment arms in the incidence of endometrial cancer (0.4 vs. 0.7%, respectively; P = 0.17) [11], or the incidence of hot flashes (42 vs. 40%, respectively; P = 0.28) [52]. Overall, gynecologic symptoms were lower with exemestane than with tamoxifen (6 vs. 9%; P < 0.001) [52]; however, vaginal dryness was significantly more common among women taking exemestane than those taking tamoxifen, while vaginal discharge was significantly more common with tamoxifen [122]. Vaginal bleeding was significantly more common in the tamoxifen arm (7.1%) than in the exemestane group (4.8%; P = 0.001) [11].
Other adverse events
Secondary cancer
The association between tamoxifen and endometrial and uterine cancers is well-established [4] and is not observed with AIs. However, a safety analysis of the ATAC trial [42] showed a surprisingly higher incidence of head and neck cancer with anastrozole compared with tamoxifen (10/3092 vs. 3/3094, respectively). Similarly, there was an excess of lung cancer (25/3092 vs. 16/3094) and lung cancer deaths with anastrozole; however, further analyses are required to confirm these findings. Of note, a higher incidence of secondary cancer was not noted in the IES (72 events exemestane vs. 107 tamoxifen) or in the BIG 1–98 trial (69 letrozole vs. 82 tamoxifen) [8, 11].
A meta-analysis showed that tamoxifen is associated with a modest but statistically significant increase in the risk of developing gastrointestinal cancer (relative risk 1.31; 95% CI 1.01, 1.69), particularly for postmenopausal women (relative risk 1.77) [93].
Gastrointestinal health
Diarrhea was significantly more common among patients receiving the steroidal AI exemestane than in those taking tamoxifen (4.2 vs. 2.2%, respectively) [123] but is not a typical side effect of the non-steroidal AIs letrozole and anastrozole. However, an updated safety analysis of the ATAC trial showed that anastrozole was associated with an increased incidence of diarrhea compared with tamoxifen (9 vs. 7%; P = 0.02) [42].
Neurologic effects and visual disturbance
It has been suggested that endocrine therapy may affect cognitive function in patients with breast cancer [124]. In a study comparing patients from the ATAC trial with healthy controls, anastrozole was associated with significant impairments in a processing speed task and on a measure of immediate verbal memory [125]. Another study conducted in healthy, estrogen-treated postmenopausal women treated with testosterone did not reveal any effects of aromatase inhibition on cognition [126].
The impact of adjuvant AI therapy on cognition and other neurologic processes is clearly an important issue that will require further studies in the future. Neurologic effects reported with exemestane, including dizziness and vertigo [127] and significantly more visual disturbances compared with tamoxifen [52], are not characteristic of non-steroidal AIs.
Dry mouth
The latest analysis of the ATAC trial demonstrated a significantly greater incidence of dry mouth in patients receiving anastrozole (4%) compared with tamoxifen (2%; P = 0.003) [42].
Cosmetic effects
Weight gain is common after breast cancer therapy and increases the risk of recurrence, cardiovascular disease, and diabetes [64]. A study of Japanese patients showed that more women reported weight gain in the anastrozole group than in the tamoxifen group (35.8 vs. 12.5%, respectively; P ≤ 0.0036) [128], but no difference was seen among patients from the ATAC trial included in a QOL sub-analysis [118].
The androgen structure of exemestane may lead to androgenic side effects. Hypertrichosis, hair loss, hoarseness, and acne were reported in about 10% of patients treated with daily exemestane doses of 200 mg or more in dose-finding studies [129, 130], but have not emerged as a significant issue in phase II or phase III trials with this agent.
Anastrozole treatment was associated with a lower incidence of nail disorders (2 vs. 3%; P = 0.002) and fungal infection (1 vs. 1%; p = 0.01) compared with tamoxifen [42].
Quality of life and patient preference
Anastrozole
The QOL of patients treated in the ATAC trial was studied during a 5-year follow-up period [118, 131]. Anastrozole and tamoxifen had similar overall effects on QOL (Functional Assessment of Cancer Therapy-Breast [FACT-B] trial outcome index plus endocrine sub-scale) in the first 2 years of treatment [118], and an initial worsening of endocrine symptoms gradually improved over time [131]. The authors concluded that the benefits of anastrozole are achieved without detrimental effects on QOL. However, another study conducted in Japanese patients demonstrated that FACT-G, FACT-B, and FACT-ES scores were significantly better with tamoxifen than with anastrozole (P = 0.012, P = 0.010, and P = 0.015, respectively) [132].
Letrozole
The MA.17 and BIG 1–98 trials have demonstrated that adjuvant letrozole is well-tolerated compared with placebo [10] and better tolerated than tamoxifen [8]. In another study of postmenopausal women who were experiencing distressing side effects while taking adjuvant tamoxifen and were switched to letrozole, after 6 weeks 66% of patients preferred to remain on letrozole, 24% preferred to go back to tamoxifen, and 10% stopped all therapy [121].
In the placebo-controlled MA.17 trial, letrozole significantly improved outcomes and did not impair overall QOL [133] (Fig. 2). Minor differences seen in some domains (physical functioning, bodily pain, vitality, vasomotor, and sexual) were consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis. A sub-analysis of US subjects in MA.17 demonstrated no significant differences between letrozole and placebo in overall QOL summary scores (mental and physical) and five of eight sub-domains of SF-36 [134]. There were no differences in SF-36 mental and physical QOL scores and MENQOL (menopause symptom scale) psychosocial and physical domains [134].
Fig. 2Mean change score in Short Form 36-item Health Survey. A positive score indicates a favorable change in quality of life. (A) Physical component summary; P = not significant for all time points. (B) Mental component summary; P = not significant for all time points. [133]. ©2005 American Society of Clinical Oncology. Reproduced with permission
Exemestane
Results from the IES QOL sub-protocol indicate that switching to exemestane from tamoxifen improves outcome without a significant detrimental impact upon QOL [135]. At entry, there was a high prevalence of severe endocrine symptoms (vasomotor complaints and sexual problems), and these persisted with exemestane and tamoxifen during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < 0.001).
Conclusions
Clinical trials show that the third-generation AIs lack the serious risks of thromboembolism and endometrial cancers associated with tamoxifen and are generally well tolerated, with the majority of adverse events occurring at mild to moderate intensity [8–11].
AIs are associated with a mild to modest increased risk of osteoporosis compared with tamoxifen, and it is therefore essential that patients have regular BMD assessments and be monitored proactively to minimize the risk of clinical fractures [20, 57]. The increased risk of fractures with an AI compared with tamoxifen needs to be balanced against the increased risk of endometrial and cerebrovascular/thromboembolic morbidity with tamoxifen [136]. Of note, the updated ATAC analysis shows that the majority of excess adverse events associated with tamoxifen occurred during the first 2.5 years of treatment; there were 142 (8%) fewer predefined adverse events in the anastrozole arm [137]. Thus, it appears that many excess gynecologic, thromboembolic, and cerebrovascular adverse effects occurring in tamoxifen-treated patients could be avoided if patients were treated initially with an AI [136].
Although AIs do not have the cholesterol-lowering and potential cardioprotective properties of tamoxifen, they do not significantly worsen total cholesterol concentrations and do not appear to increase cardiovascular risk when compared with placebo. Nevertheless, it is prudent to recommend that all patients at risk of cardiovascular effects are properly monitored and managed, and all breast cancer patients should be routinely monitored for cardiovascular disease. It is difficult to draw meaningful conclusions from comparisons of randomized trials of tamoxifen versus anastrozole, letrozole, or exemestane because of differences in assessing and reporting risk of cardiovascular disease [8, 52, 95, 138].
Current information is insufficient to determine the effects of AIs on cardiovascular disease and coronary heart disease risk [20]. Similarly, further follow-up is required to determine the late consequences of AI therapy [20]. Despite these provisos, ASCO now recommends that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an AI as initial therapy or after treatment with tamoxifen. Results from several ongoing trials, including the Femara versus Anastrozole Clinical Evaluation, MA.27, the National Surgical Adjuvant Breast and Bowel Project, LATER, and MILER, should provide more information on the long-term tolerance and the optimal duration of adjuvant AI therapy and help determine which strategy has the best ratio of efficacy to tolerance.
In conclusion, the efficacy benefits of AIs outweigh the risks when AIs are used as adjuvant therapy in postmenopausal women with early breast cancer. Safety, QOL, and patient preference must all be considered in the determination of the optimal strategy for long-term endocrine therapy, bearing in mind that patients may require treatment for 10 years or more. Every patient is unique, and endocrine therapy must be individualized according to clinical, biologic, and patient factors such as lifestyle, the presence of significant co-morbidities, and use of concomitant medications. Tolerability should no longer be an obstacle to effective, long-term endocrine therapy.

safety
aromatase inhibitors
letrozole
adjuvant therapy
early breast cancer


The Extended Learning Curve for Laparoscopic Fundoplication: A Cohort Analysis Of 400 Consecutive Cases

Many studies have looked at the learning curve associated with laparoscopic Nissen fundoplication (LNF) in a given institution. This study looks at the learning curve of a single surgeon with a large cohort of patients over a 10-year period. Prospective data were collected on 400 patients undergoing laparoscopic fundoplication for over 10 years. The patients were grouped consecutively into cohorts of 50 patients. The operating time, the length of postoperative hospital stay, the conversion rate to open operation, the postoperative dilatation rate, and the reoperation rate were analyzed. Results showed that the mean length of operative time decreased from 143 min in the first 50 patients to 86 min in the last 50 patients. The mean postoperative length of hospital stay decreased from 3.7 days initially to 1.2 days latterly. There was a 14% conversion to open operation rate in the first cohort compared with a 2% rate in the last cohort. Fourteen percent of patients required reoperation in the first cohort and 6% in the last cohort. Sixteen percent required postoperative dilatation in the first cohort. None of the last 150 patients required dilatation. In conclusion, laparoscopic fundoplication is a safe and effective operation for patients with gastroesophageal reflux disease. New techniques and better instrumentation were introduced in the early era of LNF. The learning curve, however, continues well beyond the first 20 patients.
Introduction
It is well known that there is a learning curve associated with laparoscopic Nissen fundoplication (LNF) for gastroesophageal reflux disease (GERD).1,2 A number of studies have shown a decrease in the number of complications with surgical experience and with modifications to the surgical technique of fundoplication over time. Watson et al.2 showed that the individual surgeon’s complication rate and conversion rate were highest in the first five procedures and stabilized after the first 20 operations. There are, however, few studies with large patient numbers showing the learning curve of a single surgeon and his/her trainees. We have evaluated this learning curve in our series of 400 consecutive patients undergoing laparoscopic fundoplication.
Materials and Methods
Between January 1993 and August 2002, 400 patients (262 males, 138 females) [mean age: 42.9 years (range 9–86)] underwent laparoscopic fundoplication in a District General Hospital. All procedures were performed or supervised by a dedicated upper gastrointestinal surgeon. Several trainees became the primary surgeons later in the series under direct supervision once they were deemed to have the appropriate laparoscopic skills. The indications for operation were: symptomatic GERD despite prolonged medical therapy; intolerance of medical therapy due to side effects; and volume regurgitation or patient preference for surgery.
Data were collected prospectively on a handheld computer database (Psion, Psion Ltd., England). All patients underwent preoperative endoscopy and 24 h ambulatory esophageal pH monitoring. After the first 75 cases, all patients also underwent stationary esophageal manometry using a standardized technique.
The operative technique was modified during the course of the study as new equipment became available. Initially, five 10-mm abdominal ports were used: toward the latter half of the study, two 5-mm and three 10-mm ports were used. For the first 35 patients, a 0° laparoscope was used: all subsequent operations were carried out using a 30° laparoscope. The lower esophagus was mobilized from the crural arch. All patients underwent division of the short gastric vessels initially using individually applied ligaclips: after case 215, a harmonic scalpel (Ethicon, Endosurgery, UK) was used. In the first 40 patients, the crura were repaired (using 2/0 silk) only if a hiatal defect and a hernia were present. After this, all patients underwent crural approximation. A loose wrap of 1–2 cm length was constructed over a 56 French gauge bougie using nonabsorbable sutures (initially silk; later “0” Ethibond) incorporating the anterior esophagus. During the period of the study, 63 patients, who were included in the fourth to seventh cohorts, underwent a laparoscopic partial posterior fundoplication as part of a randomized trial.3 These patients were included in this study, as there was no difference in symptomatic outcome, complication rate, or operative time between this group and those undergoing a 360° fundoplication. Fourteen pediatric patients underwent an LNF throughout the series. The surgical technique used was the same in adult and pediatric populations. Patients were encouraged to mobilize immediately and commenced on oral fluids, followed by a light diet, as soon as tolerated.
The overall patient group was divided into eight cohorts of 50 consecutive patients. These cohorts were analyzed separately to compare the following: (1) patient demographics, (2) preoperative symptom length, (3) operative time, (4) length of postoperative hospital stay, (5) conversion to open operation, (6) reoperation rate, (7) postoperative dilatation rate, and (8) perioperative mortality or other early (within 6 months) postoperative complications.
Results
The mean age, weight, and length of preoperative symptoms for each group was similar (see Table 1). This table also shows an overall decrease in the amount of time to accrue each cohort throughout the study period. There was a steady decrease in the mean operative time throughout the study period from 143 min in the first cohort to 86 min in the last cohort (Fig. 1). The mean postoperative hospital stay was reduced from 3.7 days (range 2–25) to 1.2  days (range 1–5) from the first to the last cohort. There were no perioperative deaths.
Table 1Demographics and Length of Preoperative Symptoms in Patients Undergoing Fundoplication for GERD Patient Numbers1–5051–100101–150151–200201–250251–300301–350351–400Time period to accrue cohort (months)2921121111121110Mean age (years) (range)36.3 (13–70)41.6 (9–82)43.9 (13–64)44.5 (12–86)44.3 (15–66)43.9 (17–66)45.4 (18–74)45.1 (15–81)Sex (M:F)34:1638:1228:2232:1829:2129:2134:1635:15Mean weight (kg) (range)71.1 (44–102)75.7 (29–98)76.1 (49–104)74.3 (30–102)79.5 (51–120)79.3 (44–103)78 (48–103)80.4 (53–100)Mean preoperative symptomatic period (months) (range)91 (8–420)85 (6–540)106 (3–480)92 (4–516)106 (4–430)96 (12–360)141 (6–1,152)140 (4–1,152)Figure 1Showing operative conversions to open procedure, rates of reoperation, and rates of dilatation in patients undergoing laparoscopic fundoplication for GERD.
Figure 1 also shows the rate of conversion from laparoscopic to open fundoplication, the reoperation rate, and the postoperative dilatation rate.
Conversions to Open Operation
The conversion rate in the first cohort of 50 patients was 14%. Compared to this, only one conversion was required in the last 250 patients in the series, and this was necessitated by equipment failure rather than surgical difficulties. Other conversions were undertaken for hemorrhage from short gastric vessels (seven patients), port-site bleeding (one patient), splenic bleeding (one patient), difficult access (two patient), instrumental esophageal perforation (one patient), and adhesions from previous surgery (two patients).
Patients Needing Postoperative Dilatations
In the first 50 patients, 8 of them (16%) needed endoscopic balloon dilatation for persistent dysphagia or gas bloat syndrome between 10 days and 3 months postoperatively. They were dilated between one and three times. Nine patients (18%) were dilated in the second cohort between 9 days and 10 months postoperatively on one to four occasions. In the third cohort, six patients (12%) underwent dilatation between 1 week and 7 months, whereas in the fourth cohort, five patients (10%) were dilated between 3 weeks and 2 months postoperatively. They were all dilated once or twice. Two patients (4%) had two dilatations each between 2 and 9 months in the fifth cohort. No dilatations were needed by the last 150 patients to undergo laparoscopic fundoplication.
Patients Needing Reoperation
Figure 1 illustrates a decline in the number of patients requiring reoperation from seven patients (14%) in the first 50 to three patients (6%) in the last 50 patients. Table 2 shows the number of reoperations that took place for any given reason in our overall patient group. It also highlights the number of reoperations that occurred within 3 months of the original fundoplication.
Table 2Total Number and Timing of Patients Undergoing Reoperation after Laparoscopic FundoplicationCause of ReoperationTotal Number of patientsEarly (within 3 months)Late (after 3 months)Mediastinal wrap herniation16115Persistent reflux11Dysphagia despite dilatation211Gas bloat33Perforation of wrap11Port-site hernia11
In the first cohort, five patients underwent reoperation for mediastinal “wrap” herniation between 9 and 80 months postoperatively. Two patients required revisional surgery; one underwent a Watson fundoplication, whereas the other undertook a redo Nissen fundoplication at 2 and 6 months, respectively, for persistent dysphagia failing to respond to endoscopic dilatations. One reoperation for “wrap” herniation was attempted laparoscopically but was converted to an open procedure. All other reoperations were carried out as open procedures.
In the second cohort, three patients were reoperated on "for mediastinal “wrap” herniation and wrap disruption at 2, 30, and 47 months postoperatively: one by open surgery and two laparoscopically. One patient underwent laparoscopic conversion of a 360° to 270° “wrap” for “gas bloat” at 11 months despite two endoscopic “wrap” dilatations.
There was one reoperation in the third cohort of patients for gas bloat 92 months later. The wrap was found to be mildly attenuated and was taken down laparoscopically. In the fourth cohort, one patient underwent laparoscopic conversion to a 270° “wrap” for “gas bloat” syndrome 12 months later, and one patient was converted from a 270° to a 360° wrap for a persistent reflux. Two patients underwent open reoperations in the fifth cohort: one for a perforation of the “wrap” at 4 days, the other for a port-site hernia repair at 9 months.
In the sixth cohort, two patients underwent a redo LNF for wrap herniation and disruption at 23 and 36 months postoperatively. In the seventh cohort, two patients were found to have a wrap herniation, and one patient was found to have a large crural defect with wrap herniation at 18, 19, and 23 months, respectively. All underwent redo LNF; the patient with the large crural defect had a hiatal mesh placed. In the last cohort, three patients underwent redo LNF (two with hiatal mesh placement) for wrap herniation at 20, 27, and 36 months postoperatively.
Discussion
The postoperative complications most commonly associated with open fundoplication are dysphagia and gas bloat syndrome. The advent of the laparoscopic approach to fundoplication, first described in 1991,4 has introduced a number of procedure-specific complications, including pneumothorax, pneumomediastinum, major-vessel injury, mesenteric thrombosis, and gastrointestinal perforation.5
The first prospective randomized study comparing laparoscopic and open Nissen fundoplication6 showed similar complication rates and a better symptom outcome in those who had undergone laparoscopic surgery. There has, however, been a concern as to the severity of the reported complications in the laparoscopic approach.7
Before the commencement of this study, the surgeon had a 6-year experience with open fundoplications. In the early 1990s, formal courses were not available to learn laparoscopic fundoplication: consequently, the surgeons pioneering this procedure were mentored for the first few cases. After this, the surgeon would operate independently.
Our study shows that as the surgeon’s experience of laparoscopic fundoplication increases, the mean operating time becomes comparable to that of an open operation. The mean postoperative length of stay in hospital was 1.2 days in the last 50 patients compared with an average stay of 7 days in those having an open fundoplication.8 The decrease in postoperative length of stay in hospital, which was seen throughout this series, can be partly attributed to increased knowledge of recovery from laparoscopic procedures and from patient feedback of their postoperative recovery.
The high conversion rate to an open operation in our first 50 patients (14%) can be attributed to the surgical learning curve and poorer quality equipment leading to reduced quality of vision and the reduced ability to secure bleeding. Similarly, high conversion rates were seen in other early laparoscopic series.9,2 Only 1 of the last 150 patients needed conversion to an open procedure, and this was due to equipment failure. One patient underwent a splenectomy (0.3% of all patients) due to splenic bleeding, which is comparable to other studies.10 This compares with a splenectomy rate of 3.6% in open Nissen fundoplications in one study.6 Of the 15 patients requiring conversion throughout the series, 14 were in the preharmonic scalpel era. Nine of these were converted due to bleeding. The harmonic scalpel has greatly enhanced the ease of fundal mobilization in comparison to the application of individual ligaclips to the short gastric arteries. A decreasing trend in conversion rate can, however, be seen within the first four cohorts before the introduction of the harmonic scalpel.
The number of patients undergoing endoscopic dilatation decreased significantly from 17% in the first 100 patients to none in the last 150 patients. This was probably due to a number of factors. First, none of the last 250 patients had symptomatic “wrap” disruptions/slippages causing dysphagia. The patients who were found to have wrap herniation presented with heartburn and not dysphagia. Secondly, it is now recognized that early dysphagia (less than 2 months postoperatively) is present in a significant proportion of patients but settles with time without the need for intervention.11 The exception to this is in children who are less tolerant of dysphagia after laparoscopic fundoplication and hence are more likely to require early endoscopic dilatation.12 Two studies12,13 have shown dilatation success rates of 56 and 67%, respectively, in resolving postfundoplication dysphagia. The study by Malhi-Chowla et al.13 also found that the only symptom that responded to dilatation was dysphagia.
Throughout the series, two patients had been reoperated on for persistent dysphagia beyond 2 months. Both were in the first 25 cases, and both were found to have bowstringing of the wrap due to lack of division of the posterior gastric bands. One was converted to a Watson fundoplication, whereas the other underwent a redo Nissen fundoplication. Our low incidence of dysphagia may be in part due to the laparoscopic operation used. Hunter et al.14 showed that the incidence of early and late persistent dysphagia is significantly lower in both LFNs and Toupet fundoplications than in Rosetti–Nissen fundoplications.
Two patients had undergone reoperation for gas bloat syndrome: both were converted to a 270° posterior wrap and are now either asymptomatic or mildly symptomatic.
All patients in this study had been followed up for a minimum of 4 years. Overall, 6% of our patients required reoperation because principally of wrap herniation. After the first 40 operations, a routine posterior crural approximation was carried out with nonabsorbable sutures to reduce the incidence of thoracic “wrap” migration. Two studies15,16 have emphasized the importance of a crural repair in reducing the incidence of postoperative paraesophageal hiatus hernia. Basso et al.17 have proposed a mesh repair of the hiatus to prevent “wrap” migration after finding that in several reoperations, the sutures approximating the crura had cut out with consequent wrap herniation.
Paraesophageal wrap herniation is more common in laparoscopic than in open fundoplication.16 Several reasons have been proposed for this: (1) the tendency to extend esophageal dissection further into the thorax,18 (2) the increased risk of breaching the left pleural membrane during dissection,19 and (3) the reduced postoperative pain allowing increased abdominal pressure when vomiting/coughing in the laparoscopic procedure.16 Wu et al.20 found that routine division of the short gastric arteries and posterior closure of the crura during LNF significantly reduced wrap slippage/migration. This is the procedure that we have undertaken since the 40th patient. Despite of this, 5% of the last 150 patients underwent reoperation (all for heartburn due to wrap herniation). Smith et al.21 have also concluded that wrap herniation is now the most common mechanism of failure requiring a redo fundoplication.
Of the eight patients reoperated on in the first cohort, only one procedure was attempted laparoscopically. All reoperations are now attempted laparoscopically where possible. This change in approach has occurred with increasing laparoscopic experience. Several studies22,23 have shown that laparoscopic reoperations are not only possible and safe but also produce good results.
Several studies24,25,26 have now shown a 90% satisfaction rate at 5-year follow-up after LNF. Our own study25 on patient satisfaction 2–8 years postlaparoscopic fundoplication revealed that once over the initial problem of early postoperative dysphagia, the satisfaction rate was 91%. Furthermore, 90% remained free of significant reflux symptoms, and only 14% were subsequently taking regular antireflux medication. This has changed little throughout the course of the series.
Our results show a decreasing trend in operative time, postoperative hospital stay, conversion rate, postoperative dilatation rate, and reoperation rate with increasing surgical experience and improved technology. Another factor in this improvement may be due to the increased frequency with which this procedure was performed with time.
Conclusion
Dysphagia is the Achilles’ heel of laparoscopic antireflux surgery. To avoid this, the authors have routinely divided the short gastric vessels. This has led to an increased rate of conversion owing to hemorrhage especially during the period when individual ligaclips were used. Short gastric vessel division may, in addition, increase the rate of wrap herniation and clip or thermal injury to the gastric fundus leading to perforation.
The high rate of reintervention in the first two cohorts would not be acceptable a decade later. It must be recognized that at the start of this series, the visual acuity of the optical systems and the quality of the instrumentation were both substantially inferior to those of today. Furthermore, there were no formal training courses available. The pioneers of advanced laparoscopic surgery had to suffer high conversion and complication rates in laparoscopic cholecystectomy,27 antireflux,2 and groin hernia surgery.28,29
When introducing complex techniques, surgeons tend to underestimate the learning curve: both of themselves and of their institution. Only by maintaining prospective data can these problems be identified and recognized.

learning curve
laparoscopic nissen fundoplication