Outcomes for women without conventional treatment for stage 1A (microinvasive) carcinoma of the cervix

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1 Aust N Z J Obstet Gynaecol 2018; 58: DOI: /ajo ORIGINAL ARTICLE Outcomes for women without conventional treatment for stage 1A (microinvasive) carcinoma of the cervix Charlotte Paul 1 David CG Skegg 5, Katrina J Sharples 2, Judith Baranyai 3, Ronald W Jones 4 and 1 Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand 2 Department of Medicine, University of Otago, Dunedin, New Zealand 3 Lab Plus, Auckland District Health Board, Auckland, New Zealand 4 Gynaecological Oncology Department, National Women s Hospital, Auckland, New Zealand 5 Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand Correspondence: Emeritus Professor Charlotte Paul, Department of Preventive and Social Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand. charlotte.paul@otago.ac.nz Conflict of interests: CP was a medical advisor to the judicial inquiry into the treatment of women with cervical carcinoma in situ at National Women s Hospital. Received: 29 May 2017; Accepted: 1 November 2017 Background: An unethical clinical study that entailed withholding treatment from women diagnosed with cervical intraepithelial neoplasia 3 (CIN3) was conducted at National Women s Hospital, Auckland, New Zealand. Women with microinvasive carcinoma of the cervix also had treatment withheld. Aims: To describe the management and outcomes for women with microinvasive carcinoma for many of whom conventional treatment was withheld. Materials and Methods: Retrospective cohort study of women with a diagnosis of stage 1A cervical carcinoma at National Women s Hospital. Medical records, cytology and histopathology were reviewed and data linked with cancer and death registries up to December Results: Between 1955 and 1976, 62 women were initially diagnosed with stage 1A cervical cancer and 20 were diagnosed during follow up (to 1995). Sixty of the 82 women had initial management characterised as probably non- curative ; 20 of these received only a small diagnostic excision. Women in the latter group were more likely to: (i) subsequently have positive cytology (P < ), (ii) have untreated positive cytology (P = 0.02), and (iii) undergo multiple biopsies after initial management (P = 0.001). Of the women who received only a small diagnostic excision, eight of 20 developed invasive carcinoma of the cervix ( stage 1B) or vaginal vault, compared to two of 22 women who received initial treatment characterised as probably curative. Conclusions: Women with microinvasive carcinoma were included in a natural history study of CIN3; they underwent numerous procedures designed to observe rather than treat their condition, and had a substantial risk of invasive cancer. KEYWORDS ethics, follow-up studies, New Zealand, research, Stage 1A cervical carcinoma, uterine cervical neoplasms INTRODUCTION The past management of cervical intraepithelial neoplasia 3 (CIN3) in some women at National Women s Hospital in Auckland, New Zealand, has been controversial. In 1970, Dr G. H. Green announced: The only way to settle finally the problem of what happens to in situ cancer is to follow indefinitely patients with diagnosed but untreated lesions. This is being attempted 1 Green s study had been approved by the Hospital Medical Committee in 1966, although had actually started earlier. 2 Although regular follow- up occurred, with clinical, cytological and sometimes colposcopic examinations, persistent abnormalities were not treated in a group of women. wileyonlinelibrary.com/journal/anzjog 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 321

2 322 Outcomes for stage 1A cervical carcinoma Serious concerns about the ethics of withholding treatment from women, as well as not seeking their consent, led to a judicial inquiry in Judge Silvia Cartwright concluded that the study was unethical, as well as scientifically flawed. 2 During this inquiry, the clinical records of all women were assessed and an independent clinical review was recommended when there was any doubt about the adequacy of treatment. The judge recommended that histological and other material resulting from the study should be available for future properly planned and approved research. Previous reports have analysed the risk of invasive cancer in women with CIN3, 3,4 and the consequences for women with CIN3 included in Green s study. 5 Despite continuing controversy about Green s research, 6 8 it is not widely known that his trial of withholding treatment also included women with microinvasive (stage 1A) cervical cancer. In fact such women were combined with those with carcinoma in situ in his publications. 9 The outcome for the women with microinvasive cancer has not previously been reported. The pathological diagnosis of microinvasive cancer depends on removal of the complete lesion, so Green s study cannot be used to estimate the natural history of this condition. Nevertheless, many of the women who did not receive treatment with curative intent were left with persistent CIN3 at the margin of their biopsy. There is also the possibility that separate foci of microinvasion were not detected in some cases. It is important to document the outcome for the women with microinvasive cancer who were managed in a variety of ways. Following a review of medical records, cytology and histopathology, we conducted a study of the outcomes for women with microinvasive cervical cancer. MATERIALS AND METHODS The methods for the study were similar to those used to estimate the natural history of CIN3, which have been described elsewhere. 4,5 Women originally diagnosed with microinvasive cancer of the cervix, or diagnosed during subsequent follow up, were identified from the total number (1229) of women diagnosed histologically with carcinoma in situ (CIS) or microinvasion at National Women s Hospital between 1 January, 1955 and 31 December, For any woman with an initial or subsequent histopathology report that raised the possibility of microinvasive or invasive cervical cancer, the histopathology was reviewed (by JB) to confirm a diagnosis of microinvasive carcinoma and to stage according to the modern International Federation of Gynecology and Obstetrics (FIGO) staging system. 10 Both the and FIGO Guidelines define stage 1A (microinvasion) as stromal invasion (measured from the base of the epithelium) to a maximum depth of 5 mm with a maximum horizontal spread of 7 mm. (This definition requires margins clear of microinvasive carcinoma.) This is further divided into stage 1A1, where stromal invasion is 3 mm, and stage 1A2 where stromal invasion is >3 mm and 5 mm. The process for the histopathological review has been described in detail elsewhere. 4,5 We extracted information from the medical records of National Women s Hospital on the clinical management and outcomes for the cohorts of women diagnosed with either CIN3 or stage 1A carcinoma. Most of the initial and follow- up medical procedures and treatments occurred at this hospital, and information about procedures or treatment performed elsewhere was often included in the National Women s Hospital records. Extracted information included records of cervical and vaginal cytology, biopsies of cervical and vaginal tissue, amputation of the cervix and hysterectomy. Cancers were identified through the medical records or by linkage with the New Zealand Cancer Registry, cancer registers in Australia (Queensland and New South Wales) and death registers of New Zealand and Australia. The practice at National Women s Hospital at the time was to register microinvasive cancers at the New Zealand Cancer Registry as stage 0. Hence, subsequent invasive (1B or higher) cancers were also registered. The histopathology was reviewed (by JB) for those cancers identified through medical records; diagnoses of incident invasive cancers registered at a cancer registry were accepted. Cancer outcomes in this study included stage 1B or higher cancer of the cervix (International Classification of Diseases (ICD ) or cancer of the vaginal vault (ICD ) both described here as invasive. Follow- up continued until death or 31 December, 2000, whichever was first. Women who were not known to have died or developed cancer by this date were assumed to be alive at 31 December, 2000 (16 (19.5%) of 82 women). All smears in the first 24 months after initial diagnosis and subsequent smears for women who developed stage 1A or higher carcinoma of the lower genital tract were reviewed, blind to the original report, by the Victorian Cytology Service in Melbourne, Australia, using the Australian Modified Bethesda System (AMBS). There was good agreement between the original and review coding (κ = 0.79). 12 For smears in the first 24 months we used the review cytology whenever it was available. Cytology within six months after a procedure was not considered to be informative because false positives can occur due to reparative changes. 13 Positive cytology was defined as Papanicolaou class 3, 4 or 5 or AMBS possible or definite high- grade lesion. Negative cytology was defined as Papanicolaou class 1 or 2 or AMBS normal or benign. Low- grade cytology was defined as AMBS low- grade squamous intra- epithelial lesion (LSIL) or possible LSIL, or class 2R (Repeat). The code 2R was used by the cytology laboratory at National Women s Hospital to record presence of atypical cells suggestive of dysplasia, but less advanced than CIS. 4 During the study period, women received varied management. Some surgical procedures were intended to cure (hysterectomy or cone biopsy), while others were not (wedge biopsy or ring biopsy (defined as removal of a shallow cone <2 cm, 14 or <1.5 cm 15 deep)). We classified each procedure according to the likelihood that the treatment was curative based on the procedure used to remove the lesion, whether or not the margins

3 C. Paul et al. 323 were clear of CIN3, and whether or not there was cytological evidence of persisting disease in the 6 24 months after excision. In no case was the presence of lymphovascular space invasion recorded. We classified a procedure as probably curative if it was either: (i) hysterectomy with clear or unknown margins and normal, benign, class 2 or no informative cytology within 6 24 months; or (ii) cone biopsy with clear margins and normal, benign or class 2 cytology within 6 24 months. Probably noncurative treatments included: hysterectomy or cone biopsy with evidence of persisting CIN3; cone biopsy with extent of disease in the excision margins unknown or with clear margins but without negative follow- up cytology; ring or wedge biopsy; and biopsy of unknown type. In describing the initial and follow- up management, we counted numbers of positive smears and numbers of positive smears or biopsies not followed by appropriate treatment, restricted to the first 10 years after diagnosis for comparability over time. Proportions with positive smears, untreated positive smears and additional biopsies were compared using χ 2 tests of association. For time- to- event analyses the entry date was the date of the histological diagnosis of stage 1A carcinoma of the cervix. Competing risk methods were used to describe the cumulative incidence of stage 1B or higher cancer of the cervix or vaginal vault (death from causes other than cancer of the cervix or vagina was considered as a competing risk). 16 Analyses were carried out in Stata. 17 The study received approval from the Northern X Ethics Committee, Auckland. FIGURE 1 Derivation of study cohort. RESULTS Of the 1229 women originally diagnosed with cervical CIS or microinvasion, 95 were excluded for reasons explained elsewhere, 4 leaving 1134 women (Fig. 1). Following histological review, a further nine of the 1134 women were excluded because the initial diagnostic specimen had a lower grade of CIN (two) or had stage 1B or higher (seven). Of the remaining 1125 women, 1063 had CIN3 and 62 had stage 1A carcinoma of the cervix; all of the latter group were staged as 1A1. An additional 20 women initially diagnosed with CIN3 were diagnosed with stage 1A carcinoma of the cervix during follow- up (17 were 1A1, while for three distinguishing between 1A1 and 1A2 was not possible from the clinical records or histology of the stored specimens). All 82 tumours were squamous cell carcinomas, and those diagnosed as FIGO stage 1A1 fell within the category of superficially invasive squamous cell carcinoma using Lower Anogenital Squamous Terminology (LAST) criteria. 18 Demographic characteristics for the 82 women diagnosed with stage 1A carcinoma are shown in Table 1. The median age of those diagnosed at the outset was 40, and for those diagnosed during follow up it was The majority (69.5%) of the 82 women had their stage 1A carcinoma diagnosed by cone biopsy, but for 18 (22%) a lesser procedure was used and for six the type of biopsy was unknown (Table 1). The maximum procedure within three months after diagnosis was hysterectomy or cone biopsy for 62 (75.6%). Women diagnosed with stage 1A carcinoma during follow- up (after an initial diagnosis of CIN3), were less likely to have a cone biopsy or hysterectomy within three months of the stage 1A diagnosis than those who were diagnosed with stage 1A carcinoma at the outset. For a number of the women who underwent these procedures there was evidence of persisting CIN3, either in the excision margins or from continued positive smears. Using our definition (see Methods section), the proportion of women who received probably curative treatment within the first three months after diagnosis was only 26.8% (Table 1). Overall there were 16 women (19.5%) who received no more than a ring or wedge biopsy within three months after diagnosis. During follow up, all groups of women continued to have smears the average frequencies of smear- taking (per woman) over the first 10 years after diagnosis were between one and two per year (Table 2). Comparing follow up according to initial management, those whose management included only a small excision (wedge, ring or biopsy of unknown type) had significantly higher numbers of positive smears, untreated positive smears and biopsies (P values < , 0.02 and 0.001,

4 324 Outcomes for stage 1A cervical carcinoma TABLE 1 Demographic characteristics and initial management of the cohort of women diagnosed with stage 1A carcinoma of the cervix, either at the outset or during follow up after an earlier diagnosis of cervical intraepithelial neoplasia (CIN3) Period of diagnosis Diagnosis of stage 1A carcinoma At outset (N = 62) During follow up (N = 20) Total (N = 82) n (%) n (%) n (%) (30.6) 1 (5.0) 20 (24.4) (45.2) 8 (40.0) 36 (43.9) (24.2) 6 (30.0) 21 (25.6) (20.0) 4 (4.9) (5.0) 1 (1.2) Age at diagnosis <30 5 (8.1) 1 (5.0) 6 (7.3) (38.7) 7 (35.0) 31 (37.8) (33.9) 6 (30.0) 27 (32.9) (19.3) 6 (30.0) 18 (22.0) Ethnicity Māori 11 (17.7) 4 (20.0) 15 (18.3) European 50 (80.7) 16 (80.0) 66 (80.5) Other 1 (1.6) 0 (0.0) 1 (1.2) Parity Nulliparous 6 (9.7) 2 (10.0) 8 (9.8) (64.5) 11 (55.0) 51 (62.2) 5 16 (25.8) 7 (35.0) 23 (28.0) Initial diagnostic procedure Hysterectomy 1 (1.6) 0 (0.0) 1 (1.2) Cone biopsy 46 (74.2) 11 (55.0) 57 (69.5) Ring biopsy 9 (14.5) 5 (25.0) 14 (17.1) Wedge biopsy 3 (4.8) 1 (5.0) 4 (4.9) Biopsy of unknown type 3 (4.8) 3 (15.0) 6 (7.3) Most extensive procedure within three months of diagnosis Hysterectomy 9 (14.5) 3 (15.0) 12 (14.6) Cone biopsy 40 (64.5) 10 (50.0) 50 (61.0) Ring biopsy 7 (11.3) 5 (25.0) 12 (14.6) Wedge biopsy 3 (4.8) 1 (5.0) 4 (4.9) Biopsy of unknown type 3 (4.8) 1 (5.0) 4 (4.9) Nature of treatment by three months after diagnosis Probably curative Hysterectomy 8 (12.9) 3 (15.0) 11 (13.4) Cone biopsy 8 (12.9) 3 (15.0) 11 (13.4) Probably non- curative Hysterectomy, positive cytology 1 (1.6) 0 (0.0) 1 (1.2) Cone biopsy with evidence of persisting disease 25 (40.3) 5 (25.0) 30 (36.6) Cone biopsy with clear margins but either no 2 (3.2) 2 (10.0) 4 (4.9) informative cytology or low grade cytology Cone biopsy with extent of disease in margins unknown and either no informative cytology or low grade cytology 5 (8.1) 0 (0.0) 5 (6.1) (Continues)

5 C. Paul et al. 325 TABLE 1 (Continued) Diagnosis of stage 1A carcinoma At outset (N = 62) During follow up (N = 20) Total (N = 82) n (%) n (%) n (%) Ring or wedge biopsy 10 (16.1) 6 (30.0) 16 (19.5) Biopsy of unknown type 3 (4.8) 1 (5.0) 4 (4.9) All diagnoses after 1976 were in women who were initially included in the CIN3 cohort and were later diagnosed with stage 1A carcinoma during follow-up. Procedures classified as probably curative were: (i) hysterectomy with clear or unknown margins and normal, benign, class 2 or no informative cytology within 6 24 months; or (ii) cone biopsy with clear margins and normal, benign or class 2 cytology within 6 24 months. Either CIN3 present in the margins of the excision, positive cytology or both. TABLE 2 Medical procedures and events during first 10 years of follow up, follow- up treatment and disease outcomes in women with stage 1A carcinoma of the cervix by initial management Initial management Probably curative Probably non-curative large excision Probably non-curative small excision Cervical/vaginal smears N = 22 N = 40 N = 20 Rate per woman- year P = Positive smears after initial management Number (%) of women with 1 (4.5) 11 (27.5) 12 (60.0) P < Untreated positive smears Number (%) of women with 1 (4.5) 7 (17.5) 8 (40.0) P = Biopsies of any type after initial management Rate per woman- year Number (%) of women with 1 (4.5) 6 (15.0) 10 (50.0) P = Probably curative treatment during follow-up By six months 100% 18% 5% By five years 100% 41% 16% By 10 years 100% 44% 23% By 15 years 100% 48% 30% P = < Median duration of follow- up, 26 (13 31) 25 (19 34) 15 (11 26) years (95% confidence interval) Cancer of the cervix (stage 1B or higher) or vaginal vault Death from cancer of the cervix or vaginal vault Death from any cause Procedures classified as probably curative were: (i) hysterectomy with clear or unknown margins and normal, benign, class 2 or no informative cytology within 6 24 months; or (ii) cone biopsy with clear margins and normal, benign or class 2 cytology within 6 24 months. Possible or definite high- grade cytological abnormality, excluding smears within six months after a procedure. A positive smear not followed by a procedure which was probably curative within six months. respectively) (Table 2). Among women who did not have curative treatment initially, the proportion who eventually had curative treatment was smaller in the group with only a small excision initially than in the group with a large excision (30% vs 48% by 15 years). However, this difference was not statistically significant (P = 0.12).

6 326 Outcomes for stage 1A cervical carcinoma TABLE 3 Clinical management and outcomes for women who were diagnosed with invasive carcinoma of the cervix (stage 1B or higher) or vaginal vault during follow up Initial management Initial management category Initial stage Year of stage 1A diagnosis Maximum procedure by 3 months Disease in excision margins Cytology 6 24 months after procedure Non- curative, small 1A Wedge biopsy Unknown Positive Non- curative, small 1A Wedge biopsy Yes Positive Non- curative, small 1A Wedge biopsy Yes Positive Non- curative, small 1A Ring biopsy Unknown None Non- curative, small 1A Ring biopsy Yes None Non- curative, small 1A Ring biopsy Unknown Positive Non- curative, small 1A Ring biopsy Unknown Negative Non- curative, small 1A Ring biopsy Yes Positive Non-curative, large 1A Cone biopsy Unknown Negative Non-curative, large 1A Cone biopsy Yes Positive Non- curative, large 1A Cone biopsy Yes None Non-curative, large 1A Cone biopsy Yes Positive Non-curative, large 1A Cone biopsy Yes Negative Probably curative 1A Hysterectomy Unknown Negative Probably curative 1A Hysterectomy Unknown None Classification of initial management based on procedures, examination of the excision margins and cytology 6 24 months after the procedure. Probably non- curative, small = persisting disease, small excision; Probably non- curative, large = persisting disease large excision; Probably curative = either: (i) hysterectomy with clear or unknown margins and normal, benign, class 2 or no informative cytology within 6 24 months; or (ii) cone biopsy with clear margins and normal, benign or class 2 cytology within 6 24 months. Positive cytology = class 3, 4 or high grade; negative cytology = normal, benign or class 2; none = no informative smears within 6-24 months after the procedure. Diagnosed with stage 1A carcinoma of the cervix during follow- up after diagnosis with cervical intraepithelial neoplasia (CIN3). ICD, International Classification of Diseases. During follow up, 15 of the 82 women developed stage 1B or higher cancer of the cervix or cancer of the vaginal vault, denoted as invasive cancer (Table 2); 13 were cancers of the cervix and two of the vaginal vault (ICD codes 180 and 184, respectively). There were eight deaths from cancer of the cervix or vaginal vault in the group of 82 women. Details of the medical experience of the 15 women diagnosed with invasive cancer are provided in Table 3. Three of these women were diagnosed with 1B carcinoma within a year of the stage 1A diagnosis. While the diagnosis of stage 1A was reviewed and invasion of >5 mm was excluded in the available material, it is likely that for these women there was a focus of invasion which had not been excised. Figure 2 shows the cumulative incidence of invasive cancer to 30 years according to the category of initial management. Among the 60 women whose initial management we classified as probably non- curative, the cumulative incidence at 20 years was 40% (95% CI 20 60%) in those whose initial management was a ring or a wedge biopsy, and 13% (5 25%) in those whose initial management was a cone biopsy. There were 22 women in the cohort who received treatment that we classified as probably curative within the first three months of diagnosis of stage 1A carcinoma. Two of these 22 women developed invasive cancer. One of these women received no further surveillance at National Women s Hospital, and was diagnosed with invasive carcinoma of the vaginal vault nine years after the diagnosis of stage 1A. The second woman initially had FIGURE 2 Cumulative incidence of invasive cancer of the cervix (stage 1B or higher) or vaginal vault up to 30 years after diagnosis with stage 1A cancer of the cervix, according to initial management.

7 C. Paul et al. 327 Follow- up management to diagnosis of stage 1B carcinoma Outcome Positive smears (n) Untreated positive smears (n) Biopsies (n) Years to stage 1B or higher diagnosis Stage Cancer (ICD code) Death (ICD code of cause B 180 Alive Alive B months 1B 180 Other months 1B 180 Other B B B B months Alive B B 180 Other B Other low- grade cytology after her hysterectomy, but she then had 11 untreated positive smears and four small biopsies, before being diagnosed with stage 1B carcinoma of the cervix 31 years after her diagnosis with stage 1A carcinoma. Thus, neither of these two women appeared to receive appropriate surveillance or treatment after initial treatment that was deemed to be probably curative. For three women it was not possible to judge from stored specimens whether their initial diagnosis was stage 1A1 or 1A2. None of these women developed invasive carcinoma, although only one was treated by hysterectomy. One of the others had a second cone biopsy that had clear excision margins eight months after the initial treatment. The third received only a ring biopsy, but had negative cytology in the following 10 years. DISCUSSION Among 82 women diagnosed with microinvasive carcinoma of the cervix at National Women s Hospital, 15 developed invasive cancer of the cervix or vaginal vault, and eight died from their disease. For 13 of these 15 women, their initial management was categorised as probably non- curative. The other two, although initially receiving treatment that was categorised as probably curative, subsequently received neither appropriate surveillance nor treatment. The proportion who developed invasive cancer among all 82 women (18.3%) was far in excess of invasive recurrences among Australian women treated conventionally for stage 1A carcinoma over a similar time period (3.4%); the proportion who died from their disease was also much higher (9.8 vs 1.9%). 19 This underestimates the difference because 20 of the women in our cohort were diagnosed with stage 1A cancer during the period , before Green s clinical study commenced. As we observed previously for women with CIN3, 5 the greater number of subsequent biopsies among women whose initial management was probably not curative attests to their assiduous follow up. Nevertheless, conventional warning signs often were not acted upon, as is clear from the proportions of women who had repeated positive smears and positive smears not followed by a procedure with curative intent. Indeed, among those who developed invasive cancer, three women had 11 or more positive smears and one of these also had eight biopsies under anaesthetic. All three women subsequently died of their disease. In addition, under- treatment may sometimes have resulted in missing foci of invasive cancer. As mentioned previously, this might explain why three women were diagnosed with invasive cancer only a few months after their stage 1A diagnosis. It is clear that

8 328 Outcomes for stage 1A cervical carcinoma Green s policy of following women with diagnosed but untreated (or under- treated) lesions was responsible for the excess of inappropriate follow- up interventions among women whose initial management was not curative, compared to those with initial curative treatment. The outcomes for these women with microinvasive cancer have not been reported previously, either because they were (appropriately) excluded at the outset from analyses of CIN3, 3 5 or, for those diagnosed after their initial CIN3 diagnosis, Stage 1A carcinoma served as an endpoint in the previous analyses. 4,5 The latter group are included in our present study, because the majority were managed during the period of the clinical study. Of the eight deaths reported here, only two were in the latter group and these deaths had been counted in our previous analysis of outcomes for women with CIN3. 5 The types of non- curative initial management for microinvasive cancer differ from the initial management for women with CIN3 previously reported. 5 For women with microinvasive cancer, the entire lesion had to be removed to make the diagnosis (although CIN3 may have been present at the margin, and other missed foci of microinvasion were possible). For the CIN3 cohort, the lesion was not necessarily removed. The size of the initial excision was generally larger for microinvasion (at least ring biopsy) than for CIN3 (at least punch biopsy), although the lesion size would generally also have been larger. 20 Hence, both groups were characterised by the presence of residual CIN3 after initial management, but the comparative size of the residual lesions cannot be determined. It is unlikely that bias affected the comparisons according to initial management. Careful re- analysis of medical records and reexamination of histopathology slides and cytology smears have provided an objective and systematic account of the medical experiences of these women. 5 The extent of follow- up information was enhanced by the policy of arranging (at least) annual visits to the hospital for examinations and smears. Moreover, we restricted the description of each woman s clinical management to the 10 years following her diagnosis, so that the analysis was not influenced by different periods of follow- up according to type of management (Green s study was largely confined to women first diagnosed between 1965 and 1974), nor by the review and recall of women following the judicial inquiry. 2 As ascertainment of cancers encompassed only women who remained in New Zealand or who lived in two Australian states, there may have been additional cancers among a few who emigrated elsewhere. The consequences for the women who did not receive curative treatment were profound. As we found for women with CIN3, 5 the withholding of initial treatment with curative intent led to lives being seriously disrupted by the need to attend hospital for numerous medical interventions that would have been unnecessary had curative treatment been offered at the outset. Among the women with microinvasion diagnosed during follow- up, many had further surveillance without curative treatment, despite having already suffered from having their CIN3 untreated. The shocking effect of withholding conventional treatment is clear from the experience of some of the women who subsequently developed clinically invasive cancer and died from their disease. It also needs to be remembered that the women in Green s study were not asked to consent to the management approach being followed, and most were unaware that they were not receiving conventional treatment. We are reporting these findings in order to document and acknowledge the harm suffered by these women, and also to complete the picture of the effects of Green s study. ACKNOWLEDGEMENTS Funding was from the Cancer Society of New Zealand and the University of Otago. We are grateful to Dr Margaret McCredie for her original leadership of the research and management of the data collection, Dr Wendy Stevens for contributions to data collection and analysis, Dr Gabriele Medley for supervising the cytology review, and the women who were the focus of the New Zealand Cervical Cancer Inquiry. REFERENCES 1. Green GH. Cervical carcinoma in situ: an atypical viewpoint. Aust NZ J Obstet Gynaecol 1970; 10: Cartwright SR. The Report of the Committee of Inquiry into Allegations Concerning the Treatment of Cervical Cancer at National Women s Hospital and into other Related Matters. Auckland: Government Printing Office, McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol 1984; 64: McCredie MRE, Sharples KJ, Paul C et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intrepithelial neoplasia 3: a retrospective cohort study. 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