K. K. Chan

Failure of second-look laparotomy to influence survival in epithelial ovarian cancer.

The survival benefit of second-look laparotomy after completion of primary chemotherapy in patients with epithelial ovarian cancer has been assessed in a prospective randomised trial of 166 patients. Patients were randomised into three groups. All were initially treated with cisplatin (100 mg/m2 x 5) after primary laparotomy. Group A (n = 53) was scheduled to have a second-look laparotomy, followed by cyclical oral chlorambucil. Group B (n = 56) was scheduled to have a second-look laparotomy, followed by total abdominal and pelvic irradiation, and group C (n = 57) received oral chlorambucil as for group A but had no second-look operation. With a median follow up of 46 months (range 21-64), no differences in survival were noted between the three groups. The median survival for group A was 21 months (95% CI 11-31 months), for group B 15 months (11-19), and for group C 17 months (8-26). Thus second-look laparotomy after completion of first-line single-agent cisplatin chemotherapy did not confer any survival benefit on patients with epithelial ovarian cancer.

Surgical and oncological outcome of total laparoscopic radical hysterectomy in obese women with early-stage cervical cancer.

Objective To evaluate the clinical experience of the total laparoscopic radical hysterectomy (TLRH) for the surgical management of cervical cancer in obese (body mass index [BMI] >30 kg/m2) and nonobese (BMI <30 kg/m2) women. Methods Data were collected prospectively on intraoperative and postoperative parameters and complications for all women undergoing a TLRH for cervical cancer. Patients were classified as obese, BMI >30 kg/m2, or nonobese, BMI <30 kg/m2. Assessment of surgical radicality was made by comparing the excision specimens in the 2 groups with a cohort of open radical hysterectomy cases performed before the introduction of the TLRH. Results A total of 58 women underwent a TLRH; 15 (25.9%) were obese and 43 (74.1%) were in the nonobese group. There was no significant difference in intraoperative blood loss or median duration of surgery between the obese and nonobese groups. The median hospital stay in both groups was 3 days (range, 2–13 days). Four cases were converted to laparotomy (7%); all were in the nonobese group. Postoperatively, 3 patients developed ischemic ureterovaginal fistulae (5%) between days 5 and 7 after surgery; all were in the nonobese group. There was no significant difference in the parametrial length, maximum vaginal cuff length, and number of lymph nodes excised between the 2 groups. To date, there has been one recurrence during the median follow-up period of 19 months (range, 3–42 months). She belonged to the nonobese group. Conclusions The TLRH is a surgically safe procedure for early-stage cervical cancer. Obesity did not adversely affect the performance of TLRH or the radicality of the excision. In obese women, TLRH should be the favored route of surgery for all women who require a radical hysterectomy owing to its favorable perioperative outcome and short hospital stay.

Gliomatosis peritonei associated with ovarian teratomas.

Case report An 11-year-old Negro girl presented in August, 1978, with a 2 months history of painless abdominal swelling, having previously been well with normal development. Menarche had occurred 6 months earlier. A large firm pelvic tumour with moderate ascites was found on examination but there were no other significant findings. A plain X-ray showed a mass in the lower abdomen with amorphous areas of calcification. Serum a-fetoprotein (AFP) and serum human chorionic gonadotrophin (p subunit) levels were not elevated. At laparotomy a large tumour measuring 2 3 x 2 2 ~ 2 8 cm was found arising from the left ovary. Ascites and multiple peritoneal seedlings were present. A left salpingo-oophorectomy and omental biopsy were performed. Histological examination showed the primary tumour to be a well differentiated solid teratoma with omental deposits of well differentiated circumscribed neural tissue. N o evidence of extra-abdominal disease was found, and no further active management was instituted. She remained asymptomatic for 12 months and then developed further abdominal distension. Ultrasonography confirmed the presence of ascites but no solid or cystic lesions. A second laparotomy was performed and 1.5 litres of ascitic fluid was drained. Cystic tumours in the pouch of Douglas and left ovarian pedicle were removed. An enlarged cystic right ovary was also removed. Histology confirmed well differentiated teratoma but with some areas of increased cellularity. Malignant cells were identified on cytology of the ascitic fluid. In September 1979 she was treated with 2 mg of vincristine given intravenously, 0.9 mg of actinomycin D and 450mg of cyclo-

Neuroendocrine Carcinoma of the Cervix: Review of a Series of Cases and Correlation With Outcome.

Introduction. Neuroendocrine carcinoma (NEC) of the cervix is associated with a poor prognosis despite multimodal treatment. The correct diagnosis of this tumor type is imperative to provide clinicians and patients with prognostic information and ensure that appropriate treatment is provided. Methods. A clinicopathological study was undertaken on all cervical tumors registered as NEC with the West Midlands Cancer Intelligence Unit between January 1, 1998 and December 31, 2009. Of the 45 cases diagnosed during the study period, the tumor samples of 41 cases were traced, anonymized, and then independently reviewed by 2 gynecological pathologists. Results. The review confirmed 31/41 (78%) cases to be NEC, which overall, represented 1.3% of all the cervical cancers registered in the West Midlands over the period of the study. In the correct histological context, synaptophysin was the most sensitive and specific positive immunohistochemical marker of NEC differentiation. The cases that on review were confirmed as NEC had a significantly worse outcome than the non-NEC cases: median survival for NEC cases was 33.3 months versus 315.0 months for the non-NEC cases, P = .013. Conclusions. Histological review of a series of NECs has shown significantly reduced survival in those patients with confirmed NEC in comparison with those patients where a diagnosis of NEC was not confirmed. We propose morphological and immunohistochemical criteria for the diagnosis of cervical NEC; and discourage unqualified use of the term “small cell carcinoma” as this does not accurately convey the diagnosis of SCNEC. We urge pathologists to use the 2014 World Health Organization classification when reporting these tumors.

Serial urinary cyclic guanosine monophosphate measurements in the assessment of response to treatment in epithelial ovarian cancer

Serial measurements of urinary cyclic guanosine monophosphate (cGMP) were performed in 47 patients with epithelial ovarian cancer. In 30 patients, the pre‐chemotherapy cGMP level was above the range for normal controls (marker positive); the remainder were within the normal range. Marker positive patients demonstrated a 96% correlation of disease regression with a fall in marker level and a 75% correlation of disease progression with a rise in marker level. The corresponding correlations in the marker negative group were 41% and 39%. Marker positive patients also demonstrated a rise in marker before clinical recognition of disease progression in six of 11 instances whereas only one of nine instances in marker negative patients showed such a rise. Patients with evidence of static disease had normal and stable marker levels.

Meeting the challenge of developing and maintaining radical hysterectomy skills

A radical hysterectomy (RH), in combination with bilateral pelvic lymphadenectomy, is the standard therapy for a woman with stage 1b1 cervical cancer. This complex surgical procedure carries the risk of serious complications and therefore selecting women for and safely undertaking this operation has become the responsibility of subspecialist gynaecological oncologists. The process by which this occurred evolved over the last two decades. The first step was the development of a gynaecological oncology subspecialty training syllabus by the Royal College of Obstetricians and Gynaecologists (RCOG). This was followed by the establishment of a number of training centres throughout the UK. The third step followed national organisational changes that classify hospitals as either cancer units or cancer centres and arrange them in a ‘hub and spoke’ pattern. Cancer units undertake diagnostic and simple surgical procedures whereas complex surgery has become the responsibility of cancer centres. As a result, RH caseloads achieved the critical mass that allowed not only the development of but also the maintenance of the skills and experience necessary to ensure quality care. Informal discussions within the UK gynaecological oncology community suggest a growing level of disquiet about the emergence of a number of new obstacles to the maintenance of this critical mass. First, the number of RH being undertaken is falling because overall rates of cervical cancer are falling, fertility-sparing operations have been introduced, primary chemoradiotherapy has been shown to be a viable non-surgical option, simple hysterectomy for low volume stage 1b1 tumours is acceptable and there have been efforts to limit rates of adjuvant post-RH chemoradiotherapy. Second, subspecialty trainees are entering programmes with less surgical experience – which necessitates more time on the development of basic surgical skills in the early phases of training programmes thereby leaving less time for the development of radical surgical skills and experience. Third, the introduction of laparoscopic techniques has reduced the number of RH undertaken via the open route. As the skills to undertake this complex operation laparoscopically are ideally developed against a background of experience with open operations, trainees are being placed in the unfortunate quandary of having access to too few open operations to develop the skills to undertake these operations laparoscopically. The aim of this study is to provoke formal discussions on this subject by presenting an analysis of the treatments offered to a cohort of women with newly diagnosed stage 1b1 cervical cancer managed in a moderate to large gynaecological cancer centre over a three-year period.

Should All Cases of High-Grade Serous Ovarian, Tubal, and Primary Peritoneal Carcinomas Be Reclassified as Tubo-Ovarian Serous Carcinoma?

Introduction The dualistic theory of ovarian carcinogenesis proposes that epithelial “ovarian” cancer is not one entity with several histological subtypes but a collection of different diseases arising from cells of different origin, some of which may not originate in the ovarian surface epithelium. Methods All cases referred to the Pan-Birmingham Gynaecological Cancer Centre with an ovarian, tubal, or primary peritoneal cancer between April 2006 and April 2012 were identified from the West Midlands Cancer Registry. Tumors were classified into type I (low-grade endometrioid, clear cell, mucinous, and low-grade serous) and type II (high-grade serous, high-grade endometrioid, carcinosarcoma, and undifferentiated) cancers. Results Ovarian (83.5%), tubal (4.3%), or primary peritoneal carcinoma (12.2%) were diagnosed in a total of 583 woman. The ovarian tumors were type I in 134 cases (27.5%), type II in 325 cases (66.7%), and contained elements of both type I and type II tumors in 28 cases (5.7%). Most tubal and primary peritoneal cases, however, were type II tumors: 24 (96.0%) and 64 (90.1%), respectively. Only 16 (5.8%) of the ovarian high-grade serous carcinomas were stage I at diagnosis, whereas 240 (86.6%) were stage III+. Overall survival varied between the subtypes when matched for stage. Stage III low-grade serous and high-grade serous carcinomas had a significantly better survival compared to clear cell and mucinous cases, P = 0.0134. There was no significant difference in overall survival between the high-grade serous ovarian, tubal, or peritoneal carcinomas when matched for stage (stage III, P = 0.3758; stage IV, P = 0.4820). Conclusions Type II tumors are more common than type I and account for most tubal and peritoneal cancers. High-grade serous carcinomas, whether classified as ovarian/tubal/peritoneal, seem to behave as one disease entity with no significant difference in survival outcomes, therefore supporting the proposition of a separate classification of “tubo-ovarian serous carcinoma”.

Phase II clinical trials of cisplatin-then-paclitaxel and paclitaxel-then-cisplatin in patients with previously untreated advanced epithelial ovarian cancer

PURPOSE To examine the activity and safety of two sequentially scheduled chemotherapy regimens comprising four cycles of paclitaxel (pctx) 200 mg/m2/3 hours then four cycles ofcisplatin (cisDDP) 100 mg/m2, and vice versa, in patients with previously untreated advanced ovarian cancer. PATIENTS AND METHODS Between January 1994 and February 1996, we recruited 30 patients to the pctx-then-cisDDP regimen and 29 to cisDDP-then-pctx, in parallel phase II trials. RESULTS Both regimens were predictably active with responses seen in 22 of 30 patients (OR 74%; CR 27%, PR 47%) treated with pctx-then-cisDDP, as against 13 of 21 patients (OR 62%; CR 38%, PR 24%) treated with cisDDP-then-pctx. The OR rate to four cycles of pctx (induction) was 43%, with 27% disease progression; the OR to four cycles of cisDDP (induction) was 57%, with 5% progression. However, progression rates across both induction and consolidation phases were 16% (pctx-then-cisDDP) and 29% (cisDDP-then-pctx). Both regimens were unacceptably neurotoxic. II patients suffering grade 3 sensory neurotoxicity (5 on pctx-then-cisDDP, 6 on cisDDP-then-pctx) and 20 having grade 3 deafness (9 on pctx- then-cisDDP, 11 on cisDDP-then-pctx). CONCLUSION The activity of these sequential regimens justifies their further development using the less neurotoxic platinum analogue carboplatin, perhaps combining paclitaxel with other platinum non-cross resistant drugs.

A statement for extensive primary cytoreductive surgery in advanced ovarian cancer: Correspondence

Sir, The argument of surgery versus chemotherapy in the treatment of epithelial ovarian cancer (EOC) is spurious as both modalities are equally important and complement each other. The questions, which are always raised are about the aggressiveness of the cytoreductive effort and its associated morbidity and whether there could be an effective utilisation of chemotherapy to improve surgical outcome and reduce surgical morbidity. The results of EORTC 55971 have proven that survival after neoadjuvant chemotherapy is not inferior to survival after primary cytoreductive surgery and supports the utilisation of neoadjuvant chemotherapy to reduce operative morbidity. However, this is not an excuse to perform suboptimal surgery. Surgery whether done as primary debulking or delayed primary surgery should be aimed at maximum cytoreduction with no macroscopic residual disease being the ultimate goal. Shortterm morbidity for long-term gain is acceptable. The extent of surgical debulking of advanced EOC is variable throughout the UK and even varies within centres. It is dependent on the attitude of the surgical team, surgical experience, resource availability and patient profile. As a consequence, the radicality of surgical effort to obtain an optimal result can be difficult to assess. Chemotherapy is protocol driven and is of a more uniform standard. It is also easier to assess its outcomes. Deterrents to optimal surgical debulking in our centre are the presence of miliary disease on bowel mesentery/ serosa, suprarenal retroperitoneal deposits and deposits at the porta hepatis. Outside of clinical trials, primary surgery is deferred in the presence of poor prognostic factors, e.g., poor performance status, multiple sites of extra-pelvic disease and neoadjuvant chemotherapy with delayed primary surgery is offered. We are conscious of surgical morbidity and see nothing wrong in using chemotherapy to facilitate the optimum surgical clearance of disease when the survival is not compromised. We do not use it as a substitute for proper surgery. j

Short-Duration (Three Cycles) Cisplatin Combination Chemotherapy with Alkylating Agent Consolidation in Advanced Epithelial Ovarian Cancer

Abstract Forty-eight patients with advanced epithelial ovarian cancer were treated with a twopart cytotoxic regimen consisting of three cycles of cisplatin-based induction therapy followed by five cycles of escalating doses of cyclophosphamide, all given at 3-weekly intervals. The total cisplatin dose was 225 mg/m 2 . Seventeen patients with optimal primary surgery received chemotherapy only, while 17 of the 31 patients with suboptimal primary surgery underwent optimal interval cytoreductive surgery at the end of induction (cisplatin) therapy. Median survival for all patients was 15.4 months. Median survival was 15 months for patients with optimal primary surgery and 22 months for patients who had optimal secondary cytoreduction. Only 10 patients suffered WHO grade 3 or greater toxicity during therapy. This study suggests that the total dose of cisplatin can be reduced for patients with advanced ovarian carcinoma, resulting in reduced overall toxicity, without compromising response or response duration. A randomized trial to test this concept is now underway.