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1.  Analysis of Morbidity and Clinical Implications of Laparoscopic Para-Aortic Lymphadenectomy in a Continuous Series of 98 Patients with Advanced-Stage Cervical Cancer and Negative PET–CT Imaging in the Para-Aortic Area 
The Oncologist  2011;16(7):1021-1027.
A series of patients with locally advanced cervical cancer, with no positive para-aortic nodes on positron emission tomography–computed tomography who had undergone a primary laparoscopic para-aortic lymphadenectomy was retrospectively reviewed. Morbidity was limited and the completion of treatment was not delayed when complications occurred.
Laparoscopic para-aortic lymphadenectomy (PAL) is being used increasingly to stage patients with locally advanced cervical cancer (LACC) and to define radiation field limits before chemoradiation therapy (CRT). This study aimed to define clinical implications, review complications, and determine whether surgical complications delayed the start of CRT.
We retrospectively reviewed a continuous series of patients with LACC, with no positive para-aortic (PA) nodes on positron emission tomography–computed tomography (PET–CT) and who had undergone a primary laparoscopic PAL.
From November 2007 to June 2010, 98 patients with LACC underwent pretherapeutic PAL. Two patients did not undergo PAL: extensive carcinomatosis was discovered in one case and a technical problem arose in the other. No perioperative complications occurred. Seven patients had a lymphocyst requiring an imaging-guided (or laparoscopic) puncture. Eight patients (8.4%, which corresponds to the false-negative PET–CT rate) had metastatic disease within PA lymph nodes. In cases of suspicious pelvic nodes on PET–CT, the risk for PA nodal disease was greater (24.0% versus 2.9%). When patients with and without surgical morbidity were compared, the median delay to the start of treatment was not significantly different (15 days; range, 3–49 days versus 18 days; range, 3–42 days).
The morbidity of laparoscopic PAL was limited and the completion of treatment was not delayed when complications occurred. Nevertheless, if PET–CT of the pelvic area is negative, the interest in staging PAL could be discussed because the risk for PA nodal disease is very low.
PMCID: PMC3228132  PMID: 21659610
Cervical cancer; Para-aortic lymphadenectomy; Laparoscopy; Staging; Morbidity; Lymphocyst
2.  Results of the GYNECO 02 Study, an FNCLCC Phase III Trial Comparing Hysterectomy with No Hysterectomy in Patients with a (Clinical and Radiological) Complete Response After Chemoradiation Therapy for Stage IB2 or II Cervical Cancer 
The Oncologist  2012;17(1):64-71.
The therapeutic impact of completion surgery (hysterectomy) after chemoradiotherapy was investigated in patients with stage IB or II cervical cancer. Hysterectomy had no therapeutic impact in patients with a clinical and radiological complete response after chemoradiotherapy, but this conclusion is limited by the lack of power.
Learning Objectives
After completing this course, the reader will be able to: Evaluate the therapeutic impact of hysterectomy after chemoradiation therapy in locally advanced cervical cancer.Evaluate the rate of histologic residual disease in patients with complete clinical and radiologic response after chemoradiation therapy.
This article is available for continuing medical education credit at
Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery.
A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6–8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003–2006) and are reported on here.
Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively.
Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).
PMCID: PMC3267825  PMID: 22234626
Chemoradiation therapy; Surgery; Locally advanced cervical cancer; Nodal involvement; Prognostic factors; Residual disease; Survival
3.  Rate of para-aortic lymph node micrometastasis in patients with locally advanced cervical cancer 
Gynecologic oncology  2010;119(3):422-425.
Patients with micrometastasis to para-aortic lymph nodes may benefit from extended field chemoradiation. To determine the rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer undergoing laparoscopic extraperitoneal para-aortic lymphadenectomy
We prospectively identified consecutive patients diagnosed with stage IB2-IVA biopsy-proven cervical cancer. Eligible patients included those who were candidates for treatment with radiotherapy and concurrent chemotherapy and had no evidence of para-aortic lymphadenopathy (all lymph nodes < 2 cm in diameter) by preoperative computed tomography or magnetic resonance imaging. All patients underwent preoperative positron emission tomography/computed tomography and laparoscopic extraperitoneal para-aortic lymphadenectomy. All lymph nodes were assessed for metastasis by routine hematoxylin-eosin (H&E) staining. Ultrastaging (serial sectioning) and immunohistochemical analysis were performed in H&E-negative specimens.
Thirteen (22%) of 60 consecutive patients had para-aortic lymph node metastases detected on routine H&E staining. Of the remaining 47 patients, one (2.1%) had evidence of micrometastasis, which was detected by ultrastaging. This patient completed whole pelvic radiotherapy and chemotherapy but had a recurrence 27 months after completion of therapy.
The rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer is low. The role of routine ultrastaging and immunohistochemical analysis in such patients remains uncertain. Future studies are needed to determine the clinical impact of para-aortic node micrometastasis in patients with locally advanced cervical cancer.
PMCID: PMC4286254  PMID: 20837355
4.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
An application was received to review the evidence on the ‘The Da Vinci Surgical System’ for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of ‘The Da Vinci Surgical System’ include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers.
The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men’s health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision.
Clinical Need
Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen.
Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer.
Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium.
The Da Vinci Surgical System
The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon’s console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon’s hands at the surgeon’s console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of “wristed” instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon’s console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback.
Research Questions
For endometrial and cervical cancers,
1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
For prostate cancer,
3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
Research Methods
Literature Search
Search Strategy
A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles (January 1, 2000-May 12, 2010)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)
Study design and methods must be clearly described
Health technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies
Exclusion Criteria
Duplicate publications (with the more recent publication on the same study population included)
Non-English papers
Animal or in-vitro studies
Case reports or case series without a referent or comparison group
Studies on long-term survival which may be affected by treatment
Studies that do not examine the cancers (e.g. advanced disease) or outcomes of interest
Outcomes of Interest
For endometrial and cervical cancers,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Number of complications*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of conversions to laparotomy*
Number of lymph nodes recovered
For prostate cancer,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Amount of morphine use/pain*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of transfusions*
- Duration of catheterization
- Number of complications*
- Number of anastomotic strictures*
Number of lymph nodes recovered
Oncologic factors
- Proportion of positive surgical margins
Long-term outcomes
- Urinary continence
- Erectile function
Summary of Findings
Robotic use for gynecologic oncology compared to:
Laparotomy: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.
The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.
More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.
Laparoscopy: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for length of hospitalizations and blood loss is low.
Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.
Robotic use for urologic oncology, specifically prostate cancer, compared to:
Retropubic surgery: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.
Surgeon skill had an impact on cancer control and functional outcomes.
The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. There is some suggestion that robotic surgery is safe with respect to less post-operative pain management required compared to retropubic surgery, however improved study design and measurement of complications need to be further addressed.
Clinical significance of significant findings for length of hospitalizations is low.
Laparoscopy: benefits of robotic surgery in terms of less blood loss and fewer individuals requiring transfusions likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for blood loss is low.
The potential link between less blood loss, improved visualization and improved functional outcomes is an important consideration for use of robotics.
All studies included were observational in nature and therefore the results must be interpreted cautiously.
Economic Analysis
The objective of this project was to assess the economic impact of robotic-assisted laparoscopy (RAL) for endometrial, cervical, and prostate cancers in the province of Ontario.
A budget impact analysis was undertaken to report direct costs associated with open surgery (OS), endoscopic laparoscopy (EL) and robotic-assisted laparoscopy (RAL) based on clinical literature review outcomes, to report a budget impact in the province based on volumes and costs from administrative data sets, and to project a future impact of RAL in Ontario. A cost-effectiveness analysis was not conducted because of the low quality evidence from the clinical literature review.
Hospital costs were obtained from the Ontario Case Costing Initiative (OCCI) for the appropriate Canadian Classification of Health Intervention (CCI) codes restricted to selective ICD-10 diagnostic codes after consultation with experts in the field. Physician fees were obtained from the Ontario Schedule of Benefits (OSB) after consultation with experts in the field. Fees were costed based on operation times reported in the clinical literature for the procedures being investigated. Volumes of procedures were obtained from the Ministry of Health and Long-Term Care (MOHLTC) administrative databases.
Direct costs associated with RAL, EL and OS included professional fees, hospital costs (including disposable instruments), radiotherapy costs associated with positive surgical margins in prostate cancer and conversion to OS in gynecological cancer. The total cost per case was higher for RAL than EL and OS for both gynecological and prostate cancers. There is also an acquisition cost associated with RAL. After conversation with the only supplier in Canada, hospitals are looking to spend an initial 3.6M to acquire the robotic surgical system
Previous volumes of OS and EL procedures were used to project volumes into Years 1-3 using a linear mathematical expression. Burden of OS and EL hysterectomies and prostatectomies was calculated by multiplying the number of cases for that year by the cost/case of the procedure.
The number of procedures is expected to increase in the next three years based on historical data. RAL is expected to capture this market by 65% after consultation with experts. If it’s assumed that RAL will capture the current market in Ontario by 65%, the net impact is expected to be by Year 3, 3.1M for hysterectomy and 6.7M for prostatectomy procedures respectively in the province.
RAL has diffused in the province with four surgical systems in place in Ontario, two in Toronto and two in London. RAL is a more expensive technology on a per case basis due to more expensive robot specific instrumentation and physician labour reflected by increased OR time reported in the clinical literature. There is also an upfront cost to acquire the machine and maintenance contract. RAL is expected to capture the market at 65% with project net impacts by Year 3 of 3.1M and 6.7M for hysterectomy and prostatectomy respectively.
PMCID: PMC3382308  PMID: 23074405
5.  FDG-PET-based Prognostic Nomograms for Locally Advanced Cervical Cancer 
Gynecologic oncology  2012;127(1):136-140.
Patients with cervical cancer of the same clinical FIGO stage can have distinctly different outcomes. We previously found that several individual factors determined by positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG), including primary cervical tumor maximum standardized uptake value (SUVmax), cervical tumor volume, and highest level of lymph node (LN) involvement, provide prognostic information about patient outcome. For this study, we aimed to evaluate the combined prognostic value of these three factors assessed on pretreatment FDG-PET for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS).
Patients and Methods:
The study included 482 cervical cancer patients, FIGO stage Ia2-IVa, treated with definitive radiation or chemoradiation therapy. All patients underwent FDG-PET or FDG-PET/CT at diagnosis, from which cervical tumor volume, LN status, and tumor SUVmax were recorded. Using these PET-based factors, prognostic nomograms based on Cox regression were created for RFS, DSS, and OS. The prediction accuracies of the nomograms were measured using the concordance index (c-statistic).
Fifty-seven percent of patients had FDG-avid lymph nodes on PET; the highest level of nodal involvement was pelvic in 186, para-aortic in 65, and supraclavicular in 26. The average cervix tumor SUVmax was 11.8 (range, 2.0–50.4). PET tumor volume ranged from 3.0 to 535.7 cm3 (average, 65.2 cm3). The median follow-up was 57.5 months for patients alive at the time of last follow-up. PET LN status had the greatest influence on outcome and SUVmax was the second most important factor for all 3 endpoints. The c-statistics for the 3 nomograms were 0.756 for RFS, 0.733 for DSS, and 0.649 for OS.
Pretreatment FDG-PET LN status, cervical tumor SUVmax, and PET tumor volume combined in a nomogram create good models for cervical cancer RFS, DSS, and OS.
PMCID: PMC3991305  PMID: 22735785
FDG-PET; lymph node; prognosis; cervix; nomogram
6.  Brachytherapy versus radical hysterectomy after external beam chemoradiation: a non-randomized matched comparison in IB2-IIB cervical cancer patients 
A current paradigm in the treatment of cervical cancer with radiation therapy is that intracavitary brachytherapy is an essential component of radical treatment. This is a matched retrospective comparison of the results of treatment in patients treated with external beam chemoradiation (EBRT-CT) and radical hysterectomy versus those treated with identical chemoradiation followed by brachytherapy.
In this non-randomized comparison EBRT-CT protocol was the same in both groups of 40 patients. In the standard treated patients, EBRT-CT was followed by one or two intracavitary Cesium (low-dose rate) applications within 2 weeks of finishing external radiation to reach a point A dose of at least 85 Gy. In the surgically treated patients, radical hysterectomy with bilateral pelvic lymph node dissection and para-aortic lymph node sampling were performed within 7 weeks after EBRT-CT. Response, toxicity and survival were evaluated.
A total of 80 patients were analyzed. The patients receiving EBRT-CT and surgery were matched with the standard treated cases. There were no differences in the clinicopathological characteristics between groups or in the delivery of EBRT-CT. The pattern of acute and late toxicity differed. Standard treated patients had more chronic proctitis while the surgically treated had acute complications of surgery and hydronephrosis. At a maximum follow-up of 60 months, median follow-up 26 (2–31) and 22 (3–27) months for the surgery and standard therapy respectively, eight patients per group have recurred and died. The progression free and overall survival are the same in both groups.
The results of this study suggest that radical hysterectomy can be used after EBRT-CT without compromising survival in FIGO stage IB2-IIB cervical cancer patients in settings were brachytherapy is not available. A randomized study is needed to uncover the value of surgery after EBRT-CT.
PMCID: PMC2649933  PMID: 19220882
7.  Comparative study of neoadjuvant chemotherapy before radical hysterectomy and radical surgery alone in stage IB2-IIA bulky cervical cancer 
To compare the efficacy of neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical hysterectomy with radical surgery alone in patients with stage IB2-IIA bulky cervical cancer.
From November 1999 to September 2007, stage IB2-IIA cervical cancers with tumor diameter >4 cm, as measured by MRI, were managed with two cycles of preoperative paclitaxel and platinum. As a control group, we selected 35 patients treated with radical surgery alone.
There were no significant between group differences in age, tumor size, FIGO stage, level of SCC Ag, histopathologic type and grade. Operating time, estimated blood loss, the number of lymph nodes yielded and the rate of complications were similar in the two groups. In surgical specimens, lymph-vascular space invasion (LVSI), nodal metastasis and parametrial involvement did not differ significantly between the two groups. In the neoadjuvant group, pathologic tumor size was significantly smaller and fewer patients had deep cervical invasion. Radiotherapy, alone and in the form of concurrent chemoradiation, was administered to more patients treated with radical surgery alone (82.9% vs. 52.9%, p=0.006). No recurrence was observed in patients who could avoid adjuvant radiotherapy owing to improved risk factors after neoadjuvant chemotherapy. There were no significant differences in 5-year disease free and overall survival.
As neoadjuvant chemotherapy would improve pathologic prognostic factors, adjuvant radiotherapy can be avoided, without worsening the prognosis, in patients with locally advanced bulky cervical cancer. Neoadjuvant chemotherapy would be improving the quality of life after radical hysterectomy in patients with bulky cervical cancer.
PMCID: PMC2676495  PMID: 19471665
Locally advanced cervical cancer; Neoadjuvant chemotherapy; Radical hysterectomy
8.  Adaptive 3D Image-Guided Brachytherapy: A Strong Argument in the Debate on Systematic Radical Hysterectomy for Locally Advanced Cervical Cancer 
The Oncologist  2013;18(4):415-422.
The outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy after concomitant chemoradiation were evaluated. An excellent locoregional control rate with low treatment-related morbidity was observed, justifying the elimination of hysterectomy in the absence of obvious residual disease.
Learning Objectives
Evaluate control rates of IGABT combined with CCRT for the treatment of locally advanced cervical cancer.Describe survival outcomes in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.Describe toxicities in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.
To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT).
Materials and Methods.
Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie–European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment.
Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5–79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005).
IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.
PMCID: PMC3639528  PMID: 23568003
Cervical cancer; Image-guided adaptive brachytherapy; Chemoradiation; Optimization; Dose escalation
9.  Risk Factors and Clinical Aspects of Recurrent Invasive Cervical Carcinoma 
Recurrence of cervical cancer is one of the important and plausible discussions in oncology especially in patients with advanced stages. The purpose of this study was to introduce probability invasive cervical carcinoma recurrence as well as determining characteristics and the prognostic factors of this entity.
A retrospective study was designed to identify risk factors and pattern of uterine cervical carcinoma recurrence evaluating the outcome of 36 registered patients. Recurrence was defined based on clinical or para-clinical documentation over at least 6 months after complete remission following surgery or radiotherapy. Treatment consisted of a radiosurgical combination and exclusive radiotherapy.
Mean age in selected patients is 54.8 ± 12.0 years. The pathological reports of primary diagnosis are squamous cell carcinoma in 94.44 % and adenocarcinoma in remaining patients. Mean duration of recurrence among patients is 2.75 ± 1.5 years after the initial treatment. Metrorrhagia is mostly revealing symptom which patients present in recurrent episode. Usually, the recurrence of cervical cancer is presented in pelvic cavity locally. Marginal involvement is documented in 50 % of cases and lymph node in 33.3 % of patients with recurrent episode being involved. Most important prognostic factors are improper treatment (16.66 % of cases) after initial diagnosis.
Prognostic factors such as selection of appropriate method for treatment are an important point for reducing the rate of recurrence. Moreover, warning patients about symptoms and frequent episodes of follow up is necessary for early diagnosis of recurrence.
PMCID: PMC3575903  PMID: 24293846
Uterine cervix; Recurrence; Risk factor
10.  Cervical cancer 
Clinical Evidence  2011;2011:0818.
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microinvasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib), radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of hysterectomy versus each other for treating early-stage and bulky early-stage cervical cancer.
Key Points
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33.About 80% of tumours are squamous type, and staging is based on the FIGO classification.Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.Development of cervical cancer is strongly associated with HPV infection, acquired mainly by sexual intercourse.The peak prevalence of HPV infection is 20–40% in women aged 20 to 30 years, but in 80% of cases the infection resolves within 12 to 18 months.Other risk factors for cervical cancer include early onset of sexual activity, multiple sexual partners, long-term use of oral contraceptives, tobacco smoking, low socioeconomic status, and immunosuppressive therapy.
Vaccination against HPV is effective in preventing certain types of oncogenic HPV infection, and at reducing rates of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical cancer rates.
Conisation with adequate excision margins is considered effective for microinvasive carcinoma (stage Ia1), and can preserve fertility, unlike simple hysterectomy; however, it has been associated with an increased risk of preterm delivery and low birth weight. Conisation is often performed for stage Ia1 disease, but evidence for its benefit is from observational studies only.
We don’t know how conisation of the cervix with pelvic lymphadenectomy and simple or radical hysterectomy compare with each other for stage Ia2 and low volume stage 1b cervical cancer, as we found no RCTs.
We don’t know how simple hysterectomy plus lymphadenectomy and radical hysterectomy plus lymphadenectomy compare with each other, in early cervical cancer, as we found no RCT evidence.
Limited observational evidence shows that radical trachelectomy plus lymphadenectomy results in similar disease-free survival as radical hysterectomy in women with early-stage cervical cancer; however, we found no RCTs. Radical trachelectomy plus lymphadenectomy can preserve fertility.
Limited RCT evidence shows that radiotherapy is as effective as surgery in early-stage disease. Overall and disease-free survival are similar after radiotherapy or radical hysterectomy plus lymphadenectomy, but radiotherapy is less likely to cause severe adverse effects.
Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer. Combined chemoradiotherapy improves overall and progression-free survival when used either before or after hysterectomy, but is associated with more haematological and gastrointestinal toxicity compared with radiotherapy alone.
The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.
PMCID: PMC3217784  PMID: 21791123
11.  Total Pelvic Exenteration for Primary and Recurrent Malignancies 
World Journal of Surgery  2009;33(7):1502-1508.
Complete resection is the most important prognostic factor in surgery for pelvic tumors. In locally advanced and recurrent pelvic malignancies, radical margins are sometimes difficult to obtain because of close relation to or growth in adjacent organs/structures. Total pelvic exenteration (TPE) is an exenterative operation for these advanced tumors and involves en bloc resection of the rectum, bladder, and internal genital organs (prostate/seminal vesicles or uterus, ovaries and/or vagina).
Between 1994 and 2008, a TPE was performed in 69 patients with pelvic cancer; 48 with rectal cancer (32 primary and 16 recurrent), 14 with cervical cancer (1 primary and 13 recurrent), 5 with sarcoma (3 primary and 2 recurrent), 1 with primary vaginal, and 1 with recurrent endometrial carcinoma. Ten patients were treated with neoadjuvant chemotherapy and 66 patients with preoperative radiotherapy to induce down-staging. Eighteen patients received IORT because of an incomplete or marginal complete resection.
The median follow-up was 43 (range, 1–196) months. Median duration of surgery was 448 (range, 300–670) minutes, median blood loss was 6,300 (range, 750–21,000) ml, and hospitalization was 17 (range, 4–65) days. Overall major and minor complication rates were 34% and 57%, respectively. The in-hospital mortality rate was 1%. A complete resection was possible in 75% of all patients, a microscopically incomplete resection (R1) in 16%, and a macroscopically incomplete resection (R2) in 9%. Five-year local control for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 89%, 38%, and 64%, respectively. Overall survival after 5 years for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 66%, 8%, and 45%.
Total pelvic exenteration is accompanied with considerable morbidity, but good local control and acceptable overall survival justifies the use of this extensive surgical technique in most patients, especially patients with primary locally advanced rectal cancer and recurrent cervical cancer.
PMCID: PMC2691931  PMID: 19421811
12.  Role of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of recurrence in patients with cervical cancer 
Treatment of cervical cancer is usually surgery in the early stages and radiotherapy or chemoradiotherapy in more advanced stages of the disease. Recurrence may occur in multiple sites following primary treatment. Although recurrent metastatic disease is not curable, surgical treatment may be of great help if locoregional recurrence is detected early. Fluorine-18 Fluorodeoxyglucose positron emission tomography - computed tomography (F-18 FDG PET/CT) forms an important part of investigations in the diagnosis of clinically suspicious recurrent cervical cancer.
To assess the role of F-18 FDG PET/CT in diagnosing recurrence in patients with clinical suspicion of recurrent cervical cancer.
Materials and Methods:
We retrospectively evaluated 53 histopathologically proved patients of cervical cancer. All the patients had been treated with either surgery/radiation therapy with or without chemotherapy. The standard PET/CT acquisition protocol, with delayed post void static pelvic images, wherever required, was followed in all patients. Significant uptake of FDG in the lymph nodes was considered to be a recurrence suggestive of metastasis. Para-aortic lymph nodal involvement was considered to be distant metastasis. Any significant uptake in the lung nodule on FDG PET was evaluated either by histological confirmation, by taking fine needle aspiration cytology (FNAC), or by a follow-up chest CT done after three months.
Of the 53 patients with clinically equivocal recurrence, FDG PET/CT suggested recurrence in 41 patients (local recurrence in 14 patients and distant recurrence/metastasis with or without local recurrence in 27 patients). It had a sensitivity of 97.5%, a specificity of 63.6%, positive predictive value of 90.9%, and negative predictive value of 87.5%.
PET/CT appears to have an important role in detecting recurrence following primary treatment of cervical cancer. The high positive and negative predictive values of PET/CT may be helpful in planning management of recurrent cervical cancer.
PMCID: PMC3866666  PMID: 24379531
Cancer of the cervix; chemoradiotherapy; fluorine-18 fluorodeoxyglucose; positron emission tomography - computed tomography; recurrence
13.  Optimal Timing of Surgery after Chemoradiation for Advanced Rectal Cancer: Preliminary Results of a Multi-center, Non-randomized Phase II Prospective Trial 
Annals of surgery  2011;254(1):97-102.
To determine whether extending the interval between chemoradiation (CRT) and surgery, and administering additional chemotherapy during the waiting period has an impact on tumor response, CRT-related toxicity and surgical complications in patients with advanced rectal cancer.
Locally advanced rectal cancer is usually treated with pre-operative CRT followed by surgery approximately 6 weeks later. The Timing of Rectal Cancer Response to Chemoradiation Consortium designed a prospective, multi-center, Phase II clinical trial to investigate extending the interval between CRT and surgery, and administering additional chemotherapy during the waiting period. Here, we present preliminary results of this trial, reporting the tumor response, CRT-related toxicity and surgical complications.
Stage II and III rectal cancer patients were treated concurrently with 5-Fluorouracil (FU) and radiation for 5–6 weeks. Patients in study group (SG) 1 underwent total mesorectal excision (TME) 6 weeks later. Patients in SG2 with evidence of a clinical response 4 weeks after CRT received 2 cycles of modified FOLFOX-6 (mFOLFOX-6) followed by TME 3–5 weeks later. Tumor response, CRT-related toxicity and surgical complications were recorded.
144 patients were accrued. 136 (66, SG1; 70, SG2) were evaluated for CRT-related toxicity. 127 (60, SG1; 67, SG2) were assessed for tumor response and surgical complications. A similar proportion of patients completed CRT per protocol in both SGs, but the cumulative dose of sensitizing 5-FU and radiation was higher in SG2. CRT-related toxicity was comparable between SGs. Average time from CRT-to-surgery was 6 (SG1) and 11 weeks (SG2). Pathologic complete response (pCR) was 18% (SG1) and 25% (SG2). Post-operative complications were similar between SGs.
Intense neoadjuvant therapy consisting of CRT followed by additional chemotherapy (mFOLFOX-6), and delaying surgery may result in a modest increase in pCR rate without increasing complications in patients undergoing TME for locally advanced rectal cancer.
This study is registered with Identifier: NCT00335816
PMCID: PMC3115473  PMID: 21494121
14.  Sustained Complete Response after Maintenance Therapy with Topotecan and Erlotinib for Recurrent Cervical Cancer with Distant Metastases 
Case Reports in Oncology  2014;7(1):97-101.
Recurrent cervical cancer is associated with a poor prognosis. Most treatment responses are partial and of short duration. The development of new therapies is vital to improve treatment for recurrent disease. Epidermal growth factor receptor (EGFR) inhibitors may have a role in this setting.
Case Description
A 53-year-old woman with stage IB2 squamous cell carcinoma of the cervix was initially treated with chemoradiation. Six months after completing treatment, she developed a recurrence in the common iliac and para-aortic lymph nodes above the previous radiation field and was treated with additional radiation therapy. Two years later, she developed recurrent disease in the left supraclavicular lymph nodes and was treated with chemoradiation followed by 3 cycles of adjuvant cisplatin and topotecan. She had a complete response and was placed on maintenance therapy with topotecan and erlotinib, which was well tolerated and produced minimal side effects. After 20 months of maintenance therapy, it was discontinued given the long interval without evidence of disease. The patient is currently without evidence of disease 5 years after completing the topotecan-erlotinib treatment.
We noted a sustained response in a patient with recurrent metastatic cervical cancer treated with radiotherapy, cisplatin, and topotecan followed by maintenance therapy with topotecan and erlotinib. Further evaluation of the role of EGFR inhibitors in this setting should be considered given their favorable toxicity profile and biological relevance.
PMCID: PMC3934679  PMID: 24575024
Recurrent cervical cancer; Epidermal growth factor receptor inhibitor; Erlotinib; Maintenance therapy
15.  Clinical significance of tumor volume and lymph node involvement assessed by MRI in stage IIB cervical cancer patients treated with concurrent chemoradiation therapy 
The purpose of this study was to evaluate the prognostic significance of tumor volume assessed by pretreatment MRI in stage IIB cervical cancer patients with concurrent chemoradiation therapy.
A retrospective chart review was performed on seventy five patients with cervical cancer who were treated with concurrent weekly cisplatin (40 mg/m2) and radiotherapy between January 2000 and April 2007. Potential prognostic factors were age, chemotherapy numbers, histology, tumor diameter and volume, lymph node (LN) involvement and pretreatment squamous cell carcinoma antigen (SCC-Ag) levels.
The median follow-up time was 55 months (range, 8 to 104 months). The median tumor size and volume (range) were 4.5 cm (2 to 10) and 33.1 mL (4.2 to 392.7), respectively. Pelvic LN enlargement rate was 58.7%. Para-aortic LN enlargement rate was 14.7%. Using multivariate analysis, a tumor volume (>33 mL, p=0.025), pelvic LN enlargement (p=0.044) revealed a significantly unfavorable outcome on overall survival. PFS was influenced by tumor histology (p<0.001), pelvic LN enlargement (p=0.015) and pretreatment SCC-Ag levels (p=0.018). We found that 22 (29.3%) patients had recurrences and 14 (18.7%) patients died of disease. The 5-year overall survival rate was 80.6% (standard error, 4.9%) and 5-year PFS rate was 71.3% (standard error, 5.3%).
Tumor volume and pelvic LN involvement showed possibility to predict overall survival in patient with stage IIB cervical cancer. Optimal tumor volume and pelvic LN assessment by pretreatment MRI might be helpful to predict treatment outcome.
PMCID: PMC2849943  PMID: 20379443
Cervical neoplasms; Chemoradiation therapy; MRI; Tumor volume
16.  Management of Refractory Metastatic Anal Squamous Cell Carcinoma Following Disease Progression on Traditional Chemoradiation Therapy 
Case Study
Ms. S.G., a 56-year-old woman with a poorly differentiated squamous cell carcinoma of the anal canal, American Joint Committee on Cancer stage III (T2, N1, M0), was initially diagnosed in December, 2007 at an outside institution after she had noted blood in her stool for approximately 6 months. Her medical history was unremarkable. She had no known history of HIV or other sexually transmitted diseases. At the time of presentation, Ms. S.G. had an Eastern Cooperative Oncology Group performance status of 1 related to cancer-related pain. Her appetite and weight were both stable.
A complete colonoscopy demonstrated a large, immobile, ulcerated, firm, 4-cm lesion in the distal rectum, arising from the anal canal. Initial staging positron emission tomography/computed tomography (PET/CT) scan revealed a hypermetabolic inferior anorectal mass with left perirectal and presacral nodal metastases. There was no definite evidence of distant metastatic disease.
Ms. S.G. received chemoradiation treatment following her diagnostic studies, with a total dose of 45 Gy over 26 fractions to the pelvis with concurrent infusional fluorouracil (5-FU; 2, 450 mg over 7 days) and mitomycin C (12 mg/m2 on day 1) at an outside institution. However, during her chemoradiation therapy, Ms. S.G. experienced a 3-week treatment break due to severe radiation dermatitis, as recommended by her outside treating oncologist.
Upon treatment completion, Ms. S.G. underwent a biopsy of the anal canal, which revealed no evidence of residual malignancy. As recommended by her treating oncologist, she received four additional cycles of adjuvant infusional 5-FU in combination with leucovorin. Shortly thereafter, Ms. S.G. developed progressive pelvic pain. She underwent a second PET/CT scan, revealing mixed findings: interval resolution of abnormal standardized uptake value (SUV) activity at the primary tumor in the anal canal, but an increase in the size and SUV of nodal disease within the left perirectal and presacral regions. A CT-guided biopsy noted a perirectal abscess requiring drainage but was inconclusive for disease recurrence; Ms. S.G. was treated with IV antibiotics.
Six weeks later, repeat radiographic imaging noted additional changes suspicious for regional recurrence, which was biopsy-confirmed. Ms. S.G. was subsequently referred to MD Anderson Cancer Center for consideration of salvage pelvic exenteration.
On physical exam a mass was palpated in the left lower quadrant, but there was no evidence of inguinal adenopathy. On digital rectal exam there was notable external erythema with a fixed mass and moderate sphincter tone. A chest CT scan showed no definite evidence of metastatic disease, but an MRI of the abdomen/pelvis indicated the presence of a complex partially necrotic mass (7.6 × 4.9 × 7.3 cm3) extending to the rectosigmoid junction, inseparable from the left lateral bowel wall, with partial encasement of the bowel. In addition, there was infiltration of the left piriformis muscle and cervix consistent with local recurrence. She was referred to medical oncology and radiation oncology for consideration of reirradiation with concurrent neoadjuvant chemotherapy for palliation and possible surgical resection.
In early December 2008, Ms. S.G. received intensity-modulated radiation therapy (IMRT), with a total dose of 27 Gy over 18 fractions. She received concurrent infusional 5-FU at 300 mg/m2/day, from Monday to Friday, on the days of radiation. She also received a weekly bolus dose of cisplatin at 20 mg/m2. The intent was to treat to 30 Gy, but the patient deferred further treatment early due to anorectal irritation. She then underwent restaging with a PET/CT scan and a pelvic MRI in February 2009, revealing radiographic partial response of the known pelvic recurrence and reduced pelvic pain (Figures 1A and 1B). Figure 1 Figure 1. Contrast-enhanced axial MRI image of the lower pelvis. (A) Pretreatment, complex mass at the rectosigmoid junction measuring approximately 7.6 × 4.9 × 7.3 cm3. (B) Posttreatment, large necrotic mass measuring 3–4 cm in greatest dimension.
Unfortunately, in the interim, she developed multiple bilateral liver lesions and punctate pulmonary nodules consistent with distant disease (Figures 2A, 2B, and 3A). Figure 2 Figure 2. Contrast-enhanced axial CT images of the lung. (A) Subcentimeter nodular opacity in the left upper lobe. (B) Subcentimeter opacity in the right upper lung lobe. Figure 3 Figure 3. Contrast-enhanced axial CT image of the liver. (A) Pretreatment, multiple bilateral liver lesions. (B) Posttreatment, near-complete resolution of liver lesions.
Ms. S.G. proceeded to undergo systemic chemotherapy with carboplatin at an area under the concentration-time curve of 5 and paclitaxel at 175 mg/m2 day 1, every 21 days. She tolerated the treatment well. After three cycles of chemotherapy, radiographic imaging indicated a mixed response to treatment: interval resolution of the pulmonary nodules, stability of disease in the pelvic mass, but progression of the hepatic metastases.
Given Ms. S.G.'s continuing excellent performance status, further treatment was recommended. Based on recent published literature, a regimen of cisplatin at 80 mg/m2 day 1, vinorelbine at 25 mg/m2 day 1 (repeated every 28 days), and weekly cetuximab (VCC) at 250 mg/m2 was initiated. Remarkably, following three cycles of treatment, despite receiving multiple prior lines of chemotherapy, her restaging CT scan demonstrated complete radiographic response of the intrathoracic disease, stable response of the anorectal mass, and near-complete resolution of the hepatic lesions (Figures 3A and 3B).
Overall, Ms. S.G. had tolerated her treatment very well. Given her response and tolerability, she was evaluated again for curative surgical resection. However, she opted to receive the VCC regimen closer to home and was lost to follow-up. Unfortunately, we were unable to obtain medical records confirming if she indeed received additional treatment as recommended. Ms. S.G. was noted to have passed away due to progression of her disease approximately 6 months later.
PMCID: PMC4093318  PMID: 25031942
17.  Radiotherapy and chemoradiation after surgery for early cervical cancer 
This is an updated version of the original Cochrane review first published in Issue 4, 2009. There is an ongoing debate about the indications for, and value of, adjuvant pelvic radiotherapy after radical surgery in women with early cervical cancer. Certain combinations of pathological risk factors are thought to represent sufficient risk for recurrence, that they justify the use of postoperative pelvic radiotherapy, though this has never been shown to improve overall survival, and use of more than one type of treatment (surgery and radiotherapy) increases the risks of side effects and complications.
To evaluate the effectiveness and safety of adjuvant therapies (radiotherapy, chemotherapy followed by radiotherapy, chemoradiation) after radical hysterectomy for early-stage cervical cancer (FIGO stages IB1, IB2 or IIA).
Search methods
For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 4, 2008. The Cochrane Gynaecological Cancer Group Trials Register, MEDLINE (January 1950 to November 2008), EMBASE (1950 to November 2008). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. For this update, we extended the database searches to September 2011 and searched the MetaRegister for ongoing trials.
Selection criteria
Randomised controlled trials (RCTs) that compared adjuvant therapies (radiotherapy, chemotherapy followed by radiotherapy, or chemoradiation) with no radiotherapy or chemoradiation, in women with a confirmed histological diagnosis of early cervical cancer who had undergone radical hysterectomy and dissection of the pelvic lymph nodes.
Data collection and analysis
Two review authors independently abstracted data and assessed risk of bias. Information on grade 3 and 4 adverse events was collected from the trials. Results were pooled using random-effects meta-analyses.
Main results
Two RCTs, which compared adjuvant radiotherapy with no adjuvant radiotherapy, met the inclusion criteria; they randomised and assessed 397 women with stage IB cervical cancer. Meta-analysis of these two RCTs indicated no significant difference in survival at 5 years between women who received radiation and those who received no further treatment (risk ratio (RR) = 0.8; 95% confidence interval (CI) 0.3 to 2.4). However, women who received radiation had a significantly lower risk of disease progression at 5 years (RR 0.6; 95% CI 0.4 to 0.9).
Although the risk of serious adverse events was consistently higher if women received radiotherapy rather than no further treatment, these increased risks were not statistically significant, probably because the rate of adverse events was low.
Authors’ conclusions
We found evidence, of moderate quality, that radiation decreases the risk of disease progression compared with no further treatment, but little evidence that it might improve overall survival, in stage IB cervical cancer. The evidence on serious adverse events was equivocal.
PMCID: PMC4171000  PMID: 22592722
Chemoradiotherapy, Adjuvant; Hysterectomy; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy, Adjuvant [adverse effects; methods; mortality]; Randomized Controlled Trials as Topic; Uterine Cervical Neoplasms [mortality; pathology; *radiotherapy; surgery]; Female; Humans
18.  Lymphadenectomy in Locally Advanced Cervical Cancer Study (LiLACS): A phase III clinical trial comparing surgical to radiologic staging in patients with stages IB2-IVA cervical cancer 
Radiation treatment planning for women with locally advanced cervical cancer (stages IB2-IVA) is often based on positron emission tomography (PET). PET, however, has poor sensitivity in detecting metastases in aortocaval nodes. We have initiated a study that aims to determine if pretherapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival compared to PET/CT radiologic staging alone followed by chemoradiation. This international, multicenter phase III trial will enroll 600 women with stages IB2-IVA cervical cancer and PET/CT imaging showing fluorodeoxyglucose (FDG)-avid pelvic nodes and FDG-negative paraaortic nodes. Eligible patients will be randomized to either pelvic radiotherapy with chemotherapy (standard-of-care arm) or surgical staging via a minimally invasive extraperitoneal approach followed by tailored radiotherapy with chemotherapy (experimental arm). The primary endpoint is overall survival. Secondary endpoints are disease-free survival, short- and long-term morbidity of pretherapeutic surgical staging, and determination of anatomic locations of metastatic paraaortic nodes in relationship to the inferior mesenteric artery. We believe this study will show that tailored chemoradiation after pretherapeutic surgical staging improves survival compared to chemoradiation based on PET/CT in women with stages IB2-IVA cervical cancer.
PMCID: PMC4283493  PMID: 23911560
ervix; surgical staging; PET/CT; laparoscopy
19.  What are the factors that predict outcome at relapse after previous esophagectomy and adjuvant therapy in high-risk esophageal cancer? 
Current Oncology  2010;17(6):46-51.
The present study investigated factors affecting outcome at relapse after previous surgery and adjuvant chemoradiation (crt) in high-risk esophageal cancer patients.
Patients and Methods
From 1989 to 1999, we followed high-risk resected esophageal cancer patients who had completed postoperative crt therapy. Patients who relapsed with a disease-free interval of less than 3 months were treated with palliative crt when appropriate. Patients with a disease-free interval of 3 months or more were treated with best supportive care. Post-recurrence survival was estimated using the Kaplan–Meier technique, and statistical comparisons were made using log-rank chi-square tests and Cox regression.
Of the 69 patients treated with adjuvant crt after esophagectomy, 46 experienced recurrence. Median time to relapse was 28 months (range: 0.1–40 months). Among the 46 relapsed patients, median age was 61 years (range: 37–82 years), and 42 were men. At the initial staging, 44 of 46 were node-positive; 31 of 46 had adenocarcinoma. In 33 of 46, post-esophagectomy resection margins were clear. Median follow-up after recurrence was 30.5 months (range: 1.3–100 months). Median overall survival after recurrence was 5.8 months, and the 12-month, 24-month, and 36-month survival rates were 20%, 10%, and 5% respectively. Of the prognostic factors analyzed, only resection margin status and interval to recurrence were statistically significant for patient outcome in univariate and multivariate analysis.
Patients who had positive resection margins and who relapsed 12 or fewer months after surgery and adjuvant crt had a median post-recurrence overall survival of 0.85 months as compared with 6.0 months in other patients (more than 12 months to relapse, or negative resection margins, or both; log-rank p = 0.003).
Resection margin status and interval to disease relapse are significant independent prognostic factors for patient outcome after adjuvant crt therapy.
PMCID: PMC2993440  PMID: 21151409
Esophagus; cancer; relapse; resection margin; interval
20.  Salvage radiotherapy for lymph node recurrence after radical surgery in cervical cancer 
Journal of Gynecologic Oncology  2012;23(3):168-174.
This study was to evaluate the treatment outcomes and prognostic factors of patients treated with salvage radiotherapy for the treatment of isolated lymph node recurrence of cervical cancer.
Between 1990 and 2009, 22 cervical cancer patients with lymph node recurrence who had previously undergone radical hysterectomy and pelvic lymph node dissection were treated with salvage radiotherapy with (n=18) or without (n=4) chemotherapy. Of the 22 patients, 10 had supraclavicular lymph node recurrence, 9 had para-aortic lymph node, and 3 had inguinal lymph node. The median total radiotherapy dose was 60 Gy (range, 40 to 70 Gy). Initial pathologic findings, latent period to lymph node recurrence and other clinical parameters such as squamous cell carcinoma antigen (SCC-Ag) level and concurrent chemotherapy were identified as prognostic factors for survival.
The median follow-up period after salvage radiotherapy was 31.2 months (range, 12.1 to 148.9 months). The 5-year progression-free and overall survival rates of all patients were 32.7% and 30.7%, respectively. Concurrent chemoradiotherapy (p=0.009) and longer latent period to lymph node recurrence (>18 months vs. ≤18 months, p=0.019) were significant predictors of progression-free survival and SCC-Ag level at the time of recurrence (>8 ng/dL vs. ≤8 ng/dL, p=0.008) and longer latent period to lymph node recurrence (p=0.040) for overall survival. Treatment failure after salvage radiotherapy occurred in 14 (63.6%) for the 22 patients (in field, 2; out of field, 10; both in and out field, 2). Grade 3 acute skin (n=2) and hematologic toxicity (n=1) developed in 3 patients.
For isolated lymph node recurrence of cervical cancer, salvage radiotherapy with concurrent chemotherapy should be considered, especially in patients with a long-term progression-free period.
PMCID: PMC3395012  PMID: 22808359
Cervical cancer; Lymph nodes; Salvage therapy
21.  Pathological correlation with diffusion restriction on diffusion-weighted imaging in patients with pathological complete response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results 
The British Journal of Radiology  2012;85(1017):e566-e572.
The objective of this study was to assess causative pathological factors associated with diffusion restriction on diffusion-weighted imaging (DWI) in patients who achieved pathological complete response (pCR) after treatment with neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer.
In total, 43 patients with locally advanced rectal cancer (≥T3 or lymph node positive) who underwent neoadjuvant CRT, subsequent surgery and ultimately achieved pCR were enrolled. All patients underwent pre- and post-CRT 3.0 T rectal MRI with DWI. Two radiologists blinded to pathological staging reviewed pre- and post-CRT 3.0 T rectal MRI for the presence of diffusion restriction in the corresponding tumour areas on post-CRT DWI, with a third radiologist arbitrating any disagreement. The consensus of these findings was then correlated with pathological data such as intramural mucin and the degree of proctitis and mural fibrosis seen on surgical specimen. Additionally, the pre-CRT tumour volume was measured to define the effect of this variable on the degree of radiation proctitis and fibrosis, as well as the presence of intramural mucin.
Diffusion restriction occurred in 18 subjects (41.9%), while 25 subjects remained diffusion restriction-free (58.1%). The diffusion restriction group tended to have more severe proctitis and mural fibrosis when compared with non-diffusion restriction group (p<0.001). Intramural mucin was also more common in the diffusion restriction group (p=0.052). Higher pre-CRT tumour volumes were significantly predictive of the degree of proctitis (p=0.0247) and fibrosis (p=0.0445), but not the presence of intramural mucin (p=0.0944). Proctitis and mural fibrosis severity were also identified as independent pathological risk factors for diffusion restriction on multivariate analysis (p=0.0073 and 0.0011, respectively).
Both radiation-induced proctitis and fibrosis were significant and independent predictors of diffusion restriction in patients achieving pCR after treatment with neoadjuvant CRT for locally advanced rectal cancer, and pre-CRT tumour volume significantly affects both variables.
PMCID: PMC3487069  PMID: 22422387
22.  Potential Benefits of Integration of Therapies With Chemoradiation in Rectal Cancer 
Gastrointestinal Cancer Research : GCR  2007;1(4 Suppl 2):S73-S80.
Improved pelvic control with reduced toxicity and enhanced sphincter preservation has been demonstrated with neoadjuvant chemoradiation compared with postoperative adjuvant chemoradiation in patients with stage II and III rectal cancer. However, analyses from many trials of adjuvant chemoradiation indicate that patients with T3 node-positive and T4 tumors are at high risk of pelvic recurrence even with use of chemoradiation. This limitation could be addressed with treatment intensification strategies, such as increasing the radiotherapy dose using altered fractionation, or incorporation of novel cytotoxic and targeted chemotherapeutic agents. In addition, preliminary evidence suggests that selected patients with clinically staged T2 or T3 node-negative tumors may be candidates for trials evaluating organ-preserving strategies after chemoradiation, thus eliminating the morbidity of radical surgery. These efforts could be enhanced with the availability of more effective chemoradiation regimens. This paper will discuss incorporation of molecular targeted therapy with chemoradiation regimens in the context of current standards, limitations, and new concepts in the combined modality therapy of locally advanced rectal cancer.
PMCID: PMC2666840  PMID: 19360153
23.  Pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer 
Cervical cancer is the most common cause of death from gynaecological cancers worldwide. Locally advanced cervical cancer, FIGO stage equal or more than IB1 is treated with chemotherapy and external beam radiotherapy followed by brachytherapy. If there is metastatic para-aortic nodal disease radiotherapy is extended to additionally cover this area. Due to increased morbidity, ideally extended-field radiotherapy is given only when para-aortic nodal disease is proven. Therefore accurate assessment of the extent of the disease is very important for planning the most appropriate treatment.
To evaluate the effectiveness and safety of pre-treatment surgical para-aortic lymph node assessment for woman with locally advanced cervical cancer (FIGO stage IB2 to IVA).
Search methods
We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE and EMBASE (up to January 2011). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.
Selection criteria
Randomised controlled trials (RCTs) that compared surgical para-aortic lymph node assessment and dissection with radiological staging techniques, in adult women diagnosed with locally advanced cervical cancer.
Data collection and analysis
Two reviewers independently assessed whether potentially relevant trials met the inclusion criteria, abstracted data and assessed risk of bias. One RCT was identified so no meta-analyses were performed.
Main results
We found only one trial, which included 61 women, that met our inclusion criteria. This trial reported data on surgical versus clinical staging and an assessment of the two surgical staging techniques; laparoscopic (LAP) versus extraperitoneal (EXP) surgical staging. The clinical staging was either a contrast-enhanced CT scan or MRI scan of the abdomen and pelvis to determine nodal status.
In this trial, clinical staging appeared to significantly prolong overall and progression-free survival compared to surgical staging. There was no statistically significant difference in the number of women who experienced severe (grade 3 or 4) toxicity.
There was no statistically significant difference in the risk of death, disease recurrence or progression, blood loss, severe toxicity and the duration of the operational procedure between LAP and EXP surgical staging techniques.
The strength of the evidence is weak in this review as it is based on one small trial which was at moderate risk of bias.
Authors’ conclusions
From the one available RCT we found insufficient evidence that pre-treatment surgical para-aortic lymph node assessment for locally advanced cervical cancer is beneficial, and it may actually have an adverse effect on survival. However this conclusion is based on analysis of a small single trial and therefore definitive guidance or recommendations for clinical practice cannot be made.
Therefore the decision to offer surgical pre-treatment assessment of para-aortic lymph nodes in locally advanced cervical cancer needs to be individualised. The uncertainty regarding any impact on survival from pre-treatment para-aortic lymph node assessment should be discussed openly with the women.
PMCID: PMC4170899  PMID: 21491407
Aorta, Abdominal; Disease-Free Survival; Lymph Node Excision [adverse effects]; Lymph Nodes [*pathology; surgery]; Lymphatic Metastasis; Magnetic Resonance Imaging; Neoplasm Staging [*methods]; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed; Uterine Cervical Neoplasms [*pathology; radiotherapy; surgery]; Adult; Aged; Female; Humans; Middle Aged
24.  Laparoscopic Extraperitoneal Para-aortic Lymphadenectomy in Locally Advanced Cervical Cancer: A Prospective Correlation of Surgical Findings with PET/CT Findings 
Cancer  2010;117(9):1928-1934.
Failure to detect metastasis to para-aortic nodes in patients with locally advanced cervical cancer leads to suboptimal treatment. No previous studies have prospectively compared PET/CT with laparoscopic extraperitoneal staging in the evaluation of para-aortic lymph nodes.
Sixty-five patients were enrolled; 60 were available for analysis. Patients with stage IB2-IVA cervical cancer without evidence of para-aortic lymphadenopathy on preoperative CT or MRI were prospectively enrolled. All patients underwent preoperative PET/CT. Laparoscopic extraperitoneal lymphadenectomy was performed from the common iliac vessels to the left renal vein.
The median age at diagnosis was 48 years (range, 23-84). The median operative time was 140 minutes (range, 89-252). The median blood loss was 22.5 ml (range, 5-150). The median length of hospital stay was 1 day (range, 0-4). The median number of lymph nodes retrieved was 11 (range, 1-39). Fourteen patients (23%) had histopathologically positive para-aortic nodes. Of the 26 patients with negative pelvic and para-aortic nodes on PET/CT, 3 (12%) had histopathologically positive para-aortic nodes. Of the 27 patients with positive pelvic but negative para-aortic nodes on PET/CT, 6 (22%) had 4 histopathologically positive para-aortic nodes. The sensitivity and specificity of PET/CT in detecting positive para-aortic nodes when nodes were negative on CT or MRI were 36% and 96%, respectively. Eleven patients (18.3%) had a treatment modification based on surgical findings.
Laparoscopic extraperitoneal para-aortic lymphadenectomy is safe and feasible. Surgical staging of patients with locally advanced cervical cancer should be considered prior to planned radiation and chemotherapy.
PMCID: PMC4286384  PMID: 21509770
cervical cancer; PET/CT scan; surgery; laparoscopy
25.  Gastric Cancer Surgery: East and West 
Despite declining incidence, particularly in the US and Western Europe, gastric cancer remains the second highest cause of cancer deaths worldwide.1 The marked differences in postoperative morbidity, mortality rates and long-term survival after surgery between Eastern and Western countries have been well documented.2 Although differences in treatment quality are important, other variables may also affect overall survival rates and partially explain this gap in clinical outcomes.3 These variables include the higher incidence of early-stage gastric cancers (EGC) detected through routine check-ups or screening programs in Korea and Japan, and the higher incidence of far advanced gastric cancer and esophagogastric junction (EGJ) tumors in Western countries.
Regarding the surgical treatment of gastric cancer, factors that may potentially explain the different outcomes of patients in the East and West include tumor factors (extent of disease and tumor location); patient factors (age, BMI, and co-morbidity); and treatment factors (different level of surgeon dexterity and perioperative care due to clinical volume).4
Gastric cancer surgery can be divided into three parts: 1) gastric resection, 2) lymph node dissection, and 3) reconstruction. Among these, surgeons across Western and Eastern countries have no major differences in opinion regarding gastric resection and reconstruction; however, lymph node dissection is one of the most hotly debated topics between the East and West.
Surgeons in the East favor extended D2 lymph node dissection (LND). Several factors support this opinion: First, D2 dissection can be performed safely. Even the spleen-preserving total gastrectomy procedure for advanced proximal gastric cancer can be done not only safely, but also effectively in view of lymph node dissection.5,6 Second, D2 surgery provides better local control and thus improves survival rates.7,8 Third, pathologic staging is more accurate for patients undergoing a D2 procedure.
Most surgeons in the West, however, favor D1 lymph node dissection.9,10 Their opinion is that evidence is lacking to support the superiority of D2 over D1 surgery, and D2 cannot be performed safely due to high postoperative morbidity and mortality. The Southwest Oncology Group (SWOG) American Intergroup 0116 study suggested that limited LN dissection with chemoradiation could eliminate the residual lymph node metastases that could be removed by D2.11 Furthermore, National Comprehensive Cancer Network (NCCN) guidelines recommend perioperative chemoradiation in patients with advanced gastric cancer (AGC) along with D1 lymph node dissection.
In summary, the extent of surgery for an individual patient has to be decided based on tumor-, patient-, and treatment-related factors. In the case of AGC, D2 lymph node dissection and adjuvant chemotherapy in the East, and D1 lymph node dissection and perioperative chemoradiation in the West, might be appropriate.
PMCID: PMC3047037

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