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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.
Background.
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.
Methods.
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.
Results.
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).
Conclusions.
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.
doi:10.1634/theoncologist.2011-0007
PMCID: PMC3228132  PMID: 21659610
Cervical cancer; Para-aortic lymphadenectomy; Laparoscopy; Staging; Morbidity; Lymphocyst
2.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
Objective
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
3.  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 CME.TheOncologist.com
Background.
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.
Methods.
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.
Results.
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.
Conclusions.
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).
doi:10.1634/theoncologist.2011-0276
PMCID: PMC3267825  PMID: 22234626
Chemoradiation therapy; Surgery; Locally advanced cervical cancer; Nodal involvement; Prognostic factors; Residual disease; Survival
4.  Patterns of failure after use of 18F-FDG PET/CT in integration of extended-field chemo-IMRT and 3D-brachytherapy plannings for advanced cervical cancers with extensive lymph node metastases 
BMC Cancer  2016;16:179.
Background
The study is to evaluate the patterns of failure, toxicities and long-term outcomes of aggressive treatment using 18F-FDG PET/CT-guided chemoradiation plannings for advanced cervical cancer with extensive nodal extent that has been regarded as a systemic disease.
Methods
We retrospectively reviewed 72 consecutive patients with 18F-FDG PET/CT-detected widespread pelvic, para-aortic and/or supraclavicular lymph nodes treated with curative-intent PET-guided cisplatin-based extended-field dose-escalating intensity-modulated radiotherapy (IMRT) and adaptive high-dose-rate intracavitary 3D-brachytherapy between 2002 and 2010. The failure sites were specifically localized by comparing recurrences on fusion of post-therapy recurrent 18F-FDG PET/CT scans to the initial PET-guided radiation plannings for IMRT and brachytherapy.
Results
The median follow-up time for the 72 patients was 66 months (range, 3–142 months). The 5-year disease-free survival rate calculated by the Kaplan-Meier method for the patients with extensive N1 disease with the uppermost PET-positive pelvic-only nodes (26 patients), and the patients with M1 disease with the uppermost PET-positive para-aortic (31 patients) or supraclavicular (15 patients) nodes was 78.5 %, and 41.8–50 %, respectively (N1 vs. M1, p = 0.0465). Eight (11.1 %), 18 (25.0 %), and 3 (4.2 %) of the patients developed in-field recurrence, out-of-field and/or distant metastasis, and combined failure, respectively. The 6 (8.3 %) local failures around the uterine cervix were all at the junction between IMRT and brachytherapy in the parametrium. The rate of late grade 3/4 bladder and bowel toxicities was 4.2 and 9.7 %, respectively. When compared to conventional pelvic chemoradiation/2D-brachytherapy during 1990–2001, the adoption of 18F-FDG PET-guided extended-field dose-escalating chemoradiation plannings in IMRT and 3D-brachytherapy after 2002 appeared to provide higher disease-free and overall survival rates with acceptable toxicities in advanced cervical cancer patients.
Conclusions
For AJCC stage M1 cervical cancer with supraclavicular lymph node metastases, curability can be achieved in the era of PET and chemo-IMRT. However, the main pattern of failure is still out-of-field and/or distant metastasis. In addition to improving systemic treatment, how to optimize and integrate the junctional doses between IMRT and 3D-brachytherapy in PET-guided plannings to further decrease local recurrence warrants investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2226-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2226-0
PMCID: PMC4778334  PMID: 26940959
Cervical cancer; 18F-FDG PET/CT; IMRT; Brachytherapy; Pattern of failure; Disease-free survival
5.  The Risk and Pattern of Pelvic and Para Aortic Lymph Nodal Metastasis in Patients with Intermediate and High Risk Endometrial Cancer 
There is a continuous debate about the extent and prognostic value of retroperitoneal lymphadenectomy in endometrial cancer. Systematic pelvic and para-aortic lymphadenectomy in endometrial cancer provides a more accurate assessment of neoplastic spread and may help in better individualization of patients for adjuvant therapy. To evaluate the risk and pattern of retroperitoneal lymph nodes metastasis in patients with endometrial cancers having intermediate and high risk factors for nodal metastasis and recurrence. We conducted a prospective nonrandomized study of 62 cases of high risk endometrial cancers examined and treated at our regional cancer institute between the years 2008 and 2012. The inclusion criteria: The intermediate risk; all patients having grade 3 or undifferentiated adenocarcinomas with less than half MI and the grade 1, 2 tumors having more than half MI with tumor size >2 cm. The high risk group; all the patients having grade 3 or undifferentiated adenocarcinomas with more than half MI, the grade 1, 2 tumors with lymph vascular space invasion (LVSI) or cervical stromal invasion as depicted by pre-operative MRI. The type 2 histology uterine papillary serous, clear cell and squamous cell carcinomas. The patients staging was carried out according to the classification established by the FIGO for endometrial cancer in 2009. The Chi-square test was used to analyze the correlation between tumor grade, myometrial invasion, size of the lesion and lymph nodes metastasis and Fisher’s correction done whenever the frequency distribution was less than five. The patients mean age was 58.3 (range 31 to 76 years). A total of 118 endometrial cancer patients were treated during the study period. The 56 (47.5 %) patients belonged to low risk and 62 (52.5 %) patients belonged to high risk endometrial cancers. The 52 of 62 cases were eligible for the analysis. The 10 patients’ were excluded from further analysis as the post operative specimens final histopathologic examinations in nine cases revealed carcinosarcoma uterus and one case with yolk sac tumor of endometrium. The total 17(32.7 %) of 52 cases had retroperitoneal nodes metastasis; nine of 17 (52.9 %) in this group had both pelvic and para-aortic lymph nodal metastasis and one of 17 (5.9 %) had isolated para-aortic lymph nodal metastasis. The high grade tumors (grade 3) revealed 41.4 % pelvic and 20.7 % para-aortic lymph nodes metastasis and there was statistically significant higher nodal metastasis in both pelvic and para-aortic lymph nodes with increasing depth of myometrial invasion (P = 0.0119 and P = 0.0001) and increasing size of the lesion. (P = 0.04 and P = 0.0501). The intermediate and high risk endometrial cancer is associated with greater degree of lymph node metastasis. A complete surgical staging which involves extrafascial hysterectomy or a type 3 radical hysterectomy when there is a cervical involvement, along with bilateral salphingo-oophorectomy, pelvic, para-aortic lymphadenectomy and an omentectomy when indicated as in the present study, is a valuable modality of treatment in intermediate and high risk cases of endometrial cancers for determining the prognosis and appropriate categorization of these women for adjuvant therapy. It is also possible to achieve a complete surgical staging in these groups of women with acceptable morbidity when performed by a trained gynaecologic oncologist.
doi:10.1007/s13193-014-0303-x
PMCID: PMC4116541  PMID: 25114462
Endometrial cancer; Intermediate and high risk; Retroperitoneal lymph nodal metastasis
6.  Rate of para-aortic lymph node micrometastasis in patients with locally advanced cervical cancer 
Gynecologic oncology  2010;119(3):422-425.
Objective
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
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ygyno.2010.08.012
PMCID: PMC4286254  PMID: 20837355
7.  Cost-effectiveness of para-aortic lymphadenectomy before chemoradiotherapy in locally advanced cervical cancer 
Journal of Gynecologic Oncology  2015;26(3):171-178.
Objective
To evaluate the cost-effectiveness of nodal staging surgery before chemoradiotherapy (CRT) for locally advanced cervical cancer in the era of positron emission tomography/computed tomography (PET/CT).
Methods
A modified Markov model was constructed to evaluate the cost-effectiveness of para-aortic staging surgery before definite CRT when no uptake is recorded in the para-aortic lymph nodes (PALN) on PET/CT. Survival and complication rates were estimated based on the published literature. Cost data were obtained from the Korean Health Insurance Review and Assessment Service. Strategies were compared using an incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed, including estimates for the performance of PET/CT, postoperative complication rate, and varying survival rates according to the radiation field.
Results
We compared two strategies: strategy 1, pelvic CRT for all patients; and strategy 2, nodal staging surgery followed by extended-field CRT when PALN metastasis was found and pelvic CRT otherwise. The ICER for strategy 2 compared to strategy 1 was $19,505 per quality-adjusted life year (QALY). Under deterministic sensitivity analyses, the model was relatively sensitive to survival reduction in patients who undergo pelvic CRT alone despite having occult PALN metastasis. A probabilistic sensitivity analysis demonstrated the robustness of the case results, with a 91% probability of cost-effectiveness at the willingness-to-pay thresholds of $60,000/QALY.
Conclusion
Nodal staging surgery before definite CRT may be cost-effective when PET/CT imaging shows no evidence of PALN metastasis. Prospective trials are warranted to transfer these results to guidelines.
doi:10.3802/jgo.2015.26.3.171
PMCID: PMC4510332  PMID: 25925292
Chemoradiotherapy; Cost-Benefit Analysis; Postoperative Complications; Quality-Adjusted Life Years; Uterine Cervical Neoplasms
8.  FDG-PET-based prognostic nomograms for locally advanced cervical cancer 
Gynecologic oncology  2012;127(1):136-140.
Purpose
We previously found several individual FDG/PET-based prognostic factors for cervical cancer, specifically cervical tumor SUVmax, tumor volume, and highest level of lymph node (LN) involvement. For this study, we evaluate the combined use of these three prognostic factors assessed on pretreatment FDG-PET for predicting recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS).
Patients and methods
The study included 234 cervical cancer patients, FIGO stage Ib1–IVa, treated with definitive radiation or chemoradiation therapy. All patients underwent FDG-PET or FDG-PET/CT at diagnosis, from which cervical tumor volume, SUVmax, and LN status were recorded. Using these PET-based factors, prognostic nomograms were created for RFS, DSS, and OS, and their prediction accuracies were measured using the concordance index (c-statistic).
Results
Fifty-three percent of patients had FDG-avid LN on PET; the highest level of nodal involvement was pelvic in 84, para-aortic in 41, and supraclavicular in 10. The average cervix tumor SUVmax was 12.4 (range, 2.1–50.4) and PET tumor volume average was 66.4 cm3 (range, 3.0–535.7 cm3). The median follow-up was 40.7 months for patients alive at last follow-up. PET LN status had the greatest influence on outcome. The c-statistics for the 3 nomograms were 0.741 for RFS, 0.739 for DSS, and 0.658 for OS. The PET-based nomograms performed better than FIGO stage with c-statistics of 0.605, 0.600 and 0.559 for RFS, DSS and OS, respectively.
Conclusions
Pretreatment FDG-PET LN status, cervical tumor SUVmax, and tumor volume combined in a nomogram create good models for predicting cervical cancer RFS, DSS, and OS.
doi:10.1016/j.ygyno.2012.06.027
PMCID: PMC3991305  PMID: 22735785
FDG-PET; Lymph node; Prognosis; Cervix; Nomogram
9.  Brachytherapy versus radical hysterectomy after external beam chemoradiation: a non-randomized matched comparison in IB2-IIB cervical cancer patients 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1477-7819-7-19
PMCID: PMC2649933  PMID: 19220882
10.  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.
Purpose.
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.
Results.
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).
Conclusion.
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.
doi:10.1634/theoncologist.2012-0367
PMCID: PMC3639528  PMID: 23568003
Cervical cancer; Image-guided adaptive brachytherapy; Chemoradiation; Optimization; Dose escalation
11.  Comparative study of neoadjuvant chemotherapy before radical hysterectomy and radical surgery alone in stage IB2-IIA bulky cervical cancer 
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3802/jgo.2009.20.1.22
PMCID: PMC2676495  PMID: 19471665
Locally advanced cervical cancer; Neoadjuvant chemotherapy; Radical hysterectomy
12.  Risk Factors and Clinical Aspects of Recurrent Invasive Cervical Carcinoma 
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s13224-012-0227-8
PMCID: PMC3575903  PMID: 24293846
Uterine cervix; Recurrence; Risk factor
13.  Cervical cancer 
BMJ Clinical Evidence  2011;2011:0818.
Introduction
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).
Results
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.
Conclusions
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
14.  Long-Term Outcome of Rectal Cancer With Clinically (EUS/MRI) Metastatic Mesorectal Lymph Nodes Treated by Neoadjuvant Chemoradiation: Role of Organ Preservation Strategies in Relation to Pathologic Response 
Annals of Surgical Oncology  2016;23(13):4302-4309.
Background
Organ preservation strategies are under investigation for patients with locally advanced rectal cancer (LARC) who achieve a complete pathologic response in the primary tumor (ypT0) after neoadjuvant chemoradiation therapy (CRT). This study explored the value of this approach for cN+ patients.
Methods
Data were retrieved from our institutional prospective rectal cancer database. Tumors with mesorectal lymph nodes larger than 5 mm shown on endorectal ultrasonography, pelvic magnetic resonance imaging, or both were staged as cN+.
Results
The study population comprised 226 patients (142 men and 84 women; median age, 64 years) with LARC who underwent CRT followed by surgery including total mesorectal excision (TME) (n = 179) and full-thickness local excision (LE) (n = 47) between 1996 and 2013. At staging, 123 patients (54.4 %) were cN+. In 65 cases (28.7 %), ypCR was observed. Metastatic mesorectal lymph nodes (ypN+) were detected in 41.6 % of the cN+ patients and in 2.8 % of the cN0 patients (P < 0.01). Among the cN+ patients, 16 % of the ypT0 cases were ypN+ compared with 51.8 % of the no-ypT0 cases (P < 0.01). Among the cN+ patients who underwent TME, the 5-year disease-specific survival (DSS) and disease-free survival (DFS) rates were respectively 100 and 91.6 % for the ypT0 patients compared with 71.2 and 58.0 % for the no-ypT0 patients (P = 0.01). Among the ypN+ patients, the 5-year DSS and DFS rates were both 100 % for the ypT0 cases compared with 59.1 and 43.3 % for the no-ypT0 patients. Among the cN+ and ypT0 patients, the 5-year DSS and DFS were respectively 100 and 85.7 % for the TME patients compared with 100 and 91.6 % for the LE patients. In the multivariate analysis, ypT0 was the only independent prognostic factor.
Conclusions
Protocols aimed at organ preservation in LARC that achieve ypT0 after CRT can be offered also to cN+ patients.
doi:10.1245/s10434-016-5451-5
PMCID: PMC5090010  PMID: 27489059
15.  Total Pelvic Exenteration for Primary and Recurrent Malignancies 
World Journal of Surgery  2009;33(7):1502-1508.
Introduction
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).
Methods
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.
Results
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%.
Conclusions
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.
doi:10.1007/s00268-009-0066-7
PMCID: PMC2691931  PMID: 19421811
16.  Role of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of recurrence in patients with cervical cancer 
Introduction:
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.
Objective:
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.
Results:
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%.
Conclusion:
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.
doi:10.4103/0972-3919.121966
PMCID: PMC3866666  PMID: 24379531
Cancer of the cervix; chemoradiotherapy; fluorine-18 fluorodeoxyglucose; positron emission tomography - computed tomography; recurrence
17.  Prevalence and distribution pattern of nodal metastases in advanced ovarian cancer 
Molecular and Clinical Oncology  2016;5(4):483-487.
The objective of this study was to examine the relevance of pelvic and para-aortic lymph node involvement and the tumour characteristics affecting nodal metastases and survival in primary advanced ovarian cancer. A total of 130 consecutive patients were retrospectively investigated. All the patients received stage-related surgery with pelvic and para-aortic lymphadenectomy. The median follow-up was 53.5 months. The clinicopathological parameters and distribution pattern of nodal metastases were evaluated. Lymph node metastases were detectable in 74.62% of the cases. Overall, both pelvic and para-aortic nodes were affected in 35.9% of the patients, whereas 13.3% had metastases only in the pelvic and 13.3% only in the para-aortic lymph nodes. Histological grade 1/2 and 3, serous and endometrioid histology were independent predictors of nodal metastasis. Serous and endometrioid cancers have shown a predilection for metastasis to the pelvic lymph nodes alone, both to the pelvic and the para-aortic nodes, or the para-aortic nodes alone. Overall survival was significantly positively affected by serous histology with positive nodes (P=0.043). It is crucial to investigate the risk factors and metastatic patterns of such patients in a multicenter analysis to evaluate individual subgroups. Prospective studies are required to investigate the prognostic effect of lymphadenectomy in advanced ovarian cancer and its association with histology and distribution pattern of nodal metastasis.
doi:10.3892/mco.2016.982
PMCID: PMC5038892  PMID: 27703680
nodal involvement; advanced ovarian cancer; lymphadenectomy; histology; tumour characteristics
18.  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.
Introduction
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.
Conclusion
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.
doi:10.1159/000358916
PMCID: PMC3934679  PMID: 24575024
Recurrent cervical cancer; Epidermal growth factor receptor inhibitor; Erlotinib; Maintenance therapy
19.  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.
Objective
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.
Background
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.
Methods
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.
Results
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.
Conclusions
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 ClinicalTrials.org Identifier: NCT00335816
doi:10.1097/SLA.0b013e3182196e1f
PMCID: PMC3115473  PMID: 21494121
20.  Clinical significance of tumor volume and lymph node involvement assessed by MRI in stage IIB cervical cancer patients treated with concurrent chemoradiation therapy 
Objective
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.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.3802/jgo.2010.21.1.18
PMCID: PMC2849943  PMID: 20379443
Cervical neoplasms; Chemoradiation therapy; MRI; Tumor volume
21.  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
22.  Radiotherapy and chemoradiation after surgery for early cervical cancer 
Background
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.
Objectives
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.
doi:10.1002/14651858.CD007583.pub3
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
23.  Post-radiotherapy neck dissection improves control at non-regional disease sites after definitive chemoradiation for squamous cell carcinoma of the head and neck 
Importance
After chemoradiation for head and neck cancer, over ninety percent of patients who achieved a complete response by imaging were regionally controlled without post-radiotherapy neck dissections (PRND). Since several groups have reported that lymph node involvement also predicted failure at both primary and distant sites, it remains unclear the extent to which PRND impacts non-regional sites of disease.
Objective
Here, we evaluated how PRND impacted local and distant control in patients who achieved a clinical complete response.
Design
We retrospectively reviewed patients treated for stage III/IV disease with definitive chemoradiation between 1990 to 2012.
Setting
University of Illinois at Chicago.
Participants
287 patients were treated with definitive CRT, of whom seventy-four underwent PRND. Median follow up was 25.4 months.
Interventions
Chemoradiation followed by lymph node dissection or observation.
Main Outcomes and Measures
Endpoints evaluated included local control (LC), regional control (RC), freedom from distant metastasis (FFDM), progression free survival (PFS) and overall survival (OS) using first-failure analysis.
Results
Patients with advanced nodal disease (≥N2b; n=176) had improved PFS (74.6% vs. 39.1%; P<.001) while patients with lesser nodal disease had similar PFS. For patients with advanced nodal disease, PRND improved 2-year LC (85.5 vs. 53.5%; p<.001), locoregional control with PRND (78.9% vs. 45.7%; P<.001), FFDM (79.5% vs. 67.5%%; P=.03) and OS (84.5% vs. 61.7%; P=.004) but not RC (96.9% vs. 90.1%; P=.21) The benefit in LC (87.4% vs. 66.2%; P=.02) and PFS (80.7% vs. 53.4%; P=.01) persisted for those with negative post-treatment imaging who underwent PRND. On univariate analysis, PRND, alcohol use, nodal stage and chemoradiation significantly impacted 2 year LC and/or PFS. On multivariate analysis, PRND remained strongly prognostic for 2 year LC (HR 0.22; P=.0007) and PFS (HR 0.42; P=.002).
Conclusions and Relevance
PRND improved control of non-regional sites of disease in patients with advanced nodal disease who achieved a complete response after chemoradiation. Thus, PRND may impact the control of non-nodal sites through possible mechanisms such as clearance of incompetent lymphatics and prevention of re-seeding of the primary and distant sites.
Trial Registration
None.
doi:10.1001/jamaoto.2013.5754
PMCID: PMC4662541  PMID: 24263403
24.  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.
doi:10.1016/j.jmig.2013.07.007
PMCID: PMC4283493  PMID: 23911560
ervix; surgical staging; PET/CT; laparoscopy
25.  Salvage radiotherapy for lymph node recurrence after radical surgery in cervical cancer 
Journal of Gynecologic Oncology  2012;23(3):168-174.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3802/jgo.2012.23.3.168
PMCID: PMC3395012  PMID: 22808359
Cervical cancer; Lymph nodes; Salvage therapy

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