JOURNAL CLUBGanesh Kumar M

Cervical Cancer Most common gynecologic malignancy

worldwide and the second most common cancer in women in the world

Since the advent of cytologic screening in the 1940s, the incidence of cervical cancer has been decreasing

However, a steady increase in the incidence of preinvasive and locally invasive disease of the cervix has occurred

FIGO StagingStage Description

0 Carcinoma in situ

I Strictly confined to cervix

IA Micro-invasive carcinoma

IA1 Invasion of stroma ≤ 3mm depth; ≤ 7mm width

IA2 Invasion of stroma ≤ 5mm depth; ≤ 7 mm width

IB Clinical lesions confined to cervix

IB1 Clinical lesion </= 4 cm

IB2 Clinical lesion > 4 cm

II Clinical lesions extending beyond cervix, but not to the pelvic wall

IIA No obvious parametrial involvment

IIB Obvious parametrial involvment

III No extension to pelvic wall, involvment lower 1/3 of vagina

IIIA Extension to pelvic wall or hydronephrosis or nonfunctioning kidney

IIIB Beyond true pelvis/clinically involving mucosa of bladder or rectum

IVA invades mucosa of the bladder or rectum, and/or extends beyond true pelvis

IVB Distant metastases

Lymphatic Drainage

Management of cervical cancer

determined primarily by the stage and extent of disease

0, IA1: conservative surgery (excisional conization or extrafascial/simple hysterectomy)

IA2: Modified radical hysterectomy IB1: -radical surgery (radical/modified

radical hysterectomy)

-radiation alone

-chemoradiation

Management of LACC??

Controversy still surrounds the optimal management of these bulky tumors at the primary site

Triple modality treatment often employed

Metastatic disease in the regional nodes: important factor for tumor recurrence

Introduction

Incidence of extrapelvic disease at the time of initial management of locally advanced cervical cancer (LACC) is high

10 to 30% para-aortic (PA) nodes and/or the chest

Introduction(contd)

Chemoradiotherapy(CRT) is considered the standard treatment for LACC

Newer radiotherapy modalities have been useful for local control

However, rate of nodal and/or distant failure remains a major problem, raising the question of the early detection of such potentially occult disease missed on conventional imaging

Introduction(contd)

PET/CT : improves the rate of detection of extracervical disease; but carries a false-negative results of upto 12%

Purpose of the study: evaluate the survival of patients with LACC without uptake in PA nodes on PET-CT who were thus submitted to PA staging surgery

Aim of the study

to evaluate the therapeutic impact of laparoscopic PA lymph node staging in patients with locally advanced cervical cancer with negative PET imaging outside the pelvic area

Patients and Methods

Prospective Multicenter Series

Three French comprehensive cancer centers

Similar strategy employed at all these centers for the staging procedures and treatment of LACC

Eligibility Criteria

Stages IB2 to IVA cervical cancer (as per the FIGO 2009 classification)

Adenocarcinoma, squamous cell carcinoma, or adenosquamous subtypes

No extrapelvic disease on conventional imaging(abdominopelvic MRI or CT scan and pelvic MRI)

No PA (or extrapelvic) uptake on initial PET-CT imaging

Additional Criteria

First, PA staging surgery performed using a laparoscopic extraperitoneal or transperitoneal approach

removal of PA nodes from the aortic bifurcation to the left renal vein(PA, preaortic, superficial intercavoaortic and precaval groups)

Pelvic nodes not resected, because they will subsequently be included in the RT field

Additional Criteria(contd)

Second, no macroscopic extrapelvic disease should be present during the laparoscopic peritoneal exploration

Patients with limited pelvic peritoneal carcinomatosis and/or ovarian metastasis were excluded from the study

Additional Criteria(contd)

Third, the cervical tumor was treated (if no PA node involvement after staging laparoscopy) with pelvic external radiation therapy (45 to 50 Gy)

Concomitant platinum-based chemotherapy( Cisplatin @ 40 mg/m2/week)

Few patients at the end of this study underwent IMRT, subsequently completely by uterovaginal brachytherapy

In patients with initial parametrial and/or suspicious pelvic nodes on PET/CT imaging, an additional boost EBRT of upto 60 Gy given optionally

Completion surgery only if -brachytherapy not technically feasible or

-in clinical and radiologic (using MRI exam) residual disease 6 to 8 weeks after the end of brachytherapy

Additional Criteria(contd)

Finally, patients with histologic PA node metastasis after staging laparoscopic surgery were treated using pelvic and PA CRT (45 to 60 Gy) with concomitant cisplatin chemotherapy (40 mg/m2 per week)

Morbidities Patients were evaluated weekly with a clinical examination,

a blood count, and renal function tests during treatment

Morbidities related to the laparoscopic surgical procedure (within 60 days after the staging surgery) - Clavien-Dindo classification

Morbidities during and/or after CRT - National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) classification (version 4; revised in October 2009)

To have the most reliable reports on morbidities, grade 1 complications not evaluated

Statistical Analysis and End Points of the Study Descriptive data were compared using the Chi-

square test or Fisher’s exact test for proportions

primary end point – overall survival (OS): time from the beginning of CRT to death from any cause

secondary end point - event-free survival (EFS): time from the beginning of CRT to recurrence or disease progression or death

Patients with no event at the time of analysis: censored at date of last follow-up

OS and EFS curves were calculated using the Kaplan-Meier method

Median follow-up was estimated using the Schemper method

All qualitative variables tested using the log-rank test (univariate procedure)

Continuous variables (delays between procedures) tested using a Cox proportional hazards regression model

The hazard ratio (HR) and its 95% CI were provided.

P=0.05 was set as the threshold for statistical significance

Statistically significant factors

the presence and size of metastatic PA nodes

a delay of 45 days between PET-CT and the beginning of CRT

Discussion

Addresses two important questions

Q1: accuracy of PET-CT imaging in LACC? False-negative rate between 9% and 22% Half of this group had a nodal metastasis

<5mm 5 mm cutoff: limit of PET-CT imaging for

accurately detecting tumor tissue is approximately 5mm

Q2: impact of the PA node staging on survival in LACC?

prognosis of patients with small PA metastasis ( ≤ 5 mm) after laparoscopic staging surgery and were then treated with extended-field CRT, was similar to that of patients without PA metastasis

majority (10 of 13) of these patients also had a single nodal metastasis

it is unclear whether the good prognosis among these patients could be owed to the solitary nature or the small size

The risk of distant metastasis was lower in this subgroup compared with those with a PA node measuring more than 5 mm.

The survival of this subgroup of patients (lesion < 5 mm) was excellent and again similar to that of patients without PA nodal spread.

If nodal metastasis had not been detected initially, this patient subgroup would have been undertreated

Patients with PA nodal mets ≥ 5 mm?

Prognosis after laparoscopic staging surgery remains poor, despite treatment with extended-field CRT

Review of Literature: PET/CT vs conventional imaging Yildirim et al, Gynecol Oncol. 2008 Jan:

Integrated PET/CT for the evaluation of para-aortic nodal metastasis in locally advanced cervical cancer patients with negative conventional CT findings

The accuracy, sensitivity, specificity, PPV and NPV of the PET/CT were 75%, 50%, 83.3%, 50% and 83.3%, respectively

The treatment was modified in four of sixteen (25%) patients(EFRT in combination with cisplatin chemotherapy instead of standard pelvic field radiotherapy in combination with cisplatin chemotherapy)

Chao A et al, Gynecol Oncol. 2008 Aug:

PET in evaluating the feasibility of curative intent in cervical cancer patients with limited distant lymph node metastases

Additional PET or PET/CT had positive clinical impact in 21 (44.7%) of the 47 study patients, 23 had no impact, and three had negative impact

Positive Clinical Impact: disclosing additional curable sites (n=8), down-staging (n=6), offering metabolic biopsy (n=4) or change to palliation

Review of Literature:Surgery vs conventional imaging Gold et al, Cancer. 2008 May:

Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study

550 patients: S Group; 130 patients: R Group

R group was associated independently with a poorer prognosis compared with the S group(HR for progression – 1.35 and for death – 1.46)

Delpech et al, Gynecol Obstet Fertil 2010 Jan:

Lymph node surgical staging for locally advanced cervical cancer

Even if recent studies have reported promising results with FDG PET/CT, surgical staging remains the most accurate procedure for evaluating LN metastases

Although laparoscopy allows an early start of adjuvant treatment, due to doubts over its survival benefits, needs to be validated through randomized trials

Review of Literature: Staging laporoscopy vs PET/CT

Mortier et al, Int J Gynecol Cancer. 2008 Jul-Aug:

Laparoscopic para-aortic lymphadenectomy and PET scan as staging procedures in patients with cervical carcinoma stage IB2-IIIB (90 pts)

Lymphadenectomy showed metastases in 13% of the patients. In the subgroup with negative PET scan, 11%(5 of 44) had metastases

Conclusion

Staging laparoscopy has better sensitivity to detect para-aortic nodal metastases, owing to the poor spatial resolution of PET/CT in identifying metastases < 5mm in size

Staging laparoscopy fraught with peri-operative and post-operative morbidities(29/237, 12.2%)

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