Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02067052 |
| Other study ID # |
NP 245/12 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 2012 |
| Est. completion date |
December 2022 |
Study information
| Verified date |
April 2022 |
| Source |
Instituto do Cancer do Estado de São Paulo |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Vulvar cancer is a rare disease that is treated with surgery, radiation and chemotherapy.
When tumors are large (greater than 4 cm) or compromise the urethra (urine canal) and the
anus, or when it is in the groin lymph nodes, surgery alone is not always able to be
performed. In this circumstance, is necessary to add radiotherapy, chemotherapy or both .
So far it is not known the best sequence of treatment: surgery, chemotherapy or radiotherapy.
The radical surgeries usually need long recovery term both in the region of the vulva and in
the region of the groin lymph nodes. When it is performed, convalescence can delay other
treatments, like radiotherapy and chemotherapy. On the other hand, the use of radiotherapy
and chemotherapy as a first step treatment can result in a complete elimination of the
disease in at least 30% of the cases or substantial reduction of its size, allowing less
extensive surgery.
Investigators intend to use surgery, chemotherapy and radiotherapy in the treatment of vulvar
cancer, but in a sequence that has not been studied, in order to increase benefits of these
treatments, and reduce morbidity.
This study will be offered to patients who have disease of the vulva less than 4 cm (sentinel
lymph node), or greater than 4 cm, or illness that compromises urethra and anus, or patients
with disease in groin lymph nodes (glands).
1. On the eve of the surgery, investigators will inject dextran-70 labeled with
technetium-99 m. Only patients with tumors smaller than 4 cm will do this procedure.
2. On the day of the surgery, the groin lymph nodes will be removed from the inguinal
(groin) only. If lymph nodes are disease positive, the vulvectomy will not be performed
at this time. Patients will be treated with radiation therapy with concomitant
chemotherapy for approximately six weeks.
3. At the end of treatment with chemotherapy and radiotherapy, investigators will perform a
surgery to remove the remaining tumor in the vulva.
Description:
Vulvar cancer is a rare disease, striking 2 to 3/100,000 women annually. Dissemination of
vulvar cancer is predominantly lymphatic; contiguous invasion also occurs, though much less
frequently, whereas hematogenic dissemination is quite rare, especially in the absence of
lymphatic spread. Approximately 25% - 35% of the patients in the early stages of the disease
have metastasis. The standard treatment for the initial stages consists of radical excision
of the vulvar tumor and uni- or bilateral inguinal-femoral lymphadenectomy. The latter
procedure is necessary, for the non-removal of the lymph nodes, even if the disease seems
undetectable in the nodes, may be fatal. Treatment effectiveness is good, and the likelihood
of a recurrence of the disease in the inguinal-femoral lymph nodes is 1% - 10% . The
determinants for prognosis are lymph node metastasis, tumor size and stage, depth of tumor
invasion, and lymphovascular involvement. In locally advanced stages of the disease,
involvement of the inguinal-femoral lymph node chain has consistently been demonstrated as
the most important predictive factor of survival for the patient. In the last 30 years,
changes in surgical treatment, such as separate incisions for the performance of
inguinal-femoral lymphadenectomy and vulvectomy, preservation of the saphenous vein, and a
more conservative excision of the primary vulvar lesion, have reduced morbidity. Despite of
the advances in surgical treatment, postoperative complications are still paramount. The
locally advanced disease generates greater morbidity when It involves the urethra, anus, or
rectum, for wide resections, urinary derivations, or even pelvic exenteration is then
required in order to obtain an adequate surgical margin. Such procedures entail not only
mutilation of the patient but also a high morbidity rate. A concomitant chemotherapy and
radiotherapy (CT-RT) regimen has been advocated for the patient with the purpose of
downsizing the initial disease, thereby enabling a less mutilating complementary surgical
treatment. A study by the Gynecologic Oncology Group used preoperative chemoradiation
combined with cisplatin / 5-fluouracil for stage III and IV patients. After the treatment,
only 2 (3%) out of 71 patients remained with a residual disease that showed no signs of
shrinking. A study using data from 63 patients with advanced vulvar cancer (stages III and
IV) who underwent either surgery (30 patients) first or CT-RT followed by surgery (33
patients), compared disease-free interval and survival and recurrence rates of the disease.
The patients who received CT-RT treatment before surgery were younger and had larger vulvar
growths and less lymph node metastasis. An important point is that the positive lymph node
rate of the patients just prior to surgery was 83% for those initially treated with surgery
and 54% for those treated with CT-RT plus surgery. This shows that, in advanced cases, CT-RT
reduces the mass of positive lymph nodes, but the disease persists in more than 50% of the
patients at the original site. Thus, excision of the lymph nodes is necessary to obtain as
much control over the disease as possible. As the inguinal-femoral lymph node status is the
most important prognostic factor in vulvar cancer, it is crucial to assess lymph node
condition prior to therapy in order to select the best approach strategy for the disease. At
present, the non-invasive techniques for the detection of lymph node metastasis are
insufficiently accurate.The low accuracy of the non-invasive techniques for detecting
inguinal-femoral lymph nodes, the importance of a diagnosis of lymph node metastasis in
patients with vulvar cancer in the early stages, and lymphadenectomy morbidity open the way
for the development of minimally invasive techniques, such as sentinel lymph node biopsy.
Most advantages accruing from the adoption of sentinel lymph node biopsy are related to the
lesser morbidity and mortality of the surgical procedure because of its reduced
aggressiveness. Nevertheless, the desired information concerning the metastatic potential of
the primary tumor is gained. In the case of other malignancies, such as breast cancer and
melanoma, the sentinel lymph node false negative rate is low (0%-29%; 7.3% mean).A
multicentric study that analyzed 403 patients with early-stage vulvar cancer (tumor up to 4
cm) showed that sentinel lymph node excision was a safe surgical procedure. A total of 259
patients with a negative sentinel lymph node were merely kept under observation after
surgery. Recurrence in the inguinal region was 2.5% and the survival rate in a 3-year span
was 97%. For the patients with a positive sentinel lymph node, a systematic inguinal-femoral
lymph node excision was performed. These patients benefited from a high accuracy rate in the
identification of micro-metastases with a predictive value close to 100%. A multicentric,
observational study (GROINSS-V) subsequent to the study by Van der Zee et al. examined the
evidence from 403 patients to determine the relationship between the metastasis size of the
sentinel lymph node and the metastasis risk in non-sentinel lymph nodes and disease-free
survival for early-stage vulvar cancer. It was impossible to establish a cutoff point below
which the likelihood of a non-sentinel lymph node metastasis would be close to zero, thus
insignificant. What was found, though, is that the larger the spread of the sentinel lymph
node, the greater the probability of the other lymph nodes metastasizing. Besides, if the
size of the sentinel lymph node was larger than 2 mm, the prognosis was bad. The present
study has the main purpose of outlining a new strategy for vulvar cancer treatment, combining
sentinel lymphoscintigraphy, chemotherapy, radiotherapy, and surgery in a way as yet
untested. Objectives: Analysis of the complete pathological response in patients with an
anatomicopathologic diagnosis of invasive vulva cancer, (stages II to IVa - FIGO), treated
with surgery, chemiotherapy and radiotherapy in the following proposal: nodal debulking of
the groin, chemoradiation and vulvectomy. Materials and methods: Patient enrollment: Twenty
one consecutive patients from the Outpatient Clinic of Gynecological Oncology, Cancer
Institute, São Paulo State (ICESP) with a diagnosis of vulvar carcinoma (early and advanced
stages) will be studied as long as they agree to participate and sign an informed consent
statement. All patients with tumors up to 4 cm in greatest diameter, uncompromised urethra or
anus, and lymph nodes smaller than 15 mm in greatest diameter in scan images will be
considered early-stage cases. Any other cases will be deemed advanced. In the first phase
will be included 21 patients. If there are seven or more complete clinical and pathological
response (patients who underwent surgical biopsy or surgical excision of the primary tumor
site), the study continued with the inclusion of further 30 patients. Preoperative
evaluation: Biopsy and anatomicopathologic, exam of the vulvar lesion, MRI of the pelvis and
vulvar region. Clinical evaluation and surgical risk assessment: Patients with early-stage
tumors: After sentinel lymph node analysis, patients with early-stage tumors will undergo
systematic uni- or bilateral inguinal-femoral lymphadenectomy. In addition, an intraoperative
frozen-section examination of the sentinel lymph node(s) will be conducted. On the eve of
surgery, a peritumoral infusion will be made with dextran-70 marked with technetium-99 (a
radiopharmaceutical from the Nuclear Medicine Service, Radiology Institute, School of
Medicine, USP), volume of 0.1 ml per injection point (0.3 millicurie of technetium in each
syringe) with total activity of 1.2 mCi in the 4 points. Following injection of the
peritumoral infusion, the patients will undergo lymphoscintigraphy on the very same day in
order to locate and record the inguinal lymph nodes marked by the radioactive substance. On
the next day, patients will be injected with a patent blue infusion in the peritumoral area
immediately before the inguinal-femoral lymphadenectomy. With the aid of a gamma-probe
(endoprobe model 2002, France), the supposedly compromised lymph nodes will be removed first
and then the others. Finally, the excision will be performed with a margin around the primary
vulvar lesion. After its identification and excision, the sentinel lymph node will be
dispatched for an intraoperative anatomicopathologic exam and classified as positive,
negative, or suspicious for neoplastic cells. It will be handled immediately after excision,
isolated, and subjected to transverse cuts at 1.5-mm-intervals. All fragments will be
embedded in paraffin, cross-sectioned to obtain 3- µm-thick cuts, and stained with
hematoxylin and eosin. if the initial sections of each and every paraffin block test
negative, the lymph node will be additionally submitted to serial cuts at 50- µm-intervals up
to the 6th level. From each interval of all of the fragments of all blocks, 2 sections will
be taken, one to be stained with hematoxylin and eosin and the other to be mounted on a
silane-coated slide, for immunohistochemical analysis. The initial sections of each block
with the transverse cuts of the lymph node at 1.5-mm-intervals will be immunohistochemically
examined for detection of cytokeratins anion exchanger 1 and 3(clone AE1/AE3, Dako). If the
sentinel lymph nodes are disease-free, the surgical procedure continues with the resection of
the vulvar lesion leaving a 1-cm-wide margin at the least (ideal margin=2 cm) and reaching
into deeper planes. An intraoperative anatomicopathologic evaluation of the surgical margins
is also carried out, and the patient will be excluded of the study. If the sentinel lymph
nodes test positive, it is a case of advanced-stage tumor, and the surgery will be stopped at
this time for further chemoradiation. Patients with advanced-stage tumors: Patients with
advanced-stage tumors, the superficial fascia was incised, and all palpably enlarged nodes
were removed and sent for frozen section. If proven positive for metastatic spread, no
further groin dissection will be undertaken. If negative, a full inguina-femoral
lymphadenectomy will be performed, and these patients will be excluded of the study. After
nodal debulking of the groin, patients will receive cisplatin at 40 mg/m2 once a week for 7
weeks throughout radiotherapy, which will be performed at a 45-50-Gy dose, 1.8 Gy/day, 5
times a week. A dose reinforcement of over 5-10 Gy may be given depending on the number of
compromised lymph nodes and the size or extracapsular extension of the lesion. The presence
of obvious metastatic disease will require the inclusion not only of inguinal lymphatic
drains but also of pelvic drains (even the iliac lymphatics) in the radiotherapy fields. If
after reevaluation for surgery, the lesion shows no signs of shrinking, a dose reinforcement
of up to 60 Gy or 66 Gy total dose will be administered. Surgery - resection of the vulvar
lesion with a 1-cm-margin at least (ideal margin = 2 cm) including the deeper planes and
evaluation of surgical margins by means of intraoperative anatomicopathologic exam - will be
performed 30-120 days after the end of chemoradiotherapy. Data analysis: The following data
will be analyzed: Perioperative data: % → Fisher's test; Immediate and late complications;
Disease-free interval; Survival. Predicted duration of project:3 years
