First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin.

The objective of this study was to compare the safety and efficacy of carboplatin plus epirubicin and paclitaxel (TEC) to carboplatin and paclitaxel (TC), in the treatment of epithelial ovarian, peritoneal, or tubal carcinoma. Between March 1999 and August 2001, 887 patients were randomized to receive six to nine cycles of paclitaxel (175 mg/m2, 3 h intravenously) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 intravenously prior to paclitaxel), on a 3-weekly schedule. The primary endpoint was progression-free survival. Demographic information: Residual disease <1 cm was reported on 41% of patients. At the end of treatment, 65% in the TEC and 55% in the TC arm had achieved a clinical complete response, and 18 and 25% a clinical partial response resulting in an overall response rate of 83% in the TEC and 80% in the TC arm, whereas 7 and 9% had progressive disease, respectively. The three-drug combination produced a markedly higher myelotoxicity, resulting in a higher frequency of febrile neutropenia (12.5% of the TEC and 1.5% of the TC patients) and a higher number of dose reductions and treatment delays. Cycle prolongation above seven days was seen in 7 and 5% of cycles in the TEC and TC arm, respectively. Stomatitis > or = grade 3 was also higher with TEC (4% TEC and 0.5% TC). Reductions in left ventricular ejection fraction of more than 15% after six courses were slightly more common with the TEC regimen (3% versus 1.5%), but the difference was not statistically significant (P = 0.2). In conclusion, treatment with the TEC combination produced a higher rate of complete responses than treatment with the TC combination. Toxicity was manageable. Long-term survival data are awaited.

Have patients with early squamous carcinoma of the vulva been overtreated in the past? The Norwegian experience 1977-1991.

OBJECTIVE: To evaluate different surgical approaches in early squamous vulvar cancer. METHODS: Review of clinical and histopathologic data and follow-up information of 216 patients with clinical FIGO stage I-II disease, primarily treated by surgery from 1977-1991. RESULTS: Eighty-nine patients underwent radical vulvectomy with bilateral groin dissection by en bloc excision, 60 by the triple incision technique, 20 individualized vulvar surgery with uni-or bilateral groin dissection, and 47 vulvar surgery only. Groin metastases occurred in 9% stage I and 25% stage II disease. Groin involvement was not seen in stage I tumors with invasion depth < or =/=1 mm. Bilateral metastases occurred in medially located tumors of both stages, and laterally located stage II. Metastases were ipsilateral in lateral stage 1. Separate groin dissection significantly reduced morbidity. Sixty-six patients relapsed, 14 after more than 5 years. Vulvar recurrence was related to tumor diameter and the condition of the resection borders. The single most important predictor of death from vulvar cancer was the presence of inguinal femoral lymph node metastases. Conservative and individualized surgery did not compromise 5-year survival. CONCLUSIONS: A careful selection of patients fitted for less radical surgery is essential to avoid undertreatment. Groin dissection can be omitted in tumors with diameters < or =/=2 cm and invasion depth < or =/=1 mm. At least ipsilateral groin dissection is needed in all other cases. Groin dissection should be performed through separate incisions. Modified vulvectomy is appropriate provided radicality can be obtained. Long-time follow-up is important as recurrences can be seen many years after primary therapy.

[Surgery and sentinel node examination in early vulvar cancer]. / Kirurgi og undersøkelse av vaktpostlymfeknute ved tidlig vulvacancer.

BACKGROUND: Less than radical vulvectomy for primary vulvar cancer has been controversial. Less mutilating surgery without sacrificing benefits in prognosis is warranted. MATERIAL AND METHODS: Based on relevant literature and our own experience, we give a review of surgery and sentinel node examination in early vulvar cancer. RESULTS: Regional lymph node metastasis rarely occurs when tumour thickness is less than 1 mm. Smaller lesions (< 2 cm in diameter) should therefore be treated by wide excision only and without lymph node dissection. Other T1 lesions with deeper invasion should be radically excised with at least 2 cm margins and extend deep to the inferior fascia of the urogenital diaphragm. Complete inguinal-femoral lymphadenectomy should be performed in patients without groin metastases to avoid a small, but definite risk of recurrence, although the incidence of lymph node metastases for all clinical stage I patients is less than 10%. Lymphatic mapping with 99mTechnetium and patent blue technique is a potentially valuable intraoperative tool for assuring removal of the sentinel node most likely to have metastasis, defining the extent of the superficial inguinal lymphadenectomy and identifying uncommon anatomic variations. INTERPRETATION: Until reliable data on the benefits of selective lymphadenectomy using intraoperative lymphoscintigraphy are available, the procedure should only be performed in an approved research setting.

Surgical management of stage I and II vulvar cancer: the role of the sentinel node biopsy. Review of literature.

Recognition of the psychosexual consequences of radical vulvectomy and better understanding of the lymphatic drainage and histopathologic features of vulvar cancer have led to a more conservative surgical approach, especially in patients with early-stage disease. Every patient with early vulvar cancer should be managed individually and the risk of conservative therapy balanced against the dangers and advantages of more radical therapy. The results of the sentinel node (SN) procedure in early cancer of the vulva are encouraging, and it might be possible in the near future to avoid the morbidity of inguino-femoral lymphadenectomy. This article reviews surgical management of early vulvar cancer and the place of SN biopsy.

[Fertility preservation in gynecologic cancer]. / Fertilitetsbevarende behandling ved gynekologisk kreft.

Recent advances in both the staging and the understanding of the natural history of gynecologic cancers have led to new approaches to treatment. The treatment can now often be tailored to the extent of the disease, and preservation of child-bearing ability and/or sexual function may be possible for certain women with early invasive cancers of the ovary, cervix, endometrium, vagina and vulva. Better understanding of the tumour biology and clinicopathologic factors of prognostic significance will allow for individualization of treatment. Management of patients with early gynecologic cancer should be individualized with the risks of conservative therapy balanced against the dangers and advantages of more radical therapy. Specialists in gynecologic oncology and infertility together with an informed patient and her family should make treatment decisions. In this article we present an overview of the therapeutic management of early invasive cancers of the ovary, cervix and endometrium, and present guidelines that may help preserve childbearing capacity.

[Endometrial hyperplasia--diagnosis and treatment]. / Endometriehyperplasi--diagnose og behandling.

The International Society of Gynecological Pathologists recently agreed on a classification of endometrial hyperplasia into two main groups; hyperplasias with and without atypia. The lesions were further subdivided into simple and complex hyperplasia. These guidelines were subsequently adopted by the World Health Organization. The disease is a result of oestrogen/gestagen imbalance with oestrogen overexpression. The most important prognostic factor is cellular atypia. Progress to invasive cancer is seen in about 20% of the patients with atypical hyperplasia, and most frequently occurs in postmenopausal women. The treatment of endometrial hyperplasia depends on histologic type, patients' age and whether the hyperplasia is a result of endogenous or exogenous oestrogen overexpression. The risk for progression to invasive cancer is minimal in oestrogen treated patients with simple or complex hyperplasia without atypia. Women under 40 years of age in this group can safely be treated with gestagens. In postmenopausal women with simple or complex hyperplasia with atypia, the recommended treatment is surgery including removal of the uterus and the ovaries.

p53 protein expression in squamous cell carcinoma of the vulva.

BACKGROUND: The objective of the study was to evaluate the pathogenetic and prognostic value of p53 protein expression in squamous cell carcinoma of the vulva. METHODS: The clinical data in charts of 167 patients with International Federation of Gynecology and Obstetrics (FIGO) Stages I-III primary tumors who were treated by surgery were reviewed. Samples from the primary tumor were immunostained for p53 protein. p53 overexpression was defined as immunoreactivity in > 5% of nuclei. RESULTS: p53 overexpression was observed in 92 tumors (55%). p53 overexpression did not correlate with age at diagnosis, FIGO stage, histologic grade, vessel invasion, tumor thickness, tumor greatest dimension, DNA ploidy, or inguinal lymph node metastasis. In the whole group a significantly reduced 5-year corrected survival was observed in patients with p53 overexpression compared with p53 negative patients (P = 0.04). In the different FIGO stages, disease-related survival was not influenced by p53 overexpression in 37 patients with Stage I disease (P = 0.60) or in 86 patients with Stage II disease (P = 0.96). In 44 patients with Stage III disease, p53 overexpression was significantly associated with poorer prognosis (P = 0.004). Independent prognostic factors for corrected survival in the entire group of 167 patients were: vascular invasion, groin metastasis, tumor greatest dimension, and p53 overexpression. In patients with FIGO Stage III disease p53 overexpression was not an independent prognostic factor. CONCLUSIONS: p53 protein overexpression appears to be involved in the pathogenesis of vulvar squamous cell carcinoma. p53 protein overexpression was significantly associated with disease-related survival. p53 prognostic impact was observed only in patients with advanced disease.

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience.

BACKGROUND: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m2, three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum. PATIENTS AND METHODS: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response. RESULTS: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P < or = 0.0001). No serious toxicity was registered. CONCLUSION: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses can be induced in a significant number of patients, the survival figures remain poor.

DNA ploidy and expression of p53 and C-erbB-2 in extramammary Paget's disease of the vulva.

Clinical data were retrieved from the hospital records of 34 patients with Paget's disease of the vulva treated from 1972 to 1990. Flow-cytometric (FCM) DNA measurements and p53 and c-erbB-2 immunostaining were performed on paraffin-embedded samples. Five patients had an underlying adenocarcinoma and 29 intraepithelial disease (IEP). Twenty-seven patients with IEP underwent surgery. The surgical margins were positive in 15 patients, negative in 10, and not evaluable in 2. The tumor was diploid in 15 patients, nondiploid in 11, and not evaluable in 1. Eight patients recurred, 6/15 (40%) with positive and 2/10 (20%) with negative margins. One patient with positive margins was never disease-free. Recurrence was seen in 6/11 (55%) patients with nondiploid tumors, 4 with positive and 2 with negative margins. Two of 15 (13%) patients with diploid tumors recurred/persisted, both with positive margins. None of the 6 patients with diploid tumors and negative margins recurred. p53 and c-erbB-2 were found negative in all but 4 patients. Tumor nondiploidy was associated with an increased risk of recurrence irrespective of surgical radicality. p53 and c-erbB-2 seemed to play no role in the pathogenesis or prognosis.

Malignant melanoma of the vulva FIGO stage I: Evaluation of prognostic factors in 43 patients with emphasis on DNA ploidy and surgical treatment.

Forty-three cases of malignant melanoma of the vulva FIGO stage I, primary treated from 1956 to 1987, have been reviewed. Initial surgery was local excision in 14 patients, vulvectomy in 14, and radical vulvectomy with inguinal lymph node dissection in 15. Recurrent disease was seen in 27 (63%) patients. The 5-year corrected survival was 63%; 10-year survival was 52%. Independent prognostic factors for disease-free and long-term survival were angioinvasion and DNA nondiploidy. Tumor thickness was of prognostic importance in univariate analysis, but did not obtain independent significance. Initial surgical modality did not influence long-term survival, but affected disease-free survival significantly. Local excision carried the greatest risk of local recurrence, but in some of these patients secondary surgery was successful. Because radical surgery did not improve long-term prognosis, wider local excision or vulvectomy seems to be the recommended surgical approach.

Malignant melanoma of the vulva. Evaluation of prognostic factors with emphasis on DNA ploidy in 75 patients.

BACKGROUND: To the authors' knowledge, the potential prognostic value of DNA ploidy in vulvar melanoma has not been evaluated in previous series. METHODS: Clinical data and follow-up information were retrieved from the hospital records of 75 patients treated from 1956 to 1987. Histopathologic specimens were reviewed for histologic type, depth of invasion, vessel invasion, and ulceration. Flow cytometric DNA measurements were performed on paraffin embedded samples. RESULTS: Forty-three patients had International Federation of Gynecology and Obstetrics Stage I disease, 14 Stage II, 8 Stage III and 10 Stage IV. Sixty-five patients were treated by surgery, six by radiotherapy, and four patients with advanced disease received no therapy. The surgical procedure was local excision in 17 patients, vulvectomy in 22, and radical vulvectomy with inguinal lymph node dissection in 26. Five- and 10-year corrected survival rates were 46% and 37%, respectively. Recurrences were seen in 43 (66%) of the patients treated by surgery. Independent prognostic factors for corrected survival in the entire group of 75 patients were inguinal lymph node metastases (P = 0.016), angioinvasion (P = 0.027), tumor localization to clitoris, and multifocal tumors (P = 0.043). For the 65 patients treated by surgery, independent prognostic factors for disease free survival were angioinvasion (P < 0.001), age at diagnosis (P = 0.003), DNA ploidy (P = 0.004), and ulceration (P = 0.027). The independent prognostic factors for long term survival were tumor localization to clitoris (P = 0.018), DNA ploidy (P = 0.045), and inguinal lymph node involvement (P = 0.053). Radical surgery did not improve disease free or long term survival. CONCLUSIONS: DNA ploidy is an independent factor that predicts prognosis in patients with vulvar melanoma, and should be considered together with previously known factors. Radical surgery does not improve prognosis and is not recommended when the inguinal lymph nodes are clinically negative.

Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva.

Forty-two patients with advanced squamous cell carcinoma of the vulva were treated with a combination regimen of bleomycin 180 mg and external irradiation 30-45 Gy. Twenty patients had primary lesions, and 22 patients had recurrent disease. Fifteen (75%) of the patients with primary disease showed objective response (five complete and ten partial response). Four underwent surgery. Of these, one is alive after 60 months with no evidence of disease. Two have died of unrelated causes without signs of recurrence. Seventeen relapsed and died of carcinoma of the vulva. Median survival for patients treated for primary disease was 8.0 months. Thirteen (59%) of 22 patients treated for recurrence showed objective response (two complete and eleven partial responses). None underwent surgery. All these patients died of carcinoma of the vulva. Median survival was 6.4 months. Toxicity was acceptable, and there were no treatment-related deaths. Even taking into account that our patients had very advanced disease, the results are disappointing. An increase of the radiation dose beyond the maximum of 45 Gy given, and more aggressive surgery, might have improved the results.

Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer.

A total of 61 patients with recurrent or persistent clinically measurable platin-resistant epithelial ovarian carcinoma were treated with 260 mg/m2 oral hexamethylmelamine daily for 14 days, repeated at 4-week intervals. Platin resistance was defined as progression or stable disease during cis- or carboplatin treatment (used alone or in combination with other drugs), or relapse within 6 months after the end of that therapy. Fifty patients were evaluable for response and 57 for toxicity. The objective response rate was 14% (3 complete and 4 partial responses). The response rate was higher in patients with relapse within 6 months than in patients with progression or stable disease on platin-based therapy. This observation underscores the importance of defining response and time to progression after first-line chemotherapy. The median duration of response was 8 months and the median survival in responding patients was 9+ months versus 5 months for patients with progression on hexamethylmelamine. Nausea and vomiting requiring antiemetic treatment occurred in 8 (14%) patients and reversible peripheral neuropathy in 3 patients. Two patients developed agitation, insomnia, and depression during hexamethylmelamine therapy. In conclusion, the 14% objective response rate and the occurrence of complete responses with oral hexamethylmelamine treatment in a group of ovarian cancer patients with true platin resistance are noteworthy.

[Laser treatment of premalignant diseases of the uterine cervix. Experiences from a central hospital]. / Laserbehandling av premaligne sykdommer i cervix uteri. Erfaringer fra et sentralsykehus.

During the six-year period 1984-89, 387 patients with cervical intraepithelial neoplasia were treated with CO2-laser. The procedures were performed under local anesthesia in the outpatient clinic. 342 patients underwent conization, 45 vaporization. Complications occurred in 28 patients treated with conization; the most common being postoperative bleeding, seen in 12 cases. In 75% of the cases there was good correlation between histologic examination of the cone biopsy and cervical biopsy/curettage. In 41 patients (12%) the resection borders were involved or indeterminate. Persistence or recurrence was observed in two patients treated by vaporization and 11 treated by conization. Recurrence was diagnosed after 9-65 months of follow-up.