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PubMedDate not supplied

Neoadjuvant progesterone therapy for primary breast cancer: rationale for a clinical trial.

The hormonal milieu at the time of surgery may influence mortality and disease-free survival in patients with primary breast cancer. Indeed, there is evidence that circulating unopposed estrogen is detrimental and that the presence of circulating progesterone results in an improved disease-free and overall survival rate. Thus patients who receive neoadjuvant progesterone therapy may have a better outcome. A randomized controlled trial in which women with primary breast cancer receive either progesterone or placebo before surgery is urgently needed to confirm this hypothesis.

Breast Neoplasms↗
PubMed1999

Neoadjuvant Hormone Therapy Before Radical Prostatectomy: Update on the Memorial Sloan-Kettering Cancer Center Trials.

We report here the latest follow-up of the Phase II and III trials evaluating pathologic results and relapse-free survival, as judged by serum prostate specific antigen (PSA), in patients with localized prostate cancer who had radical prostatectomy performed at the Memorial Sloan-Kettering Center (MSKCC) either with or without neoadjuvant hormone therapy (NHT). Pelvic lymphadenectomy (PLND), radical prostatectomy, or both with or without NHT was performed in 141 patients enrolled in a Phase II trial comparing patients receiving NHT with concurrent controls and 140 patients in a randomized Phase III trial. In the Phase II study, there was a significant difference in the pathologic results, with only 35 (49%) of the 72 patients in the control group having organ-confined margin-negative disease compared with 48 (70%) of the 69 patients in the NHT arm (P = 0.0057; chi(2) test). With a median follow-up of 57 months, there was no significant difference in the PSA relapse rates in the two arms (P = 0.92; log-rank test). In the Phase III study, 39 (59%) of the 66 patients in the control arm had organ-confined margin-negative disease compared with 52 (70%) of the 74 patients in the NHT arm (P = 0.17; chi(2) test). However, the positive-margin rate was significantly lower in the NHT arm (19%) than in the control arm (37%) (P = 0.023; chi(2) test). With a median follow-up of 35 months, there was no significant difference in the PSA relapse rates in the two arms (P = 0.73; log-rank test). Thus, although NHT improves the pathologic results, further follow-up is necessary to determine if this marked reduction in the positive-margin rate will translate into improved disease-free survival.

Journal Article↗
PubMed2004

Neoadjuvant hormonal therapy for ductal carcinoma in situ: trial design and preliminary results.

For some women, the treatment for ductal carcinoma in situ (DCIS) may be even more aggressive than treatments undertaken for early-stage invasive disease. Expectant management is not a tenable alternative, given that in a significant percentage of patients, DCIS eventually progresses to invasive cancer. Nevertheless, if this progression could be halted or reversed with primary medical therapy alone, a significant portion of the 50,000 women diagnosed with DCIS in the United States annually could potentially avoid the morbidity of surgery and radiation for this disease. The most promising therapeutic candidates in this regard are those treatments targeting hormone receptors on breast cancer cells. We have initiated a clinical trial of neoadjuvant hormonal therapy for women with hormone receptor-positive DCIS. We discuss the clinical rationale and study design for this trial and present our preliminary results.

Antineoplastic Agents, Hormonal↗
PubMed2002

Preliminary toxicity and prostate-specific antigen response of a Phase I/II trial of neoadjuvant hormonal therapy, 103Pd brachytherapy, and three-dimensional conformal external beam irradiation in the treatment of locally advanced prostate cancer.

PURPOSE: Standard therapies for locally advanced prostate cancer have resulted in suboptimal disease control rates. A Phase I/II trial was designed for patients with positive seminal vesicle biopsies, prostate-specific antigen (PSA) >15 ng/ml, Gleason score > or =8 or clinical classification T2c-T3 to improve local control and to test the tolerance of the prostate to high-dose radiation by using neoadjuvant hormonal therapy, 103Pd brachytherapy, and conformal three-dimensional external beam radiation therapy (EBRT). This article outlines treatment-related morbidity and PSA response to this regimen and analyzes the effect of escalating doses of brachytherapy. METHODS AND MATERIALS: Forth-three patients with T1c-T3 prostate cancer were enrolled in a Phase I/II trial from March 1994 through September 1997. Follow-up ranged from 12 to 64 months (median, 32 months). Pretreatment PSA ranged from 2.1 to 202 ng/ml (median, 16 ng/ml). Seventy-seven percent (33 of 43) of patients had high-grade tumors (score > or =7). Seventy-four percent (32 of 43) had stage > or =T2c. A total of 21 (49%) patients had positive seminal vesicle biopsies. Treatment consisted of hormonal therapy for 3 months with leuprolide and flutamide followed by a 103Pd implant and, 2 months later, 59.4 Gy of three-dimensional EBRT. Hormonal therapy was continued for 9 months. The planned 103Pd dose was escalated from 57 Gy (13 patients) to 77 Gy (13 patients) to 86 Gy (17 patients). RESULTS: The actuarial freedom from PSA failure (PSA>0.5 ng/ml) at 4 years was 74%. There were no significant differences found when analyzing patients by presenting PSA or seminal vesicle status. There was a trend toward improved outcome with higher doses delivered to the prostate via the implant. Patients receiving doses > or =65 Gy (31 patients) had a freedom from PSA failure rate at 4 years of 89.5%, compared with 52.5% for those receiving doses <65 Gy (10 patients; p=0.08). The last PSA values for those patients free from PSA failure were < or =0.1 ng/ml in 25 (69%), >0.1-0.2 ng/ml in 5 (14%), and >0.2-0.5 ng/ml in 6 (17%). The actuarial freedom from developing Grade 2 proctitis was 75% at 4 years. There was a trend toward increased proctitis with increasing prostate implant doses. Patients with doses < or =70 Gy (n=12) had a 92% freedom from Grade 2 proctitis compared with 67.5% for those with doses delivered to 90% of the gland from a dose-volume histogram of >70 Gy (n=29) (p=0.15). There were no cases of Grade 3 or 4 proctitis. The 3-year actuarial preservation of sexual potency rate was 43%. CONCLUSIONS: The preliminary results from this regimen show an improvement in PSA control for this group of locally advanced prostate cancer patients over more standard therapies. To maximize control while minimizing toxicity, doses of 65-70 Gy of 103Pd should be used when 59.4 Gy of three-dimensional EBRT is delivered. Longer follow-up will be needed to further substantiate these findings.

Aged↗
PubMed2004

Neoadjuvant chemotherapy for locally advanced breast cancer results in alterations in preoperative tumor marker status.

Neoadjuvant therapy followed by breast-conserving surgery has become an acceptable option for patients with locally advanced breast cancer. Although a distinct survival benefit has not been demonstrated using this approach, several questions have been raised following such therapy including its effects on receptor status and tumor markers. The current study retrospectively reviews estrogen receptor (ER), progesterone receptor (PR), and HER2-neu status in 55 consecutive patients treated by neoadjuvant chemotherapy. Preoperative and postoperative tumor markers were available for 43 of the 55 patients (78%). The pathologic complete tumor response rate (pCR) for this group was 19 per cent (8/43). Of those patients who did not achieve a pCR (n = 35), a change in tumor markers was seen in 25.7 per cent (9/35) of patients. When compared to a control group not undergoing neoadjuvant therapy, a significantly higher percent change in marker expression was noted in the neoadjuvant group (25.7% vs 5.9%, P = 0.046). ER, PR, and HER2-neu status remain important prognostic indicators for breast cancer. Tumor markers are useful in planning adjuvant therapy regimens. In this review, nearly 19 per cent of patients achieved a pCR. In patients not achieving a pCR, one in four patients had at least one change in tumor marker status. This study demonstrates the importance of establishing receptor and marker status prior to neoadjuvant therapy, as many patients will achieve a pCR and make tumor analysis impossible. Postoperative marker studies should be performed given the possibility of a change in status. The clinical relevance of this data will require further long-term follow-up. Until such data becomes available, caution should be considered when basing adjuvant therapy regimens on preoperative tumor marker studies alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Bax to Bcl-2 ratio and Ki-67 index are useful predictors of neoadjuvant chemoradiation therapy in bladder cancer.

OBJECTIVE: In this study, locally advanced bladder cancer was treated by radiation combined with cisplatin therapy and a retrospective analysis was conducted to predict the clinical response to chemoradiotherapy (CRT) based on the immunohistochemistry of apoptosis-related proteins. METHODS: Sixty-two patients (median age, 68 years; range, 45-89 years) with transitional cell carcinoma of the bladder (pT1G3-pT4M0) treated with CRT (median dose: 40.5 Gy of radiation and 230 mg of cisplatin) were studied. Mucosal biopsy was performed before and after CRT. Paraffin-embedded tumor specimens were examined with TUNEL and were immunostained for Ki-67, p53, Bcl-2 and Bax; the Bax/Bcl-2 ratio and apoptosis index (AI) were calculated. Clinical features of the patients and response to CRT were compared with data obtained from examination of the tumors. RESULTS: The 62 patients had a median follow-up period of 34 months (range, 3-84 months). Responses to CRT were as follows: CR, 34%; PR, 45%; NC, 21%. The survival rate of patients with Ki-67-positive tumors was significantly lower than those of patients with Ki-67-negative tumors (P < 0.05). No significant correlation was observed between the expression of any protein, the AI and the clinical response. However, the Bax/Bcl-2 ratio showed a significant association with the CR rate (P = 0.0289). CONCLUSIONS: The results of this study suggest that the combined assessment of Bcl-2 and Bax protein expression may be used to predict a clinical response to CRT based on the Bax/Bcl-2 ratio determined before therapy. The Ki-67 index may be a useful predictor of prognosis in patients treated by CRT.

Aged↗
PubMed2004

Clinical implications of quantification of mesorectal tumor invasion by endoscopic ultrasound: All T3 rectal cancers are not equal.

BACKGROUND: Depth of invasion beyond the muscularis propria (MP) by T3 rectal cancer can vary. The purpose of the present paper was to determine if depth of invasion beyond MP, as assessed by preoperative endoscopic ultrasound (EUS), can predict tumor recurrence in patients with T3 rectal tumors. METHODS: Patients with T3NxM0 rectal cancer, as determined by EUS, who underwent surgical resection (without preoperative neoadjuvant therapy) were reviewed by two blinded endosonographers. Tumors were classified as minimally invasive T3 (invasion </= 2 mm beyond MP by EUS) and advanced T3 disease (invasion > 2 mm). RESULTS: Forty-two patients with T3 rectal tumors underwent surgical resection without receiving preoperative neoadjuvant therapy, of whom 14 had minimally invasive T3 and 28 had advanced T3 disease, as determined by preoperative EUS. Median follow up was 19 months. Tumor recurrence rates in minimally invasive and advanced T3 tumors were 14.3% and 39.3%, respectively, P = 0.02 (log-rank test). Adjusting for nodal status and postoperative adjuvant therapy administration, Cox proportional hazards model demonstrated advanced T3 disease (by EUS) to predict tumor recurrence, hazard ratio, 2.28 (95% confidence interval: 1.17-5.81), P = 0.01. CONCLUSIONS: All T3 rectal tumors are not equal, with minimally invasive disease carrying a more favorable prognosis. By discriminating minimally invasive from advanced T3 disease, preoperative EUS provides important prognostic information. Further subclassification of T3 tumors, based on preoperative EUS staging, should be considered to enhance selection of patients for neoadjuvant therapy.

Aged↗
PubMed2001

[Interrelationship between response to neoadjuvant hormone therapy and hormonal-metabolic status in breast cancer patients].

Twenty seven breast cancer patients with receptor-positive tumors stage IIb-IIIa (TNM) were treated with an aromatase inhibitor--letrozole, 2.5 mg/day, or an antiestrogen--tamoxifen, 20 mg/day, 4 months before surgery. Complete or partial response (CP + PR) was recorded in patients older than those with stabilization or progression of the disease. Moreover, the former group tended to show higher of suppression of blood-estradiol and progesterone receptors levels in tumor and lower suppression of serum-FSH concentration after treatment. These, practically, first findings of the kind suggest that the search for hormonal markers to predict the efficiency of neoadjuvant hormonal therapy for breast cancer should be continued.

Aged↗
PubMed2002

[Surgical therapy of locally advanced and primary inoperable pancreatic carcinoma after neoadjuvant preoperative radiochemotherapy].

INTRODUCTION: So far, surgery represents the only prospect for cure in patients with pancreatic cancer. Most patients, however, present with locally advanced pancreatic cancer at primary diagnosis. Recently, novel therapeutic regimens with preoperative radiochemotherapy have been developed that may improve long-term survival and resectability rates of patients with locally advanced pancreatic cancer. METHODS: This feasibility study evaluates the preliminary results of neoadjuvant therapy with gemcitabine and 5-fluorouracil (5-FU) or cisplatin. Twenty-six patients suffering from locally advanced pancreatic cancer were considered for preoperative radiochemotherapy. They received radiation (45 Gy) and chemotherapy with simultaneous or sequential gemcitabine and 5-FU (n = 15) or gemcitabine and cisplatin (n = 11) administration prior to surgical resection. RESULTS: Mean patient age was 62.4 +/- 2.6 years and 62% (n = 16) were male. The response rate was 69%, and 11 patients underwent curative surgical resection of the pancreatic cancer. Nine Whipple procedures and two complete pancreatectomies were carried out. In five patients a total of eight surgical complications were observed. Median overall survival was 9.8 months after primary cancer diagnosis (mean 12.0 +/- 1.2). During follow-up no local recurrent disease was detected. CONCLUSIONS: Our findings lead us to conclude that preoperative chemoradiation with 45 Gy, gemcitabine and 5-FU or cisplatin is a powerful therapeutic tool in patients with locally advanced non-resectable pancreatic cancer. Major resections, including vascular reconstructions, are nonetheless associated with increased mortality. Preoperative chemoradiation contributes to improved survival in patients with primary non-resectable pancreatic cancer.

Aged↗
PubMed2005

Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study.

OBJECTIVE: To examine, in a prospective study, the influence that temporary reversible medical castration for localized prostate cancer has on cognition, by assessing whether temporary 3-5 month treatment with a luteinizing-hormone releasing hormone (LHRH) agonist before radical radiotherapy had a short- or long-term affect on cognitive function. PATIENTS, SUBJECTS AND METHODS: Thirty-two patients with localized prostate cancer had cognitive assessments at baseline (T1) before the start of drug treatment, at 3 months (T2) or on completing drug treatment but before radiotherapy, and 9 months later (T3). Eighteen men with no prostate cancer (controls subjects) completed the cognitive tests at the same times. In addition, psychological functioning and quality of life were assessed at the same times, together with serum free and bound testosterone, beta-oestradiol and sex hormone-binding globulin levels. RESULTS: There was a significant cognitive decline (on at least one cognitive task) at T2 in 15 (47%) patients vs three (17%) of controls (odds ratio 4.412, P = 0.033). Most patients (nine of 15) who had a change in performance declined on tasks of spatial memory and ability. At T3 there was significant cognitive decline in 11 (34%) patients and five (28%) control subjects (odds ratio 1.37, P = 0.631). CONCLUSION: This pilot study suggests that short-term LHRH therapy for early-stage prostate cancer has modest short-term consequences on men's cognitive functioning; a larger prospective study is warranted.

Aged↗
PubMed1997

[Histopathological effect of neoadjuvant chemohormonal therapy for prostatic cancer].

To improve the therapeutic results in prostatic cancer, radical prostatectomy or total cystoprostatectomy were performed with chemohormonal therapy before operation. Radical prostatectomies were conducted in eight patients with localized prostatic cancer and total cystoprostatectomies in ten patients with severe cystic infiltration. The administration schedule of chemohormonal therapy was as follows: prior to operation, 30-60 mg/sqm/day of etoposide was administered for 7 days every 3 weeks, 250-500 mg/day of diethylbestrol diphosphate for 30 days, and 3.6 mg of LH-RH agonist was also administered. Sixteen of the subjects survived, and were socially rehabilitated (14 cases of NED, 1 case of NC and 1 case of PD) and 2 of the subjects died of cancer. Histopathological findings showed 9 cases of poorly differentiated adenocarcinoma, 4 cases of well differentiated adenocarcinoma and 5 cases of moderately differentiated adenocarcinoma. Histopathological effect of neoadjuvant chemohormonal therapy in surgical specimen showed that 2 of the subjects had grade 0a effect, grade 0b in 7 cases, grade 1 in 5 cases and grade 2 in 4 cases.

Adenocarcinoma↗
PubMed1995

Preoperative chemotherapy for stage III-IV gastric carcinoma: feasibility, response and outcome after complete resection.

Despite extensive resection and systematic lymphadenectomy the prognosis of patients with locally advanced gastric carcinoma remains poor. The effect of preoperative outpatient chemotherapy with etoposide, doxorubicin and cisplatin was evaluated prospectively in 30 patients who had been shown by preoperative staging (including endosonography and surgical laparoscopy) to have gastric carcinoma stages IIIA, IIIB or IV. Haematological side-effects were common and necessitated hospitalization in 13 of 30 patients. Complete clinical response to neoadjuvant therapy was observed in eight of 27 evaluable patients. Resection was performed in 27 of 30 patients, with complete macroscopic and microscopic tumour removal in 24. There were no deaths and no major morbidity following operation. On multivariate analysis complete clinical response (P < 0.01) and complete tumour resection (P < 0.01) were the major independent predictors of long-term survival after neoadjuvant chemotherapy. Actuarial survival after complete tumour removal was superior with neoadjuvant therapy compared with results in an age-, sex- and tumour stage-matched control population who had primary resection (P = 0.07). Recurrence occurred in 17 of 23 evaluable patients who had complete tumour removal, with relapse in the tumour bed or area of lymphatic drainage in 11. These data show that neoadjuvant therapy in patients with locally advanced gastric carcinoma is feasible and appears to increase the rate of complete tumour removal. More powerful and less toxic regimens are, however, required to improve the response rate and to delay or avoid recurrence after neoadjuvant chemotherapy.

Adult↗
PubMed2004

[Two cases of breast cancer markedly responded to neoadjuvant chemoendocrine therapy (2 cycles of CMF and tamoxifen, pCR and near pCR)].

Case 1 is a 38-year-old woman with a 6 cm tumor in her right breast. After incisional biopsy she received 2 cycles of CMF and tamoxifen in order to effect down staging. The tumor markedly decreased in size. She next underwent breast conserving surgery. Histopathologically, malignant cells completely disappeared (pCR). Case 2 is a 34-year-old woman with a 5.5 cm tumor in her left breast. After incisional biopsy she received the same regimen as in case 1. The tumor diminished significantly in size, and she underwent breast conserving surgery. Histopathologically, only a few fragments of degenerated tumor cells remained. Case 1 was hormone receptor positive, while case 2 was negative. The remarkable responsiveness (pCR and near pCR) to 2 cycles of CMF combined with tamoxifen was interesting. From these results we conclude that the CMF regimen is an useful neoadjuvant chemotherapy alternative to avoid alopecia and GI tract side effects.

Adult↗
PubMed2005

Lymph node micrometastasis in stage II distal rectal cancer following neoadjuvant chemoradiation therapy.

OBJECTIVE: The objective was to determine the presence and frequency of micrometastasis in lymph nodes of patients with rectal cancer treated by preoperative chemoradiation followed by curative resection. PATIENTS AND METHODS: All 56 patients included were treated with 5-FU and leucovorin plus 5,040 cGy, followed by radical surgery and were diagnosed with stage II distal rectal adenocarcinoma after complete pathological examination (ypT3-4N0M0). Immunohistochemistry was assessed with cytokeratin monoclonal antibody AE1/AE3. Three 4-microm paraffin sections were obtained from each lymph node, cut at 50 microm apart from each other. The results were reviewed by two independent pathologists. RESULTS: Mean number of lymph nodes was 9.6 per patient. Four patients (7%) and seven lymph nodes (1.35%) were positive for micrometastasis. Three patients had pT3 and one a pT4 tumor. One of the patients had positive micrometastasis and the presence of mucinous deposits. One other patient had mucinous deposits without any micrometastasis. All four patients are alive with no evidence of recurrent disease. Fourteen patients negative for micrometastasis had recurrent disease (25%), eight systemic (14.7%) and six locoregional (10.3%). There were two cancer-related deaths. The mean follow-up period was 39 months. CONCLUSION: Patients with rectal cancer treated by preoperative chemoradiation showed a surprisingly low rate of micrometastasis detection (7%), even in high-risk patients (T3 and T4 tumors). Lymph node micrometastasis was not associated with decreased overall or disease-free survival. The identification of mucinous deposits on lymph nodes with no viable tumor cells may be direct evidence of lymph node downstaging. The downstaging effect of preoperative chemoradiation therapy may be significant in reducing even micrometastasis detection in low rectal cancer managed by this treatment strategy.

Adenocarcinoma↗
PubMed2003

Glycoprotein A-80 in the human prostate: immunolocalization in prostatic intraepithelial neoplasia, carcinoma, radiation failure, and after neoadjuvant hormonal therapy.

OBJECTIVES: To review the expression of A-80 in prostate cancer and prostatic intraepithelial neoplasia and compare it with that of normal and hyperplastic prostatic tissue. The ability to recognize cancer after androgen deprivation therapy and residual and/or recurrent cancer after radiotherapy using A-80 staining was also examined. A-80 is a glycoprotein linked to exocrine differentiation that shows little or no expression in normal exocrine cells, but is selectively overexpressed in dysplasias and adenocarcinomas. METHODS: We studied 277 prostate samples with a monoclonal antibody (MAb) to A-80. We applied this MAb to paraffin sections of specimens of fetal (n = 12), benign prostatic hyperplasia (n = 26, from transurethral prostate resection specimens), atypical adenomatous hyperplasia (n = 11), prostate cancer (n = 103, from radical prostatectomy specimens), and autopsy (n = 7) tissue. In addition, 54 prostatectomy specimens after androgen-deprivation therapy and 64 specimens after radiotherapy were similarly studied. RESULTS: MAb A-80 stained the epithelial component of all 12 prostate specimens from fetal tissue; no staining was seen in normal adult prostatic tissue (0 of 7). In benign prostatic hyperplasia, sporadic cells reacted in 13% of cases (4 of 30); the atypical adenomatous hyperplasia samples were all negative (0 of 11). In patients with prostate cancer, more than 99% (102 of 103) stained positive, regardless of the grade or stage of cancer. Low and high-grade prostatic intraepithelial neoplasia reacted in 73% (38 of 52) and 92% (77 of 84) of cases, respectively. All 64 (100%) salvage prostatectomy samples after external beam radiotherapy stained positive for A-80. Carcinoma subsequent to neoadjuvant hormonal therapy stained positive in 98% (53 of 54) of cases. CONCLUSIONS: A-80 is useful in differentiating benign prostatic hyperplasia and atypical adenomatous hyperplasia from prostate cancer. Also, the strong A-80 reactions in most high-grade prostatic intraepithelial neoplasia provide strong molecular support to the precancerous nature of the lesion. In particular, A-80 staining of biopsies may be useful in detecting residual and/or recurrent prostate carcinoma after radiation or hormonal therapy.

Adenocarcinoma↗