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PubMed2006

Primary systemic therapy in operable breast cancer: clinical data and biological fall-out.

Primary systemic chemotherapy (PST) was first used in early 1970s for the treatment of locally advanced breast cancer; in this setting primary chemotherapy was administered to allow for radical surgery and the objective response rates were high with a substantial proportion of patients amenable to surgery. On the basis of this activity, PST was subsequently used to treat operable locally advanced or large primary tumors to increase the rate of conservative surgery. First generation clinical trials demonstrated that breast conservation rates were improved, that a proportion of patients experienced a complete pathologic response and that response to PST was a good predictor of long term outcome. Second generation of clinical trials were designed to compare PST to postoperative adjuvant chemotherapy: here again the rate of conservative surgery was significantly improved and the pathologic response rate demonstrated its prognostic value, however no progression free or survival improvement was obtained in comparison with postoperative treatments. Another interesting observation from these trials was that some tumor parameters (histology, grade, hormone receptor status) can predict the likelihood of achieving a pathologic complete response. On the basis of these data, PST can now be considered the standard of care for locally advanced disease, an reasonable option in case of large primary breast tumors not eligible for conservative surgery and an acceptable alternative for all the patients who are candidate to adjuvant treatment. It however clear that PST represents an excellent in vivo model to test new regimens, to evaluate biomarkers with predictive value and to evaluate the treatment induced modifications in tumor biology. Availability of new technologies able to measure the expression of thousands of genes and of new molecularly directed drugs will increase further the interest in this treatment strategy.

Anthracyclines↗
PubMed1999

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature.

A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

Journal Article↗
PubMed2003

A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer.

BACKGROUND: Esophagectomy is a standard treatment for resectable esophageal cancer but relatively few patients are cured. Combining neoadjuvant chemoradiation with surgery may improve survival but treatment morbidity is a concern. We performed a meta-analysis of randomized controlled trials (RCTs) that compared the use of neoadjuvant chemoradiation and surgery with the use of surgery alone for esophageal cancer. METHODS: Medline and manual searches were done to identify all published RCTs that compared neoadjuvant chemoradiation and surgery with surgery alone for esophageal cancer. A random-effects model was used and the odds ratio (OR) was the principal measure of effect. Systematic quantitative review was done for outcomes unique to the neoadjuvant chemoradiation treatment group, such as pathological complete response. RESULTS: Nine RCTs that included 1,116 patients were selected with quality scores ranging from 1 to 3 (5-point Jadad scale). Odds ratio (95% confidence interval [CI]; P value), expressed as chemoradiation and surgery versus surgery alone (treatment versus control; values <1 favor chemoradiation-surgery arm), was 0.79 (0.59, 1.06; P = 0.12) for 1-year survival, 0.77 (0.56, 1.05; P = 0.10) for 2-year survival, 0.66 (0.47, 0.92; P = 0.016) for 3-year survival, 2.50 (1.05, 5.96; P = 0.038) for rate of resection, 0.53 (0.33, 0.84; P = 0.007) for rate of complete resection, 1.72 (0.96, 3.07; P = 0.07) for operative mortality, 1.63 (0.99, 2.68; P = 0.053) for all treatment mortality, 0.38 (0.23, 0.63; P = 0.0002) for local-regional cancer recurrence, 0.88 (0.55, 1.41; P = 0.60) for distant cancer recurrence, and 0.47 (0.16, 1.45; P = 0.19) for all cancer recurrence. A complete pathological response to chemoradiation occurred in 21% of patients. The 3-year survival benefit was most pronounced when chemotherapy and radiotherapy were given concurrently (OR 0.45, 95% CI 0.26 to 0.79, P = 0.005) instead of sequentially (OR 0.82, 95% CI 0.54 to 1.25, P = 0.36). CONCLUSIONS: Compared with surgery alone, neoadjuvant chemoradiation and surgery improved 3-year survival and reduced local-regional cancer recurrence. It was associated with a lower rate of esophageal resection, but a higher rate of complete (R0) resection. There was a nonsignificant trend toward increased treatment mortality with neoadjuvant chemoradiation. Concurrent administration of neoadjuvant chemotherapy and radiotherapy was superior to sequential chemoradiation treatment scheduling.

Antineoplastic Agents↗
PubMed2004

Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer.

BACKGROUND: Pulmonary resection after chemotherapy and concurrent full-dose radiotherapy (>59 Gy) has previously been associated with unacceptably high morbidity and mortality. Subsequently neoadjuvant therapy protocols have used reduced and potentially suboptimal radiotherapy doses of 45 Gy. We report a series of 40 patients with locally advanced non-small-cell lung cancer who successfully underwent pulmonary resection after receiving greater than 59 Gy radiation and concurrent chemotherapy. Operative results and midterm survival follow-up are presented. METHODS: Data were reviewed from 40 consecutive patients who underwent lung resection after receiving high-dose radiotherapy and concurrent platinum-based chemotherapy between January 1994 and May 2000. The follow-up closing interval for this study was until August 2003 or time of death. RESULTS: Preoperative stage was IIb (7 patients), IIIA (21 patients), IIIB (10 patients), and IV (2 patients with isolated brain metastasis). Thirteen patients exhibited Pancoast tumors. Median time from completion of induction therapy to surgery was 53 days. Twenty-nine lobectomies and 11 pneumonectomies (7 right, 4 left) were performed. There were no postoperative deaths. Intercostal muscle flaps were used prophylactically in all but one pneumonectomy patient. Seven patients required perioperative transfusions. Median intensive care unit (ICU) time averaged 2 days and the total length of stay was 6 days. One patient exhibited postpneumonectomy pulmonary edema and a bronchopleural fistula developed in another patient (not receiving an intercostal muscle flap). Thirty-four of 40 patients (85%; 95% CI: 70%-94%) were downstaged pathologically, 33 out of 40 patients (82.5%, 95% confidence interval [CI]: 67%-93%) indicated no residual lymphadenopathy, and 18 out of 40 patients (45%, 95% CI: 29%-61%) exhibited a complete pathologic response. Median follow-up was 2.8 years. The 1-, 2-, and 5-year overall survival rates were 92.4%, 66.7%, and 46.2%, respectively. Disease-free 1-, 2-, and 5-year survival rates were 73.0%, 67.2%, and 56.4%, respectively. Median disease-free survival has not been reached. CONCLUSIONS: Pulmonary resection may be performed safely after curative intent concurrent chemotherapy and radiotherapy to greater than 59 Gy. High pathologic complete response rates and sterilization of mediastinal lymph nodes were observed accompanied by highly favorable survival rates. This experience, though promising, will require confirmation in a prospective multiinstitutional clinical trial.

Adult↗
PubMed1994

Preoperative radiotherapy for muscle-invasive bladder carcinoma. Long term follow-up and prognostic factors for 338 patients.

BACKGROUND: This study was performed to determine the importance of various potential prognostic factors in a large cohort of patients with transitional cell carcinoma of the bladder who were treated relatively uniformly at a single institution. METHODS: Between 1960 and 1983, 338 patients with muscle-invasive bladder carcinoma received preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later with radical cystectomy. Lymph node sampling was performed only when suspicious adenopathy was encountered. Ninety-eight percent of the patients completed the treatment as planned. The median followup for those living was 90 months. RESULTS: Actuarial 5-year pelvic control, disease free, and overall survival rates were 84, 51, and 44%, respectively, for all patients, and 88, 58, and 50%, respectively, for those who treatment completed. The overwhelming majority of failures were from distant metastases (43% at 5 years). The pathologic complete response rate was 42%, and downstaging was seen in 65% of the patients. Univariate actuarial analyses revealed clinical stage, clinical perivesical extension, tumor size, pretreatment hemoglobin level, pretreatment blood urea nitrogen (BUN) concentration, results of intravenous pyelography, sex, age, pathologic response, and pathologic complete response, correlated with disease outcome. A Cox proportional hazards model showed pathologic response (P < 0.0001), clinical stage (P = 0.01), hemoglobin level (P < 0.02), pathologic complete response (P < 0.05), and BUN concentration (P < 0.05), were correlated significantly with pelvic control. When only pretreatment factors were analyzed, clinical stage, hemoglobin level, and BUN concentration remained the only factors predictive of pelvic control. Similar results were obtained when overall survival was used as the endpoint, except that pathologic complete response and BUN concentration were replaced by sex as significant covariates. A Cox proportional hazards model using disease free status as the endpoint revealed pathologic response and tumor size to be independent predictors of patient outcome. Restricting this analysis only to pretreatment factors showed that pretreatment hemoglobin and tumor size were the only factors correlated with disease free status. CONCLUSIONS: The most significant prognostic factor was pathologic response, which correlated highly with all disease endpoints investigated. The most consistently significant pretreatment factors were hemoglobin level and clinical stage, although tumor size, sex, and BUN concentration also were independent predictors of patient outcome. These factors should be considered in patients receiving radiotherapy for bladder preservation.

Carcinoma, Transitional Cell↗
PubMed1995

Long-term prognosis following macroscopic complete response at second-look laparotomy in advanced ovarian cancer patients treated with platinum-based chemotherapy. The Gruppo Oncologico Nord Ovest.

Survival (S) and progression-free survival (PFS) were evaluated in 129 advanced ovarian cancer patients, who achieved a macroscopic complete response (112 pathological complete response and 17 microscopic disease) at second-look after platinum-based combination chemotherapy with or without doxorubicin (DX). The impact on S and PFS of age, performance status (PS), stage, histology, grade (G), residual disease after first surgery (RD), chemotherapy regimen, disease status at second-look and consolidation therapy were evaluated by univariate and multivariate analysis. In the 118 months observation period, median S and PFS were 81 and 34 months, respectively. Stage, G, RD, PS and disease status at second-look had significant impact on both S and PFS in univariate analysis, whereas consolidation therapy did not influence outcome. Cox's regression analysis showed that G, RD and PS had an independent impact on PFS. Test for interaction demonstrated no statistically significant relationship between RD, chemotherapy regimen and outcome. In conclusion, advanced ovarian cancer patients with macroscopically complete remission at second-look have a substantial risk of relapse after aggressive treatment. The risk of recurrence was estimated to be maximal in the first 3 years after restaging, and was correlated with poor PS, RD > 2 cm after first surgery and undifferentiated tumour.

Adult↗
PubMed2005

Pretreatment serum hemoglobin level as a predictive factor of response to neoadjuvant chemotherapy in patients with locally advanced squamous cervical carcinoma: a preliminary report.

OBJECTIVE: The aim of this study was to evaluate the predictive value of pretreatment serum hemoglobin level (Hb) together with a series of clinical and pathological variables available before neoadjuvant chemotherapy in locally advanced squamous cervical cancer. METHODS: The influence on response to neoadjuvant chemotherapy of a series of pretreatment clinico-pathological features: hemoglobin level at diagnosis, age, parity, menopausal status, body mass index, clinical stage, tumor diameter, and nuclear grading were analyzed on 73 patients with locally advanced cervical cancer treated with platinum-based neoadjuvant chemotherapy followed by radical surgery. The relationships between pretreatment variables and response to chemotherapy were assessed in univariate and multivariate settings. A univariate and multivariate logistic regression model was adapted to predict an "optimal" response (pathological complete response or more than 50% reduction in tumoral diameter) or "sub-optimal" response (<50% reduction in tumoral diameter). RESULTS: Seventy-three patients-clinical stage: Ib2: 29 (39.7%) IIa: 22 (30.1%) IIb: 22 (30.1%)-received 3 cycles of platinum-based neoadjuvant chemotherapy followed by type III radical hysterectomy. A complete response to neoadjuvant chemotherapy was significantly associated with higher level of pretreatment hemoglobin (mean 14.0 mg/dl) compared to patients with > or =50% response (12.7 mg/dl) or <50% (11.9 mg/dl) (P = 0.002). At multivariate analysis, Hb level was found to be the most powerful and significantly related factor to response to neoadjuvant chemotherapy. A hemoglobin threshold of 12 mg/dl was able to distinguish between patients-with > or =12 mg/dl-at higher probability to respond to neoadjuvant chemotherapy from the ones at lower probability (hemoglobin level under 12 mg/dl). Patients with a complete response to chemotherapy had a 100% survival compared to 93.1% and 53.8% for patients with responses > or =50% and <50% respectively (P = 0.0001). Patients with a pretreatment hemoglobin level of > or =12 mg/dl showed a survival of 87% compared to 63% for patients with a lower hemoglobin level (P = 0.008). CONCLUSIONS: Pretreatment Hb level showed a prognostic and independent predictive value for response to neoadjuvant chemotherapy in locally advanced cervical cancer. In our preliminary report, performed on a limited sample, a threshold of 12 mg/dl seems to be helpful to distinguish between "optimal" and "non-optimal" response.

Analysis of Variance↗
PubMed2006

Alternating intravenous and oral vinorelbine plus epirubicin with pegfilgrastim as neoadjuvant treatment of locally advanced breast cancer.

In order to downstage locally advanced breast cancer, neoadjuvant chemotherapy consisting of intravenous vinorelbine 25 mg/m plus epirubicin 75 mg/m given on day 1 and oral vinorelbine 60 mg/m on day 8 was administered every 3 weeks for four courses. On day 2, all patients received a single subcutaneous injection of pegfilgrastim (6 mg). From March 2004 to June 2005, 22 patients were enrolled. Patients characteristics were: median age, 53 years (range: 39-70 years); postmenopausal, 7/22; clinical TNM stage, T2 (n=14), T3 (n=8), N0 (n=17) and N1 (n=5). The median number of courses was four (range: two to six courses) with full dose intensity. National Cancer Institute grade 3 haematological toxicities observed were neutropenia in 9% of patients, anaemia in 13% of patients and thrombocytopenia in 9% of patients; no toxicity grade 4 occurred. Two patients (9%) registered grade 2 polyneuropathy; no cardiac failure was observed. Conservative surgery was performed in 14 patients (63%). All patients were evaluable for response: complete pathological response was documented in three patients (13.6%); three patients (13.6%) obtained more than 75% of tumour size reduction; 11 other patients (50%) had 50% of tumour size reduction; stable disease was observed in five patients (22.7%). The present findings indicate that vinorelbine in combination with epirubicin is an effective and safe treatment in locally advanced breast cancer: this regimen obtained more than 50% of tumour size reduction in 77% of patients; the use of pegfilgrastim allowed full dose intensity. Oral vinorelbine on day 8 offers greater convenience to the patient by reducing the need for intravenous injection and the time spent in hospital.

Administration, Oral↗
PubMed2004

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy.

BACKGROUND: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. METHODS: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. RESULTS: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. CONCLUSION: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

Adenocarcinoma↗
PubMed2004

The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial.

PURPOSE: To evaluate the use of an alternate, non-cross-resistant adjuvant chemotherapy regimen in women with a poor pathologic response to a preoperative doxorubicin-based regimen. PATIENTS AND METHODS: Patients with locally advanced breast cancer received three cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery. Patients with less than 1 cm(3) residual tumor at mastectomy received an additional five cycles of VACP. Those with more than 1 cm(3) residual tumor were randomly assigned to receive an additional five cycles of VACP or five cycles of vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF). RESULTS: One hundred ninety-three patients were evaluable. Overall clinical response was seen in 83.4% after three cycles of VACP, whereas the pathologic complete response was 12.2%. One hundred six patients were randomly assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free survival (RFS) and overall survival (OS) than those who received additional VACP, although the differences did not reach statistical significance. Initial stage of tumor, clinical complete response, and pathologic complete response were all associated with statistically superior survival rates. CONCLUSION: Clinical and pathologic response to preoperative doxorubicin-based chemotherapy predicted for improved survival in women with operable breast cancer. For those with a poor response to initial neoadjuvant chemotherapy, treatment with VbMF was associated with a trend toward improved RFS and OS compared with those continuing with the doxorubicin regimen.

Adolescent↗
PubMed1998

Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer.

PURPOSE: We performed a pilot phase II study to evaluate the potential for delivery of rapidly sequenced high-dose chemotherapy treatments rescued with autologous peripheral-blood progenitor cells (PBP) in patients with previously untreated, advanced ovarian cancer. PATIENTS AND METHODS: A single cycle of mobilization was used, primed with cyclophosphamide (CPA)/paclitaxel (Txl) and filgrastim (granulocyte colony-stimulating factor [G-CSF]), followed by three cycles of high-dose carboplatin (CBDCA)/Txl and one cycle of high-dose melphalan (MEL), each rescued by PBP. We then analyzed the outcome for a total of 56 consecutive patients treated with high-dose chemotherapy as part of this program. RESULTS: In the phase II pilot, 21 patients were enrolled. There were no treatment-related deaths through 98 high-dose treatments, although 34 treatments were complicated by hospitalization, primarily for neutropenic fever. Seventy-six percent of patients experienced grade 3 to 4 gastrointestinal toxicity and 62% experienced grade 2 to 3 neuropathy. Five of 15 (33%) patients who underwent second-look surgery attained a pathologic complete response. In the overall analysis, 56 patients were reviewed. Forty-four patients were assessable for response by second-look surgery or clinical progression. Fifteen of 44 patients achieved a pathologic complete response (34%). The pathologic complete response rate in optimal-disease patients was 12 of 22 (55%), while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response. CONCLUSION: The Gynecologic Oncology Group has initiated a pilot phase II trial of this approach in patients with optimally debulked stage III ovarian cancer. There is no evidence to support the use of this or other aggressive regimens outside of a clinical trial.

Adult↗
PubMedDate not supplied

Postchemotherapy MRI overestimates residual disease compared with histopathology in responders to neoadjuvant therapy for locally advanced breast cancer.

UNLABELLED: The utility of breast magnetic resonance imaging in patients receiving neoadjuvant chemotherapy is not well defined. We compared serial magnetic resonance imaging examinations with histologic posttreatment examinations in patients treated with primary chemotherapy for locally advanced breast cancer. PATIENTS AND METHODS: Eligible patients with locally advanced breast cancer received doxorubicin 60 mg/m(2) and docetaxel 60 mg/m(2) (with granulocyte colony stimulating factor support) every 14 days for a maximum of six cycles. Breast magnetic resonance imaging was performed at baseline and repeated every two cycles. Surgery (either local excision or mastectomy) was performed after six cycles in responding or stable patients. Residual tumor size on pathology and preoperative magnetic resonance imaging was compared; concordance was defined as a < or = 0.5-cm difference. RESULTS: To date, three of 17 enrolled subjects (17.6%) attained pathologic complete response, and three additional patients attained near pathologic complete response, with residual foci of < or = 1 mm. Of these six patients, only one was disease-free by magnetic resonance imaging. Discordance between magnetic resonance imaging findings and pathologic evaluation was found in four of six patients (66.6%) who obtained pathologic complete response or near pathologic complete response. In the three patients in whom four axillary lesions were followed with magnetic resonance imaging, discordance was found in all four lesions, with magnetic resonance imaging overestimating pathologic disease in all cases. DISCUSSION: Our findings caution that magnetic resonance imaging may frequently overestimate residual invasive carcinoma after neoadjuvant chemotherapy. These results contradict previous studies suggesting that postchemotherapy magnetic resonance imaging may underestimate residual cancer. The use of magnetic resonance imaging in evaluating response to therapy in locally advanced breast cancer should be further studied.

Adult↗
PubMed2004

Complete response to irinotecan hydrochloride and nedaplatin in a patient with advanced ovarian clear cell carcinoma.

A 55-year-old multiparous woman was diagnosed with stage IIIc ovarian clear cell carcinoma. Three years after the first surgery and adjuvant chemotherapy with irinotecan hydrochloride and mitomycin C, she developed common iliac lymph node recurrence. Two cycles of chemotherapy with irinotecan hydrochloride and nedaplatin led to a complete response. Surgical resection revealed pathological complete response. The chemosensitivity of ovarian clear cell carcinoma has been reported to be very poor. No standard chemotherapeutic regimens for this carcinoma have been established. The present study is the first report of a pathological complete response in a patient with advanced ovarian clear cell carcinoma. Future studies are needed to confirm the efficacy of this regimen for this carcinoma.

Adenocarcinoma, Clear Cell↗
PubMed1994

Response to second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with a cisplatin- or carboplatin-based regimen.

Response to a second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with cisplatin- or carboplatin-based regimens was analysed in a clinical series observed between 1984 and 1991. Women who achieved pathological complete response or pathological optimal partial remission after first-line cisplatin- or carboplatin-based regimens were treated at recurrence or progression, occurring at least 4 months after first-line treatment, with second-line chemotherapy. A total of 72 women were included in the analysis. Second-line chemotherapy regimens were: cisplatin 1 mg/kg weekly for seven courses plus epirubicin 70 mg/m2 intravenously (i.v.) every 3 weeks for three courses (28 subjects), cisplatin 1 mg/kg plus etoposide 90 mg/m2 i.v. weekly for a total of seven courses (11 subjects) and cisplatin 1 mg/kg weekly for nine courses plus carboplatin 250 mg/m2 every 3 weeks for three courses (33 subjects). Of the 72 women, 22 (31%, 14 clinical, 8 pathological) had a complete response and 28 (39%), a partial response (24 clinical, 4 pathological). The 24-month cumulative survival probability was 63% in women with complete response, 32% in those who had partial response, but all the 22 non-responders died within 24 months from diagnosis of recurrence (log rank test P < 0.05). The frequency of complete response and partial response increased with the interval between first diagnosis and recurrence: among the 33 women who had recurrent disease to < 18 months from first diagnosis, complete response or partial response was obtained in 20 (61%) subjects, this figure was 67% (14 out of 21 women) among subjects who had recurrent disease between 18 and < 36 months from first diagnosis and 89% (16/18) among those who had recurrence > or = 36 months. In comparison with women who had recurrence 4- < 18 months from first diagnosis, the OR of response was 1.3 (95% CI 0.4-4.1) for those who had recurrence between 18 and < 36 and 5.2 (95% CI 1.1-24.3) for those who had recurrence > or = 36 months from surgery (chi 1(2) trend p < 0.05). Survival rate after the end of second line chemotherapy for women who relapsed 4- < 18 months, 18- < 36 or 36 months or more after surgery were, respectively, 24, 20 and 67% (log rank test, P < 0.05). Age at first diagnosis, histology, stage, and grading of the disease at first diagnosis and site of recurrence were not associated with response to second-line therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Neoadjuvant chemotherapy for locally advanced urothelial cancer of the upper urinary tract.

Cisplatin-based multiple-drug chemotherapy is currently considered the most effective treatment for advanced and metastatic urothelial cancers. We treated 15 patients with locally advanced urothelial cancers of the upper urinary tract using the cisplatin-based multiple-drug regimen in a neoadjuvant setting. The regimens administered were: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin); MEC (methotrexate, etoposide and cisplatin), or M-VEC (methotrexate, vinblastine, epirubicin and cisplatin). Total nephroureterectomy was performed in all patients and response was evaluated pathologically Of 15 patients 2 (13%) achieved a pathological complete response, 6 (40%) a pathological partial response, for an overall response rate of 53% (95% confidence limits 29-77%). The median durations of response were 54 months for patients with a pathological complete response and 15.5 months for patients with a pathological partial response. One of six patients with a pathological partial response and 4 of 7 with no remission died of cancer. While a positive relationship between the pathological response and prognosis was observed, adequate follow-up is needed to assess the ability of neoadjuvant chemotherapy to improve the prognosis of patients with locally advanced urothelial cancer of the upper urinary tract.

Adenocarcinoma↗
PubMed1997

Preoperative 5-FU, low-dose leucovorin, and radiation therapy for locally advanced and unresectable rectal cancer.

PURPOSE: We report the local control and survival of two Phase I dose escalation trials of combined preoperative 5-fluorouracil (5-FU), low-dose leucovorin (LV), and radiation therapy followed by postoperative LV/5-FU for the treatment of patients with locally advanced and unresectable rectal cancer. METHODS AND MATERIALS: A total of 36 patients (30 primary and 6 recurrent) received two monthly cycles of LV/5-FU (bolus daily x 5). Radiation therapy (50.40 Gy) began on day 1 in the 25 patients who received concurrent treatment and on day 8 in the 11 patients who received sequential treatment. Postoperatively, patients received a median of four monthly cycles of LV/5-FU. RESULTS: The resectability rate with negative margins was 97%. The complete response rate was 11% pathologic and 14% clinical for a total of 25%. The 4-year actuarial disease-free survival was 67% and the overall survival was 76%. The crude local failure rate was 14% and the 4-year actuarial local failure rate was 30%. Crude local failure was lower in the four patients who had a pathologic complete response (0%) compared with those who either did not have a pathologic complete response (16%) or who had a clinical complete response (20%). CONCLUSION: Our preliminary data with the low-dose LV regimen reveal encouraging downstaging, local control, and survival rates. Additional follow-up is needed to determine the 5-year results. The benefit of downstaging on local control is greatest in patients who achieve a pathologic complete response.

Adult↗
PubMed2005

Primary docetaxel chemotherapy in patients with breast cancer: impact on response and survival.

Primary chemotherapy achieves high clinical response rates and facilitates breast conservation in many patients with large and locally advanced breast cancer. It may also serve to indicate responsiveness to chemotherapeutic agents. A pathological complete response to primary chemotherapy is a primary predictor and surrogate marker of long-term outcome, but occurs in only approximately 15% of patients. Docetaxel is of particular interest in this setting. Primary docetaxel chemotherapy has single-agent activity in both dose-dense and traditional schedules, with acceptable tolerability. Furthermore, concomitant docetaxel-anthracycline schedules have shown promise in Phase II trials, achieving clinical overall response rates (ORRs) of 77-96%, pathological complete responses of up to 24%, and breast conservation in up to 89% of patients. Two Phase III studies have shown that pathological complete response is significantly improved with the addition of docetaxel to anthracycline-based therapy versus the latter alone: the Aberdeen study achieved a rate of 34% versus 16%, respectively (p = 0.04), and the NSABP-B27 study a rate of 26% versus 14%, respectively (p < 0.001). The Aberdeen study has suggested that the addition of docetaxel may yield a survival benefit at 5 years (p = 0.04). The Phase II GEPAR-DUO study hints at a benefit for sequential over concomitant docetaxel-based therapy, with improvements in both clinical response (ORR 87% versus 77%, respectively) and pathological complete response (23% versus 12%, respectively). Non-anthracycline docetaxel-based primary regimens have shown early promise. As we continue to define the optimal regimen, a growing body of evidence supports the use of docetaxel in primary chemotherapeutic regimens for breast cancer.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Twice-daily radiotherapy as concurrent boost technique during two chemotherapy cycles in neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: mature results of phase II study.

PURPOSE: To determine the toxicities of neoadjuvant chemoradiotherapy using a three-drug regimen (cisplatin, 5-fluorouracil, and paclitaxel) and a conventional radiotherapy (RT) schedule combined with a concurrent boost technique during chemotherapy cycles, and to determine the rate of tumor response, overall survival, and impact of pathologic tumor response on survival. METHODS AND MATERIALS: The eligibility criteria included resectable adenocarcinoma or squamous cell carcinoma (T2-T3N0-N1M0), performance score < or =2, and no significant comorbidities for trimodality therapy. Chemotherapy consisted of two cycles of cisplatin, 5-fluorouracil, and paclitaxel. A concurrent boost technique was used in RT for 2 levels of radiation doses: 58.5 Gy in 34 fractions within 5 weeks to the gross tumor volume and 45 Gy in 25 fractions within 5 weeks to the clinical target volume by administering a boost dose of 13.5 Gy in 9 fractions, 1.5 Gy/fraction, as a second daily fraction for 9 days on Days 1-5 and 29-32 of the chemotherapy cycles. RESULTS: We enrolled 46 patients in the study. The paclitaxel dose was started at 75 mg/m(2) (n = 7) and escalated to 125 mg/m(2) (n = 5), at which point, dose-limiting toxicities occurred. Thereafter, paclitaxel at 100 mg/m(2) was used for an additional 34 patients. Toxicities included Grade 4 neutropenia (22%), febrile neutropenia requiring hospital admission (20%), Grade 3 (48%) and Grade 4 (7%) acute esophagitis, and paclitaxel-associated anaphylaxis (4%). Of the 46 patients, 3 (6.5%) died of treatment-related complications, 1 of pneumonia during induction therapy and 2 of postoperative complications (5% of the 40 patients who underwent resection). The histopathologic tumor response was a pathologic complete response (pT0N0) in 18 (45%) of 40 patients who underwent resection and 18 (39%) of all 46 registered patients. Minimal residual disease (pT1N0) at the primary site was present in 5 (11%) and residual disease in 23 (50%) of all 46 patients. The minimal follow-up for all long-term survivors (n = 16) was 5.5 years. The median survival time was 34 months, and the overall survival rate was 57%, 50%, and 37% at 2, 3, and 5 years, respectively. The 5-year overall survival (56% vs. 24%, p = 0.0214) and disease-free survival (48% vs. 6%) were significantly better statistically for patients with a pathologic complete response and minimal residual disease than for those with residual disease. All long-term survivors beyond 5.5 years without recurrence accrued from patient cohorts with a pathologic complete response or minimal residual disease. CONCLUSION: An incorporation of twice-daily RT as a concurrent boost to the conventional daily RT schedule during chemotherapy cycles is feasible and warrants additional study for radiation dose intensification. Such research would be prudent for both improved long-term survival and organ preservation in esophageal carcinoma.

Adenocarcinoma↗