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A case of rapidly growing ovarian squamous cell carcinoma successfully controlled by weekly paclitaxel-carboplatin administration.

BACKGROUND: Primary squamous cell carcinoma of the ovary is uncommon and has a poor prognosis. Because of its rarity, the effective postoperative treatment is unknown. We describe a remarkable response of this tumor to weekly paclitaxel-carboplatin administration. CASE: A 53-year-old woman had rapidly growing primary squamous cell carcinoma of the ovary that metastasized to the abdominal wall and transverse colon after maximum cytoreductive surgery. The tumor was resistant to primary chemotherapy with cisplatin, vincristine, mitomycin C, and bleomycin. A combination of paclitaxel and carboplatin was used for second-line chemotherapy and was repeated every week. The patient tolerated the chemotherapy well and demonstrated a pathological complete response in the abdominal metastases following the five courses of chemotherapy. CONCLUSION: Weekly paclitaxel-carboplatin administration may be a safe and effective treatment for advanced and rapidly growing ovarian squamous cell carcinoma with primary resistance to chemotherapy.

Abdominal Neoplasms↗

Neoadjuvant chemotherapy in stage X ovarian carcinoma.

Seventeen patients with presumed advanced ovarian cancer were treated initially with platinum-based chemotherapy. All patients had either cytologic or histologic findings consistent with an ovarian adenocarcinoma. Eight patients subsequently had surgery: one patient had a complete pathological response and one patient had microscopic disease; both are alive without evidence of disease. Five patients were surgically debulked to less than 1 cm, and one patient had large residual disease after surgery. Four of these patients are alive with disease and one died of disease. Nine patients did not have surgery; two patients had no response to chemotherapy and four patients had stabilization of disease. These six patients have died. Two patients had initial partial responses and are alive with disease. One patient with a complete clinical response at autopsy was without evidence of disease. The follow-up ranged from 7 to 109 months; the median survival was 15 months. Comparison of these 17 patients with 21 patients with stage IV disease and 38 suboptimally debulked patients with stage III disease treated during the same period with aggressive surgery followed by chemotherapy revealed no statistical difference in overall survival between these 17 patients and the two groups of patients. The postoperative hospital stay and complication rate were significantly lower for the 9 patients who had surgery than for the 21 patients with stage IV disease. This report suggests that in patients with presumed ovarian cancer and significant medical problems or with a priori nondebulkable tumor, initial chemotherapy and then surgery should be considered.

Antineoplastic Combined Chemotherapy Protocols↗

Intraperitoneal administration of cisplatin and 5-fluorouracil in residual ovarian cancer: a Phase II Gynecologic Oncology Group trial.

Forty-eight patients with persistent or recurrent epithelial ovarian cancer who had persistent or recurrent disease following intravenous (i.v.) cisplatin-based chemotherapy were treated with intraperitoneal (ip) cisplatin and 5-fluorouracil (5-FU) as salvage therapy. All patients had surgically documented minimal residual disease (1.0 cm or less maximum tumor diameter) at the completion of surgery and were without clinical, radiographic, or histologic evidence of extraperitoneal disease. Of the 45 patients evaluable for response, 13 had a documented partial response (PR) or complete response (CR) to previously administered i.v. cisplatin (cisplatin-sensitive) while the remaining 32 patients were noted to have stable or progressive disease on the previous i.v. cisplatin regimen (cisplatin-refractory). The median number of treatment cycles was six. At the completion of eight cycles of chemotherapy, 22 patients had no clinical or radiographic evidence of persistent disease and were thus eligible for a third-look laparotomy. Seven patients refused surgical evaluation. Three of the 15 patients who underwent a third-look laparotomy had a pathologic complete response (PCR) while 3 other patients had surgically documented partial response. All the surgically documented responses were in cisplatin-sensitive patients for a surgically documented response rate in this patient population of 66.7% (3 of 9 PCR and 3 of 9 PR). The remaining nine patients, who were all previously cisplatin-refractory, had stable or progressive disease documented at third-look laparotomy. Thirty-four patients experienced leukopenia with a median WBC nadir of 2800/microliters while 12 patients experienced thrombocytopenia with the median platelet nadir of 122,000/microliters. There was one treatment-related death secondary to sepsis. Four patients experienced catheter-related complications, ip cisplatin and 5-FU as salvage therapy is feasible in a multi-institutional cooperative group trial and, in cisplatin-sensitive patients, is an effective treatment option.

Adenocarcinoma↗

Detection and chemoradiotherapeutic evaluation of advanced esophageal squamous cell carcinoma using gallium-67 SPET: a preliminary study.

About 20 years ago, gallium-67 planar scintigraphy was introduced for the evaluation of advanced esophageal squamous cell carcinoma (AESCC). Although single-photon emission tomography (SPET) is now available in many institutions, there have been no reports regarding the evaluation of AESCC using (67)Ga SPET. The aims of this preliminary study were to assess the potential of (67)Ga SPET for the detection of AESCC and to further evaluate whether (67)Ga SPET can predict the effect of preoperative chemoradiotherapy on AESCC. Thirty-eight patients with histologically proven AESCC (35 men and 3 women, mean age 62+/-6.9 years) underwent (67)Ga SPET before and after preoperative chemoradiotherapy. The histological response to the chemoradiotherapy was determined from a surgical specimen of the esophagus: grade 0, 100% viable tumor cells; grade 1a, 99%-67%; grade 1b, 66%-34%; grade 2, 33%-1%; grade 3, no viable cells. Thirty-seven out of 38 AESCCs (97.4%) were detected on pre-chemoradiotherapy SPET. In these 37 cancers, the tumor-to-lung ratio (TLRpre) was 3.5+/-2 (range 1.5-9.6). Post-chemoradiotherapy SPET exhibited positive results in 22 cancers, with a TLRpost of 1.8+/-0.4 (range 1.1-2.6). No patient exhibiting a pathologically complete response had a positive post-chemoradiotherapy SPET result, whereas 80% of patients with negative post-chemoradiotherapy SPET (12/15) results had residual tumor. The percent reduction rate was defined as (TLRpre-TLRpost)/TLRpre x100 and did not correlate with histological response grade ( P=0.5169 for Kruskal-Wallis test). These results suggest that (67)Ga SPET is a powerful tool for the detection of AESCC. However, (67)Ga SPET seems to be of little use in predicting the effects of preoperative chemoradiotherapy on AESCC. Further studies are warranted in order to further clarify the clinical usefulness of (67)Ga SPET in patients with AESCC.

Aged↗

Resectable gastric carcinoma. An evaluation of preoperative and postoperative chemotherapy.

Patients with locoregional gastric carcinoma often die because of the low rates of curative resection and frequent appearance of distant metastases (mainly peritoneal and hepatic). To evaluate the feasibility of preoperative and postoperative chemotherapy, 25 consecutive previously untreated patients with potentially resectable locoregional gastric carcinoma received two preoperative and three postoperative courses of etoposide, 5-fluorouracil, and cisplatin (EFP). Ninety-eight courses (median, five courses; range, two to five courses) were administered. Six patients had major responses to EFP. Eighteen patients (72%) had curative resections, and three specimens (12%) contained only microscopic carcinoma. At a median follow-up of 25 months, the median survival of 25 patients was 15 months (range, 4 to 32+ months). Peritoneal carcinomatosis was the most common indication of failure. One patient died of postoperative complications, but there were no deaths due to chemotherapy. EFP-induced toxic reactions were moderate. Preoperative and postoperative chemotherapy for locoregional gastric carcinoma is feasible, and additional studies to develop regimens that could result in 5% to 10% complete pathologic responses may be warranted.

Adenocarcinoma↗

Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response.

Gene expression analysis in breast cancer patients undergoing neoadjuvant chemotherapy is an interesting tool for identification of gene signatures and new markers to predict tumor response. However, the detection of predictive markers strongly depends on the drugs used in the specific therapeutic setting. There is growing evidence that topoisomerase II-alpha (TOPO IIalpha) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER-2 has been described as a marker of both anthracycline and taxane sensitivity. We performed gene expression profiling of 50 patients within the GEPARTRIO study, an anthracycline and taxane neoadjuvant chemotherapy trial. Here we investigate the predictive value of TOPO IIalpha, MAPT and HER-2 mRNA expression for pathological complete response (pCR) in this setting. Interestingly, HER-2 gene expression was strongly predictive of pCR (P=0.017) as well as overall response (P=0.037) and clinical complete response (cCR, P=0.050). In contrast, for both TOPO IIalpha and MAPT no correlation with pCR was observed in our sample group.

Adult↗

Differential response to preoperative chemoradiation and surgery in esophageal adenocarcinomas based on presence of Barrett's esophagus and symptomatic gastroesophageal reflux.

BACKGROUND: Barrett's esophagus and gastroesophageal reflux disease (GERD) are recognized to predispose to esophageal adenocarcinoma. Abdel-Latif and colleagues recently suggested that esophageal adenocarcinoma patients with GERD might be resistant to multimodality treatment. In this study, we investigated potential differences in clinical outcomes in esophageal adenocarcinoma patients based on the presence of identifiable Barrett's mucosa and/or history of symptomatic GERD. METHODS: Eighty-four patients with resectable esophageal adenocarcinoma, who completed the planned preoperative chemoradiation and underwent a potentially curative esophageal resection were retrospectively evaluated. Postoperative survival was compared between patients with or without underlying Barrett's esophagus and history of symptomatic GERD. Patients with pathologic complete response (path CR) and those with partial or no response (path PR) were compared to determine if presence of Barrett's esophagus and history of symptomatic GERD influence the path CR rates. RESULTS: We found significantly lower postoperative survival in patients with Barrett's associated adenocarcinoma (vs adenocarcinoma arising de novo, p = 0.031) and patients with symptomatic GERD (vs patients without symptomatic GERD, p = 0.019). Furthermore, the subset of patients with path PR (vs path CR) after chemoradiation have a significantly higher proportion of patients with Barrett's esophagus (HR = 4.38, confidence interval [CI] = 1.39 to 13.83, p = 0.012) and patients with GERD (HR = 2.71, CI = 1.13 to 6.50, p = 0.026). CONCLUSIONS: Patients with esophageal adenocarcinoma may have differences in response to preoperative chemoradiation based on the presence of Barrett's esophagus and history of symptomatic GERD.

Adenocarcinoma↗

Type III radical hysterectomy after induction chemotherapy for patients with locally advanced cervical carcinoma.

Neoadjuvant chemotherapy followed by surgery is a promising approach in locally advanced cervical carcinoma. The aim of this study was to evaluate the feasibility, technical aspects, and clinical results of surgery after induction chemotherapy in this patient population. Forty-one untreated cervical carcinoma patients staged as IB2 to IIIB received three 21-day courses of cisplatin 100mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 followed by surgery or concomitant chemoradiation. The response to chemotherapy, operability, surgical/pathological findings, disease-free period, and survival of the surgically treated patients were evaluated. All 41 patients were evaluated for toxicity and 40 were evaluated for response. The overall objective response rate was 95% (95% confidence interval 88%-100%), and was complete in three patients (7.5%) and partial in 35 (87.5%). Granulocytopenia grades 3/4 occurred in 13.8% and 3.4% of the courses, respectively, whereas nonhematological toxicity was mild. Twenty-three patients underwent type III radical hysterectomy. Mean duration of surgery was 3.8 h (range 2:30-5:20), median estimated blood loss was 670 ml and median hospital stay was 5.2 days. Intraoperative complications occurred in one case (venous injury). In all but one case the resection margins were negative. Four patients (17%) had positive nodes (one node each); six (26%) had complete pathologic response, three (13%) had microscopic; and 14 (60%) macroscopic residual disease. At 24 months of maximum follow-up (median 20), the disease-free and overall survival rates were 59% and 91%, respectively. Induction chemotherapy with cisplatin/gemcitabine produced a high response rate and did not increase the difficulty of surgery. Operating time, blood loss, intraoperative complications, and hospital stay were all within the range observed for type III hysterectomy in early stage patients. We therefore conclude that type III radical hysterectomy is feasible in locally advanced cervical cancer patients who respond to chemotherapy.

Adolescent↗

Monitoring response to primary chemotherapy in breast cancer using dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer. PATIENTS AND METHODS: Thirty patients with breast cancer, clinical diameter > 3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR). RESULTS: Univariate analysis showed that a > 65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438-464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263-23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5). CONCLUSIONS: DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Adolescent↗

High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

Antineoplastic Combined Chemotherapy Protocols↗

The role of multimodality therapy for resectable esophageal cancer.

BACKGROUND: There is an increasing interest in the role of combined therapy to achieve long-term survival for patients with resectable esophageal neoplasms. Surgery provides excellent palliation with relatively low morbidity and mortality rates, but cure remains elusive. MATERIAL AND METHODS: From January 1988 to January 1998, a total of 137 patients met eligibility criteria for a combined multimodal therapy, prospective, nonrandomized protocol of induction chemoradiation therapy followed by surgical resection, based on radiological and endoscopic assessment of the extension (all patients were initially considered to be at clinical stages I to III, locoregional). Consequently, patients with high grade Barrett's dysplasia or any squamous carcinoma in situ (stage 0) and those with distant metastatic disease (stage IV) were excluded. Among this group, 48 operable patients with biopsy-proven esophageal cancer finally entered and completed the protocol and are the sample of the present study. Multivariate logistic regression models were used to identify risk factors for death or recurrence. Actuarial survival was calculated since the beginning of the induction protocol by the Kaplan-Meier method, and comparisons between groups were made by the log-rank test. RESULTS: Mean age was 61.6 (range 45 to 71), and 72.9% were male. The majority of the tumors (70.8%) were located at the lower third/cardia and as many as 18.8% were adenocarcinoma. After a mean of 7.5 weeks (range 5 to 12) after the completion of the induction phase, 68.7% underwent a transthoracic esophagectomy and 31.3% a transhiatal esophagectomy. The in-hospital mortality rate was 10.4% (5 patients). A complete response (no evidence of tumor within the specimen: pT0) was achieved in 25% (12 patients). After a mean follow-up of 20.2 months, mean survival for the entire group was 18.2 months (95% confidence interval 14 to 22). At the end of the study, 25% (12) remained alive. Actuarial survival rates at 12, 23, and 37 months were 56.2%, 36.9%, and 21.9%, respectively. CONCLUSIONS: Esophageal resection after induction therapy seems to be related to a slightly higher mortality rate compared with historical series, and for this reason, neoadjuvant therapy must be considered still experimental. However, no statistical significant difference in survival is showed in those cases with complete pathological response (pT0). Factors influencing survival are recurrence and age. Surgery alone remains the standard therapy for esophageal cancer.

Aged↗

Irinotecan in esophageal cancer.

The limited effectiveness of chemotherapy in esophageal cancer used to palliate metastatic disease or to combine with radiotherapy in locally advanced disease has prompted the evaluation of new systemic agents. Irinotecan (CPT-11, Camptosar) has shown promising activity in a number of gastrointestinal cancers, including esophageal cancer. The phase II evaluation of the combination of weekly irinotecan and cisplatin has shown encouraging response rates exceeding 30% to 50% in esophageal and gastric cancer. Novel regimens include the combination of irinotecan with mitomycin (Mutamycin), the taxanes docetaxel (Taxotere) and paclitaxel, and continuous infusion fluorouracil (5-FU). Irinotecan is an active radiosensitizer, and trials have evaluated the combination of irinotecan with concurrent radiotherapy. We completed a phase I trial combining weekly irinotecan, cisplatin, and concurrent radiotherapy in locally advanced esophageal cancer. Minimal toxicity has been observed, with no grade 3/4 esophagitis or diarrhea, and hematologic toxicity was also surprisingly minimal. Full doses of weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2) could be combined safely with concurrent radiotherapy, with a significant rate of pathologic complete response. Phase II evaluation of this chemoradiotherapy regimen as preoperative therapy is planned at single institutions and at the cooperative group level in the United States. Further phase I and II investigation of combined irinotecan, cisplatin, and concurrent radiation is ongoing with the addition of targeted agents, including celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab (Avastin). Alternative combinations of irinotecan with radiotherapy, including the addition of docetaxel and continuous infusion 5-FU, are also undergoing phase I and II evaluation.

Antineoplastic Combined Chemotherapy Protocols↗

Posttreatment TNM staging is a prognostic indicator of survival and recurrence in tethered or fixed rectal carcinoma after preoperative chemotherapy and radiotherapy.

PURPOSE: To evaluate the prognostic value of the posttreatment TNM stage as a predictor of outcome in locally advanced rectal cancers treated with preoperative chemotherapy and radiotherapy. METHODS AND MATERIALS: Between 1993 and 2000, 128 patients with tethered (103) or fixed (25) rectal cancers were treated with 50 Gy preoperative pelvic radiotherapy and two cycles of concurrent 5-fluorouracil infusion (20 mg/kg/d) and leucovorin (200 mg/m(2)/d) chemotherapy on Days 1-4 and 22-25 and a single bolus mitomycin C injection (8 mg/m(2)) on Day 1. Of the 128 patients, 111 had Stage T3 and 17 Stage T4 according to the rectal ultrasound or CT findings and clinical evaluation. All 128 patients underwent surgery 8 weeks after chemoradiotherapy. Postoperatively, the disease stage was determined according to the surgical and pathologic findings using the American Joint Committee on Cancer TNM staging system. RESULTS: Of the 128 patients, 32 had postchemoradiotherapy (pCR) Stage 0 (T0N0M0), 37 pCR Stage I, 26 pCR Stage II, 28 pCR Stage III, and 5 pCR Stage IV disease. Of the 128 patients, 79 had pCR Stage T0-T2, 35 pCR Stage T3, and 14 pCR Stage T4. The rate of T stage downstaging was 66% (84 of 128). Of the 128 patients, 25% achieved a pathologic complete response, and 31 (24%) had positive nodal disease. Lymphovascular or perineural invasion was found in 13 patients (10%). The 5-year disease-specific survival rate was 97% for pCR Stage 0, 88% for pCR Stage I, 74% for pCR Stage II, 44% for pCR Stage III, and 0% for pCR Stage IV (p = 0.0000059). The 5-year relapse-free survival rate was 97% for pCR Stage 0, 80% for pCR Stage I, 72% for pCR Stage II, 42% for pCR Stage III, and 0% for pCR Stage IV (p < 0.000001). In univariate analysis, the pretreatment tumor status (fixed vs. tethered tumors), the pCR TNM stage, T stage downstaging, pathologic T4 tumors, node-positive disease after chemoradiotherapy, and lymphovascular or perineural invasion were statistically significant prognosticators of disease-specific survival and relapse-free survival. pCR Stage T4 disease was a strong predictor of local recurrence. The 5-year local control rate was 98% for pCR T0-T2, 89% for pCR T3, and 65% for pCR T4 disease (p = 0.00044). In multivariate analysis, the pCR TNM stage was the most statistically significant independent predictor of survival (p = 0.003) and relapse-free survival (p < 0.001). CONCLUSION: For patients who underwent preoperative chemoradiotherapy for locally advanced rectal cancer, the pCR TNM stage was a strong prognosticator of recurrence and survival. It can be used to identify high-risk patients for additional postoperative therapy.

Adult↗

Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma.

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Adenocarcinoma↗

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE: To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS: For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS: Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS: Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

Adenocarcinoma↗

Pretreatment surgical lymph node staging predicts results of trimodality therapy in esophageal cancer.

OBJECTIVE: Prediction of responders to induction therapy in esophageal cancer (EC) patients is important. In this study, we evaluated the role of thoracoscopic/laparoscopic (Ts/Ls) staging in prediction of treatment response and survival in EC patients with trimodality treatment. METHODS: Retrospective study of EC patients who had undergone Ts/Ls staging and received trimodality treatment at the University of Maryland Medical Center and the Baltimore Veterans Administration Hospitals from July, 1991 to December, 1999. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. RESULTS: Forty-four EC patients who underwent pretreatment Ts/Ls staging during the study period were able to complete concurrent chemoradiotherapy followed by surgical resection. There were 36 men and 8 women aged 40 to 77 (median age 62). Twenty-seven (61.4%) patients were found to have lymph node metastasis by surgical staging. Fourteen patients (31.8%) had a pathologic complete response. Patients with positive lymph nodes had a lower response rate than those with negative lymph nodes (14.8% vs. 58.8%, P=0.006). Other clinicopathologic features including gender, weight loss, clinical TNM stage, surgical T stage, and histology did not correlate with treatment response. Univariate analysis showed that weight loss and treatment response were important prognostic factors for disease-free survival (P=0.01 and P=0.02, respectively). Histology, surgical N stage and surgical TNM stage appeared to be associated with prognosis (P=0.067-0.097). Multivariate analysis revealed that only surgical N status and weight loss were significant prognostic factors (P=0.05, and P=0.006, respectively). CONCLUSIONS: Surgical Ts/Ls staging provides accurate evaluation of tumor spread in EC patients. Pretreatment N status was the single most important predictor of response to induction treatment as well as a reliable prognosticator of survival.

Aged↗

The use of mitomycin in esophageal cancer.

Concurrent administration of chemotherapeutic agents and radiation with or without surgery has yielded better local disease control and more prolonged survival than has standard radiation therapy or surgery alone in patients with esophageal cancer. Combinations of 5-fluorouracil (5-FU) and either cisplatin or mitomycin have proven most effective in this setting. As a single agent, mitomycin has generated response rates of 14-42% in patients with squamous cell carcinoma of the esophagus. The response of patients with esophageal adenocarcinoma to single-agent mitomycin is unknown. The clinical use of mitomycin concurrent with 5-FU and radiation is well established in esophageal cancer. There is some experimental evidence to suggest that synergy may occur between 5-FU and mitomycin. Mitomycin is preferentially cytotoxic to hypoxic cells, which are relatively radioresistant. It is not clear whether use of mitomycin with radiation is additive or supra-additive as experimental evidence exists to support both types of interaction. Nonrandomized clinical trials suggest that using either cisplatin or mitomycin concurrently with 5-FU and relatively low-dose radiation (30 Gy) prior to esophagectomy can result in comparable rates of pathologic complete response (20-30%) and median survival (12-19 months). Hematologic toxicity is frequently severe if all 3 drugs are used concurrently in combination with radiation. In patients with advanced disease (stage III or IV), combination chemotherapy/radiation therapy can result in significant palliation with tolerable morbidity. The use of concurrent chemotherapy and radiation has changed the pattern of failure in esophageal cancer from one dominated by inability to control local disease to one where systemic failure predominates. Current and proposed trials in esophageal cancer have changed their focus accordingly to meet this new treatment challenge.

Adenocarcinoma↗

Preoperative concurrent chemotherapy and radiation therapy followed by surgery for esophageal cancer.

Currently, the most promising strategy to improve the prognosis of advanced esophageal cancer is preoperative chemoradiation (CRT) followed by surgery. The superiority of CRT over radiation therapy alone has been demonstrated by several randomized studies. Many phase II studies of CRT followed by surgery have shown that the pathologic complete response (CR) rate ranges from 17 to 40%, and the median survival time (MST) is 12 to 31.3 months. Five randomized trials have compared preoperative CRT followed by surgery with surgery alone for resectable esophageal cancer, and four of them did not find any significant survival benefit for the combined treatment group. There are several issues in interpreting these findings, such as the quality of the surgery, the accuracy of the preoperative staging, the statistical power and design of the trials. Until comprehensive evaluation can be done, the standard therapy for resectable esophageal cancer should be considered to be surgery alone. The histological response in the resected specimen correlates well with the prognosis. Patients with pathologic CR display significantly better survival than those with microscopic residual cancer cells in the resected specimens. These findings suggest that more potent regimens leading to higher pathologic CR rates should improve the prognosis. Chemotherapy or radiation therapy sensitivity testing needs to be established. If accurate prediction of the response is possible prior to therapy, non-responders can be excluded. Cell cycle-related genes, apoptosis-related genes, and drug metabolizing genes have been investigated in many pilot studies and need to be evaluated by large-scale clinical studies. At present, pathologic CR can not be accurately diagnosed before surgery. Endoscopic biopsy is also unreliable for the diagnosis. In the future, new diagnostic tools such as positron emission tomography scanning, a sensitivity test or molecular markers may enable accurate diagnosis of pathologic CR to guide the choice of treatment strategies for individual patients.

Antineoplastic Combined Chemotherapy Protocols↗