Ronelle A. DuBrow

Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience

PURPOSE To evaluate the rates of tumor downstaging after preoperative chemoradiation for locally advanced rectal cancer. MATERIALS AND METHODS Preoperative chemoradiotherapy (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. RESULTS The pathological tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4NI in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor downstaging occurred in 72 (62%) cases. Only 3% of cases had pathologic evidence of progressive disease. Pretreatment tumor size (< 5 cm vs. > or = 5 cm) was the only factor predictive of tumor downstaging (p < 0.04). A decrease of > 1 T-stage level was accomplished in 45% of those downstaged. Overall, a sphincter-saving (SP) procedure was possible in 59% of patients and an abdominoperineal resection (APR) was required in 41 % of cases. Factors predictive of SP included downstaging (p < 0.03), age > 40 years (p < 0.007), pretreatment tumor distance, 3 to 6 cm from the anal verge (p < 0.00001), tumor size <6 cm (p < 0.02), mobility (p < 0.004), tumor stage <T4 (p < 0.01), and uN negative (p < 0.008). SP was performed in 23 patients (72%) with a CR and in 48 (67%) of downstaged cases. Among the 69 tumors located < 6 cm from the anal verge, 29 (42%) were resected with a SP. The level of response was important for tumors located < 6 cm from the anal verge because a SP was performed in 9 of the 17 (53%) CRs in this group while only 20 of 52 patients (38%) had a SP when residual disease was present after CTX/XRT. For tumors located > 6 cm from the anal verge, SP was performed in 14 of the 15 (93%) patients with a CR and 32 of 33 (97%) of patients with residual disease (p < 0.00004). CONCLUSIONS Significant tumor downstaging results from preoperative chemoradiation allowing sphincter sparing surgery in over 40% of patients whose tumors were located < 6 cm from the anal verge and who otherwise would have required colostomy.

Preoperative infusional chemoradiation therapy for Stage T3 rectal cancer

PURPOSE To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. METHODS AND MATERIALS Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m2/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. RESULTS Posttreatment tumor stages were T1-2, N0 in 35%, T3 N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute, perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. CONCLUSIONS Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further.

Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer

The aim of this study was to determine if the response to preoperative radiation and chemotherapy with continuous infusion 5-fluorouracil (5-FU) was predictive for survival among patients with locally advanced rectal cancer. Preoperative chemoradiation (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-FU (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. Adjuvant chemotherapy, consisting of 400 to 425 mg/m2 of 5-FU plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for 4 to 6 cycles after surgical resection. Among the 74 patients treated with adjuvant chemotherapy, the preoperative stage of disease was 31 with T3N0 and 43 T3N1. Median follow-up was 46 months (range 2 to 89 months). The pathologic tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4N1 in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor down-staging occurred in 72 (62%) cases. A sphincter-saving procedure (SP) was possible in 59% of patients. The median DFS and overall survival rates for responders were 46 months and 47 months, respectively; for non-responders these outcome measures were 38 months and 41 months, respectively. Log-rank analysis showed that the distant metastatic-free survival rates improved with any response to CTX/XRT (p < 0.00001), CR to CTX/XRT (p < 0.009) and SP (p < 0.012). Likewise, these parameters also significantly influenced DFS rates (CTX/XRT p < 0.00001; CR p < 0.006; and SP p < 0.008). Control of pelvic disease was influenced by clinical size (p < 0.002) and SP (p < 0.016) on univariate analysis. On multivariate analysis only clinical size (p < 0.002) continued to be a significant factor for local control. Factors on multivariate analysis that resulted in significant improvements in cancer-specific survival included any response to preoperative CTX/XRT (p < 0.017) and administration of adjuvant chemotherapy (p < 0.034). Any response to preoperative CTX/XRT improved distant metastatic-free and disease-free survival rates. Multivariate analysis confirmed that a response to preoperative CTX/XRT predicted for improvements in overall survival among patients with locally advanced rectal cancer. Patients who fail to respond to preoperative 5-FU based chemotherapy given concomitantly with radiation have higher rates of distant metastases with adjuvant 5-FU therapy.

Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer.

BACKGROUND AND PURPOSE To evaluate the influence of response to preoperative infusional chemoradiation on outcome parameters among patients with locally advanced rectal cancer. MATERIALS AND METHODS Preoperative chemoradiotherapy, 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2 per day), was given to 117 patients. As determined by pretreatment endorectal ultrasound (EUS), 96% of cases were Stage T3, and 51% had EUS evidence of perirectal adenopathy. Surgery was performed approximately 6 weeks after chemoradiation therapy. Postoperatively adjuvant systemic therapy, consisting of 400-425 mg/m2 of 5-fluorouracil plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for six cycles. Outcome parameters of local control (LC), freedom from distant metastases (DMC), disease-free survival (DFS) and cancer specific survival (CSS) were evaluated relative to primary tumor characteristics. RESULTS The final post-treatment pathological tumor stages were complete response in 27%, Tis-2 N0 in 26%, T2 N1 in 5%, T3 N0 in 21%, T3 N1 in 15%, T4 N0 in 5% and T4 N1 in 1%. Down-staging occurred in 61% of cases. The pretreatment primary tumor size only influenced rates of local control (P < 0.03) and had no other influence on outcome parameters. Pretreatment evidence of perirectal lymph node involvement had no impact on outcome parameters. Pathologic evidence of nodal involvement did affect DMC (P < 0.002) and DFS (P < 0.003). Pathologic evidence of response did influence freedom from the development of distant metastases (P < 0.004). On pairwise analysis this relationship held only when responders were compared to non-responders. No difference was observed based on the level of downstaging at the primary tumor. Correspondingly, DFS was improved when non-responders were compared to downstaged patients (P < 0.01). Response to preoperative chemoradiation failed to affect rates of LC or CSS. For the group as a whole, adjuvant chemotherapy improved only CSS (P < 0.03). Adjuvant chemotherapy was given to 74 patients, 36 of whom had responded to preoperative chemoradiation. Improvements were only seen in DFS (P < 0.03) when down-staged patients were compared to the non-responders who received adjuvant chemotherapy. In addition, the DFS rates were lower in the non-responder group who received adjuvant chemotherapy even when they were compared to down-staged patients who did not receive adjuvant chemotherapy (P < 0.04). CONCLUSION Consistent with other reports, disease free survival and subsequent development of distant metastases is reduced in the more than 60% of patients who respond to preoperative infusional chemoradiation. Evidence of response appears more significant than the degree of response. At present, no impact is seen on cancer specific survival rates. Consideration should be given for strategies that base selection of subsequent adjuvant chemotherapy on response to preoperative chemoradiation.

Vascular involvement in pancreatic adenocarcinoma:reassessment by thin-section CT

Abstract. We defined computed tomographic (CT) criteria of vascular involvement by pancreatic carcinoma and used these criteria to assess vascular involvement in 56 patients with pancreatic adenocarcinoma. CT of the pancreas was performed at 1.5-mm section thickness and 5-mm section intervals during a bolus phase of intravenous contrast enhancement. The type of vascular involvement was correlated with surgical and pathologic findings. When there was fat-plane (type A) or normal pancreatic parenchyma (type B) separating the tumor from adjacent vessels, the tumor could be resected without venous resection in 21 of 22 patients (95%). When the tumor was inseparable from the vessels but the points of contact formed a convexity against the vessel (type C), CT was not reliable in predicting whether or not the tumor was fixed against the vessel. When the tumor was partially encircling (type D) the vessel, the tumor was fixed against the vessels in most cases. The resectable rate was 47%, but resection would also require venous resection. When the tumor was completely encircling (type E) or occluding (type F<+>) the vessel, all tumors were not resectable with a negative margin. Thin-section CT with bolus intravenous contrast enhancement improved the ability to assess vascular involvement in pancreatic adenocarcinoma.

Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer

BACKGROUND Docetaxel and vinorelbine as combined treatment for metastatic breast cancer can have the dose-limiting toxic effects of mucositis and neutropenic fever. We report unexpected ischaemic colitis in six patients associated with docetaxel-based therapy, three of whom were treated in a phase I study designed to establish the maximum tolerated dose of this combination with the prophylactic use of granulocyte-colony-stimulating factor. METHODS Between August, 1997, and December, 1998, 14 patients with metastatic breast cancer were treated with vinorelbine, docetaxel, and granulocyte-colony-stimulating factor in a phase I study. Three patients developed colitis similar to that seen in typhlitis. Three additional patients were identified during scheduled review of toxic effects in patients participating in clinical trials involving docetaxel. FINDINGS Three patients on combined vinorelbine and docetaxel developed colitis-like symptoms. Two patients died, one from necrotic bowel and the other from neutropenic fever and colitis. Two of the patients presented on day 7 and day 8 of chemotherapy, respectively, with neutropenic fever and abdominal pain; the third patient developed neutropenia without fever and abdominal pain on day 8. The other three patients were treated with docetaxel, docetaxel and pamidronate disodium, or docetaxel and cyclophosphamide. All three patients presented with abdominal pain on days 10, 5, and 4, respectively. One had non-neutropenic fever, another had neutropenic fever, and the third was afebrile and non-neutropenic at the time of presentation with abdominal pain. Three patients had blood in their diarrhoea, abdominal tenderness, or both. Computed tomography of the abdomen and pelvis showed features of colitis in three patients. INTERPRETATION This serious complication may result from the use of docetaxel and may be exacerbated by its combination with vinorelbine. Study of hospital-based patients treated with taxane-based chemotherapy is underway to find out the frequency of such complications.

Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer

RATIONALE To evaluate the response to a concomitant boost given during standard chemoradiation for locally advanced rectal cancer. METHODS AND MATERIALS Concomitant boost radiotherapy was administered preoperatively to 45 patients with locally advanced rectal cancer in a prospective trial. Treatment consisted of 45 Gy to the pelvis with 18 mV photons at 1.8 Gy/fraction using a 3-field belly board technique with continuous infusion 5FU chemotherapy (300mg/m(2)) 5 days per week. The boost was given during the last week of therapy with a 6-hour inter-fraction interval to the tumor plus a 2-3 cm margin. The boost dose equaled 7.5 Gy/5 fractions (1.5 Gy/fraction); a total dose of 52.5 Gy/5 weeks was given to the primary tumor. Pretreatment tumor stage, determined by endorectal ultrasound and CT scan, included 29 with T3N0 [64%], 11 T3N1, 1 T3Nx, 2 T4N0, 1 T4N3, and 1 with TxN1 disease. Mean distance from the anal verge was 5 cm (range 0-13 cm). Median age was 55 years (range 33-77 years). The population consisted of 34 males and 11 females. Median time of follow-up is 8 months (range 1-24 months). RESULTS Sphincter preservation (SP) has been accomplished in 33 of 42 (79%) patients resected to date. Three patients did not undergo resection because of the development of metastatic disease in the interim between the completion of chemoradiation (CTX/XRT) and preoperative evaluation. The surgical procedures included proctectomy and coloanal anastomosis (n = 16), low anterior resection (n = 13), transanal resection (n = 4). Tumor down-staging was pathologically confirmed in 36 of the 42 (86%) resected patients, and 13 (31%) achieved a pathologic CR. Among the 28 tumors (67%) located <6 cm from the anal verge, SP was accomplished in 21 cases (75%). Although perioperative morbidity was higher, toxicity rates during CTX/XRT were comparable to that seen with conventional fractionation. Compared to our contemporary experience with conventional CTX/XRT (45Gy; 1.8 Gy per fraction), improvements were seen in SP (79% vs. 59%; p = 0.02), SP for tumors <6 cm from the anal verge (75% vs. 42%; p = 0.003), and down-staging (86% vs. 62%; p = 0.003). CONCLUSION The SP rate with concomitant boost radiation has been highly favorable with rates of response which are higher than those previously reported for chemoradiation without administration of a boost. Further evaluation of this radiotherapeutic strategy appears warranted.

Preoperative infusional chemoradiation, selective intraoperative radiation, and resection for locally advanced pelvic recurrence of colorectal adenocarcinoma.

OBJECTIVE The results of preoperative infusional chemoradiation, resection, and selective intraoperative radiation (IORT) boost in 43 previously nonirradiated patients with locally advanced pelvic recurrence of colorectal adenocarcinoma are described. SUMMARY BACKGROUND DATA After surgery alone 10% to 30% of patients with carcinoma of the distal colon and rectum will develop isolated pelvic recurrence. In most cases, the disease is locally advanced and not amenable to curative resection. Preoperative infusional chemoradiation has been shown to increase resectability and decrease local recurrence in primary locally advanced colorectal cancer. Based on this experience, we initiated a multimodality treatment protocol to treat patients with pelvic recurrence of colorectal adenocarcinoma. METHODS Forty-three consecutive patients with histologically proven pelvic recurrence of colorectal adenocarcinoma were enrolled on a multimodality treatment protocol. The treatment plan consisted of 5 weeks of concurrent pelvic external beam radiotherapy (45 Gy) with continuous intravenous infusion of 5-fluorouracil and/or cisplatin. This was followed by surgery that included IORT boost (10-20 Gy) for 21 patients and brachytherapy for 4 patients. RESULTS Forty patients (93%) underwent operation and 33 (77%) underwent resection with curative intent. There were 29 (88%) margin-negative resections. Fifteen patients (48%) underwent sphincter-preserving operations. There were no treatment-related deaths. Twenty-two patients experience perioperative complications. Median follow-up for the 43 patients was 26 months. The local recurrence rate was 36%. Median survival for the patients who underwent resection was 34 months, and actuarial 5-year disease-free and overall survival were 37% and 58%, respectively. CONCLUSIONS Tumor cytoreduction by preoperative chemoradiation can increase resectability and enable sphincter-preserving surgery in patients with locally advanced pelvic recurrence of colorectal cancer.

Carcinoid Tumors: Imaging Procedures and Interventional Radiology

Abstract. The hypervascular nature of carcinoid tumors and their metastases allows a more aggressive role by the radiologist in diagnosis and interventional management. Double-contrast gastrointestinal studies still best define the primary neoplasms. Appendiceal tumors, the most frequent site of carcinoids, frequently escape radiologic detection until large enough to be discovered by computed tomography (CT). Superior mesenteric arteriography of the small bowel and cecum is useful when the scanning procedures are not revealing. The “spokewheel” configuration of the desmoplastic mesenteric masses and lymph node metastases are best seen by CT, whereas hepatic metastases can be demonstrated by CT, CT-angioportography (CTAP), ultrasonography (US), magnetic resonance imaging (MRI), and octreotide scintigraphy. Percutaneous needle biopsy with radiologic guidance confirms the diagnosis of carcinoid tumors and their metastases. Hepatic arteriography is frequently performed in preparation for hepatic embolization or chemoembolization. Hepatic vascular occlusion therapy, the procedure of choice for the management of inoperable carcinoid liver metastases, results in a partial response in at least 50% of patients and a mortality rate of 5%. Chemoembolization with microencapsulated cytotoxic agents and direct percutaneous ethanol injection should also be considered for the treatment of liver metastases.

Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy

BackgroundPreoperative chemoradiation can potentially improve outcomes in patients with pancreatic cancer. This study addresses its effect on staging pancreatic cancer with multidetector computed tomography (MDCT).MethodsFifty-five patients underwent a dual-phase MDCT pancreas protocol for proved pancreatic cancer. Of these, 16 patients underwent preoperative chemoradiation. Three radiologists independently reviewed images to assess for locally advanced disease, liver and peritoneal metastases on baseline studies of all 55 patients, and on follow-up preoperative studies for the 16 patients receiving preoperative therapy. Overall score for resectability was graded on a scale from 1 to 5 (1, definitely resectable; 5. definitely unresectable). Receiver operating characteristic curves and weighted (κ statistics were determined.ResultsThe areas under the receiver operating characteristic curves for readers 1, 2, and 3 were 0.98, 0.96, and 0.90, respectively. Weighted κ values for reader 1 versus reader 2, reader 1 versus reader 3, and reader 2 versus reader 3 were 0.90, 0.57, and 0.54, respectively. Interpreting scores of 1 to 3 for resectability as resectable disease, the mean values for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 0.92, 0.91, 0.74, 0.98, and 0.92 respectively.ConclusionThe negative predictive value for MDCT for identifying unresectable pancreatic cancer in the setting of preoperative therapy is comparable to that reported in the absence of neoadjuvant therapy.