OBJECTIVE

The tumor-activated fluoropyrimidine capecitabine achieves response rates superior to those of bolus 5-fluorouracil/leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer (CRC), with favorable safety and fewer hospitalizations. Capecitabine is also at least as effective as bolus 5-FU/LV in the adjuvant setting, again with a favorable safety profile. Improved outcomes with capecitabine versus bolus 5-FU/LV in the adjuvant setting have been shown in overall trial populations and in patients aged>>or= 70 years. Capecitabine/oxaliplatin (XelOx) is a safe and active combination for the first-line treatment of metastatic CRC.

METHODS

This post hoc analysis of a large phase II trial compared data from older and younger patients treated with first-line XelOx: oxaliplatin 130 mg/m(2) intravenously on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks.

RESULTS

The median age of the overall population (N = 96) was 64 years (range, 34-79 years), including 52 younger patients (< 65 years of age) and 44 older patients >>or= 65 years of age). Both age groups received a median of 8 cycles (range, 1-26 cycles) of XelOx. The XelOx regimen had similar high activity in both groups, with response rates of 58% (95% CI, 43%-71%) and 52% (95% CI, 37%-68%) in younger and older patients, respectively. In addition, time to disease progression and overall survival were similar in both groups (P>> 0.5 for both outcomes). The XelOx regimen also had a favorable safety profile, with no clinically relevant differences between older and younger patients. The overall incidence of adverse events (including grade 3/4), dose reductions, and withdrawals because of adverse events were similar in both groups.

CONCLUSIONS

In the context of an aging population, XelOx provides a highly effective and tolerable first-line treatment for patients with metastatic CRC.

Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX (5-flourouracil, leucovorin, oxaliplatin and irinotecan) have provided some limited survival advantage in advanced pancreatic cancer. Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer.

OBJECTIVE

We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy.

METHODS

Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue.

RESULTS

There was no difference in cognitive outcomes between radiated and unirradiated patients (P>> .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001).

CONCLUSIONS

We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.

Piritrexim, a lipid-soluble antifolate, was evaluated for its activity against Pneumocystis carinii and Toxoplasma gondii. The concentration of piritrexim needed to inhibit 50% of the catalytic activity of P. carinii dihydrofolate reductase (DHFR) was 19.3 nM, and that for T. gondii DHFR was 17.0 nM, concentrations that were 40- to over 1,000-fold less than those needed for the inhibition of activity by trimethoprim and pyrimethamine, the antifolates conventionally used in treating these organisms. Piritrexim was able to inhibit replication of T. gondii in a mouse peritoneal macrophage model at concentrations of 0.1 to 1.0 microM. Leucovorin, a reduced folate that can bypass the inhibition of DHFR by antifols in mammalian cells but not in protozoa, did not affect the ability of piritrexim to inhibit T. gondii replication. The addition of sulfadiazine, which alone was ineffective, to piritrexim allowed inhibition of T. gondii replication at lower concentrations of piritrexim than when piritrexim was used alone. These results suggest that piritrexim, alone or combined with a sulfonamide, may be a highly potent antitoxoplasma and antipneumocystis agent that could provide major pharmacologic and clinical advantages over available agents.

OBJECTIVE

The purpose of this study was to assess the longitudinal impact of stoma formation on the health-related quality of life of rectal cancer patients treated with adjuvant chemotherapy.

METHODS

Health-related quality of life data was prospectively collected in a randomized trial designed to compare 24 weeks of bolus 5-fluorouracil/leucovorin with 12 weeks of continuous 5-fluorouracil in patients with resected Dukes B and C colorectal cancer. Health-related quality of life data was collected at baseline, during adjuvant treatment, and at one and three years after completion of chemotherapy.

RESULTS

Between 1993 and 2003, 186 rectal cancer patients were enrolled. One hundred thirty-nine patients had anterior resection, of whom 46 had a temporary defunctioning colostomy. Forty-seven patients had abdominoperineal resection with formation of a permanent colostomy. There was no significant difference in global health-related quality of life between patients with and patients without a stoma at any time point. However, during adjuvant treatment, role (P = 0.04) and social (P = 0.005) functioning were significantly worse in stoma patients than in nonstoma patients. Moreover, the impairment in social functioning persisted at one (P = 0.03) and three years (P = 0.04) after adjuvant chemotherapy.

CONCLUSIONS

Our results demonstrate important adverse effects of either temporary or permanent stoma formation on subsequent health-related quality of life in patients with rectal cancer.

BACKGROUND

Concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer is an important modality for curative resection, but tumors show wide spectrum response. The purpose of this study was to investigate any correlation among related genetic mutations, proliferative index, and tumor response after CCRT.

METHODS

This study included 23 patients with rectal cancer, who were preoperatively staged as at least T3 N1 or T4 (determined by transrectal ultrasonography and MRI). Enrolled patients were given 5-FU 450 mg/m2/day and leucovorin 20 mg/m2/day intravenously for 5 days during weeks 1 and 5 of radiotherapy (45-54 Gy). Surgical resection was performed 4 weeks after completion of the scheduled treatment. Tumor response was classified as CR (complete response), PR (partial response: 50% diminution of tumor volume and downstaging), and NR (no response). Paraffin-embedded tissue obtained before chemoradiotherapy was studied by immunohistochemical staining for p53, BCL-2, and Ki-67. The extent of tumor response was correlated with proliferative activity and was measured by immunostaining Ki-67 proliferative antigen and the expression of p53 and BCL-2 oncoproteins.

RESULTS

All patients were resectable. CR was obtained in 4 patients, PR in 10 patients, and NR in 9 patients. The p53 mutation was noted in 16 patients: NR in 5 patients, PR in 9 patients, and CR in 2 patients (P = .638). BCL-2 expression was noted in 11 patients: NR in 4 patients, PR in 3 patients, and CR in 4 patients (P = .799). The Ki-67 labeling index was NR: 615.4+/-47.2; PR: 663.2+/-20.4; and CR: 765.5+/-58.3 (CR + PR vs. NR, P = .029).

CONCLUSIONS

Immunohistochemical expression of p53 and BCL-2 does not correlate with tumor response after CCRT, but Ki-67 labeling may be a useful parameter for radiosensitive tumors selected for CCRT.

OBJECTIVE

To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines.

METHODS

Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given.

RESULTS

The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively.

CONCLUSIONS

Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.

An analysis of dose and schedule dependence of calcium leucovorin rescue during high-dose methotrexate therapy of ascitic forms of l1210 leukemia and Sarcoma 180 is reported. Schedules with very delayed "low-dose" leucovorin rescue following lethal doses of methotrexate were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both ascites tumor models. Best results were obtained on a schedule of methotrexate (400 mg/kg s.c.) followed 16 to 20 hr later by calcium leucovorin (12 mg/kg s.c.) given once every 2 hr for a total of 5 doses. Progressive increases in the calcium leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of methotrexate in each model. Following a single course of therapy, essentially no toxicity was observed, and the antitumor effects were 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater than a single, maximally tolerated dose (24/kg s.c.) methotrexate alone. An increase in the methotrexate dosage to 800 mg/kg s.c. with or without an increase in calcium leucovorin dosages on the same schedule did not appreciably increase the antitumor effect observed. Two courses of high-dose methotrexate (400 mg/kg s.c.) with leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 hr after drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with Sarcoma 180. The results, overall, are in close agreement with prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochemical studies in murine tumor models reported from this laboratory.

ZD1694 (Tomudex) is a new antifolate which is a specific inhibitor of thymidylate synthase (TS). Evidence suggests that ZD1694 has a spectrum of activity that only partially overlaps with 5-fluorouracil (modulated with leucovorin) against colon tumours in vitro. Potent cytotoxic activity is dependent upon active uptake into cells via the reduced folate/methotrexate cell membrane carrier (RFC) and subsequent metabolism to polyglutamated forms (tri, tetra and pentaglutamates). These polyglutamates are approximately 60-fold more active as TS inhibitors and are not effluxed readily from cells. Extensive polyglutamation also occurs in various mouse tissues (e.g. small intestinal epithelium, liver and kidney), resulting in high tissue/plasma drug ratios which persist for a prolonged period. ZD1694 has antitumour activity in mice, although the high plasma thymidine in this species complicates: (1) the interpretation of therapeutic index; (2) tumour types in which activity is likely to be observed; and (3) translation of doses and schedules for clinical evaluation. ZD1694 entered clinical study and has completed Phase I and II evaluation, with activity observed in several tumour types. Appreciable activity in the Phase II colorectal study (29% objective response rate on interim analysis) led to the current Phase III study, randomised against 5-fluorouracil/leucovorin.

The patient presented here is a 30-year-old woman who underwent anterior resection for the initial treatment of rectal cancer. A postoperative study showed a single liver metastasis. The patient received adjuvant pelvic radiotherapy with concomitant 5-fluorouracil (5-FU) treatment followed by liver metastasectomy 6 weeks after the completion of radiation therapy and chemotherapy. Adjuvant therapy with 5-FU, leucovorin, and oxaliplatin (FOLFOX 4 regimen) was continued. The initial five cycles were well tolerated with the occurrence of only paresthesia that did not interfere with function. After the sixth cycle of the treatment, progressive dyspnea and persistent cough developed in the patient, although her clinical history was negative for lung disease. A chest radiograph revealed diffuse bilateral interstitial infiltrates, and a chest CT scan showed bilateral alveolar infiltrates predominant in the right lung. Lung biopsy by video-assisted thoracoscopy was performed, and the histologic report showed cryptogenic organizing pneumonitis (COP). Prednisone therapy (1 mg/kg/d) resulted in a very good clinical response. In fact, the patient had complete remission of respiratory symptoms including cough and dyspnea after 4 days of treatment, and the chest CT scan showed complete resolution of lung infiltrates after 4 weeks. One month later, the patient continued adjuvant treatment with six cycles of 5-FU, leucovorin, and irinotecan (ie, the FOLFIRI regimen) without complications. Thus, oxiplatin was implicated as the likely cause of this drug-induced lung toxicity, which is a very rare complication associated with platins. Diffuse interstitial lung disease, particularly COP, has been described following the administration of the cytotoxic agents bleomycin and busulfan, but a connection to oxaliplatin has not been reported before this case.

BACKGROUND

Due to the westernization of the diet in Japan, the incidence of colorectal cancer has increased 4.5 times in the last 25 years. In this review, the recent results of surgical treatment for colonic cancer and the future perspectives in Japan are described.

METHODS

A multi-institutional registry of large bowel cancer in Japan of 10,809 patients with colonic cancer treated from 1991 to 1994 was investigated. The data have been published in the Guidelines of the Japanese Society for Cancer of the Colon and Rectum (2005). Regarding laparoscopic surgery, 1,495 patients with colon cancer were examined in a multicenter study between April 1993 and August 2002.

RESULTS

Radical resection with a curative intent is appropriate for 83-99% of the patients with stage I-III localized colon carcinoma. Adequate lymphadenectomy, including paracolic, intermediate and principal node dissection (D3 lymphadenectomy), is of critical importance for both the accurate staging and local control of the disease. This treatment protocol has now been accepted as a 'standard' operation by Japanese colorectal surgeons. For patients undergoing a curative resection for colon cancer, the 5-year survival rates vary between 62 (stage III) and 91% (stage I). Adjuvant chemotherapy using 5-FU/leucovorin or oral compounds is commonly administered to patients with stage III disease. Laparoscopic surgery for colonic cancer yielded a comparable oncological outcome to that reported for conventional open surgery in the Japanese registry for all disease stages.

CONCLUSIONS

Radical resection with a D3 lymphadenectomy provided satisfactory 5-year survival for patients with stage I-III colon cancer in Japan. However, the survival of patients with stage IV disease is still unsatisfactory (only a 14% 5-year survival). Any further improvements depend on both identifying such patients at an earlier stage as well as developing new and effective treatment modalities.

OBJECTIVE

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.

METHODS

Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2).

RESULTS

Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU.

CONCLUSIONS

The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.

OBJECTIVE

In previous studies, humanized A33 (huA33) demonstrated modest antitumor activity in chemotherapy-resistant colorectal cancer patients. In addition, unexpected major tumor responses were observed in patients treated with a specific chemotherapy regimen [carmustine, vincristine, fluorouracil, and streptozocin (BOF-Strep)] administered after huA33 protocols. We designed the present Phase I, open label, cohort, dose-escalation study of huA33 and a fixed dose of BOF-Strep to (a) determine the maximum tolerated dose of huA33 immunotherapy administered with chemotherapy, (b) determine whether chemotherapy modifies huA33 immunogenicity, and (c) develop preliminary information regarding antitumor activity.

METHODS

Stage IV fluorouracil/leucovorin and irinotecan-refractory colorectal cancer patients (n = 16) received escalating weekly doses of huA33 (5-40 mg/m(2)) with BOF-Strep chemotherapy.

RESULTS

Four patients requiring radiotherapy or surgery were removed early. Of 12 evaluable patients, grade 3 and 4 neutropenia (n = 2) and grade 3 thrombocytopenia (n = 1) were observed. Seven of 12 (58.3%) patients developed anti-huA33 activity. Three patients had radiographic partial responses for 7.5, 5.5, and 14 months with greater than 85% decline in serum carcinoembryonic antigen levels. One mixed response (4.5 months with a serum carcinoembryonic antigen decline of 38%) was also observed.

CONCLUSIONS

huA33 can be safely combined with BOF-Strep chemotherapy. The present report provides compelling evidence supporting our previous observations of major antitumor activity with the combination of huA33 and BOF-Strep chemotherapy. huA33 is still immunogenic when administered with chemotherapy. Future studies to evaluate the immunogenicity of new huA33 antibodies and identify which drugs in the BOF-Strep regimen are critical for enhanced antitumor efficacy are planned.

The inhibition of thymidylate synthase (TS) by the 5-fluorouracil (5FU) metabolite 5-fluorodeoxyuridine monophosphate can be biochemically modulated by leucovorin (LV). LV administration increases the level of reduced folates in tissues, which promotes the inhibition of TS. We have studied the antitumor effect, free 5-fluorodeoxyuridine monophosphate levels, and inhibition of TS in two murine colon tumors at several time points after weekly 5FU or LV and 5FU administration. The antitumor effect of 5FU alone could be potentiated by LV in both tumors. 5-Fluorodeoxyuridine monophosphate levels (212 and 46 pmol/g wet wt. after 2 h for Colon 26 and Colon 38, respectively) were sufficient to mediate TS inhibition, but the levels were not related to antitumor activity. Untreated controls of the 5FU-sensitive tumor Colon 38 had 3 times lower TS levels than did those of the more resistant tumor Colon 26. One course of treatment resulted in a comparable extent and retention of TS inhibition for 5FU and LV/5FU therapy in both tumors. After 1 week there was complete recovery of TS inhibition, but the TS levels in tumors from 5FU-treated mice tended to be higher than the controls, which was more pronounced after three courses of therapy. A 4-fold increase of TS levels was seen in Colon 26 after 5FU therapy. The elevation of TS in this tumor affected the extent of TS inhibition. Tumors treated with 5FU and LV also showed an increase of TS, but to a lesser extent, while the absolute effect on TS inhibition remained the same. This might be related to the potentiating effect of LV on 5FU antitumor activity in vivo in these tumors.

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

BACKGROUND

We report the results of postoperative chemoradiotherapy after curative resection in gastric cancer patients.

METHODS

Patients with gastric cancer staged IB to IV(M0) were treated with chemoradiotherapy after curative resection with extensive (D2) lymph node dissection. Nodal metastases were observed in 261 (90%) patients. The chemotherapy consisted of fluorouracil 400 mg/m(2) plus leucovorin 20 mg/m(2) for 5 days, followed by 4500 cGy of radiotherapy for 5 weeks with fluorouracil and leucovorin on the first 4 days and the last 3 days of radiotherapy. Two 5-day cycles of chemotherapy were given 4 weeks after the completion of radiotherapy.

RESULTS

Of 290 patients accrued, 229 (79%) patients completed chemoradiotherapy as planned. With a median follow-up of 49 months, 114 (34%) patients have relapsed: 33 (29%) locoregional relapses, 76 (67%) peritoneal relapses and 41 (36%) distant metastases. The 5-year overall and relapse-free survivals were 60% and 57%, respectively. Tolerance was acceptable, the main toxicity being neutropenia.

CONCLUSIONS

This postoperative chemoradiotherapy after curative resection of gastric cancer was feasible, with acceptable toxicities. Whether this adjuvant therapy in gastric cancer patients that have undergone a D2 lymph node dissection impacts on survival or reduces the incidence of relapses remains to be studied.

This study aimed at assessing the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in patients with advanced small bowel adenocarcinoma (SBA). Thirty-three eligible patients with previously untreated SBA received 85 mg/m(2) of oxaliplatin intravenously over a 2-h period on day 1, together with 400 mg/m(2) of leucovorin over 2 h, followed by a 46-h infusion of 5-FU 2600 mg/m(2) every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of nine cycles (range 3-18) was administered. The objective response rate was 48.5% [95% confidence interval (95% CI): 31-67%], with one complete response, 15 partial responses, 12 stable diseases, and five progressions. The median time to progression was 7.8 months (95% CI: 6.0-9.6) and the median overall survival was 15.2 months (95% CI: 11.0-19.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (12.1%), thrombocytopenia (3.0%), nausea (6.1%), vomiting (3.0%), diarrhea (3.0%), peripheral neuropathy (9.1%), and fatigue (3.0%), and grade 4 toxicities occurred in none of the patients. The modified FOLFOX regimen is highly active and well tolerated as first-line chemotherapy for advanced SBA patients.

BACKGROUND

The encouraging results seen in patients who received postoperative combined modality therapy in the adjuvant setting have prompted increased interest in preoperative combined modality therapy for patients with unresectable rectal cancer. The authors report the local control and survival of a previously reported Phase I dose escalation trial of combined preoperative 5-fluorouracil (5-FU), high-dose leucovorin (LV), and sequential radiation therapy followed by postoperative LV-5 FU for the treatment of patients with unresectable rectal cancer.

METHODS

Twenty patients (13, primary and 7, recurrent disease) received LV-5-FU for one cycle. Radiation therapy (5040 cGy) began on day 8. A second cycle of LV-5-FU was given concurrently with week 4 of radiation. Six patients received intraoperative brachytherapy. Postoperatively, the patients received LV-5-FU. The pathologic complete response rate was 20%, and 89% underwent a complete resection with negative margins.

RESULTS

The crude local failure rate was 26%, and the 3-year actuarial local failure rate was 29% (95% confidence interval [CI], +/- 8.94%). The crude abdominal and distant failure rates were 40% and 30%, respectively. The 3-year actuarial disease-free survival was 64% (95% CI, +/- 6.75%), and the overall survival was 69% (95% CI, +/- 7.65%).

CONCLUSIONS

These preliminary data revealed encouraging local control and survival rates. Preoperative combined modality therapy is an attractive approach in patients with unresectable rectal cancer.

OBJECTIVE

Leucovorin and extracorporeal removal of methotrexate (MTX) have limited efficacy in delayed MTX elimination after high-dose methotrexate (HD-MTX) therapy. Glucarpidase (carboxypeptidase G2) cleaves MTX into nontoxic metabolites, but experience with this enzyme is limited in adult patients. We evaluated the effects of glucarpidase intervention in adult and elderly patients with delayed MTX elimination.

METHODS

Forty-three patients (age, 18-78 years) with MTX serum concentrations (sMTX) of 1-1,187 micromol/l received glucarpidase, leucovorin rescue guided by MTX immunoassay, and standard supportive care. MTX and MTX metabolites were quantified in serum (24 patients) and urine (8 patients) by high-performance liquid chromatography. Contributory risk factors, toxicities, and survival were recorded in all patients.

RESULTS

Glucarpidase was well tolerated and resulted in an immediate >97% reduction in sMTX, with a 0.2%-35% urinary recovery of the total MTX dose as inactive MTX metabolites. Forty (93%) of 43 patients had normalization (n = 25) or improvement (n = 15) of their serum creatinine. Frequent grade III-IV MTX toxicities were hematological (60%) and mucositis (35%); only eight (19%) patients developed grade III-IV nephrotoxicity. Ten (23%) of 43 patients experienced fatal complications associated with HD-MTX therapy. Patients with three or more contributory risk factors for delayed MTX elimination had a significantly poorer survival than patients with fewer than three risk factors (hazard ratio, 3.64; confidence interval, 1.14-17.54).

CONCLUSIONS

Glucarpidase is well tolerated and produces a rapid inactivation of substantial amounts of MTX. However, overall results are still unsatisfactory in adult and elderly patients, suggesting that earlier recognition of delayed MTX elimination and more rapid intervention are needed.

To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol.

This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education.

Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue.

Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.

OBJECTIVE

Bevacizumab and chemotherapy is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). So far, no predictive markers have been identified. The aim was to investigate the possible predictive value of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) system in this setting.

METHODS

Pre-treatment blood samples and response evaluations were available from 218 of the 249 included patients. All patients received bevacizumab and chemotherapy comprising fluorouracil and leucovorin or capecitabine combined with either oxaliplatin (FOLFOX or XELOX, n = 183) or irinotecan (FOLFIRI or XELIRI, n = 66). Germline DNA was isolated from whole blood, and five SNPs in the VEGF-A gene, one SNP in the VEGF receptor 1 (VEGFR-1) gene and three SNPs in the VEGFR-2 gene were analysed by polymerase chain reaction. Response was evaluated according to RECIST version 1.0, and the association to genotypes was analysed using Fisher's exact test.

RESULTS

The VEGFR-1 319 C/A SNP was significantly associated with response. Objective response was observed in 36% of the patients with CC genotype, 40% with CA and 56% with AA, p = 0.048. The response rates also differed significantly between patients with C-allele containing genotypes (CC + CA) (39%) and patients homozygous for the A-allele (AA) (56%), p = 0.015. There was no correlation between response rates and the remaining SNPs.

CONCLUSIONS

The VEGFR-1 319 C/A SNP is a potential predictive marker for bevacizumab plus chemotherapy in patients with mCRC. Patients with the A allele appeared to have increased response rates. The results call for validation.

OBJECTIVE

To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC).

METHODS

Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome.

RESULTS

Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P < or = .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061).

CONCLUSIONS

The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.

The spine is the most common site for bone metastases. Radiation therapy is a common treatment for palliation of pain and for prevention or treatment of spinal cord compression. Helical tomotherapy (HT), a new image-guided intensity modulated radiotherapy (IMRT), delivers highly conformal dose distributions and provides an impressive ability to spare adjacent organs at risk, thus increasing the local control of spinal column metastases and decreasing the potential risk of critical organs under treatment. However, there are a lot of non-target organs at risk (OARs) occupied by low dose with underestimate in this modern rotational IMRT treatment. Herein, we report a case of a pathologic compression fracture of the T9 vertebra in a 55-year-old patient with cholangiocarcinoma. The patient underwent HT at a dose of 30 Gy/10 fractions delivered to T8-T10 for symptom relief. Two weeks after the radiotherapy had been completed, the first course of chemotherapy comprising gemcitabine, fluorouracil, and leucovorin was administered. After two weeks of chemotherapy, however, the patient developed progressive dyspnea. A computed tomography scan of the chest revealed an interstitial pattern with traction bronchiectasis, diffuse ground-glass opacities, and cystic change with fibrosis. Acute radiation pneumonitis was diagnosed. Oncologists should be alert to the potential risk of radiation toxicities caused by low dose off-targets and abscopal effects even with highly conformal radiotherapy.

BACKGROUND

Chemotherapy can induce cognitive impairment in cancer patients. The main goal of this longitudinal study was to determine the incidence, characteristics, and duration of cognitive dysfunction in patients treated with adjuvant chemotherapy for colon cancer.

METHODS

We assessed cognitive function, quality of life, anxiety and depression, fatigue, and hemoglobin levels in colon cancer patients at three assessment points: pre-chemotherapy (n=81), post-chemotherapy (n=73), and after 6-month follow-up (n=54). All patients were treated with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) for 6 months.

RESULTS

Thirty patients (37%) had cognitive impairment in the pre-chemotherapy evaluation, mainly in processing speed and psychomotor executive function (Trail Making Test A and B). At the end of treatment, the main domain affected was the verbal memory, with an acute decline detected in 56% of patients. Fifty-four percent of the patients improved their dysfunction after 6 months of follow-up, whereas 18 (33%) of them showed worsening in at least one test. Cognitive impairment was most common in older patients and in those with less years of education. Quality of life, anxiety, depression, fatigue, and hemoglobin did not influence the results of the cognitive tests.

CONCLUSIONS

Adjuvant FOLFOX4 in patients with colon cancer can have a negative effect on verbal memory. This deterioration is usually mild and transient.