OBJECTIVE

Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin.

METHODS

Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed.

RESULTS

Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area.

CONCLUSIONS

Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition.

OBJECTIVE

Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome.

METHODS

In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers.

RESULTS

Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade>> or = 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or>> or = 4, the median survival was 24 and 14 months, respectively (P = .17).

CONCLUSIONS

HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.

OBJECTIVE

To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable colorectal liver metastases (CLMs).

METHODS

After resection of their primary tumors, patients with KRAS wild-type synchronous nonresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI [fluorouracil, leucovorin, and irinotecan] or mFOLFOX6 [modified fluorouracil, leucovorin, and oxaliplatin]) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response and survival.

RESULTS

The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0 resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68 patients) in arm B, which were significantly different (P < .01). Patients in arm A had improved objective response rates (57.1% v 29.4%; P < .01), increased 3-year OS rate (41% v 18%; P = .013) and prolonged MST (30.9 v 21.0 months; P = .013) compared with those in arm B. In addition, in arm A, patients who had resection of liver metastases had a significantly improved MST (46.4 v 25.7 months; P < .01) compared with those who did not undergo surgery.

CONCLUSIONS

For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.

OBJECTIVE

In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients.

METHODS

From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year.

RESULTS

After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival.

CONCLUSIONS

The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

OBJECTIVE

Oxaliplatin is active in colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. It may come from an effect on neuronal voltage-gated Na channels, via the liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate chelators.

METHODS

A retrospective cohort of 161 patients treated with oxaliplatin + 5-fluorouracil and leucovorin for advanced colorectal cancer, with three regimens of oxaliplatin (85 mg/m(2)/2w, 100/2w, 130/3w) was identified. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not.

RESULTS

Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group versus 31% in the control group (P = 0.000003). The tumor response rate was similar in both groups. The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7 versus 26%, P = 0.001). Acute symptoms such as distal and lingual paresthesia were much less frequent and severe (P = 10(-7)), and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P = 0.003). Patients with grade 2 and 3 at the end of the treatment in the 85 mg/m(2) oxaliplatin group recovered significantly more rapidly from neuropathy than patients without Ca/Mg.

CONCLUSIONS

Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage.

OBJECTIVE

Selective internal radiation therapy (SIRT) with SIR-Spheres(R) is a new technique for selectively targeting high doses of radiation to tumours within the liver. The primary objectives of this randomised trial were to compare the response rate, time to progressive disease (PD), and toxicity of a regimen of systemic fluorouracil/leucovorin chemotherapy versus the same chemotherapy plus a single administration of SIR-Spheres in patients with advanced colorectal liver metastases. The trial was designed to presage a larger trial that would have survival as the primary outcome.

METHODS

Twenty-one patients with previously untreated advanced colorectal liver metastases, with or without extrahepatic metastases, were randomised into the study.

RESULTS

Using RECIST criteria, the response rate for 11 patients receiving the combination treatment was significantly greater than for 10 patients receiving chemotherapy alone (First Integrated Response; 10 PR, 1 SD vs. 0 PR, 6 SD, 4 PD, P < 0.001 and Best Confirmed Response; 8 PR, 3 SD vs. 0 PR, 6 SD, 4 PD P < 0.001). The time to PD was greater for patients receiving the combination treatment (18.6 months vs. 3.6 months, P < 0.0005). Median survival was significantly longer for patients receiving the combination treatment (29.4 months vs. 12.8 months, P = 0.02). One patient in the combination arm died from chemotherapy induced neutropenic sepsis after the fourth chemotherapy cycle. There were more Grade 3 and 4 toxicity events in patients receiving the combination treatment. There was no difference in quality-of-life over a 3 month period between the two treatments when rated by patients (P = 0.96) or physicians (P = 0.98).

CONCLUSIONS

This small phase 2 randomised trial demonstrated that the addition of a single administration of SIR-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to PD, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit.

OBJECTIVE

To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies.

METHODS

Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) +/- semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU +/- leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%.

RESULTS

Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P <.001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT.

CONCLUSIONS

Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.

Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.

To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.

Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.

Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.

The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.

Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).

Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.

clinicaltrials.gov identifier: NCT00265850.

OBJECTIVE

We tested the hypothesis that polymerase chain reaction (PCR) quantitation of the enzyme thymidylate synthase (TS) within a primary adenocarcinoma of the stomach, has an inverse relationship to response and survival for patients who receive fluorouracil (5FU)-based chemotherapy.

METHODS

Before systemic chemotherapy, the genetic expression of TS (TSmRNA level) was determined using a PCR method. Gene expression was calculated by determining the ratio between the amount of radiolabeled PCR product with the linear amplification range of the TS gene and the beta-actin gene. Chemotherapy consisted of two cycles of protracted infusion (PI) 5FU 200 mg/m2/d administered for 3 weeks with leucovorin 20 mg/m2/w. Cisplatin 100 mg/m2 was administered on day 1.

RESULTS

Sixty-five patients with primary gastric cancer had a median TS mRNA level of 4.6 x 10(-3) (range, 0.9 to 20.1 x 10(-3)). Thirty-five percent of patients had measurable responses in their primary tumors. The mean gastric cancer TSmRNA level in responding and resistant patients is statistically significant (P < .001). The median survival time was 43+ months for treated patients with TSmRNA levels less than the median and 6 months for those with TS m-RNA levels greater than the median (P = .003).

CONCLUSIONS

The genetic expression of TS (TSmRNA level) influences response to 5FU-based chemotherapy and survival for a cohort of patients with primary gastric cancer. Confirmation of these data could lead to therapeutic decisions based on specific molecular properties within a tumor.

OBJECTIVE

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.

METHODS

Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).

RESULTS

Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.

CONCLUSIONS

Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

OBJECTIVE

The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma.

METHODS

Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV.

RESULTS

Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v>> or = 60 years), stage, or number of involved nodes (none v one to three v>> or = four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV.

CONCLUSIONS

UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

OBJECTIVE

Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU.

METHODS

Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient.

RESULTS

TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02).

CONCLUSIONS

For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.

Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP) from 2'-deoxyuridine-5'-monophosphate (dUMP), for which 5,10-methylene-tetrahydrofolate (CH(2)-THF) is the methyl donor. TS is an important target for chemotherapy; it is inhibited by folate and nucleotide analogs, such as by 5-fluoro-dUMP (FdUMP), the active metabolite of 5-fluorouracil (5FU). FdUMP forms a relatively stable ternary complex with TS and CH(2)THF, which is further stabilized by leucovorin (LV). 5FU treatment can induce TS expression, which might bypass dTMP depletion. An improved efficacy of 5FU might be achieved by increasing and prolonging TS inhibition, a prevention of dissociation of the ternary complex, and prevention of TS induction. In a panel of 17 colon cancer cells, including several variants with acquired resistance to 5FU, sensitivity was related to TS levels, but exclusion of the resistant variants abolished this relation. For antifolates, polyglutamylation was more important than the intrinsic TS level. Cells with low p53 levels were more sensitive to 5FU and the antifolate raltitrexed (RTX) than cells with high, mutated p53. Free TS protein down-regulates its own translation, but its transcription is regulated by E2F, a cell cycle checkpoint regulator. Together, this results in low TS levels in stationary phase cells. Although cells with a low TS might theoretically be more sensitive to 5FU, the low proliferation rate prevents induction of DNA damage and 5FU toxicity. TS levels were not related to polymorphisms of the TS promoter. Treatment with 5FU or RTX rapidly induced TS levels two- to five-fold. In animal models, 5FU treatment resulted in TS inhibition followed by a two- to three-fold TS induction. Both LV and a high dose of 5FU not only enhanced TS inhibition, but also prevented TS induction and increased the antitumor effect. In patients, TS levels as determined by enzyme activity assays, immunohistochemistry and mRNA expression, were related to a response to 5FU. 5FU treatment initially decreased TS levels, but this was followed by an induction, as seen with an increased ratio of TS protein over TS-mRNA. The clear retrospective relation between TS levels and response now forms the basis for a prospective study, in which TS levels are measured before treatment in order to determine the treatment protocol.

BACKGROUND

Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy.

OBJECTIVE

We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible.

METHODS

From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size >> 5 cm), multinodular >> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team.

RESULTS

In 151 patients, the size of liver metastases decreased by>> 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61).

CONCLUSIONS

This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

OBJECTIVE

The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation.

METHODS

Patients with resectable T3-4 rectal carcinoma without sphincters' infiltration and with a lesion accessible to digital rectal examination were randomised into: preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation to a total dose of 50.4Gy (1.8Gy per fraction) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4-6 weeks. Surgeons were obliged to base the type of operation on the tumour status at the time of surgery.

RESULTS

Between 1999 and 2002, 316 patients from 19 institutions were enrolled. The sphincter preservation rate was 61% in the 5x5Gy arm and 58% in the radiochemotherapy arm, P = 0.57. The tumour was on average 1.9 cm smaller (P < 0.001) among patients treated with chemoradiation compared with short-term schedule. For patients who underwent sphincter-preserving procedure, the surgeons generally followed the rule of tailoring the resection according to tumour downsizing; the median distal bowel margin was identical (2 cm) for both randomised groups. However, in the chemoradiation group, five patients underwent abdominoperineal resection despite clinical complete response.

CONCLUSIONS

Despite significant downsizing, chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy. The surgeons' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders.

OBJECTIVE

The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials.

METHODS

Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons.

RESULTS

Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms.

CONCLUSIONS

This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.

OBJECTIVE

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC).

METHODS

The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2).

RESULTS

The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.

CONCLUSIONS

Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

OBJECTIVE

To review and assign attribution for the causes of early deaths on two National Cancer Institute-sponsored cooperative group studies involving irinotecan and bolus fluorouracil (5-FU) and leucovorin (IFL).

METHODS

The inpatient, outpatient, and research records of patients treated on Cancer and Leukemia Group B protocol C89803 and on North Center Cancer Treatment Group protocol N9741 were reviewed by a panel of five medical oncologists not directly involved with either study. Each death was categorized as treatment-induced, treatment-exacerbated, or treatment-unrelated.

RESULTS

The records of 44 patients who experienced early deaths on C89803 (21 patients) or N9741 (23 patients) were reviewed. Patients treated with irinotecan plus bolus 5-FU/leucovorin had a three-fold higher rate of treatment-induced or treatment-exacerbated death than patients treated on the other arm(s) of the respective studies. For C89803, these rates were 2.5% (16 of 635) for IFL versus 0.8% (five of 628) for bolus weekly 5-FU and leucovorin. For N9741, these rates were 3.5% (10 of 289) for IFL, 1.1% (three of 277) for oxaliplatin plus bolus and infusional 5-FU and leucovorin, and 1.1% (three of 275) for oxaliplatin plus irinotecan. Multiple gastrointestinal toxicities that often occurred together were characterized into a gastrointestinal syndrome. Sudden, unexpected thromboembolic events were characterized as a vascular syndrome. The majority of deaths in both studies were attributable to one or both of these syndromes.

CONCLUSIONS

Close clinical monitoring, early recognition of toxicities and toxicity syndromes, aggressive therapeutic intervention, and withholding therapy in the presence of unresolved drug-related toxicities is recommended for patients receiving IFL or other intensive chemotherapy regimens.

OBJECTIVE

To compare the use of capecitabine plus oxaliplatin (CAPOX) with infusional fluorouracil (FU)/folinic acid plus oxaliplatin (FUFOX) as first-line therapy for patients with metastatic colorectal cancer (MCRC).

METHODS

A total of 474 patients with MCRC received either CAPOX (capecitabine 1,000 mg/m2 bid, days 1 to 14 plus oxaliplatin 70 mg/m2 days 1 and 8, repeated every 22 days) ) or FUFOX (oxaliplatin 50 mg/m2 followed by leucovorin 500 mg/m2 plus FU 2,000 mg/m2 as a 22-hour infusion days 1, 8, 15, and 22, repeated every 36 days). The primary end point was progression-free survival (PFS). Secondary end points were response rate (RR), overall survival (OS), time to treatment failure, and toxicity. The study was designed to determine noninferiority for the CAPOX regimen.

RESULTS

Median PFS was 7.1 months in the CAPOX arm and 8.0 months in the FUFOX arm (hazard ratio [HR], 1.17; 95% CI, 0.96 to 1.43; P = .117). Median OS was 16.8 months (CAPOX) and 18.8 months (FUFOX; HR, 1.12; 95% CI, 0.92 to 1.38; P = .26). Overall RRs were 48% for CAPOX (95% CI, 41% to 54%) and 54% for FUFOX (95% CI, 47% to 60%). Both regimens were generally well tolerated, although there was a significantly higher incidence of grade 2/3 hand-foot syndrome (HFS) in the CAPOX arm (P = .028).

CONCLUSIONS

CAPOX resulted in a slightly inferior efficacy than FUFOX. With respect to PFS, the best estimate of the HR of 1.17 was within the prespecified equivalence range. However, a relevant inferiority cannot be excluded. Both regimens were generally well tolerated but there was a significantly higher rate of grade 2/3 HFS in the CAPOX arm.

OBJECTIVE

This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer.

METHODS

Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC).

RESULTS

Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively.

CONCLUSIONS

The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.

OBJECTIVE

Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy.

METHODS

Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate.

RESULTS

Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%).

CONCLUSIONS

For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.

OBJECTIVE

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles.

METHODS

Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis.

RESULTS

No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.

CONCLUSIONS

In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.

OBJECTIVE

UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.

METHODS

In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.

RESULTS

UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant.

CONCLUSIONS

The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.