A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma : cancer and Leukemia Group B (CALGB) 80003

BACKGROUND:

The purpose of this study was to assess the efficacy and safety of 5‐fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer.

METHODS:

Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m² 5 days/week) and weekly gemcitabine (200 mg/m²). After a 3‐week break, patients received weekly gemcitabine at 1000 mg/m² for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19‐9 response, overall survival (OS) time to progression (TTP), and toxicity.

RESULTS:

Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow‐up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9‐14.9) and the median TTP was 10 months (95% CI, 6.4‐12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19‐9 at baseline, 29 (52%) had a sustained CA19‐9 response. Overall, 41% of patients had grade 3 or greater treatment‐related gastrointestinal adverse events.

CONCLUSIONS:

The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. Cancer 2011;. © 2010 American Cancer Society.     

A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3‐times‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², administered in 3 doses of 100 mg/m² each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival.

RESULTS:

Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug‐related ≥ grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a 3‐times‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck

BACKGROUND:

Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisp latin and 5‐f luorouracil [5‐FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction na b‐paclitaxel and c etuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.

METHODS:

Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab‐paclitaxel 100 mg/m²/week; cetuximab 250 mg/m²/week; cisplatin 75 mg/m² on day 1; 5‐FU 750 mg/m²/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m² on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.

RESULTS:

Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty‐nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2‐year overall and progression‐free survival rates were 84% and 65%, respectively.

CONCLUSIONS:

Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted. Cancer 2013. © 2012 American Cancer Society.     

Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases

BACKGROUND.

The current study evaluated the effect of bevacizumab added to fluoropyrimidine‐plus‐oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology.

METHODS.

A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated.

RESULTS.

Bevacizumab‐containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX‐only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had <25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P < .01).

CONCLUSIONS.

In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM. Cancer 2007. © 2007 American Cancer Society.     

A phase I and II trial of epirubicin, cisplatin, 24-hour infusion 5 fluorouracil and sodium folinate in patients with advanced esophagogastric carcinomas

Aim: Advanced esophagogastric carcinoma has a poor prognosis. Palliative chemotherapy provides a survival advantage and improved quality of life. Epirubicin, cisplatin and continuous infusional 5‐fluorouracil (5‐FU) (ECF) is a well‐established chemotherapy regimen but a continuous chemotherapy infusion is not always feasible or acceptable. Methods: We conducted a phase I and II trial of a modified version of ECF, utilizing 5‐FU as a 24‐h infusion on day 1 and day 8 of a 21‐day cycle, administered with sodium folinate as a modulator of 5‐FU (ECSF). In the phase I study the dose of 5‐FU was increased in successive cohorts from 1250 mg/m², 1500 mg/m², and 1750 mg/m² to 2000 mg/m² per 24 h. Results: Dose limiting toxicity of febrile neutropenia was encountered at 2000 mg/m. The recommended dose for 5‐FU was 1750 mg/m². Overall 29 patients were treated with ECSF of whom 27 were evaluable for toxicity. The response rate was 45% on an intention‐to‐treat analysis with a complete response rate of 3%. The median response rate was 4.1 months and the median survival was 10.7 months. A total of 23 patients (72%) obtained clinical benefit with improvement in dysphagia or weight gain. central venous catheter (CVC) complications were observed in 12 (41%) patients. Conclusion: ECSF was associated with a response rate and survival similar to that reported with standard ECF. ECSF may provide an alternative regimen to standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient. CVC complications are a limitation.     

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5‐fluorouracil continuous infusion,and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long‐lasting pathological complete response

BACKGROUND:

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5‐fluorouracil (5‐FU) and concomitant radiotherapy (RT) in untreated stage II‐III adenocarcinoma and squamous cell carcinoma of mid‐distal thoracic esophagus.

METHODS:

The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m² and cisplatin 25 mg/m² on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5‐FU c.i. (180 mg/m² on days 1‐21 and 150 mg/m² on days 29‐63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation.

RESULTS:

A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3‐4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow‐up was 55 months (range, 3‐108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3‐ and 5‐year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001).

CONCLUSIONS:

This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long‐term durable survival rates. Cancer 2013. © 2012 American Cancer Society.     

A phase 2 study of a fixed combination of uracil and ftorafur and leucovorin given orally in a twice‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS).

RESULTS:

Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug‐related ≥ grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a twice‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

Radioguided occult lesion localisation (ROLL) in breast-conserving surgery after neoadjuvant chemotherapy

Background

An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with ^99mTechnetium (ROLL-^99mTc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique.

Methods

A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-^99mTc technique afterwards. The status of the margins and the weight of the resected specimen were assessed.

Results

The median weight of the resected specimen in these 83 patients was 53 g (range: 11–204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld.

Conclusion

The ROLL-^99mTc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients.     

Phase 2 study of preoperative radiation with concurrent capecitabine,oxaliplatin, and bevacizumab followed by surgery and postoperative 5‐fluorouracil,leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: ECOG 3204

BACKGROUND:

Recent studies have demonstrated the feasibility of combining oxaliplatin with 5‐fluorouracil (5‐FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5‐FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer.

METHODS:

Fifty‐seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m² twice daily from Monday to Friday), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles.

RESULTS:

Fifty‐four of 57 enrolled patients were eligible. Forty‐nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%‐27%) achieved pathologic complete response. Thirty‐two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty‐seven percent of patients who underwent surgery experienced a surgical complication.

CONCLUSIONS:

The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound‐healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long‐term morbidity and efficacy of this combined modality approach. Cancer 2013. © 2012 American Cancer Society.     

Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma

BACKGROUND.

Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5‐FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5‐FU provided any benefit in the treatment of patients with metastatic SBA.

METHODS.

The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression‐free survival (PFS), and overall survival (OS) were compared between patients who received 5‐FU and a platinum compound and patients who received other chemotherapy combinations.

RESULTS.

The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5‐FU and a platinum compound, 41 patients (51%) received 5‐FU without a platinum compound, and 10 patients (13%) received non‐5‐FU–based treatment. Compared with other chemotherapy regimens, treatment with 5‐FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P ≤ .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5‐FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3‐15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29‐0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37‐1.07; P = .08).

CONCLUSIONS.

To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5‐FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted. Cancer 2008. © 2008 American Cancer Society.     

Technetium-99m methoxyisobutylisonitrile chest imaging for small-cell lung cancer

Aims:This is a retrospective and adaptive randomizationstudy. The purpose of this study was to evaluate the relationshipbetween technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI)chest-imaging results, chemotherapy response and P-glycoprotein (Pgp) ormultidrug resistance related protein (MRP) expression in small-cell lungcancer (SCLC). Patients and methods:Beforechemotherapy, 30 patients (11 females, 19 males, ages: 52–69years) with SCLC, including 14 extensive diseases without localizedproblems and 16 limited diseases in excess of solitary pulmonary nodule,underwent early chest imaging, including visual interpretation andquantitative analyses of tumor uptake ratio (TUR), 10 minutes afterintravenous injection of Tc-99m MIBI. Immunohistochemical analyses wereperformed, using multiple nonconsecutive sections of the biopsyspecimens, to detect Pgp and MRP expressions. Chemotherapy response wasevaluated in the third month after completion of treatment by clinicaland radiological methods. Results:All 15 (100%)of the SCLC patients with complete or partial response had positiveTc-99m MIBI chest SPECT results, but negative ones for both Pgp and MRPexpression. Twelve of the 15 (80%) SCLC patients with no responseor progressive disease had negative Tc-99m MIBI chest SPECT results andwere positive for either Pgp or MRP expression(P < 0.05). Negative Tc-99m MIBI chest SPECTresults predicted complete or partial response. The TUR of patients withcomplete or partial response (1.91 ± 0.29 with a 95%confidence interval (95% CI): 1.75–2.07) was significantlyhigher than that of patients with no response or progressive disease(1.19 ± 0.28 with a 95% CI: 1.04–1.35). Conclusion:Tc-99m MIBI chest images are a potential toolfor understanding Pgp and MRP expressions in SCLC and for predictingpatient chemotherapy response.     

Concurrent chemoradiation followed by adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma in Korea

Purpose

Concomitant approach using cisplatin and 5-fluorouracil (5-FU) has shown an excellent local control rate and significantly reduced distant metastasis in patients with locally advanced nasopharyngeal carcinoma (NPC). However, optimal schedule and dosing of chemotherapy still need to be developed to reduce distant metastasis. This retrospective study was conducted to evaluate the efficacy, toxicity, and tolerability of a concurrent chemoradiation therapy (CCRT) regimen using cisplatin and 5-FU followed by adjuvant chemotherapy (AC) in patients with locoregioanlly advanced NPC.

Methods

Forty-three NPC patients who had AJCC stage T3/T4 or N2/N3 and M0 disease were evaluated. The chemotherapy during CCRT consisted of cisplatin (75 mg/m² on day 1) plus 5-FU (750 mg/m²/day on day 1–5), delivered every 4 weeks for two cycles. Three cycles of AC were given with cisplatin (75 mg/m²), epirubicin (37.5 mg/m²) on day 1, and bleomycin (7.5 mg/m² bolus iv. on day 1 followed by 9 mg/m² on day 1–5 by continuous infusion) every 3 weeks.

Results

The overall response rate after CCRT was 95% (22 CRs and 19 PRs in 43) and 100% (16 CRs and 8 PRs in 24) after AC. Grade 3/4 neutropenia, mucositis, and weight loss were observed during CCRT phase in 18, 44, and 26% of patients, respectively. AC caused grade 3/4 neutropenia and emesis in 12.5 and 20.8% of patients, respectively.

Conclusions

CCRT regimen using cisplatin and 5-FU followed by three cycles of BEC chemotherapy was effective in locally advanced NPC patients, with acceptable and reversible acute toxicities.     

Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

The sodium/iodide symporter (NIS) is involved in iodide uptake and has been used for the diagnosis and treatment of thyroid cancer. Transfection of the NIS gene in A549 human lung cancer cells can induce radioactive iodine (¹³¹I) and radioactive technetium (^99mTc) uptake. The aim of the present study was to assess the role of NIS in ^99mTc and ¹³¹I uptake by the A549/DDP human cisplatin-resistant lung cancer cell line. To do so, recombinant adenovirus, adenovirus-enhanced green fluorescent protein-human NIS (Ad-eGFP-hNIS) and Ad-eGFP-rat NIS (Ad-eGFP-rNIS) vectors were established. These vectors were transfected into A549/DDP cells and xenograft tumors in nude mice. Assessment of ^99mTc and ¹³¹I uptake was performed. Results showed that the transfection efficiency of Ad-eGFP-hNIS and Ad-eGFP-rNIS in A549/DDP cells was at least 90 % in all experiments, and that the uptake ability of ^99mTc and ¹³¹I was highly enhanced (14–18 folds for ^99mTc, and 12–16 folds for ¹³¹I). However, the radionuclide concentration in transfected NIS genes’ A549/DDP cells reached a plateau within 30–60 min, indicating that NIS transport led rapidly to ^99mTc and ¹³¹I saturation in cells. In xenograft tumor models, uptake of ^99mTcO₄ ^? was obviously higher in the hNIS and rNIS groups compared with controls. In conclusion, these results support the hypothesis that A549/DDP cells can effectively uptake ^99mTc and ¹³¹I when transfected with the hNIS and rNIS gene. The rNIS or hNIS gene could be used as an effective method for the effective delivery of radioactive products to specific tissues for imagery and/or treatment.     

The cisplatin,epirubicin, 5‐fluorouracil,gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma

BACKGROUND:

Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5‐fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA.

METHODS:

PEFG (cisplatin 40 mg/m² and epirubicin 40 mg/m² on Day 1; gemcitabine 600 mg/m² on Days 1 and 8; and 5‐fluorouracil [FU] 200 mg/m² daily as a continuous infusion) was administered to chemotherapy‐naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged ≤75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment.

RESULTS:

Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1‐year OS rate was 52%. The median progression‐free survival (PFS) was 7.9 months, and the 6‐month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles.

CONCLUSIONS:

The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA. Cancer 2010. © 2010 American Cancer Society.     

Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer

Purpose

This study sought to determine the feasibility and safety of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) triple combination chemotherapy (TPF) followed by concurrent chemoradiotherapy (CCRT) for locoregionally advanced nasopharyngeal cancer (NPC).

Methods

Patients with advanced NPC were treated with three cycles of induction chemotherapy. Docetaxel (70 mg/m²) and cisplatin (75 mg/m²) were given on day 1, followed by 5-FU (1,000 mg/m²) as a continuous infusion for 4 days. After induction chemotherapy, cisplatin was given at a dose of 100 mg/m² every 3 weeks with radiotherapy.

Results

Thirty-three patients were enrolled; all patients were stage III (n = 4, 12.1%) or IV (n = 29, 87.9%). Among the patients, 32 patients completed both induction TPF therapy and CCRT, with responses as follows: five patients (15.2%) achieved a complete response (CR), and 27 patients (81.8%) a partial response (PR). At 6 weeks after CCRT, 23 patients (69.7%) had a CR and 9 patients (27.3%) a PR. The 3-year progression-free survival was 75.6% and the 3-year overall survival was 86.1%. Neutropenia (72.7%), febrile neutropenia (9.1%), and nausea (9.1%) were the most severe toxicities (grade 3–4) during induction chemotherapy, and mucositis (39.4%), fatigue (15.2%), and nausea (9.1%) were the most common toxicities (grade 3–4) during CCRT.

Conclusions

Although most patients had stage IV NPC, the TPF induction chemotherapy followed by CCRT showed promising activity with manageable toxicity. These results demonstrated the possibility of effective treatment with the aim of not only a palliative, but also a curative, approach to the treatment of advanced NPC.     

Using technetium-99m methoxyisobutylisonitrile lung single-photon-emission computed tomography to predict response to chemotherapy and compare with p-glycoprotein expression in patients with untreted small cell lung cancer

The purpose of this study was to predict chemotherapy response by technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) lung single-photon-emission computed tomography (SPECT) and compare P-glycoprotein (Pgp) expression in patients with untreated small cell lung cancer (SCLC). Before chemotherapy, 40 patients with untreated SCLC underwent Tc-99m MIBI lung SPECT. Immunohistochemical analyses were performed using multiple nonconsecutive sections of the biopsy specimens to detect Pgp expression. Chemotherapy response was evaluated in the third month after completion of treatment by clinical and radiological methods. Based on quantitative analyses, the tumor uptake ratios (TUR) of the 20 patients with good response (1.89 +/- 0.28) were significantly higher than that of the 20 patients with poor response (1.21 +/- 0.28) (p value < 0.05). Based on visual interpretation, all of the 20 patients (100%) with good response had positive Tc-99m TF lung SPECT findings and negative Pgp expression. Five of the other 20 patients (25%) with poor response had positive Tc-99m MIBI lung SPECT findings, and 12 of the other 20 patients (60%) with poor response had negative Pgp expression (p value < 0.05). Negative Tc-99m MIBI lung SPECT findings could predict poor response. Therefore, we concluded that Tc-99m MIBI lung SPECT can accurately predict the chemotherapy response, and Tc-99m MIBI lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.     

Sequential chemoradiotherapy with gemcitabine and cisplatin for locoregionally advanced nasopharyngeal carcinoma

We investigated a new chemoradiotherapy (CRT) regimen for locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 240 patients were randomly assigned to three different CRT regimens: sequential CRT [1 cycle chemotherapy + Phase I radiotherapy (RT) + 1 cycle chemotherapy + Phase II RT + 2 cycles chemotherapy] with a cisplatin–gemcitabine (GC) regimen (800 mg/m² gemcitabine on Days 1 and 8 and 20 mg/m² cisplatin on Days 1–5, every 4 weeks) (sGC‐RT); sequential chemoradiotherapy with a cisplatin–fluorouracil (PF) regimen (20 mg/m² DDP and 500 mg/m² 5‐FU on Days 1–5, every 4 weeks) (sPF‐RT) and cisplatin‐based concurrent chemoradiotherapy plus adjuvant PF chemotherapy (Con‐RT + PF). The complete response rate was higher in the sGC + RT group than in the other two groups (98.75% vs. 92.50%, p < 0.01). The 3‐year overall survival (OS), disease‐free survival (DFS) and distant metastasis‐free survival (DMFS) rates in the sGC‐RT group were significantly higher than those observed in the Con‐RT group (OS, 95.0% vs. 76.3%, p < 0.001; DFS, 89.9% vs. 67.5%, p < 0.001; DMFS, 92.5% vs. 76.0%, p = 0.004) and in the sPF + RT group (OS, 95.0% vs. 73.6%, p < 0.001; DFS, 89.9% vs. 63.3%, p < 0.001; DMFS, 92.5% vs. 74.7%, p = 0.002). There were no significant differences in 3‐year OS, DFS and MFS rates between the Con‐RT and the sPF‐RT groups. The GC‐RT group experienced more hematologic toxicity, constipation and rash; however, there were no differences in late RT toxicity between the groups. These results demonstrate that a sGC‐RT regimen is effective and well tolerated in patients with locoregionally advanced NPC.     

Relationship of cell proliferation (Ki-67) to 99mTc-(V)DMSA uptake in breast cancer

Introduction

The aim of the present study was to identify the relationships between the uptake of radiotracers – namely pentavalent dimercaptosuccinic acid [(V)DMSA] and sestamibi (MIBI) – and the following parameters in primary breast cancer: steroid receptor concentrations (i.e. estrogen receptor [ER] and progesterone receptor [PR]), Ki-67 expression, tumor size, tumor grade, age, and levels of expression of p53 and c-erbB-2. In addition, by multivariate regression analysis, we further isolated those factors with independent associations with (V)DMSA and/or MIBI uptake in primary breast cancer.

Methods

Thirty-four patients with histologically confirmed breast carcinoma underwent preoperative scintimammography with technetium-99m (^99mTc)-(V)DMSA and/or ^99mTc-MIBI in consecutive sessions 10 and 60 min after administration of 925–1110 MBq of each radiotracer. The tumor-to-background ratio was calculated and correlated with the presence of ER, PR, Ki-67, tumor size, tumor grade, p53, and c-erbB-2. ER, PR, p53, and c-erbB-2 were determined immunohistochemically. The analysis included tumor-to-background ratio of (V)DMSA and MIBI uptake as dependent and all of the other parameters as independent variables.

Results

Correlation was positive between Ki-67 and (V)DMSA (r = 0.37 at 10 min, P = 0.038; r = 0.42 at 60 min, P = 0.018) and inverse between PR and (V)DMSA uptake (r = -0.46 at 10 min, P = 0.010; r = -0.51 at 60 min, P = 0.003). Multivariate regression analysis demonstrated a positive correlation between Ki-67 and (V)DMSA at 60 min (P = 0.045). Ki-67 was not significantly correlated with MIBI uptake, whereas tumor size was positively correlated with MIBI uptake at 60 min both in univariate (r = 0.45, P = 0.027) and multivariate analysis (P = 0.024). Negative correlations were observed between (V)DMSA uptake and ER, as well as between ER/PR and MIBI uptake, but these were not significant.

Conclusion

Ki-67 appears to represent the major independent factor affecting (V)DMSA uptake in breast cancer. Tumor size was the only independent parameter influencing MIBI uptake in breast cancer. (V)DMSA appears to have an advantage over MIBI in that it can be used to visualize tumors with intense proliferative activity, and thus it can identify those tumors that are more aggressive.     

Experience with combination of docetaxel, cisplatin plus 5-fluorouracil chemotherapy, and intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma

Background

Our aim was to evaluate the efficacy and toxicity of cisplatin, fluorouracil, and docetaxel chemotherapy plus intensity-modulated radiotherapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC).

Methods

Sixty patients with locoregionally advanced NPC were enrolled. Patients received IMRT plus three courses of neoadjuvant chemotherapy and two courses of adjuvant chemotherapy consisting of docetaxel (60 mg/m²/day on day 1), cisplatin (25 mg/m²/day on days 1–3), and 5-fluorouracil (500 mg/m²/day on days 1–3).

Results

The overall response rate to neoadjuvant chemotherapy was 89 %. Three months after the completion of radiotherapy, 53 (93 %) patients achieved complete regression, 3 (5 %) achieved partial response (PR), and 1 experienced liver metastasis. However, among the 3 PR patients, 2 patients had no evidence of relapse in the follow-up. With a median follow-up of 27 months (range, 6–43), the 2-year estimated locoregional failure-free survival, distant failure-free survival, progression-free survival, and overall survival were 96.6, 93.3, 89.9, and 98.3 %, respectively. Leukopenia was the main adverse effect in chemotherapy; 14 patients experienced grade 3 or grade 4 neutropenia, and 1 patient developed febrile neutropenia. The nonhematological adverse events included alopecia, nausea, vomiting, anorexia, and diarrhea. The incidence of grade 3 acute radiotherapy-related mucositis was 28.3 %; no grade 4 acute mucositis was observed. No grade 3 or grade 4 hematological toxicity occurred during radiotherapy. None of the patients had interrupted radiotherapy. The common late adverse effects included xerostomia and hearing impairment.

Conclusions

Neoadjuvant–adjuvant chemotherapy using cisplatin, fluorouracil, plus docetaxel combined with IMRT was an effective and well-tolerated alternative for advanced NPC.     

Efficacy of sequential methotrexate and 5-fluorouracil (MTX/5FU) in improving oral intake in patients with advanced gastric cancer with severe peritoneal dissemination

Background

Although peritoneal dissemination of gastric cancer is common and often causes deterioration of the patient’s condition and quality of life (QOL), these patients are usually excluded from clinical trials. We retrospectively investigated the clinical benefit and toxicity of sequential methotrexate and 5-fluorouracil (MTX/5FU) therapy for patients with peritoneal dissemination.

Methods

The subjects were 31 patients with severe peritoneal dissemination of gastric cancer who were treated with MTX/5FU. The treatment schedule comprised weekly administration of MTX (100 mg/m²) followed by 5FU (600 mg/m²). Leucovorin (10 mg/m²) was administered six times, every 6 h, starting 24 h after MTX administration.

Results

The median survival time was 255 days, and the median progression-free survival was 127 days. Of the 21 patients with measurable lesions, 4 (19%) patients achieved a partial response. Ascites volume decreased markedly in 14 (54%) of the 26 patients with ascites. Seventeen patients had adequate oral intake, but the other 14 patients had required nutritional support before treatment. The median dripinfusion free survival was 100 days in the former 17 patients, and oral intake improved in 3 (21%) of the latter 14 patients. Grade 3 or 4 neutropenia was observed in 26% of the patients and anemia was observed in 45%. The grade 3 nonhematological toxicities were vomiting (6%) and fatigue (10%). Early death, within 30 days of the last administration of MTX/5FU, occurred due to disease progression in 2 patients, but there were no treatment-related deaths.

Conclusion

MTX/5FU chemotherapy may be effective in treating peritoneal dissemination of gastric cancer and might improve the patient’s condition in terms of reducing ascites and improving oral intake.