We have previously found that conformal radiation therapy (RT) and hepatic arterial fluorodeoxyuridine was associated with durable responses and long-term survival for patients treated for nondiffuse ...primary hepatobiliary tumors and colorectal liver metastases. Further improvements in hepatic control may result from the addition of selective radiosensitization using bromodeoxyuridine (BrdU) infused through the hepatic artery (HA) concurrently with RT. This is a Phase I study of escalating doses of HA BrdU combined with our standard hepatic RT.
Patients with unresectable primary hepatobiliary cancer or colorectal liver metastases were treated with concurrent HA BrdU and conformal RT (1.5 Gy per fraction, twice a day). Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of RT (24, 48, or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. HA BrdU was escalated in standard Phase I fashion with at least three patients receiving each combination of RT dose and BrdU dose. The starting dose of HA BrdU was 10 mg/kg/day, with two potential escalations to a maximum of 25 mg/kg/day (the maximum tolerable dose of HA BrdU when given alone on this same schedule). Grade > or = 3 toxicity was considered dose limiting. Patients receiving 24 Gy had one cycle of HA BrdU, while those receiving either 48 or 66 Gy had two cycles. Patients were followed for toxicity, complications, and response (when evaluable).
A total of 41 patients (18 with colorectal liver metastases, 16 with cholangiocarcinoma and 7 with hepatoma) were treated. Five patients were removed from the protocol (three had HA catheter complications, one developed atrial fibrillation, and one was removed due to recurrent Grade 4 toxicity), although all five are included for toxicity purposes. Dose-limiting toxicity was primarily thrombocytopenia and there was no obvious relationship with the RT dose. Only 2 of 17 cycles given at 25 mg/kg/day had Grade > or = 3 toxicity. Complications developed in four patients, including one patient with radiation-induced liver disease. Response rates were not improved compared to our previous experience.
The appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by this method of BrdU administration. It is anticipated that these, or still newer methods of therapy, can improve treatment results in the near future.
The use of chemotherapy with concurrent radiation therapy remains a standard treatment option for patients with unresectable or resected adenocarcinoma of the pancreas. This treatment strategy is ...based in large part on data from serial Gastrointestinal Tumor Study Group (GITSG) trials, which have included 5-fluorouracil (5-FU). Unfortunately, the majority of patients continue to succumb to the disease process. Recently, there has been a resurgence in clinical trials investigating alternative combined modality treatment strategies for patients with pancreatic cancer. In this review, we will summarize both the mature and more recent data pertaining to combined modality therapy for patients with unresectable or resected pancreatic cancer. Strategies utilizing concurrent gemcitabine, alternative radiation therapy techniques, and/or altered sequencing of therapies will be highlighted. Such modifications to the approach in use since the 1980s will need to be fully considered as clinical trials utilizing chemoradiotherapy regimens and new systemic agents or novel targeted therapies are designed.
Purpose
The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and ...toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS.
Patients and Methods
Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m
2
and either SD ifosfamide (1.5 g/m
2
/d, days 1 through 4) or HD ifosfamide (3.0 g/m
2
, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity.
Results
The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm.
Conclusion
When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.
Combined modality therapy McGinn, C J; Kinsella, T J
Current opinion in oncology,
1991-December, Letnik:
3, Številka:
6
Journal Article
Encouraging results continue to emerge with the use of chemoradiotherapy. This review of the current literature demonstrates some of the advances that have been achieved in a variety of common ...malignancies with strategies based on well-defined rationales. Preliminary randomized trials now reveal a survival advantage for chemoradiotherapy in patients with inoperable non-small cell lung cancer and patients with rectal cancer at high risk for recurrence following resection. Other studies report that concurrent chemoradiotherapy may improve local control in patients with limited-stage, small cell lung cancer or esophageal malignancies. The additional toxicity of these approaches is discussed.
Radiosensitization has previously been demonstrated in a human colon cancer cell line (HT-29) following a 2 h exposure to low, clinically relevant concentrations (0.05-0.5 microM) of ...fluorodeoxyuridine (FdUrd) (15). The sensitizer enhancement ratio value (measured at 10% survival) plateaued at approximately 1.7 between 16 and 32 h following removal of drug. Parallel studies investigating the effect of FdUrd on the distribution of cells throughout the cell cycle found that the percentage of cells in early S-phase increased to approximately 70% during the same period that maximal radiosensitization was noted. As a follow-up to these findings, experiments have been designed to investigate the contribution of this early S-phase delay to radiosensitization.
Synchronized populations of HT-29 cells have been obtained with three separate techniques. Two involve the induction of a reversible metaphase arrest (with high pressure N2O or colcemid) followed by a shakeoff of mitotic cells. The third uses a plant amino acid, mimosine, to induce a reversible block at the G1/S boundary. Flow cytometry was used to analyze the degree of synchrony based on bromodeoxyuridine (BrdUrd) uptake and propidium iodide (PI) staining. Radiation survival curves were obtained on these synchronized populations to investigate changes in radiosensitivity through the cell cycle. Additionally, levels of thymidylate synthase (TS), the primary target of FdUrd cytotoxicity, were measured in each phase of the cell cycle using the TS 106 monoclonal antibody against human TS.
Synchronization with mitotic shakeoff produced relatively pure populations of cells in G1; however, the degree of synchrony in early S-phase was limited both by cells remaining in G1 and by cells progressing into late S-phase. These techniques failed to reveal increased radiosensitivity in early S-phase at 10% survival. An 18 h exposure to mimosine resulted in populations that more closely resembled the early S-phase enrichment following FdUrd exposure and revealed increased radiosensitivity during early S-phase. TS levels were noted to be only 1.3 times higher in S phase than in G0/G1.
Radiation survival data from cells synchronized with mitotic shakeoff techniques suggest that early S-phase delay is unlikely to be the primary mechanism of FdUrd radiosensitization. In contrast, the increased sensitivity seen in early S-phase with mimosine synchronized cells is similar to that seen with FdUrd. Although confounding biochemical pertubations cannot be ruled out, these data continue to suggest an association between early S-phase enrichment and radiosensitization. The significance of TS inhibition as a mechanism of FdUrd radiosensitization remains unclear.
Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that may have a substantial impact on local control following ...conventional radiotherapy. Strategies to improve locoregional control include the use of S-phase-specific radiosensitizers, such as the halogenated pyrimidine analogues (5-iododeoxyuridine, 5-bromodeoxyuridine, fluorodeoxyuridine, 5-fluorouracil) and hydroxyurea. These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization. Although the initial clinical trials with these agents were inconclusive, several recent reports have rekindled interest in these radiosensitizers. Ongoing laboratory research has provided further insight into the basic mechanisms of radiosensitization. However, many questions remain unanswered. We will review the data that suggest rapid tumor proliferation, experimental studies with the S-phase-specific drugs, and the results of clinical trials. We will also consider the possible design of future trials based on our current understanding of tumor proliferation and the mechanisms of radiosensitization of S-phase-specific agents.
Radiation therapy has played a minor role in the conventional management of patients with unresectable primary hepatobiliary malignancies and liver metastases. This can be attributed to normal tissue ...toxicity, which has limited the dose of radiation that can be safely administered, and imaging limitations, which have prevented focal irradiation of involved regions. Trials of whole-liver irradiation with and without 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUdR) suggest that the addition of fluoropyrimidines results in a slight increase in median survival without an increase in radiation-induced liver disease (RILD). The development of three-dimensional radiotherapy techniques has now allowed high-dose focal irradiation to be safely delivered, which, when combined with hepatic arterial FUdR, produces a much higher rate of response and, in some cases, prolonged survival particularly for patients with primary hepatobiliary cancers. Further investigations into the optimal methods of combining the fluoropyrimidines and radiation to permit higher doses of both agents to be delivered as well as methods of protecting the normal liver are expected to yield significant improvement in the outcome of treatment for patients with intrahepatic malignancies.
Evidence for clinically significant radiosensitization by the halogenated pyrimidine 5-iododeoxyuridine (IdUrd) continues
to accumulate. In vitro radiosensitization has been demonstrated in human ...colon tumor cell lines following exposure to 1-10
micrometer. Coadministration of leucovorin (LV) increases radiosensitization, which correlates directly with increased IdUrd
DNA incorporation. Clinical data regarding proliferation rates and thymidine kinase levels in tumors versus normal tissues
suggest selective incorporation of IdUrd into gastrointestinal tumors may occur. The objectives of this Phase I study were:
(a) to assess the feasibility of LV modulation of IdUrd radiosensitization by determining the maximum tolerated dose (MTD)
of IdUrd plus LV; and (b) to perform correlative laboratory studies to investigate the potential of IdUrd plus LV to increase
radiosensitization in vivo. Seventeen patients with unresectable or recurrent gastrointestinal adenocarcinomas received a
14-day course of continuous i.v. infusion of IdUrd prior to initiation of radiotherapy. Two additional 14-day infusions of
IdUrd with LV were given during the course of radiotherapy (60 Gy in 6 weeks). The initial dose of IdUrd was 250 mg/m2/day
and was escalated in subsequent patients to 400 and 600 mg/m2/day. The LV dose remained fixed at 250 mg/m2/day. Leukopenia
was the dose-limiting toxicity, and 400 mg/m2/day was the MTD for this trial. At the MTD, the mean +/- SD steady-state plasma
concentration of IdUrd during the infusion, measured by high-performance liquid chromatography, was 0.66 +/- 0.23 micrometer.
There was no significant influence of LV on IdUrd DNA incorporation in peripheral blood granulocytes as measured by high-performance
liquid chromatography. Based on toxicity data and correlative laboratory studies, a meaningful increase in radiosensitization
would not be achieved with the IdUrd infusion schedule and dose of LV investigated compared with IdUrd alone.
