|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Bromodeoxyuridine Alternating With Radiation for Advanced Uterine Cervix Cancer: A Phase I and Drug Incorporation StudyFrom the Departments of Radiation Oncology, Obstetrics-Gynecology, and Pathology, University of Michigan, Ann Arbor, MI. Address reprint requests to Avraham Eisbruch, MD, Department of Radiation Oncology, University of Michigan Hospitals, Ann Arbor MI 48109; Email eisbruch{at}umich.edu
PURPOSE: Preclinical studies show a significant increase in the ratio of the radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during drug infusion. We constructed a phase I study in patients with locally advanced cervix cancer, using alternating cycles of BUdR and radiation therapy (RT). PATIENTS AND METHODS: Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followed by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After three cycles, additional BUdR was infused, followed by brachytherapy. The fraction of thymidine replaced by BUdR and the fraction of cells incorporating BUdR were determined in rectal mucosa and tumor biopsies at the end of the first BUdR infusion (day 5), at the middle of the first RT week (day 10), and at the time of brachytherapy. RESULTS: Dose-limiting toxicity was observed in one of 16 patients receiving 1,000 mg/m2/d x 4 days and inboth patients receiving 1,333 mg/m2/d x 4 days each cycle. After a median follow-up of 39 months, 12 patients (66%) were free of pelvic disease and nine (50%) were alive and disease free. The ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did not differ significantly between day 5 and day 10. A trend toward reduced ratio was observed at brachytherapy. Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface. CONCLUSION: In this schedule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR. BUdR incorporation levels in tumors were consistent with clinically significant radiosensitization. The migration of BUdR-containing rectal mucosa cells from the crypts to the surface at the time of RT suggests that this regimen may offer a relative sparing of the mucosa from radiosensitization.
THE STANDARD THERAPY for locally advanced uterine cervix cancer is radiation, which confers generally poor locoregional control and survival. The 5-year survival rates, according to International Federation of Gynecology and Obstetrics stages, range from 60% to 70% in stage IIB to 30% to 45% in stage IIIB and 15% to 20% in stage IVA when patients are treated with radiotherapy (RT) alone.1,2 Persistent or recurrent pelvic disease remains the most significant obstacle to survival, with about one third to two thirds of treatment failures occurring within the irradiated fields.2-4 Attempts at improving local control and survival have included the administration of preirradiation chemotherapy. This may induce substantial tumor regression, but most randomized studies have not shown improvement of local control or survival compared with radiation alone.5,6 Another approach is to use concurrent irradiation and chemotherapy agents known to have radiation-sensitizing capabilities (eg, hydroxyurea or cisplatin). This approach has recently demonstrated potential improvement in tumor control and survival.7,8 A disadvantage of most of the strategies aiming at radiosensitization is lack of selectivity in the enhancement of the radiation effect. Normal tissues that contain rapidly proliferating stem cells, eg, bowel mucosa and hematopoietic tissue, may be affected by the combined radiation and sensitizing drugs to a similar extent as the tumor. This may increase the risk and severity of acute side effects, limit the dose and schedule of drug administration, or require significant radiotherapy treatment delays.9,10 It is possible that further gains could be achieved if the therapeutic index of tumor to normal tissue sensitization could be improved. One strategy aiming to improve the therapeutic index of radiosensitization is to optimize the schedule of drug and radiation delivery. The thymidine analogs are promising in this regard. Two of them, iododeoxyuridine (IUdR) and bromodeoxyuridine (BUdR), have long been known to be among the most effective radiation sensitizers. They produce radiosensitization by incorporation into DNA, increasing the susceptibility of DNA to double-strand breaks from radiation-produced free radicals.11 Trials combining concurrent BUdR or IUdR and radiation have demonstrated a high response rate, but at the expense of increased toxicity affecting rapidly proliferating tissue.12 Therefore, their clinical application has been limited to tumors that proliferate rapidly compared with the surrounding normal tissue (eg, brain tumors and hepatic malignancies).11 We wished to develop a treatment strategy applicable to cervix cancer, bearing in mind that in this cancer the surrounding normal tissues (small bowel mucosa, rectal mucosa, and pelvic bone marrow) proliferate rapidly compared with the tumor. We have previously shown that during the infusion of BUdR to athymic mice bearing tumors, the incorporation of drug into the bone marrow and intestine was higher than its incorporation into the tumor.13 This phenomenon may increase substantially the potential toxicity of a regimen that delivers concurrent abdominal or pelvic irradiation and halogenated pyrimidines. However, the fraction of thymidine replaced by BUdR in tumors might exceed that of highly proliferative normal tissue after discontinuation of the infusion. This would occur if the normal tissue continued to proliferate more rapidly than the tumor, since the fraction of thymidine replaced by BUdR would be decreased by newly incorporated thymidine. To test this hypothesis, we infused athymic mice bearing human tumor xenografts with BUdR and measured incorporation in the tumor and in normal tissue up to 7 days after the infusion was discontinued. We found a significant increase in BUdR in the tumor compared with the bone marrow and intestine during the drug elimination period.14 These findings were in agreement with earlier, less quantitative preclinical studies with IUdR.15,16 They suggest that when the radiation dose–limiting organ, such as the intestinal mucosa and bone marrow, is rapidly proliferating, delivery of radiation during the drug elimination period might improve the therapeutic index of the combined regimen. On the basis of these preclinical data, we constructed a phase I clinical trial for advanced cervix cancer using cycles of continuous infusion BUdR alternating with radiation. In each cycle, radiation started 3 days after the completion of drug infusion. The total dose and duration of the radiation regimen were planned to be comparable to standard curative radiation. The primary goal of this trial was to find the maximum-tolerated dose of BUdR administered in this schedule. We also asked patients to undergo biopsies of the tumor and rectal mucosa at the end of drug infusion, midway through the first week of radiation, and at the time of brachytherapy (near the completion of treatment). The goal of these biopsies was to assess whether our strategy was producing a pattern of incorporation which suggested that we were achieving selective sensitization of tumors compared with normal tissue.
Patients were eligible for this study if they had stage IIB to IVA or recurrent carcinoma of the cervix confined to the pelvis according to clinical staging; Karnofsky status of at least 60; adequate bone marrow (granulocyte count > 1,500/µL and platelet count > 100,000/µL), renal function (serum creatinine < 2.0 mg/dL), and hepatic function (serum bilirubin < 1.5 mg/dL); and no prior history of pelvic irradiation. Pretreatment evaluation included history and physical examination, including cystoscopy and proctoscopy, routine laboratory studies, chest radiograph, intravenous pyelogram, lymphangiogram, and pelvic and abdominal computed tomographic (CT) scans. Patients with clinical or radiologic findings suggesting para-aortic lymph node or distant metastases were excluded. Clinical stage was assigned according to the International Federation of Gynecology and Obstetrics criteria. All patients signed an informed consent approved by the University of Michigan Institutional Review Board. Patients also signed a separate informed consent for biopsies; refusal to undergo biopsies did not exclude patients from the clinical study.
Treatment
External RT was delivered on weeks 2, 4, and 6 (Fig 1), Monday through Friday, starting 3 days after the completion of BUdR infusion in the preceding week. Radiation doses of 1.5 Gy per fraction were delivered twice daily, at least 6 hours apart, 15 Gy per week up to a total of 45 Gy over 5 elapsed weeks. Radiation was delivered using high-energy (10 to 15 MV) photons. In the initial five patients, a four-fields ("box") technique that encompassed the pelvis was used, including the external and common iliac nodes (the cephalad border was set at the L4–5 interspace; it was set higher to include distal para-aortic lymph nodes if common iliac adenopathy was clinically suspected). The lateral fields bisected the sacrum without an attempt to spare the posterior rectal wall. The caudal field borders were set at least 4 cm distal to the palpable cervix or tumor (Fig 2). In the 13 patients treated subsequently, an effort was made to exclude the iliac wings from the radiation fields to reduce bone marrow suppression. In these patients, the cephalad borders of the four pelvic fields were set at the bottom of the sacroiliac joints. To these borders, anterior and posterior fields were abutted, encompassing the common iliac nodes but excluding the iliac wings (the fields were nondivergent at the abutment lines, using asymmetric jaws) (Fig 2). This fields arrangement spared the iliac crest from irradiation by the lateral pelvic fields but delivered adequate irradiation to the pelvic lymph nodes at risk. Small bowel contrast medium, prone treatment position, and false tabletop were used to maximize sparing of the bowel.
On week 8, a brachytherapy boost was planned to be performed 4 to 5 days after the completion of the fourth (last) BUdR infusion. In 12 patients, brachytherapy consisted of an intracavitary implant using Fletcher-Suit applicators, repeated 10 to 14 days later with a second intracavitary implant. Radiotherapy doses in these implants were prescribed to "point A," according to standard guidelines, taking into account established limits on rectal and bladder doses.17 The prescribed dose was in most cases 85 Gy to point A and 50 to 65 Gy to point B, depending on disease extension to the parametria or pelvic lymphadenopathy. In cases with suboptimal anatomy or very large tumors in which intracavitary implants were judged at the completion of external RT to be inadequate, a CT-guided interstitial implant was performed. Radiation dose was prescribed in these cases to the periphery of the gross target volume. Details of the interstitial implant techniques have been reported elsewhere.18 Patients with pelvic lymphadenopathy or parametrial disease extending to the pelvic side wall received an additional pelvic side wall external RT boost after brachytherapy. Toxicity grade 3 or 4, using Gynecologic Oncology Group criteria, was considered dose limiting. Exceptions were transient grade 3 skin toxicity, grade 3 nausea/vomiting (significant nausea not requiring parenteral support) that responded to medication, grade 3 hematologic toxicity (WBC count 1,000 to 1,900/mm2, platelets 25,000 to 50,000/mm2, or hemoglobin 6.5 to 7.9/dL) persisting for no more than 4 days, or asymptomatic grade 3 hepatic toxicity that returned to the normal range within 1 month after the completion of therapy. The starting dose of BUdR was 1,000 mg/m2/d with a planned escalation to 1,333 mg/m2/d, or de-escalation to 800 mg/m2/d if dose-limiting toxicity (DLT) occurred. Doses were not escalated in the same patient. A minimum of three patients were planned to be treated at each dose level; if DLT was encountered in one in a group of three patients, the subsequent group would be treated at the same dose. If DLT was encountered in more than one of three patients at any dose level, the subsequent group would be treated at the next lower dose level. The maximum-tolerated dose was defined as the dose level immediately below that at which two or more patients out of six at a particular dose level developed DLT. In patients experiencing DLT, BUdR was held until toxicity resolved to grade 1 or lower, then reinstituted at the next lower dose level if reinstitution was judged to be medically appropriate. We did not plan to modify drug dose or schedule for grade 3 elevation of transaminases, based on our previous experience that such elevations are transient and asymptomatic. Radiation dose and schedule were not planned to be modified unless clinically indicated. Patients were assessed for toxicity at least once a week during therapy with physical examination, complete blood count, and liver function tests. Patients were seen at monthly intervals after treatment for 3 months and then every 3 months. Posttherapy evaluations included routine cervical cytology. Locoregional response was recorded on the basis of visible and palpable disease, and complete response was defined as complete disappearance of disease for at least 3 months as well as negative cervical cytology.
Drug Incorporation Studies The labeling index was assessed using immunohistochemistry as described previously.20 Briefly, the biopsy tissue was fixed in 70% ethanol, dehydrated, and embedded in paraffin. Deparaffinized microtome sections were then treated with HCl and Triton X-100, boiled for 10 minutes, and then exposed to the primary antibody (B44 mouse anti-BUdR antibody) and the anti-mouse immunoglobulin G secondary antibody, which is coupled to peroxidase. Sections were treated with diaminobenzidine and hydrogen peroxide and counterstained lightly with hematoxylin. The labeling index in the tumor or rectal mucosa biopsy specimens was scored as the fraction of tumor cell or mucosa cell nuclei, respectively, that stained positive for BUdR (minimum of 1,000 nuclei in 10 random fields scored for each determination).
Statistical Analysis
Eighteen patients were accrued between June 1992 and October 1997. Patient and tumor characteristics are listed in Table 1. All patients with stage IIIB tumors had parametrial extension to the pelvic side wall (two had bilateral involvement); four of these patients also had hydronephrosis. One of the patients had bilateral hydronephrosis and compromised renal function, which improved after percutaneous nephrostomy. Both patients with stage IVA disease had biopsy-proven involvement of the bladder mucosa with tumor. Four patients (three with stage IIIB and one with stage IVA) had evidence of pelvic lymph node metastases according to lymphangiography and CT.
All patients received 45 Gy to the pelvis over 5 elapsed weeks except for three patients who had an extension of the treatment course by 1 week. The reasons for extension were grade 3 transient neutropenia, nausea, and diarrhea, each in one patient. Ten patients had intracavitary brachytherapy, consisting of two insertions of Fletcher-Suit applicators. The median cumulative point A dose (external and brachytherapy) in these patients was 85 Gy (range, 76 to 87 Gy). An additional patient received only one of the two planned insertions owing to thrombocytopenia after the last BUdR course. Five patients had an interstitial implant. The median cumulative minimal target dose in these patients was 80 Gy (range, 75 to 80 Gy). One patient had an intracavitary implant followed by an interstitial implant. One patient had a large tumor that precluded any brachytherapy. She received an additional week of twice daily external RT boost, preceded by BUdR infusion, to a total tumor dose of 60 Gy. The total course of radiation, external and brachytherapy, lasted from 6 to 9 weeks (median, 8 weeks). Sixteen patients were treated at a BUdR dose level of 1,000 mg/m2/d. Eleven of these patients received all four planned drug cycles. Four patients received one to three cycles of 1,000 mg/m2/d followed by cycles of reduced dose (800 mg/m2/d) because of hematologic toxicity. One patient received the full dose for two cycles, after which BUdR was not resumed, owing to DLT (skin toxicity). The median total BUdR dose delivered was 16,000 mg/m2 (range, 8,000 to 16,000; the intended total dose was 16,000 mg/m2). Three patients received doses of 50%, 85%, or 95%, and two patients received 90% of the intended total dose; the rest of the patients received all of the intended dose. Two patients were assigned to the dose level of 1,333 mg/m2/d. One received three cycles, and one received two cycles. Hematologic and gastrointestinal toxicity precluded the completion of BUdR cycles in both patients. All patients were assessable for toxicity and response, and no patient was lost to follow-up. Hematologic toxicity is summarized in Table 2. Among five initial patients receiving BUdR 1,000 mg/m2/d and four-field pelvic RT, one patient had grade 4 WBC toxicity (nadir, 900/µL) and neutropenic sepsis. The rest had grade 1 or 2 WBC toxicity. In this group, two patients had platelet toxicity grade 3 (nadirs, 36,000/µL and 48,000/µL). Eleven additional patients received the same BUdR dose and a modification in the radiation fields that excluded the iliac crests from the lateral fields (see Patients and Methods). No hematologic DLT was observed in these patients; the range of nadir platelet counts was 80,000 to 160,000/µL (median, 122,000/µL), and the range of WBC nadir counts was 1,300 to 3,800/µL (median, 2,200/µL). Three patients receiving 1,000 mg/m2/d required two to three units of packed RBC transfusions during the treatment course.
Dose-limiting hematologic toxicity (nadir platelet count, 10,000/µL) was observed in one of two patients receiving the higher BUdR dose level (1,333 mg/m2/d), despite using modified RT fields. This patient required multiple platelet and RBC transfusions. Nonhematologic toxicity in most patients receiving 1,000 mg/m2/d consisted of transient grade 1 to 2 diarrhea, nausea, mild elevation of liver function tests, and skin toxicity manifested as transient palm desquamation, hair thinning, and nail peeling. There was no evidence of increased radiation-related skin effects. No difference in nonhematologic toxicity was noted between patients receiving four-field or modified RT fields. Transient hemorrhagic cystitis grade 2 was observed in one patient. Persistent moderate gastrointestinal toxicity was observed in two patients who had received 1,000 mg/m2/d. They had diarrhea grade 1 to 2 (an increase of two to four stools per day over baseline), no other symptoms suggesting proctitis, and no blood in the stool 1 and 3 years after the completion of treatment. Acute nonhematologic toxicity grade 3 or 4 is summarized in Table 3. In patients receiving 1,000 mg/m2/d, one had grade 3 nausea and vomiting that responded to medication, and she completed treatment according to schedule. After the second BUdR cycle, one patient developed generalized maculopapular and vesicular skin eruption (skin toxicity grade 3), which responded to prednisone. It was considered a DLT, and drug infusions were not resumed after the skin toxicity subsided. Liver toxicity grade 3 manifested in three patients as transient elevation of liver enzymes (five to six times the normal range), bilirubin in the normal range, and no related symptoms.
Late severe toxicity was observed in one patient, who developed rectovaginal and cystovaginal fistulae requiring pelvic exenteration 16 months after treatment was completed; no tumor was found. Both patients receiving the second dose level (1,333 mg/m2/d) experienced nonhematologic DLT; gastrointestinal toxicity was observed in both patients (severe diarrhea in both and oral mucositis in one) and skin toxicity grade 4 (exfoliative dermatitis) in one. One of these patients required loop colostomy and ileostomy because of persistent small bowel damage. No patient died of treatment-related toxicity. In summary, one case with nonhematologic DLT was observed among 16 patients receiving the first BUdR dose level, 1,000 mg/m2/d. At this level, an additional case of hematologic DLT was observed among five patients receiving standard four-field pelvic irradiation, and no hematologic DLT occurred in 11 patients whose fields were modified to exclude the iliac crests. In contrast, both patients receiving the second dose level, 1,333 mg/m2/d, experienced DLT. We therefore consider the first dose level to be the maximum-tolerated dose in this regimen.
Response and Disease Outcome
Drug Incorporation Studies
Examination of the immunohistochemistry slides used for assessing the labeling index in the rectal mucosa biopsies revealed that, at the completion of BUdR infusion, almost all labeled cells resided in the mucosal crypts, the sites of mucosal stem cells (Fig 4). Five days later, in the middle of the first RT week, many of these cells had migrated to the surface of the mucosa. A similar redistribution of BUdR-positive cells away from the crypts toward the surface was observed in rectal mucosa biopsies obtained at brachytherapy. This pattern was noted in almost all biopsy specimens.
Continuous infusion of BUdR 1,000 mg/m2/d over 4 days alternating with pelvic irradiation according to our regimen was found to be the maximum-tolerated dose. The dose-limiting toxicities in our trial were hematologic and acute bowel toxicity. Blood-forming stem cells in the bone marrow, which proliferate rapidly, are radiosensitized by BUdR. In addition, BUdR itself has hematologic toxicity when no RT is delivered.22 Enhanced hematologic toxicity would therefore be expected in trials combining halogenated pyrimidines and radiation. A modification in the radiation fields that excluded the iliac crests from irradiation seemed to reduce hematologic toxicity in patients receiving 1,000 mg/m2/d but was not sufficient to prevent DLT in patients receiving the next dose level, 1,333 mg/m2/d. The extent of irradiated bone marrow in patients treated with thymidine analogs has an obvious effect on the maximum-tolerated drug dose. We have previously reported that in a similar alternating BUdR and radiation regimen for pancreatic cancer, in which radiation involved the pancreatic tumor bed and abdominal lymph nodes, the maximum-tolerated dose was 800 mg/m2/d, with hematologic toxicity limiting the ability to deliver a higher dose.23 In a regimen using prolonged (2 weeks) infusion of IUdR concurrent with irradiation for large sarcomas, thrombocytopenia prevented the completion of the drug infusion in several patients, particularly those in whom the size and location of tumors required extensive bone marrow irradiation.24 In contrast, when conformal radiation techniques were used to minimize noninvolved tissue irradiation, it was possible to deliver at least two 4-day cycles of IUdR 1,600 mg/m2/d, alternating with abdominal radiation, for retroperitoneal sarcomas without severe hematologic toxicity.25 An effort to limit the extent of irradiated bone marrow, as clinically permissible, should be made in patients participating in trials of radiation and halogenated pyrimidines. Hematologic toxicity may also be tempered by modifying the drug and radiation schedule. We have previously found that the ratio of BUdR in bone marrow cells compared with levels in tumor in athymic mice was significantly reduced 1 to 3 days after the completion of BUdR infusion, compared with the ratio at the completion of drug delivery.14 In a study of alternating IUdR and radiation in sarcoma patients, Sondak et al26 reported a significant decrease of drug levels in bone marrow cells 3 days after the completion of infusion, compared with the levels noted soon after the drug infusion was concluded. Mitchell et al22 have demonstrated that 2 weeks after the completion of drug infusion, radiosensitization of a patient's bone marrow stem cells disappeared, most probably owing to dilution of incorporated BUdR by virtue of several cell divisions. Kinsella et al27 reported a regimen of continuous intravenous infusions of BUdR concurrent with RT. Hematologic toxicity, primarily thrombocytopenia, limited the duration of infusion to 9 to 14 days (median, 12 days) in patients receiving 1,000 mg/m2/d. We did not measure BUdR incorporation into bone marrow, but the data mentioned above suggest that the administration of alternating BUdR and radiation has a potential benefit regarding bone marrow toxicity relative to the toxicity expected in concurrent drug and radiation administration. Another dose-limiting toxicity in this study was severe acute diarrhea, observed in both patients receiving 1,333 mg/m2/d. In contrast, 15 of 16 patients receiving 1,000 mg/m2/d had grade 1 to 2 diarrhea, which is expected in patients receiving radiation alone. Although two of these patients had persistent mild to moderate diarrhea, none had late severe proctitis or small bowel damage. The minimal follow-up of patients who received the lower dose level and are alive is 33 months. Although cases of late toxicity occurring with longer follow-up are still possible, they are expected to be uncommon. In trials using a similar schedule of alternating BUdR and radiation for upper abdominal malignancies, there was no increase in acute or late bowel toxicity compared with the gastrointestinal toxicity expected after radiation alone.23,25 These clinical results suggest that a relative sparing of the bowel from radiosensitization is being achieved, as suggested by our preclinical studies. Hepatic toxicity consisted of a transient increase in liver enzymes, which was asymptomatic and returned to normal levels in all patients. Similar experience was reported in other studies using comparable doses of halogenated pyrimidines.28 We therefore do not consider such toxicity to be dose limiting in our current studies. Two cases of late normal tissue toxicity requiring surgery were observed in this trial. One case was observed among 16 patients receiving 1,000 mg/m2/d, the maximum-tolerated dose. This patient had rectovaginal and cystovaginal fistulae with no evidence of tumor recurrence. The second patient with late toxicity was one of the two patients receiving 1,333 mg/m2/d. This patient had multiple pelvic abscesses requiring repeated laparotomies for drainage, as well as noncontrolled pelvic tumor. In addition, a small bowel obstruction required ileostomy and colostomy. It is unknown whether pre-existing pelvic inflammatory disease, multiple surgeries, higher BUdR dose, or persistent disease played the major role in her late complications. Overall, the rate of late complications in this study (11% in all patients, 6% in patients receiving 1,000 mg/m2/d) is similar to the rate reported in patients receiving radiation alone for advanced cervical cancer (10% to 17%)2,29 or radiation concurrent with chemotherapy (12%).30 The level of BUdR incorporation correlates linearly with radiosensitization in a wide variety of model systems, including both tumor and normal cells.11 Incorporation of BUdR into tumor cell DNA in patients receiving 1,000 mg/m2/d in our study reached on average 4.9% immediately after the completion of drug infusion and remained stable 5 days later in biopsies obtained at the middle of the first radiation week. These incorporation levels would be predicted to result in a radiation enhancement ratio of 1.2 to 1.3,31-34 a clinically significant radiosensitization. The similar tumor incorporation levels at the end of drug infusion and in the following week that were found in this study are consistent with our previous in vitro studies, which showed that incorporation of halogenated pyrimidines in tumor cells remained constant for several days after the removal of drug from the medium31 and with our findings, in human tumor xenograft models, that BUdR levels in tumors are relatively stable over time.14 The findings in this trial suggest that alternating BUdR and radiation in our regimen did not compromise tumor radiosensitization, compared with the sensitization that would be expected in a concomitant regimen of drug and radiation administration. A trend (not statistically significant) was noted for increased BUdR incorporation in tumor biopsies obtained at the time of brachytherapy, after the fourth cycle of BUdR infusion. An accurate assessment of this trend was hampered by the small number of biopsies containing viable tumor cells near the completion of treatment. The kinetics of halogenated pyrimidine incorporation in tumor and normal tissue after several cycles of drug administration and radiation is complex. We have previously found that radiation affected neither the incorporation into nor the elimination of BUdR from human tumor xenografts.35 On the other hand, using a stable isotope of BUdR, we have previously reported that incorporation of the drug retarded both further incorporation into and elimination from DNA.14 Taking into account the wide variety in tumor cell kinetics during treatment, a large number of patient biopsies near the completion of treatment would be required to fully assess BUdR incorporation in surviving tumor cells. Also, it is unknown whether BUdR in tumor cells in biopsies obtained at brachytherapy represents "new" drug administered in the fourth cycle or predominantly drug administered in earlier cycles. Verifying this would enable us to determine whether administering drug cycles after the initial treatment stage contributes significantly to tumor drug incorporation. We plan to address this issue in a future study by examining tumor biopsies in patients who will receive BUdR in the initial treatment cycles and IUdR or stable isotopic BUdR (which would be expected to produce similar radiosensitization) in the later cycles. No significant differences in rectal biopsy BUdR incorporation or labeling index were noted between the end of BUdR infusion and the following week, in which radiation was delivered, resulting in similar ratios (1.5 to 1.8) of tumor to rectal BUdR incorporation. Similar findings of stable rectal mucosa halogenated pyrimidine levels between day 5 and 8 of drug infusion were found in a trial of alternating IUdR and radiation for sarcoma patients, using a schedule similar to that used in the current study.26 These findings are inconsistent with the preclinical data in which a higher ratio of tumor to rectal mucosa drug incorporation was found after the completion of BUdR infusion.14 In both clinical studies, however, a pattern of altered distribution of halogenated pyrimidine-containing cells, which is expected to decrease rectal radiosensitization, was found. It consists of migration of drug-containing cells from the crypts, the sites of mucosal stem cells, to the mucosal surfaces, which contain cells that are fated to shed. Inasmuch as no additional drug was infused during this 5-day interval and the incorporation in the mucosa (crypts and surface combined) remained unchanged, the degree of incorporation in crypt cells must have decreased. Because the crypt cells are required to repopulate the mucosa after radiation, it is anticipated that irradiation during this drug elimination period produces less toxicity compared with a regimen of concurrent radiation and BUdR. Rectal mucosa specimens obtained at brachytherapy, after the fourth BUdR infusion, demonstrated a favorable distribution of BUdR-containing cells toward the mucosal surface and away from the crypts, similar to the distribution at day 10. However, a trend toward higher total rectal mucosa BUdR incorporation and a lower ratio of tumor to rectal BUdR was noted at brachytherapy. We do not know the reasons for these differences. They could be related to changes in the kinetics of rectal mucosa proliferation during the course of treatment or to saturation of the mucosal cells with repeated BUdR infusions. It is possible that the therapeutic benefit of our treatment strategy is obtained primarily in the earlier BUdR infusion cycles. These issues will be addressed in a future study using IUdR or stable isotopic BUdR in the later phase of a similar protocol. The relatively small number of patients in this study produced wide confidence intervals for the actuarial survival and disease-free survival estimates. A comparison with the outcome of other studies that used radiation concurrent with chemotherapy is therefore difficult. In general, the rates of pelvic control (62%) and disease-free survival (48%) in our study are comparable to those in other studies using concurrent radiation and hydroxyurea or cisplatin for advanced cervix cancer.7,8,30,36,37 Some of these series7,8,30 used surgical para-aortic lymph node staging and excluded patients with microscopic lymph node metastases, introducing a patient selection factor which was not practiced in our study. Pelvic disease recurrence constituted the major failure site in our study. This failure pattern is similar to that observed in other studies using radiation and chemotherapy.4,38 The radiosensitizing levels of BUdR achieved in the tumors in our study are encouraging, but they may not be sufficient to have significant impact on the locoregional recurrence pattern in advanced tumors like those treated in this study. Further efforts to improve the efficacy of this regimen without increasing toxicity are warranted. Such efforts may include the addition of cisplatin. Its activity in cervix cancer,6 its relative lack of hematologic or hepatic toxicity, and the preclinical data suggesting sensitization of cisplatin cytotoxicity by BUdR39 make it an attractive agent for incorporation into the regimen we have described.
Supported in part by grant no. RO1-RR00042 from the National Institutes of Health; and by an ASCO Career Development Award from the American Society of Clinical Oncology (J.M.R.). We acknowledge the Analytical Core of the Upjohn Center for Pharmacology at the University of Michigan for bromodeoxyuridine measurements.
Presented in part at the 40th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, Phoenix, AZ, October 1998.
1. Montana GS, Fowler WC, Varia MA: Carcinoma of the cervix stage III: Results of radiation therapy. Cancer 57:148-154, 1986[Medline] 2. Perez CA, Camel HM, Kuske RR, et al: Radiation therapy alone in the treatment of carcinoma of the uterine cervix: A 20-year experience. Gynecol Oncol 23, 127-140, 1986 3. Jampolis S, Andras EJ, Fletcher GH: Analysis of sites and causes of failure of irradiation in invasive squamous cell carcinoma of the intact uterine cervix. Radiology 115:681-685, 1975[Abstract] 4. Thomas G, Dembo A, Fyles A, et al: Concurrent chemoradiation in advanced cervix cancer. Gynecol Oncol 38:446-451, 1990[Medline] 5. Shueng PW, Hsu WL, Jen YM, et al: Neoadjuvant chemotherapy followed by radiotherapy should not be a standard approach for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 40:889-896, 1998[Medline] 6. Grigsby PW: Lack of proven efficacy of chemotherapy for patients with carcinoma of the uterine cervix. Semin Radiat Oncol 4:30-33, 1994[Medline]
7.
Stehman FB, Bundy BN, Thomas G, et al: Hydroxyurea versus misonidazole with radiation in cervical carcinoma. J Clin Oncol 11:1523-1528, 1993 8. Rose P, Bundy B, Thigpen J, et al: Significant preliminary results of a phase III randomized study of concomitant chemotherapy with weekly cisplatin vs hydroxyurea, 5-fluorouracil infusion and bolus cisplatin vs hydroxyurea in advanced cervical cancer: A Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 17:360a, 1998 (abstr) 9. Lin JC, Ho ESC Jan JS, et al: High complete response rate of concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the uterine cervix. Gynecol Oncol 61:101-108, 1996[Medline] 10. Wong LC, Choo YC, Choy D, et al: Long-term follow-up of potentiation of radiotherapy by cisplatinum in advanced cervical cancer. Gynecol Oncol 35:159-163, 1989[Medline]
11.
McGinn CJ, Scewach DS, Lawrence TS: Radiosensitizing nucleosides. J Natl Cancer Inst 88:1193-1203, 1996 12. Bagshaw MA, Doggette RLS, Smith KC, et al: Intraarterial 5-bromodeoxyuridine and X-ray therapy. AJR Am J Roentgenol 99:886-894, 1967
13.
Lawrence TS, Davis MA, Maybaum J, et al: The potential superiority of bromodeoxyuridine to iododeoxyuridine as a radiation sensitizer in the treatment of colorectal cancer. Cancer Res 52:3698-3704, 1992
14.
Lawrence TS, Davis MA, Stetson PL, et al: Kinetics of bromodeoxyuridine elimination from human colon cancer cells in vitro and in vivo. Cancer Res 54:2964-2968, 1994 15. Rotenberg AD, Bruce WR, Baker RG: Incorporation of 5-iododeoxyuridine I-131 in spontaneous C3H mouse mammary tumors. Br J Radiol 35:337-342, 1962 16. Clifton KH, Szybalski W, Heidelberger C, et al: Incorporation of I-125-labeled iododeoxyuridine into the deoxyribonucleic acid of murine and human tissues following therapeutic doses. Cancer Res 23:1715-1723, 1963 17. International Commission on Radiation Units and Measurements. Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology. ICRU Report No. 38.Washington, DC, International Commission on Radiation Units and Measurements, 1985 18. Eisbruch A, Johnston CM, Martel MK, et al: Customized gynecologic interstitial implants: CT-based planning, dose evaluation, and optimization aided by laparotomy. Int J Radiat Oncol Biol Phys 40:1087-1093, 1998[Medline] 19. Maybaum J, Kott MJ, Johnston NJ, et al: Analysis of bromodeoxyuridine incorporation into DNA: Comparison of gas chromatographic/mass spectrometric, CsCl gradient sedimentation, and specific radioactivity methods. Anal Biochem 161:164-171, 1987[Medline] 20. Beisker W, Dolbeare F, Gray JW: An improved immunocytochemical procedure for high sensitivity detection of incorporated bromodeoxyuridine. Cytometry 8:235-239, 1987[Medline] 21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 78:427-481, 1958 22. Mitchell JB, Kinsella TJ, Russo A, et al: Radiosensitization of hematopoietic precursor cells in glioblastoma patients receiving intermittent intravenous infusions of bromodeoxyuridine. Int J Radiat Oncol Biol Phys 457-463, 1983 23. Robertson JM, Ensminger WD, Walker S, et al: A phase I trial of intravenous bromodeoxyuridine and radiation therapy for pancreatic cancer. Int J Radiat Oncol Biol Phys 37:331-335, 1997[Medline] 24. Goffman T, Tochner Z, Glatstein E: Primary treatment of large and massive adult sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation. Cancer 67:572-576, 1991[Medline] 25. Robertson JM, Sondak VK, Weiss SA, et al: Preoperative radiation therapy and iododeoxyuridine for large retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys 31:87-92, 1995 26. Sondak VK, Stetson PL, McKeever PE, et al: IUdR incorporation and washout in normal human tissue after i.v. infusion. Proc Am Assoc Cancer Res 33:2985, 1992 (abstr) 27. Kinsella TJ, Mitchell JB, Russo A, et al: Continuous infusions of bromodeoxyuridine as a clinical radiosensitizer. J Clin Oncol 2:1144-1150, 1984[Abstract] 28. Urtasun RC, Cosmatos D, DelRowe J, et al: Iododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: A comparison of short versus long intravenous dose schedules (RTOG 86-12). Int J Radiat Oncol Biol Phys 27:207-214, 1993[Medline] 29. Thoms WW, Eifel PJ, Smith TL, et al: Bulky endocervical carcinoma: A 23-year experience. Int J Radiat Oncol Biol Phys 23:491-499, 1992[Medline] 30. Fields AL, Anderson PS, Goldberg GL, et al: Mature results of a phase II trial of concomitant cisplatin/pelvic radiotherapy for locally advanced squamous cell carcinoma of the cervix. Gynecol Oncol 61:416-422, 1996[Medline] 31. Lawrence TS, Davis MA, Maybaum J, et al: The dependence of halogenated pyrimidine incorporation and radiosensitization on the duration of drug exposure. Int J Radiat Oncol Biol Phys 18:1393-1398, 1990[Medline] 32. Kinsella TJ, Dobson PP, Mitchell JB, et al: Enhancement of X ray induced DNA damage by pretreatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys 13:733-739, 1987[Medline] 33. Ling LL, Ward JF: Radiosensitization of Chinese hamster V79 cells by bromodeoxyuridine substitution of thymidine: Enhancement of radiation-induced toxicity and DNA strand break production by monofilar and bifilar substitution. Radiat Res 121:76-83, 1990[Medline] 34. Phillips TL, Bodell WJ, Uhl V, et al: Correlation of exposure time, concentration and incorporation of IdUrd in V-79 cells with radiation response. Int J Radiat Oncol Biol Phys 16:1251-1255, 1989[Medline] 35. Lawrence TS, Chang EY, Davis MA, et al: Effect of irradiation on bromodeoxyuridine incorporation in human colon cancer xenografts. Int J Radiat Oncol Biol Phys 34:617-621, 1996[Medline] 36. Pearcy RG, Stuart GCE, MacLean GD, et al: Phase II study to evaluate the toxicity and efficacy of concurrent cisplatin and radiation therapy in the treatment of patients with locally advanced squamous cell carcinoma of the cervix. Gynecol Oncol 58:34-41, 1995[Medline] 37. John M, Flam M, Caplan R, et al: Final results of a phase II chemoradiation protocol for locally advanced cervical cancer: RTOG 85-15. Gynecol Oncol 61:221-226, 1996[Medline] 38. Roberts WS, Hoffman MS, Kavanagh JJ, et al: Further experience with radiation therapy and concomitant intravenous chemotherapy in advanced carcinoma of the lower female genital tract. Gynecol Oncol 43:233-236, 1991[Medline] 39. Poot M, Schuster A, Hoehn H: Cytostatic synergism between bromodeoxyuridine, bleomycin, cisplatin and chlorambucil demonstrated by a sensitive cell kinetic assay. Biochem Pharmacol 41:1903-1909, 1991[Medline] Submitted July 2, 1998; accepted September 14, 1998.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
