Intraperitoneal radioimmunochemotherapy of ovarian cancer: a phase I study.

A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu-CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity.

Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).

Radioimmunotherapy of B-cell NHL.

Much progress has been made in the development and implementation of radionuclide-carrying antibody therapy (radioimmunotherapy or RIT) of non-Hodgkin's lymphomas (NHL) in the past decade. Response rates have generally exceeded 60% for nonmyeloablative single dose RIT (85% - 100% for myeloablative) in patients who have relapsed after primary therapy. It is also encouraging that the duration of such responses has often been greater than the response to the last chemotherapeutic regimen administered. These results, as well as a favorable toxicity profile, have resulted in the successful earlier and more widespread use of this new therapeutic modality. Although unlabeled antibody therapy alone has had a positive impact on the treatment of NHL, the response rates for RIT have been higher than (sometimes nearly double) those for unlabeled antibody therapy. This has been demonstrated in trials that have directly compared radiolabeled antibody with unlabeled antibody, as well as in separate trials for similar patient groups. Use of radionuclides in conjunction with antibodies adds transient marrow suppression and a small risk of second malignancy over unlabeled antibody therapy. However, the toxicity from a single course of RIT is very favorable compared to chemotherapy. Despite the enormous progress of RIT, much remains to be learned to fully optimize the role of this exciting modality in the treatment of NHL.

Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers.

PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.

Clinical radioimmunotherapy.

Radioimmunotherapy (RIT) is a promising new therapy for the treatment of a variety of malignancies. General principles of RIT are discussed, including important considerations in the selection of monoclonal antibodies (MAb) and radionuclides for RIT. Results of clinical trials using RIT for the treatment of lymphoma, leukemia, and solid tumors are summarized. The results from many of these trials are promising, especially for the treatment of lymphohematopoietic malignancies, in which a variety of MAb, radionuclides, and study designs have resulted in high response rates with a number of durable responses. Encouraging results have also been obtained using RIT to treat some solid tumors, primarily in patients with relatively low tumor burdens. RIT is generally well tolerated, with the primary toxicity being transient reversible myelosuppression in most nonmyeloablative studies. Nonhematologic toxicity, especially at nonmyeloablative doses, has been minimal in most studies. Approaches for increasing the therapeutic index of RIT are reviewed, which may further potentiate the efficacy and decrease the toxicity of RIT.

A strategy to reduce red marrow dose for intraperitoneal radioimmunotherapy.

The aim of this study was to determine whether shorter-lived radionuclides can reduce red marrow (RM) toxicity for i.p. radioimmunotherapy (RIT). The potential radionuclides, which included Lu-177, I-131, Y-90, Re-186, Re-188, and Ho-166, were attached to antibody CC49. Each radiopharmaceutical was assumed to have identical in vivo pharmacokinetics. Blood and whole body retention data acquired from 26 patients who received i.p. RIT with Lu-177 CC49 were used as input. The average biological half-time of Lu-177 CC49 in the whole body was 280 h, and the average Lu-177 concentration in plasma increased to a maximum at 2 days postinfusion, followed by steady clearance. The residence time and RM doses were calculated for each radionuclide. In the current model, Re-188 was found to deliver the lowest RM dose, primarily because it had the shortest half-life, whereas Y-90 delivers the highest dose. Re-188 delivers 60% of the RM dose as compared with Lu-177 and can increase the dose to metastatic sites in the i.p. space by a similar factor. Based on limiting the RM dose to 200 cGy, the maximum administered activity of each radionuclide is as follows: (a) 106 mCi, Lu-177; (b) 58 mCi, I-131; (c) 34 mCi, Y-90; (d) 70 mCi, Re-186; (e) 169 mCi, Re-188; and (f) 110 mCi, Ho-166. Because of the delayed steady leakage of radiopharmaceuticals from the i.p. cavity to the plasma, short-lived radionuclides may offer special advantages for i.p. RIT.

Phase II study of interferon-enhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer.

Adjuvant Interferon (IFN) was given to increase tumor antigen expression and enhance localization with 131I-labeled CC49 radioimmunotherapy in a Phase II trial for hormone resistant metastatic prostate cancer. Patients received four doses of alpha-IFN (3 x 10(6) IU) s.c. on alternate days, from day -5 to day +1 of 75 mCi/m2 131I-CC49 treatment. Toxicity was well tolerated, with the majority of patients experiencing transient grade 3 or 4 neutropenia and/or thrombocytopenia (maximal at 4-6 weeks). The absorbed dose was >25 Gy in four of eight tumors visualized, which represents an increase of >20 fold over whole body radiation dose. Two patients had radiographic minor responses by 6 weeks post-therapy, whereas five of six patients experiencing pain had symptom relief without radiographic changes. The protocol provided modest antitumor effects (pain relief in five of six patients and two minor radiographic responses). This study suggests that the addition of IFN enhanced tumor uptake and antitumor effects as compared to a prior Phase II trial of 131I-CC49 alone.

Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck.

Thirty-five patients with inoperable recurrent head and neck cancer previously treated with definitive irradiation were treated with reirradiation and concomitant chemotherapy. Patient records were retrospectively reviewed to assess toxicity, response, and survival. Patients received one of three regimens: 1) 40 Gy total (2 Gy daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 2 g hydroxyurea orally daily for 5 days; 2) 48 Gy total (1.2 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days; 3) 60 Gy total (1.5 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days. For all regimens, treatment was given only on weeks 1, 3, 5, and 7. Acute toxicity was mainly hematologic and was less severe with the lower hydroxyurea dose. Acute mucosal and skin toxicity was acceptable for all regimens. Late toxicity was noted in 4 of 17 patients who survived 12 months or more. Late effects were Radiation Therapy Oncology Group grade 3 or less. Fifteen of 35 patients achieved a complete response, and 11 of 35 patients achieved a partial response. The median survival rate was 10.5 months. There was no significant difference in responses or median survival between the groups. Reirradiation of head and neck cancer with 5-fluorouracil and hydroxyurea offers acceptable acute toxicity and minimal late effects. The clinical response rates and median survival are encouraging. Further investigation is warranted.

Combined modality therapy of A431 human epidermoid cancer using anti-EGFr antibody C225 and radiation.

BACKGROUND: Monoclonal antibodies (mAb) to epidermal growth factor receptor (EGFr) inhibit tumor cell proliferation and enhance cytotoxicity of chemotherapeutic agents. The purpose of this study was to investigate the interaction of the anti-EGFr antibody C225 combined with radiotherapy (RT) on EGFr expressing A431 human epidermoid cancer cells. METHODS: Cell proliferation, apoptosis, EGFr expression and phosphorylation, and clonogenic survival were assayed in vitro. A431 tumor growth inhibition and immunohistochemistry analysis of EGFr expression and apoptosis were assessed in vivo. RESULTS: C225 plus RT produced greater inhibition of A431 cell proliferation than C225 or RT alone which was corroborated by enhanced apoptosis. Similar clonogenic survival occurred following the addition of C225 to RT, although colonies were smaller in the presence of C225. C225 produced inhibition of EGF-induced phosphorylation of EGFr without concurrent down-regulation of surface receptor, which was not altered by RT. Combined treatment of mice bearing tumors demonstrated enhancement of complete regressions, reduction in time to tumor size doubling, and prolongation of survival. Significant apoptosis occurred in xenograft tumors treated with C225 with or without RT. CONCLUSIONS: These data demonstrate an interaction between C225 and RT. C225-mediated apoptosis and inhibition of EGFr phosphorylation may be critical in the interaction. Studies to define the precise influence of combined modality treatment on the EGFr signal transduction cascade need to be pursued. The combination of growth factor receptor antibodies and RT has potential application in clinical oncology.

Chimeric antibodies with specificity for tumor antigens: demonstration of in situ localization to tumors after antibody therapy.

In this study, we compare various methods for the detection of a tumor-associated target antigen and deposition of the bound therapeutic monoclonal antibody in patients enrolled in two separate trials, one involving the administration of two radiolabeled monoclonal antibodies and the other involving an unlabeled antibody. In the first trial, patients with TAG-72 expressing metastatic colon cancer scheduled for surgical intervention received radiolabeled murine and chimeric B72.3 antibody followed by radioimmune imaging and subsequent laparotomy. Normal and tumor tissues obtained at surgery were processed for routine histology, immunohistochemistry, radiometry, and autoradiography. Both anti-TAG-72 antibodies localized to known tumor sites as evidenced by radioimmune imaging. Resected tissue revealed a high tumor-to-normal radiolocalization ratio, and autoradiography demonstrated even deposition of the radiolabeled antibodies throughout the entire tumor deposit with sparing of surrounding normal tissue. In contrast, immunohistochemistry on the same sections revealed comparatively weak antigen expression and patchy antibody localization. In the second trial, patients with GD2 antigen expressing metastatic melanoma received the unlabeled chimeric anti-GD2 antibody C14.18. Immunologic detection of the GD2 antigen and C14.18 deposition was performed on biopsy section as well as on single cell suspension. FACS analysis of the single cell suspension proved more sensitive for the detection of bound antibody than immunohistochemistry, although both methods yielded comparable results for GD2 antigen expression. Our findings demonstrate that the optimal method for the detection of tumor-associated antigen and bound therapeutic antibody can vary depending upon the nature of the antibody (radiolabeled vs. unlabeled and murine vs. chimeric), fixation stability of the target antigen, and the type of pathologic material available for study.

Recent progress in radioimmunotherapy for cancer.

Radioimmunotherapy allows for the delivery of systemically targeted radiation to areas of disease while relatively sparing normal tissues. Despite numerous challenges, considerable progress has been made in the application of radioimmunotherapy to a wide variety of human malignancies. The greatest successes have occurred in the treatment of hematologic malignancies. Radioimmunotherapy, with or without stem-cell transplant support, has produced substantial complete remission rates in chemotherapy-resistant B-cell lymphomas. Nonmyeloablative regimens have shown so much promise that they are now being tested as initial therapy for low-grade B-cell lymphomas. Although solid tumor malignancies have been less responsive to radioimmunotherapy, encouraging results have been obtained with locoregional routes of administrations, especially when the tumor burden is small. Greater tumor-to-normal tissue ratios are achievable with regional administration. Even with intraperitoneal and intrathecal administration, bone marrow suppression remains the dose-limiting toxicity. Ongoing research into new targeting molecules, improved chelation chemistry, and novel isotope utilization is likely to extend the applications of this strategy to other tumor types. The potential for radioimmunotherapy will be enhanced if this modality can be optimally adapted for integration with other agents and if the administration method can be tailored to the type and distribution of malignancy.

Intraperitoneal radioimmunotherapy of ovarian cancer with 177Lu-CC49: a phase I/II study.

BACKGROUND: Twenty-seven ovarian cancer patients who failed chemotherapy entered a phase I/II trial of intraperitoneal 177Lu-CC49 antibody. METHODS: Patients had disease confined to the abdominal cavity +/- retroperitoneal lymph nodes, adequate organ function, and no previous radiation. RESULTS: The most common side effects were delayed, transient arthralgia (10/27) and marrow suppression with 1.665 GBq/m2 (45 mCi/m2), which was considered the maximum tolerated dose. One of thirteen patients with gross disease had >50% tumor reduction after therapy, whereas most others with gross disease progressed (one went off study with stable disease at 11 weeks). Seven of nine patients with <1-cm nodules progressed in < or =21 months, and two of nine remain without evidence of disease at 4 to 5 months. Of patients with microscopic or occult disease, one relapsed at 10 months and four of five remain without evidence of disease at >6 to 35 months. CONCLUSIONS: Marrow suppression was the dose-limiting toxic effect of intraperitoneal immunotherapy with 177Lu-CC49. Antitumor effects were noted against chemotherapy-resistant ovarian cancer, even at lower dose levels, and resulted in prolonged disease-free survival of most patients with microscopic disease. This form of treatment deserves further study.

Correlation of toxicity with treatment parameters for 131I-CC49 radioimmunotherapy in three phase II clinical trials.

Analyses were performed on 40 patients with TAG-72 expressing metastatic cancer who were entered into three phase II clinical trials. The dose selected was the maximum tolerated dose in phase I studies. Patients all had unresectable metastatic colon or prostate cancer and had recovered from prior therapies. Patients in trials #1 and #2 received 75 mCi/m2 131I-CC49 antibody whereas those in trial #3 received a total of 75 mCi/m2 with equal amounts of 131I-CC49 and 131I-COL-1. The three trials have resulted in a reproducible degree of reversible marrow suppression; 72.5% of patients experienced moderate or severe toxicity. Comparisons were made between demographic, clinical and pharmacokinetical variables and the grade of WBC toxicity, platelet toxicity and the sum of the two as total toxicity. Whole body radiation dose had a statistically significant relationship with platelet toxicity (r = 0.38, p = 0.015) and total toxicity (r = 0.34, p = 0.035). The bone marrow radiation dose is significantly related to all toxicity indicators with correlation coefficients with WBC and platelet toxicities of 0.47 (p = 0.002) and 0.34 (p = 0.033), respectively. Plasma half-life had the strongest correlation with WBC toxicity and combined toxicities. Multivariate models were developed to help describe the simultaneous effect of these variables on toxicity. The results show that the MTD dose was safely given to patients who varied in age, disease burden and degree of marrow compromise. This supports the contention that a fixed dose of radiolabeled antibody per body mass or m2 can be given to a diverse group of non-lymphoma patients with a predictable toxicity range.

Postsurgical recurrent carcinoma of the cervix: reassessment and results of radiation therapy options.

PURPOSE: To evaluate outcome and reassess the radiation therapy options in pelvic recurrences of cervical cancer treated initially with surgery. MATERIALS AND METHODS: In 30 patients, the prognostic factors analyzed for local control included site of recurrence (central, pelvic wall), tumor size, modality of radiation therapy, and radiation dose. Mean follow-up in survivors was 111.5 months. RESULTS: Local control was attained in (a) nine of 20 patients with central recurrence and in two of 10 with pelvic wall recurrence (p = .25); (b) none of four who received less than 50 Gy, five of nine who received 50-60 Gy, and six of 17 who received greater than 60 Gy (p = .27); and (c) five of 11 with tumor smaller than 3 cm, five of nine with tumor size 3-6 cm, and one of 10 with tumor larger than 6 cm. Multivariate analysis revealed a significant benefit of local control on survival (P = .05). Median survival for patients with central recurrence was 14.5 months compared with 9 months for those with pelvic wall recurrence. CONCLUSION: Local pelvic control depends on site and size of recurrence and radiation therapy modality and dose. Appropriate choice of brachytherapy modality is important. To improve local control and survival, more aggressive treatment is indicated, but attendant higher complications may be expected.

Phase II study of dual 131I-labeled monoclonal antibody therapy with interferon in patients with metastatic colorectal cancer.

The combination of COL-1 (anti-CEA) and CC49 (anti-TAG-72) has shown an increase in binding and distribution in colon cancer by immunoperoxidase staining compared to either antibody alone. To overcome tumor heterogeneity and allow delivery of higher radiation dose, 131I-labeled COL-1 and CC49 at a total dose of 75 mCi/m2 (2775 MBq/m2) were simultaneously administered to 14 patients with metastatic colon cancer. alpha-IFN (3 x 10(6) IU) was given s.c. on days -5 to +3 to increase carcinoembryonic antigen and TAG-72 antigen expression. Most patients had mild symptoms during IFN therapy, including mild neutropenia, fever, and malaise, which rapidly subsided after IFN cessation. No acute allergic reactions occurred with radioimmunotherapy; two patients experienced transient, delayed grade 2 arthralgias. Transient neutropenia and/or thrombocytopenia, which was maximal at 4-6 weeks, were consistent side effects without adverse events. All patients had tumor localization, and 13 of 14 patients achieved 4+ (highest grade) localization readings to at least one known site of disease. No objective responses occurred; 4 patients were stable and 10 progressed. Tumor dose estimates varied from 393 to 1327 cGy, including liver and extrahepatic sites. Combining two complementary antibodies and IFN administration appeared to increase localization intensity and radiation doses at tumor sites as compared to historical controls. The amount of radiation delivered to tumor sites was still below that required to cause tumor regressions in metastatic colorectal cancer.

Intraperitoneal radioimmunotherapy of ovarian cancer with lutetium-177-CC49.

UNLABELLED: Twelve ovarian cancer patients who failed chemotherapy entered a Phase I trial of intraperitoneal 177Lu-CC49 antibody. METHODS: Patients had disease confined to the abdominal cavity +/- retroperitoneal lymph nodes, adequate organ function and no previous radiation. RESULTS: Side effects included mild discomfort with administration (1/12), delayed transient arthralgia (2/12), and mild marrow suppression (calculated marrow doses of 11-54 cGy). The maximum tolerated dose has not been reached with levels of 10, 18, 25 and 30 mCi/m2. Radioimmunoscintigraphy revealed localization consistent with tumor in 11 of 12 patients. One of eight patients with gross disease had > 50% tumor reduction after therapy, while six progressed and one went off study with stable disease. Of patients with microscopic or occult disease, one relapsed at 10 mo and three remain without evidence of disease after 18 mo. CONCLUSION: Intraperitoneal radioimmunotherapy with 177Lu-CC49 is well tolerated and appears to have antitumor activity against chemotherapy-resistant ovarian cancer in the peritoneal cavity.

Initial clinical evaluation of iodine-125-labeled chimeric 17-1A for metastatic colon cancer.

UNLABELLED: The internalizing properties of murine antibody 17-1A in human colon cancer cells make it attractive as a carrier for radionuclides with short range emissions such as 125I. Murine 17-1A IgG2a antibody, which reacts against human gastrointestinal cancers, has been chimerized by joining its variable region with human IgG1 k constant region. A pilot clinical trial of increasing doses of 125I-chimeric 17-1A in patients with metastatic colorectal cancer has been conducted. METHODS: Patients were treated in groups of 2-4; 2 patients at Hahnemann University and 26 at the University of Alabama at Birmingham. Groups 1-5 received single administrations with 125I doses of 20, 40, 60, 80 or 100 mCi. Subsequent groups received therapeutic doses of 150, 200 or 250 mCi, with the dose subdivided into infusing of 50 or 100 mCi at 4-day intervals. All treatments were delivered in an outpatient setting using radiation precautions. Labeling at 10 mCi/mg antibody was performed on the day of treatment. RESULTS: Pharmocokinetics of circulating antibody was studied for initial patients, showing alpha T 1/2 of 17-27 hr and beta T 1/2 of 100-190 hr. Whole-body T 1/2 of radioactivity was determined by measuring urinary excretion or gamma emissions. Treatment was well tolerated without significant acute or late side effects. No significant bone marrow suppression or other dose-limiting toxicities were noted over this dose range. No objective responses were noted. CONCLUSION: These results show that high-dose outpatient radioimmunotherapy with an 125I-labeled internalizing antibody can be achieved without significant patient toxicity or radiation hazard.

Major geometric variations between multiple high-dose-rate applications of brachytherapy in cancer of the cervix: frequency and types of variation.

PURPOSE: To evaluate major geometric variations in multiple intracavitary applications for carcinoma of the cervix. MATERIALS AND METHODS: Orthogonal radiographs were reviewed of 17 consecutive patients with carcinoma of the cervix treated with 70 applications of high-dose-rate brachytherapy. In seven patients, conscious sedation was used for all applications. In 10 patients, general anesthesia was used for the first application and conscious sedation for subsequent applications. Major geometric variation between applications in axis, length, and slippage in tandem placement and separation, packing, and slippage in colpostats placement were reviewed. A major variation was defined as more than 1.0-cm deviation. RESULTS: Major variations between applications occurred more commonly in colpostats placement than in tandem placement. For tandems, the rates of variation were 5.7% in axis, 4.3% in length, and 1.4% in slippage. For colpostats, rates of variation were 7.1% in separation, 25.7% in vaginal packing, and 7.1% in slippage. No consistent pattern of variation was found between applications except in vaginal packing. CONCLUSION: Awareness of geometric variations should improve proper placement of intracavitary applicators for brachytherapy.

Conventional four-field pelvic radiotherapy technique without computed tomography-treatment planning in cancer of the cervix: potential geographic miss and its impact on pelvic control.

PURPOSE: To evaluate the impact of inadequate margins on pelvic control using the conventional four-field pelvic portals without computed tomography (CT)-treatment planning. METHODS AND MATERIALS: Between 1986 and 1991, 34 patients with invasive cancer of the cervix were eligible for outcome study of conventional four-field radiation therapy (10 Stage I, 16 Stage II, 8 Stage III). The eligibility for this study includes four-field pelvic technique, definitive radiation therapy, and diagnostic CT scan of the pelvis. For this study, an inadequate margin is arbitrarily defined as < or = 1.0 cm of normal tissue around the CT-defined tumor volume. RESULTS: All 34 patients had adequate margins for anterio-posterior/posterio-anterior portals. However, 19 patients had an inadequate margin at the posterior border (S2-S3 interspace) and/or custom-shaped rectal block for lateral pelvic portals. Two patients had inadequate margins at the anterior border (level of symphysis pubis) due to an enlarged uterus. With a median follow-up of 36 months, pelvic control for adequate margins and inadequate margins was 100% and 71% for Stage IB disease and 88% and 50% for Stage IIB disease, respectively. However, pelvic control for Stage IIIB disease was 50% for both groups. There was no difference in total dose to point A or point B between the two groups. CONCLUSION: Our preliminary data show higher local failure in patients with an inadequate margin. For four-field pelvic radiation therapy, we strongly recommend CT-treatment planning. Otherwise, anterio-posterior/posterio-anterior pelvic therapy is the most reliable treatment for cancer of the uterine cervix.