Clinical investigation
Cervix
Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy

Presented at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), Denver, Colorado, October 16–20, 2005.
https://doi.org/10.1016/j.ijrobp.2006.03.018Get rights and content

Purpose: To identify dosimetric parameters associated with acute hematologic toxicity (HT) and chemotherapy delivery in cervical cancer patients undergoing concurrent chemotherapy and intensity-modulated pelvic radiotherapy.

Methods and Materials: We analyzed 37 cervical cancer patients receiving concurrent cisplatin (40 mg/m2/wk) and intensity-modulated pelvic radiotherapy. Pelvic bone marrow (BM) was contoured for each patient and divided into three subsites: lumbosacral spine, ilium, and lower pelvis. The volume of each region receiving 10, 20, 30, and ≥40 Gy (V10, V20, V30, and V40, respectively) was calculated. HT was graded according to the Radiation Therapy Oncology Group system. Multivariate regression models were used to test associations between dosimetric parameters and HT and chemotherapy delivery.

Results: Increased pelvic BM V10 (BM-V10) was associated with an increased Grade 2 or worse leukopenia and neutropenia (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.24–3.53; p = 0.006; and OR, 1.41; 95% CI, 1.02–1.94; p = 0.037, respectively). Patients with BM-V10 ≥90% had higher rates of Grade 2 or worse leukopenia and neutropenia than did patients with BM-V10 <90% (11.1% vs. 73.7%, p < 0.01; and 5.6% vs. 31.6%, p = 0.09) and were more likely to have chemotherapy held on univariate (16.7% vs. 47.4%, p = 0.08) and multivariate (OR, 32.2; 95% CI, 1.67–622; p = 0.02) analysis. No associations between HT and V30 and V40 were observed. Dosimetric parameters involving the lumbosacral spine and lower pelvis had stronger associations with HT than did those involving the ilium.

Conclusion: The volume of pelvic BM receiving low-dose radiation is associated with HT and chemotherapy delivery in cervical cancer patients undergoing concurrent chemoradiotherapy.

Introduction

Cervical cancer is a leading cause of cancer incidence and mortality in women worldwide (1). Many women present with advanced or high-risk disease, for which concurrent chemoradiotherapy (CRT) is standard. The delivery of cisplatin-based chemotherapy with radiotherapy (RT) improves survival compared with RT alone (2, 3, 4, 5) and non–platinum-containing CRT regimens (6, 7) but may be associated with high rates of acute hematologic toxicity (HT), particularly leukopenia and neutropenia (2, 7, 8). Severe HT, although rarely life-threatening, can lead to delayed or missed chemotherapy (7, 8, 9, 10), hospitalizations, the need for growth factors, and a limited ability to delivery combination chemotherapy (11, 12, 13). The reduction of HT is, therefore, an important goal.

Pelvic radiotherapy contributes significantly to the development of HT. More than one-half of the body’s bone marrow (BM) is located in the os coxae, sacrum, proximal femora, and lower lumbar spine (Fig. 1) (14); these areas are included in the treatment volume with conventional pelvic RT. BM activity declines after RT (15), and BM regeneration varies with radiation doses used clinically (15, 16, 17, 18, 19). Reducing BM irradiation may, therefore, reduce CRT toxicity, enabling improved delivery of chemotherapy, and, consequently, treatment efficacy. Despite improved outcomes in patients undergoing CRT, local progression and distant metastasis rates are still significant, particularly with advanced disease (3, 6, 7), and salvage rates for recurrent or persistent disease are low (20, 21), indicating a need for improved initial therapy.

In gynecologic cancer, dosimetric analyses have shown that intensity-modulated RT (IMRT) can reduce the radiation dose delivered to the bladder, small bowel, rectum, and BM (22, 23, 24, 25, 26, 27, 28, 29). In clinical studies, intensity-modulated pelvic RT (IM-PRT) has been associated with decreased acute and chronic GI toxicity compared with conventional whole pelvic RT (30, 31). Even without intentional BM sparing, IM-PRT is associated with reduced BM irradiation (primarily iliac BM) and reduced HT compared with conventional whole pelvic RT (25). IMRT plans optimized to limit BM irradiation further reduce the radiation dose delivered to the BM (27, 28, 29).

The clinical significance and optimal technique of BM sparing in gynecologic patients, however, are still unknown. Although methods for optimizing BM-sparing IMRT (BMS-IMRT) plans have been tested preclinically (27, 28, 29), the approaches have varied. BM-sparing techniques have primarily focused on iliac crest BM sparing; however, data from clinical, pathologic, and radiologic studies have suggested that other regions, such as the lumbosacral spine, ischium, pubis, and proximal femora, are also important (32, 33, 34). Moreover, optimizing plans to spare iliac BM alone could shift the dose into these regions, negating the BM-sparing effect. Dosimetric parameters correlated with HT would be useful to guide IMRT plan optimization and evaluation, but are lacking. To explore these issues, we examined our institution’s experience with cervical cancer patients treated with concurrent cisplatin and IM-PRT.

Section snippets

Patients

We analyzed 37 patients with cervical carcinoma undergoing treatment with concurrent cisplatin and IM-PRT at our institution between February 2000 and December 2004. Patients receiving a portion of their treatment with conventional RT, extended-field (para-aortic) RT, or chemotherapy other than cisplatin were excluded from the analysis. All patients had weekly comprehensive metabolic panels and complete blood counts with differentials during treatment.

Chemotherapy delivery

Patients were treated with weekly cisplatin

Patient and treatment characteristics

Most patients in our study had clinical Stage IB-IIB disease (86.4%), and most (64.8%) were black (Table 2). Three patients with International Federation of Gynecology and Obstetrics clinical Stage IB1 underwent postoperative CRT because of high-risk pathologic findings.

The median baseline WBC, ANC, Hgb, and platelet count was 8.3 × 109/L (range, 4.4–15.2), 4.9 × 109/L (range, 1.7–11.5), 12.8 g/dL (range, 7.0–15.3), and 295 × 109/L (range, 148–448), respectively. At baseline, 2 patients (5.4%)

Discussion

The results of this study have provided quantitative evidence of an association between the volume of pelvic BM receiving low-dose radiation (V10, V20) and acute HT in patients undergoing concurrent cisplatin and IM-PRT. In addition, better delivery of chemotherapy was noted in the patients with decreased BM RT. The association with low-dose dosimetric parameters were consistent with the known radiosensitivity of BM (18, 19, 35, 36, 37, 38).

We did not find significant associations between HT

Conclusion

These results suggest the potential to optimize IM-PRT plans to reduce the toxicity of CRT and possibly improve treatment outcomes by allowing better chemotherapy delivery. Future research in BMS-IMRT is needed, including prospective studies evaluating its efficacy.

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