Chemoradiation

Although RT is the single most effective modality for treatment of locoregional disease not amenable to surgical intervention, the cure rates for patients with bulky central or regionally metastatic disease treated with RT alone left room for improvement. Because RT doses and techniques typically used already approached those associated with conventionally accepted adjacent normal tissue complication rates, many trials have been conducted over the past 3 decades to evaluate the potential benefit of adding systemic agents to primary radiotherapy.

Initial efforts to identify a drug providing radiosensitization focused on the potential role of hydroxyurea with RT. Although several studies reported possible benefits, a recent meta-analysis has concluded that there was no evidence to support the use of hydroxyurea combined with RT in the treatment of cervical cancer.⁹⁵

With data postulating that tumor hypoxia represented a significant cause of treatment failure following RT in patients with bulky cervical cancer, multi-institutional phase III trials consistently showed no improvement in outcome with the use of the first-generation nitroimadazole hypoxic-cell radiosensitizers misonidazole or pimonidazole combined with RT.^96–100 On this basis, in 1996 the National Institutes of Health Consensus Statement on Cervical Cancer stated that there was “no proven benefit to combining chemotherapy with radiation” in locally advanced cervical cancer.¹⁰¹

Subsequently, over a relatively short time span, there was a profound shift in the paradigm of RT in the management of cervical cancer. In February 1999, the National Cancer Institute (NCI) issued a clinical announcement stating that “strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.”¹⁰² This recommendation was based on the results of five phase III randomized clinical trials, conducted in North America under the aegis of the NCI-sponsored Clinical Trials Cooperative Groups. The five studies had different eligibility criteria, but in total included a broad spectrum of clinical presentations: (1) patients with locally advanced tumors for whom chemoradiation represented primary therapy, (2) bulky early-stage cancers in which chemoradiation was delivered prior to adjuvant hysterectomy, and (3) postradical hysterectomy cases with high-risk pathologic factors (positive lymph nodes, positive parametria, positive margins) for whom adjuvant chemoradiation was given. There was a consistent statistically significant survival advantage favoring the RT arm that included a concurrent cisplatin-based regimen, as compared with RT alone or RT combined with hydroxyurea, with a dramatic 30% to 50% decrease in the risk of death from cervical cancer.^103–111 Although now a decade old, the outcome benefit represents the single largest contemporary therapeutic gain in the management of patients with cervical cancer, especially in those with locoregionally advanced disease. Several of these studies, which initially had relatively short follow-up intervals of approximately 3 years, have been updated with significantly longer follow-up periods.^108–110 These confirm that the statistically significant survival advantage of cisplatin-based chemoradiation is maintained over the long term, and they validate the 1999 NCI clinical alert. They also suggest that for future trials in locally advanced cervical cancer, estimates of PFS and OS with median follow-up intervals of 3 years represent fairly mature results.

Cisplatin was a drug of interest because it is the single most active systemic cytotoxic agent in cervical cancer, demonstrated radiosensitizing properties in vitro, had limited adverse effects on hematopoiesis, and showed promise when combined with RT in pilot studies.^112–114 The relatively nonmyelosuppressive properties of cisplatin are important when considering the impact of whole-pelvis irradiation on bone marrow function.

GOG Protocol 85/SWOG 8695

From 1986 to 1990, a total of 368 evaluable patients were entered into the two-arm joint phase III randomized trial of the Gynecologic Oncology Group (GOG) and the Southwest Oncology Group (SWOG).¹⁰³ Eligible cases included locally advanced squamous cell cancer, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix (FIGO stage IIB to IVA), with negative para-aortic nodes and negative intra-abdominal metastases based on surgical staging. Radiotherapy guidelines were identical in both arms. Patients with stage IIB tumors were prescribed 40.8 Gy of EBRT directed to the whole pelvis in 24 fractions (1.7 Gy per fraction), followed by low-dose-rate (LDR) brachytherapy in one or two applications, for an additional dose of 40 Gy to point A, or a cumulative point A dose of 80.8 Gy. Further limited supplemental parametrial EBRT was permitted to bring the point B dose to 55 Gy (combining both EBRT and brachytherapy contributions). Patients with stage III or IVA tumors received 51 Gy of EBRT in 30 fractions to the whole pelvis, followed by intracavitary brachytherapy delivering an additional dose of 30 Gy to point A (cumulative point A dose of 81 Gy), plus an optional parametrial boost to bring point B to a total dose of 60 Gy. Patients randomized to the control arm received hydroxyurea orally at a dose of 80 mg/kg twice weekly during EBRT. Patients in the experimental arm received cisplatin and 5-fluorouracil (5-FU) during weeks 1 and 5 of EBRT. Cisplatin was given as a slow intravenous bolus at 50 mg/m² on days 1 and 29, and 5-FU was delivered as a 4-day infusion of 1000 mg/m² per 24 hours on days 2 to 5 and 30 to 33 of EBRT.

With a median at-risk follow-up interval of 8.7 years, there were statistically significant improvements in disease-free survival (DFS) and OS favoring the patients treated with cisplatin and 5-FU (5-year OS of 62% in the cisplatin/5-FU arm vs. 50% in the hydroxyurea arm; p = .018) (Fig. 56-3). Analysis of patterns of first sites of relapse did not identify significant differences between the two treatment groups. The cisplatin/5-FU arm was associated with a lower incidence of severe or life-threatening leukopenia. Although there was a slight increase (not statistically significant) in acute gastrointestinal toxicity in the cisplatin/5-FU arm, the overall late complication rates at 3 years were identical for both patient cohorts.¹⁰³

Figure 56-3 Overall survival by treatment arm in GOG 85 (p = .018).

From Whitney CS, Sause W, Bundy BN, et al: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17:1344, 1999, Figure 2. Reprinted with permission from the American Society of Clinical Oncology.

GOG Protocol 120

While awaiting the maturation of data from GOG 85/SWOG 8695, the GOG conducted another phase III randomized trial of concurrent chemoradiation in patients with locally advanced cervical cancer.¹⁰⁴ Eligibility criteria for GOG 120 were similar to those in the previously described GOG 85, and included patients with locally advanced (FIGO stage IIB to IVA) cervical cancer with negative para-aortic nodal and intraperitoneal metastases following surgical staging. Radiation guidelines in this study were identical to those in GOG 85/SWOG 8695, and were held constant across all three study arms. Given that the results from GOG 85/SWOG 8695 were not yet known, the control arm was also set up as hydroxyurea given concurrently with RT, with the drug given at 3 g/m² twice weekly during EBRT. The two experimental arms each contained cisplatin but with different schedules. In one arm, patients received cisplatin at 50 mg/m², followed by infusional 5-FU at 1000 mg/m²/day for 4 days, starting on days 1 and 29 of EBRT (similar to GOG 85/SWOG 8695), and hydroxyurea at 2 g/m² twice weekly throughout EBRT. In the other cisplatin treatment group, patients received cisplatin as the sole chemotherapy agent at 40 mg/m² weekly during EBRT.

A total of 526 analyzable patients were entered into this trial from 1992 to 1997. With a median at-risk follow-up interval of 35 months, there was a significant improvement in PFS and OS favoring both cisplatin-containing arms over the arm with RT and hydroxyurea alone. Actuarial 3-year OS was 65% for both cisplatin-containing arms versus 47% for the hydroxyurea alone group (p <.005 for both cisplatin-containing arms compared with the hydroxyurea cohort) (Fig. 56-4). Patients in both cisplatin-treated groups had a significantly lower frequency of pelvic relapse (19% to 20%) compared with the patients receiving hydroxyurea alone (30%). There was also a slight reduction in distant failures favoring the cisplatin-treated patients, but this did not reach statistical significance. Although both cisplatin-containing arms had essentially identical PFS and OS, treatment with cisplatin alone resulted in significantly less acute toxicity than with the three-drug regimen, and hence it was selected as the preferred regimen from this study.¹⁰⁴

Figure 56-4 Overall survival by treatment arm in GOG 120 (p <.005 for both cisplatin-containing arms compared with the hydroxyurea control group).

From Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based chemoradiation improves progression-free and overall survival in advanced cervical cancer. Results of a randomized Gynecologic Oncology Group study. N Engl J Med 340:1144-1153, 1999.

A published update of this study, with a median at-risk follow-up interval of 106 months, confirmed prolonged improved PFS and OS favoring the cisplatin-containing chemoradiation arms, with the survival benefit seen for both stage IIB and IIIB presentations.¹⁰⁹ Within the limitations of the available follow-up data, there was no observed increase in late toxicity with cisplatin-based chemoradiation.

RTOG Protocol 90-01

One of the many studies performed is of particular importance because it influences understanding of potential control of clinically occult para-aortic nodal disease. From 1990 to 1997, the Radiation Therapy Oncology Group (RTOG) conducted a phase III randomized trial (RTOG 90-01) comparing RT alone with concurrent chemoradiation^105,108 (Fig. 56-5). Eligible patients included women with FIGO stage IIB to IVA locally advanced epithelial cervical cancers, as well as those with earlier-stage IB to IIA tumors if the primary lesion size was 5 cm or larger or if there were biopsy-proved pelvic nodal metastases. Patients with known extrapelvic disease, as evaluated by bipedal lymphangiography or retroperitoneal surgical staging, were ineligible. Based on an earlier RTOG study that indicated a benefit of prophylactic para-aortic nodal RT in patients with stage IB2 to IIB cancers,¹¹⁵ the control arm of RT alone included contiguous extended-field coverage to the L1 to L2 vertebral interspace. The pelvis and para-aortic nodes were prescribed a dose of 45 Gy in 25 fractions, supplemented by LDR intracavitary brachytherapy to boost the point A cumulative dose to at least 85 Gy. Institutions were allowed to initiate brachytherapy earlier, at an EBRT dose of 20 to 30 Gy, provided that the final point A dose specification was adhered to and that further pelvic EBRT be delivered with a midline block. In the experimental arm, patients were selected to receive pelvic RT only, with the superior field edge defined at the L4 to L5 vertebral interspace. With the exception of eliminating prophylactic para-aortic coverage, EBRT parameters for the experimental arm were similar to those of the control group. Concurrent with RT, patients randomized to the experimental group received three cycles of cisplatin/5-FU chemotherapy (cisplatin 75 mg/m², 5-FU 1000 mg/m²/day for 4 days) administered at 3-week intervals, with the third cycle often given at the time of brachytherapy insertion.^105,108

Figure 56-5 Updated overall survival by treatment arm in RTOG 90-01, comparing concurrent chemoradiation (CT-RT) with extended-field radiotherapy alone (EFRT) (p <.0001).

From Eifel PJ, Winter K, Morris M, et al: Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer. An update of Radiation Therapy Oncology Group trial (RTOG) 90-01. J Clin Oncol 22:876, 2004, Figure 1. Reprinted with permission from the American Society of Clinical Oncology.

A total of 388 analyzable patients were included. At a median at-risk follow-up interval of 43 months, preceding the NCI clinical announcement, there was a statistically significant advantage for DFS and OS favoring the chemoradiation arm.¹⁰⁵ Actuarial 5-year OS was 73% in patients treated with chemoradiation compared with 58% in patients treated with extended-field RT alone (p = .004).

The initial results of RTOG 90-01 were updated in the 388 analyzable patients with a median at-risk follow-up duration of 6.6 years.¹⁰⁸ The significant outcome benefit of concurrent chemoradiation over RT alone has been maintained, with an 8-year OS of 67% versus 41%, respectively (p <.0001) (see Fig. 56-5). In a post hoc analysis, the advantage of chemoradiation was noted regardless of FIGO stage (IB and II vs. III and IVA), pelvic nodal involvement, or the method of pretherapy nodal evaluation (lymphangiography vs. retroperitoneal nodal staging). The rate of cumulative overall grade 3 or higher late complications was similar in both treatment groups (14% at 5 years). Analysis of patterns of failure noted a significant reduction in locoregional and distant metastasis (excluding the para-aortic nodes) relapse rates favoring the patients treated with RT and concurrent cisplatin/5-FU. Although there was a slightly higher para-aortic failure rate in patients receiving chemoradiation compared with extended-field RT alone, this did not reach statistical significance.

The patterns of failure recorded in RTOG 90-01 (Table 56-3) may allow the hypothesis that concurrent chemotherapy not only provides locoregional radiosensitization but also addresses preexisting micrometastases, although it should be recognized that the risk of distant metastases is closely linked to the incidence of pelvic failure, which was higher in the control arm.³⁹ At the very least, this trial indicates that for patients at some but variable risk of para-aortic nodal metastases, albeit without grossly identifiable disease, chemoradiation with irradiation limited only to the pelvis achieves better outcomes than extended-field irradiation alone without chemotherapy.

GOG Protocol 123

From 1992 to 1997, the GOG conducted a phase III randomized trial comparing preoperative treatment with RT versus RT and concurrent cisplatin in patients presenting with an earlier tumor stage than those included in the preceding three described studies.¹⁰⁶ Eligible patients were those with stage IB2 cervical cancers (≥4 cm tumor diameter), with no evidence of retroperitoneal adenopathy on radiologic (CT or lymphangiography) or surgical assessment. Radiotherapy specifications were identical in both treatment arms. The pelvis was prescribed a dose of 45 Gy in 25 fractions with EBRT, followed by LDR intracavitary brachytherapy to boost the cumulative point A dose to 75 Gy. In the experimental arm, patients received weekly cisplatin at a dose of 40 mg/m² (with a maximal dose of 70 mg/week) for up to six doses. The final dose of cisplatin could be given during brachytherapy insertion. Based on the interim results of a previous GOG trial that evaluated the role of adjuvant hysterectomy in centrally bulky tumors (GOG 71), all patients in this study underwent extrafascial hysterectomy following either RT alone or RT plus concurrent cisplatin.

A total of 369 patients were evaluated, with a median at-risk follow-up interval of 36 months. Patients who received concurrent cisplatin had a significantly higher incidence of pathologic complete response in the hysterectomy specimen, as well as improved rates of pelvic control, PFS, and OS compared with those treated without chemotherapy. Three-year OS was 83% and 74% in the chemoradiation versus RT arms, respectively (p = .008)¹⁰⁶ (Fig. 56-6). Although there was an increase in acute toxicities in the patients treated with cisplatin and radiation, these reactions were predominantly of transient hematologic perturbations, and severe late toxicities were infrequent and equally divided between the two groups. An updated analysis of this study, with an extended at-risk follow-up duration of 101 months, confirmed that concurrent weekly cisplatin with RT maintained significant long-term PFS and OS benefit compared with RT alone, without a reported increase in serious late effects.¹¹⁰

Figure 56-6 Overall survival by treatment arm in GOG 123 (p = .008).

From Keys HW, Bundy BN, Stehman FB, et al: A comparison of weekly cisplatin during radiation therapy versus irradiation alone, each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma. A randomized trial of the Gynecologic Oncology Group. N Engl J Med 340:1154-1161, 1999. Copyright © Massachusetts Medical Society. All rights reserved.

Intergroup 0107 (SWOG 8797/GOG 109/RTOG 91-12)

The last of the five phase III trials that formed the basis for the 1999 National Institutes of Health (NIH) clinical announcement investigated the role of chemoradiation as an adjunct to primary surgery for patients with clinical early-stage disease in whom postoperative high-risk pathologic features had been discovered.¹⁰⁷ Patients eligible for this intergroup study were those with stage IA2, IB, or IIA carcinoma of the cervix who were initially treated with radical hysterectomy and pelvic lymphadenectomy and who were found to have positive pelvic lymph nodes, positive margins, and/or positive parametrial infiltration on microscopic evaluation. Taken together, these high-risk factors have the unifying theme of pathologically identified extracervical/extrauterine disease extension. In this two-arm trial, patients were randomized to pelvic RT alone (EBRT to 49.3 Gy in 29 fractions, without brachytherapy) or to the same irradiation combined with chemotherapy. Chemotherapy consisted of cisplatin (70 mg/m²) and 5-FU (1000 mg/m²/day for 4 days) given for four cycles beginning on days 1, 22, 43, and 64 of therapy. Two of the chemotherapy cycles were delivered concurrently with pelvic RT, followed by two additional cycles after completion of EBRT.

A total of 243 eligible patients were entered into the trial from 1991 to 1996. With a median at-risk follow-up time of 42 months, patients receiving combined adjuvant chemoradiation had statistically significant improvement in PFS and OS compared with those receiving RT alone. Estimated 4-year OS was 81% versus 71% for the chemoradiation and RT only arms, respectively (p = .007) (Fig. 56-7). The outcome benefit for adjuvant chemoradiation appeared to arise from reduction in both pelvic and distant failures, although comparisons of relapse patterns between treatment arms did not reach statistical significance. There was an increase in acute toxicities in the combined-modality arm, but these were mostly limited to transient and manageable hematologic and gastrointestinal effects.¹¹¹

Figure 56-7 Overall survival, by treatment arm, in Intergroup protocol 0107, comparing postoperative chemoradiation (CT+RT) with irradiation alone (RT) (p = .007).

From Peters WA, Liu PY, Barrett RJ II, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjunctive therapy after radical surgery in high-risk, early-stage carcinoma of the cervix. J Clin Oncol 18:1609, 2000, Figure 2. Reprinted with permission from the American Society of Clinical Oncology.

National Cancer Institute of Canada Trial

In contrast to the consistent therapeutic benefits seen for combining cisplatin-based chemoradiation in the preceding five phase III trials, the National Cancer Institute of Canada (NCIC) published the results of another randomized study that questioned the role of concurrent chemoradiation in locally advanced cervical cancers.¹¹¹ Eligible patients included those with stage IIB to IVA squamous cell cancers or earlier-stage disease (IB to IIA) if the primary tumor was at least 5 cm in diameter or if there was histologically positive pelvic nodal involvement. Radiation specifications, which were identical in both treatment arms, prescribed a dose of 45 Gy in 25 fractions to the pelvis with EBRT. This was followed by intracavitary brachytherapy using various allowable dose rates, but each calibrated to provide an LDR biologically equivalent dose of 35 Gy to point A (total cumulative point A dose of 80 Gy in conventional equivalents). Careful quality control was maintained to complete all RT within 7 weeks. Patients randomized to receive chemotherapy were given weekly cisplatin at a dose of 40 mg/m² for a total of five administrations concurrently with EBRT.

Between 1991 and 1996, 253 eligible patients were entered into the trial. With a median at-risk follow-up of 82 months, there were no observable differences in PFS or OS in the two treatment arms (Fig. 56-8).

Figure 56-8 Overall survival by treatment arm (chemoradiation; irradiation alone) in the National Cancer Institute of Canada (NCIC) study (p = .53).

From Pearcey R, Brundage M, Drouin P, et al: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20:970, 2002, Figure 3. Reprinted with permission from the American Society of Clinical Oncology.

Various reasons for the lack of a demonstrable effect of cisplatin concurrent with RT in the NCIC study have been promulgated by the authors and others. These include the lack of surgical staging, a relatively small sample size, the confounding factor of treatment-related anemia in the chemotherapy arm, and the omission of 5-FU (which may be synergistic with cisplatin) from the chemotherapy regimen. Perhaps most provocative is the suggestion that concurrent cisplatin-containing chemoradiation exhibits its greatest benefit primarily in patients with suboptimal and prolonged overall RT durations. In contrast to the studies reported by Whitney¹⁰³ and Rose,^104,109 where the median duration of the treatment course was 64 and 62 days, respectively, the timing for completion of RT in the NCIC study was carefully controlled, with a median duration of 51 days.¹¹¹ The potential reduced impact of concurrent cisplatin with optimum RT schedules has been refuted by others, however.¹¹⁶ Nonetheless, the NCIC authors conclude that despite their negative trial, “the balance of evidence favors the use of combined-modality treatment for the types of patients studied in this trial. The best results are certainly achieved by careful attention to RT details, including dose and overall delivery time, the use of brachytherapy whenever possible, and probably the addition of concurrent cisplatin chemotherapy to RT.”¹¹¹

Chemotherapy Concurrent with Irradiation: A Synopsis

In an overview, Rose and Bundy¹¹⁶ summated the collective results of the six North American randomized trials (including the NCIC study) and showed a cumulative and statistically significant 36% reduction in the risk of death favoring combined cisplatin-based chemoradiation over RT alone or combined with hydroxyurea¹¹⁶ (Fig. 56-9). The generalizability of concurrent chemoradiation for cervical cancer to an unselected, non–study-limited patient population has also been raised. In part, this has been addressed by a provocative population-based cohort study of cervical cancer outcome in Ontario, Canada. In this analysis, Pearcey and colleagues¹¹⁷ showed a significant improvement in cervical cancer OS at the population level between 1992 and 2001, without a coincident change in stage presentation or an imbalance in cases selected for primary surgery. The investigators attribute the survival gains to the generalized and appropriate use of concurrent, predominantly cisplatin-based chemoradiation in the majority of patients receiving RT for cervical cancer.¹¹⁷

Figure 56-9 Reduction in the risk (1, relative risk) of death from six chemoradiation clinical trials in cervical cancer, with 95% confidence intervals. A value above 0 represents a benefit for cisplatin-containing chemoradiation. Cis, cisplatin; 5-FU, 5-fluorouracil; H, hydroxyurea; SWOG, Southwest Oncology Group (Intergroup protocol 0107).

From Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer. Does it help? J Clin Oncol 20:891, 2002, Figure 1. Reprinted with permission from the American Society of Clinical Oncology.

Although cisplatin-based chemoradiation has formed the basis for most discussions and conclusions regarding the superiority of combined-modality therapy, more recent data suggest that other nonplatinum agents, most notably 5-FU and/or mitomycin C, may also provide benefit when used concurrently with definitive radiotherapy. A recent updated and comprehensive meta-analysis of chemoradiation for locally advanced cervical cancer confirmed the general applicability of this treatment algorithm for all women and endorsed the NCI alert regarding the use of concomitant cisplatin-based chemoradiotherapy but also indicated that similar gains could be derived from non–platinum-based chemotherapy.¹¹⁸

In North America, where cisplatin-based chemoradiation is currently considered the standard of care, there remains ongoing debate as to what specific regimen to use when cisplatin is combined with RT. The GOG has selected weekly cisplatin at 40 mg/m² (maximum 70-mg weekly dose) for up to six cycles, concurrent with EBRT, as its foundation for chemoradiation of cervical cancer. Others believe that 5-FU should not be omitted and therefore combine cisplatin at 50 to 75 mg/m² with 5-FU at 1000 mg/m²/day for 4 days, given on a 3-week cycle. It is clear that hydroxyurea is no longer a drug of interest in the context of chemoradiation for cervical cancer. Taken in total, the overall data provide compelling support for the use of chemoradiation in all cervical cancer patients, except perhaps for those with the earliest presentations of disease.

It should be emphasized, however, that RT remains the single most effective modality in the management of patients with locally advanced cervical cancer, where surgical extirpation of tumor is infeasible or incomplete. Even in the absence of chemotherapy, RT alone is able to cure many patients with bulky cervical tumors. Some patients present with hydronephrosis and renal dysfunction or other medical comorbidities that preclude the use of cisplatin. The use of concurrent carboplatin, which avoids nephrotoxicity, has been suggested by some as an alternative to cisplatin, but its comparative efficacy remains unproven.¹¹⁹ Ultimately, the selection of concurrent cisplatin-based chemotherapy requires sound medical judgment, balancing the potential improvement in tumor control with patient physiology, disease presentation, and the increased acute toxicities (notably, hematologic, metabolic, and gastrointestinal) associated with the addition of chemotherapy.

Neoadjuvant Chemotherapy

Although concurrent cisplatin-based chemoradiation has become the widely accepted standard of care, caution is raised regarding the use of strategies employing neoadjuvant chemotherapy before RT. Multiple randomized trials, most with small patient numbers, have failed to identify an effective strategy of neoadjuvant chemotherapy followed by definitive RT. A systematic review and individual patient data meta-analysis showed no benefit and, indeed, an overall trend to detriment, for patients receiving neoadjuvant chemotherapy (predominantly cisplatin-based) before radical RT.¹²³ In two of the randomized trials, it was reported that the neoadjuvant chemotherapy approach, although associated with a reasonable initial response, ultimately resulted in statistically significant inferior pelvic control and OS compared with definitive RT alone.^124,125

A plausible explanation for the lack of benefit seen with chemotherapy preceding RT is that although responses can be seen with systemic cytotoxics alone, the remaining clonogens undergo accelerated repopulation, thereby offsetting the efficacy of RT.¹²⁶ Questions remain regarding the potential benefit of initial chemotherapy in surgical candidates or where the dose and intercycle interval of systemic agents are optimized, but the use of neoadjuvant chemotherapy strategies should be considered only in the context of carefully designed clinical trials. Unless more effective cytotoxic agents are identified, there is no current reason to consider neoadjuvant chemotherapy followed by definitive RT or chemoradiation in patients with localized, curable cervical cancer.

Brachytherapy Plus External Beam Irradiation

The importance of brachytherapy in the curative treatment of intact cervical cancer is indisputable. Clinicians have sometimes been inclined to deemphasize the use of brachytherapy in patients with FIGO stage III disease, arguing that disease at the pelvic wall is beyond the reach of traditional intracavitary therapy. Reports from the Patterns of Care Study¹²⁷ and from the M.D. Anderson Cancer Center (MDACC),⁹⁴ however, have demonstrated significantly better survival rates for patients treated with a combination of EBRT and intracavitary irradiation. In the MDACC report of 1007 patients treated with irradiation for FIGO stage IIIB disease, the disease-specific survival (DSS) was 43% for patients who had intracavitary irradiation versus 21% for those treated with EBRT alone. Patients treated during periods when policies emphasized the use of brachytherapy had significantly better survival rates. Patients who received higher doses of EBRT (and concomitantly lower doses of intracavitary irradiation) to the central pelvis had poorer survival rates. The rate of major complications was also correlated with the proportion of central pelvic treatment given with EBRT, and this correlation suggested that the therapeutic ratio narrows when the dose of EBRT given to the whole pelvis exceeds 45 Gy.⁹⁴ Nonetheless, a careful balance between EBRT and brachytherapy components of therapy, accounting for tumor volume, anatomic presentation, and disease regression rate, represents the hallmark of appropriate cervical cancer radiotherapy planning.

Radiation Dose and Duration

In general, a cumulative dose (linear-quadratic dose equivalent [LQED] 2 Gy per fraction or LDR equivalent) of 80 to 85 Gy or higher to point A is considered desirable for patients receiving primary RT for locally bulky cervical cancer (stage IB2 to IVA), with a dose of at least 45 Gy to all volumes at risk for microscopic tumor spread. These dose levels represent current protocol standards for large cooperative groups such as the GOG and the RTOG. Although these dose guidelines are widely quoted, the dose prescription should clearly be carefully tailored to tumor- and patient-specific factors. Smaller and earlier tumors (stage IA to IB1) may be treated to somewhat lower overall doses of 75 to 80 Gy. There are no widely accepted and generalized guidelines for the balance of dose delivery from one component versus the other, and decisions are often guided by institutional preference. Many centers favor initiating whole-pelvis EBRT to a dose of 40 to 45 Gy before proceeding with brachytherapy. Gross parametrial or pelvic nodal disease can then be boosted with limited and conformal EBRT fields, blocking critical central pelvic structures, to a cumulative dose of 55 to 65 Gy, or even higher (combining EBRT and brachytherapy components), depending on disease volume and the ability to avoid adjacent normal tissues. Other institutions prefer to emphasize and initiate brachytherapy earlier, at whole-pelvis EBRT doses of 20 to 30 Gy, especially for patients with earlier-stage and smaller-volume disease. EBRT is then continued to the pelvis, with or without midline blocking. Although recommendations have been made to try to limit the rectal and bladder reference points to maximal summated doses of 70 Gy and 75 Gy, respectively, it is recognized that the most important consideration is to deliver adequate tumoricidal doses, even if the normal tissue dose recommendations are somewhat exceeded. On the other hand, a total point A dose of 85 to 90 Gy for intact bulky cervical cancer probably represents a reasonable limit, based on integral doses to surrounding normal pelvic structures, and there is no evidence that continued escalation of the RT dose to central structures will result in further therapeutic gain. For adjuvant RT following primary surgery, where there is no gross tumor residual, an EBRT dose of 45 to 50 Gy to the pelvis is considered tolerable.

These preceding dose discussions are based on a conventional EBRT fractionation of 1.8 to 2 Gy daily and LDR brachytherapy. The use of altered fractionation or, in particular, high-dose-rate (HDR) brachytherapy necessitates a different system of reference doses and is discussed in greater detail later.

The adverse impact of treatment duration protraction in cervical cancer has been evaluated by several investigators. There is general consensus that prolonging a course of radical RT beyond approximately 7 weeks is associated with a 0.5% to 1% decrease in pelvic control per extra day.^128–133 Although debate remains about whether an increase in treatment duration adversely affects outcome or is simply a reflection of unfavorable tumor or patient characteristics, there is compelling radiobiologic demonstration of accelerated tumor repopulation that mitigates the efficacy of RT.¹²⁶ In contrast, there is no evidence that prolongation of treatment duration results in a reduction of late normal tissue sequalae.¹³³ Therefore it is now considered prudent to complete a course of definitive RT for cervical cancer within 7 to 8 weeks by eliminating all elective treatment breaks, delivering EBRT parametrial boosts between, or interdigitated with, brachytherapy insertions, and actively supporting patients through acute toxicities so as to avoid RT interruptions.

Role of Extended-Field Irradiation

The prognosis of patients with cervical carcinoma is inversely related to the extent of regional and nodal involvement. Because hematogenous metastasis is usually a late event in the course of this disease, however, patients with lymph node metastases often can be cured with regional EBRT if pelvic disease can be controlled. Even patients with documented para-aortic lymph node metastases have 5-year OS of 20% to 50%, depending on the extent of pelvic disease.^134–139

Two groups have explored the use of prophylactic extended-field EBRT in patients who do not have overt para-aortic metastases. A trial from the European Oncology and Radiation Therapy Consortium (EORTC)¹⁴⁰ was conducted prior to the use of concurrent chemotherapy. Randomized patients had more locally advanced pelvic disease (bulky FIGO stage IIB, FIGO stage III, or biopsy-proved pelvic lymph node metastases). DFS of patients in the two treatment arms was not significantly different at 4 years, although the rate of relapse in the para-aortic lymph nodes was higher in patients who had not received RT to this site. OS was not reported. Results from RTOG 90-01 were previously discussed.

Although the role of prophylactic para-aortic nodal RT remains to be fully defined, the results of RTOG 90-01 clearly indicate that concurrent chemotherapy with pelvic RT leads to significant outcome benefits over extended-field EBRT without chemotherapy.¹⁰⁸ Underlying the question of benefits of prophylactic para-aortic RT is the assumption that the para-aortic nodes may represent isolated occult extrapelvic disease in some patients for whom sterilization by RT would translate to cure (assuming achievable pelvic control and no distant metastases). The results of RTOG 90-01, which showed significant reductions in both pelvic and distant relapse with chemoradiation, suggest that the use of concurrent chemotherapy to some degree addresses subclinical metastases beyond the volume of RT. Unanswered is the question of whether prophylactic extended-field RT in addition to systemic chemotherapy would provide additional therapeutic gain.

Practice patterns vary for patients with negative para-aortic nodes but who are deemed to be at elevated risk for occult disease in this nodal chain. At the University of Washington, prophylactic para-aortic nodal EBRT to 45 Gy, concurrent with chemotherapy (to the level of the renal vessels, or at the L1 to L2 vertebral interspace), is often considered for patients with the highest potential risk of subclinical para-aortic disease (i.e., those with common iliac adenopathy on surgical staging or those who have negative para-aortic nodes but extensive pelvic lymphadenopathy by radiologic imaging [recognizing the limitations of even the best imaging modalities to detect microscopic tumor]). Whereas the efficacy of such an extended-field prophylaxis approach has not been proven, especially in the era of chemoradiation, the use of concurrent cisplatin-based chemotherapy with extended-field RT has been shown to be tolerable in several phase II trials.^138,139

Impact of Anemia and Tumor Hypoxia on Radiation Therapy Outcome: Potential as Therapeutic Targets

The adverse association of anemia on outcome following primary RT for cervical cancer has been well documented in many previous clinical reviews.^140–142 Whether this association reflects cause and effect or whether anemia is simply a surrogate for worse prognostic and predictive variables, such as larger and more radiation-refractory tumors, is still being debated. Potential mechanisms for a negative impact of anemia on cervical cancer RT outcomes may be linked to tumor hypoxia and consequent radioresistance, as well as induction of angiogenesis, increased tumor aggressiveness, and enhanced metastatic potential.

Some retrospective reports have suggested that anemia is an independent negative prognostic factor, with the average hemoglobin level during RT being more predictive than the level before therapy.^143,144 Only one small prospective randomized trial directly addressing the value of transfusion has been completed, in the 1970s. This study indicated improved pelvic control for irradiated patients whose hemoglobin level was corrected by transfusion, but the analysis was hampered by limited patient numbers and lack of stratification.¹⁴⁵

In an attempt to provide definitive answers, the GOG conducted a prospective phase III trial (GOG protocol 191) in which patients with locally advanced cervical cancer undergoing primary chemoradiation (concurrent weekly cisplatin at a dose of 40 mg/m²) were randomized to hemoglobin maintenance at a level of 10 g/dL versus aggressive intervention to raise hemoglobin levels to 12 to 13 g/dL (by transfusion and erythropoietin). However, concerns about an increased incidence of thromboembolic events and a possible negative impact on survival associated with erythropoietin in several other disease sites, while not statistically significant in this trial, led to its early closure, leaving the impact of maintaining optimal hemoglobin levels on outcome following chemoradiation still undetermined.¹⁴⁶ Although erythropoiesis-stimulating agents have been previously used to correct anemia, and may be considered in highly selected cases, their generalized use is currently discouraged, due to concerns of thromboembolism and possible tumor progression.¹⁴⁷

As standard of practice, radiation oncologists attempt to maintain patient hemoglobin levels at generally 10 g/dL during treatment for cervical cancer. Although the impact of maintaining this hemoglobin level on tumor control is unclear (recognizing that the studies discussed above had noted optimal outcome at hemoglobin levels of 12 g/dL), it is recognized that lower hemoglobin levels adversely affect patient quality of life and may affect the ability to tolerate aggressive chemoradiation. Besides the use of transfusion, every effort should be made to minimize cervical trauma and blood loss during a patient’s evaluation and treatment. Local hemostatic agents (Monsel’s solution) and vaginal packing should minimize blood loss after necessary biopsies and examinations. When local hemostatic measures fail to control bleeding, radiotherapeutic hemostasis may be achieved with prompt initiation of EBRT, possibly using 2 or 3 days of hyperfractionated pelvic RT. In patients with curable cancers, use of a hyperfractionated EBRT approach (e.g., 1.5 to 1.8 Gy per fraction twice daily for 2 to 3 days) achieves the same likelihood of hemostasis as larger daily fractions while preserving normal tissue tolerance and ultimate treatment planning flexibility. Although some authors have recommended emergency intracavitary therapy to control bleeding, this approach may likely compromise subsequent curative treatment or be infeasible.

Tumor hypoxia, as measured by oxygen electrodes, has been identified in many cervical cancers and is a predictor of poor outcome.¹⁴⁸ Although there may be a link, the relationship between host status (anemia and hemoglobin level) and tumor milieu (hypoxia) remains ambiguous. To exploit hypoxia as a potential therapeutic target, the GOG opened a randomized phase III trial (GOG 219) that investigated the efficacy of a new-generation bioreductive drug, tirapazamine, added to the present standard of concurrent cisplatin and RT for locally advanced cervical cancer. In addition to its radiosensitizing effects, tirapazamine had generated significant interest because it is itself a potent and selective hypoxic cell cytotoxin and is also potentially synergistic with cisplatin.^149,150 However, the lack of expected benefit for the combination of tirapazamine, cisplatin, and radiotherapy in a large phase III trial of head and neck cancer,¹⁵¹ and subsequent loss of sponsorship support, led to premature closure of GOG 219.

The issue of anemia and hypoxia as prognostic factors, and therapeutic targets, in cervical cancer remains unresolved. Future trials in this arena will require safer and more tolerable pharmacologic agents and should be limited only to patients in whom radiobiologically significant anemia and/or hypoxia can be accurately and reliably measured.

Recent studies have identified significant modulations of gene expression in hypoxic tumors that may be associated with tumor aggressiveness and progression, including hypoxia-inducible factor 1, TP53, vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor, nitric oxide synthase, and matrix metalloproteinases.¹⁵² These biomolecular markers provide potential new targets for future therapeutic investigations.

Preinvasive Disease

Preinvasive lesions are usually treated with local ablative procedures (cryosurgery or laser ablation) or excisional procedures (loop excision or cervical conization). Hysterectomy is an appropriate treatment option for women with high-grade cervical dysplasia who no longer desire fertility preservation. Ablative treatment is contraindicated if the entire transformation zone has not been well visualized, if there is a marked discrepancy between Pap smear results and colposcopy findings, or if colposcopy evaluation with biopsies leaves unresolved the presence of invasive disease. In these situations, conization should be performed to exclude the presence of invasion. In particular, given the associated challenges in pathologic assessment, patients with adenocarcinoma in situ on cervical biopsy should always undergo conization to assess the presence of invasive adenocarcinoma.

Microinvasive Disease (FIGO Stage IA Disease)

Early microinvasive (FIGO stage IA1) disease is conventionally treated with nonradical abdominal or vaginal hysterectomy after the depth of invasion has been confirmed by cone biopsy. However, for selected patients who wish to maintain fertility and who agree to close follow-up, therapeutic conization of the cervix may be adequate treatment.

Although early microinvasive carcinomas of the cervix (FIGO stage IA1 lesions) are usually treated with hysterectomy, patients with medical contraindications to surgery can be treated very effectively with brachytherapy alone, for which 10-year PFS of 98% to 100% have been reported. Treatment usually consists of one or more intracavitary insertions that deliver a total of 65 to 75 Gy to point A in LDR equivalents, with a maximal vaginal surface dose of 100 to 120 Gy, depending on the extent of microinvasive disease, size of the cervix, and normal tissue anatomy.^158–160

Although the risk of regional lymph node spread from FIGO stage IA2 carcinomas is less than 5%, early reports of conservative surgery for IA2 cervical cancer yielded suboptimal cancer control results.¹⁶¹ Most patients with stage IA2 cervical cancer have, therefore, traditionally undergone radical hysterectomy with node dissection.

More recent analyses, with contemporary emphasis on quality of life, have led to a reappraisal of the surgical extent required for these early-stage tumors. Gadducci and colleagues¹⁶² reviewed the hospital records of 166 patients with microinvasive squamous cell carcinoma of the cervix. Among the 143 cases of stage IA1 and 23 cases of stage IA2 disease, there were 67 patients (stage IA1, 44; stage IA2, 23) who underwent pelvic lymph node dissection, and none had lymph node metastasis. For patients with stage IA2 cervical cancer, the authors concluded that nonradical hysterectomy might be adequate therapy and the need for lymph node dissection was questioned.¹⁶² In another clinicopathologic review of specimens from 394 patients with stage I squamous cell cervical carcinoma, none of the patients with depth of stromal invasion of less than 5 mm had pelvic lymph node metastasis and none of these patients died from recurrent cancer. The authors recommended simple hysterectomy for these early, stage IA tumors (or modified radical hysterectomy with pelvic lymph node dissection for cases of stage IA2 cervical squamous cell carcinoma where lymphovascular space involvement is present).¹⁶³

As with stage IA1 disease, the use of irradiation for stage IA2 cancer is usually reserved for those who refuse, or have medical contraindications to, primary surgery. Brachytherapy alone may be used, with doses to point A of 70 to 80 Gy (LDR equivalents). For patients with lymphovascular space invasion on the cone specimen, a combination of EBRT and intracavitary irradiation may be used, in which 40 to 45 Gy of pelvic EBRT (often with midline blocking) is combined with intracavitary brachytherapy to deliver a cumulative point A dose of 70 to 80 Gy. The five-year cancer-specific survival rate with either surgical or radiation treatment is at least 95%.

Recognizing the outstanding cure rates with RT alone in stage IA cervical cancer, combined with the fact that irradiation is typically used in lieu of primary surgery in such early-stage patients who have significant medical comorbidities, the use of concurrent chemoradiation for these cases is not routinely justifiable. Furthermore, clinical trials to evaluate the role of chemoradiation in this population of patients, who have an excellent cancer control rate, would not be statistically feasible.

Most reports of “microinvasive” cervical cancer have focused on squamous cell tumors. Ceballos and colleagues¹⁶⁴ reported on a series of 32 patients with stage IA1 or IA2 cervical adenocarcinomas treated with hysterectomy (29 patients), radical trachelectomy (2 patients), or cervical conization (1 patient). Postoperative RT was administered to one patient. There were 27 patients who also underwent pelvic lymph node dissections, and none had lymph node metastasis. With a mean follow-up of 54 months, there were no relapses. The researchers recommended less radical surgery for these patients.¹⁶⁴ In another series, none of the 48 women with stage IA1 or IA2 cervical adenocarcinomas had parametrial disease or involved lymph nodes on pathologic assessment of the operative specimens.¹⁶⁴ Smith and co-workers¹⁶⁵ identified 560 cases of early cervical adenocarcinoma (200 with stage IA1, 286 with stage IA2, and 74 with “localized” disease) in the SEER (Surveillance, Epidemiology, and End Results) registry. Simple hysterectomy was performed in 272 (49%) and radical hysterectomy in 210 (38%). Combining their data with all other published series of early cervical adenocarcinomas, they identified 1170 cases, including 585 stage IA1, 358 stage IA2, and 227 “others” with less defined early disease. Among 531 patients who underwent lymph node biopsy, 15 (1.3%) had one or more positive nodes; of these 15 patients, 11 (73%) later relapsed or died. For IA1 versus IA2 disease, there were no significant differences in the frequency of positive lymph nodes, relapse, or death. However, the cases that were considered “others” based on less well defined tumor dimensions, as well as those with lesions larger than IA2, were at increased risk of relapse.¹⁶⁵ The authors concluded that well-defined early invasive adenocarcinoma (stages IA1 and IA2) has an excellent prognosis, and conservative surgery may be appropriate.¹⁶⁶ These retrospective data suggest that the management of patients with stage IA1 and stage IA2 cervical adenocarcinomas need not differ from their counterparts with squamous cell lesions.

FIGO Stages IB and IIA Disease

Primary surgical management is probably best suited for physiologically fit patients with small FIGO stage IB or IIA cervical cancers without clinical evidence of regional metastasis. Depending on the size of the cervical tumor, surgeons may vary somewhat in the extent of resection of the paracervical tissues and uterosacral ligaments (Fig. 56-10). The risk of major complications, particularly bladder and rectal dysfunction or ureteral injury, is proportional to the extent of surgical resection and may therefore be greater when radical hysterectomy is used to treat larger tumors. The ovaries of premenopausal women are usually not removed, which provides an advantage for radical surgery over irradiation in young women with relatively small tumors. Massive obesity and other medical problems that increase the risk of a major pelvic surgical procedure are usually considered relative contraindications to a primary surgical approach.

Figure 56-10 Sites of ligation of the vesicouterine and uterosacral ligaments for a type II or type III radical hysterectomy.

From Berek JS, Hacker NF: Practical Gynecologic Oncology. Baltimore, Williams & Wilkins, 1994, p 256.

Reported results of treatment with radical hysterectomy versus those of RT for FIGO stage IB cervical carcinomas are comparable, with 80% to 90% of patients surviving after 5 years. However, because surgeons tend to select young patients who have relatively small tumors for surgical treatment and to refer patients who have large tumors or evidence of regional spread for RT, the compared findings may be misleading.

For patients with FIGO stages IB and IIA disease, treatment results are strongly correlated with tumor size, and this factor thus influences the appropriate selection of primary therapy. Most FIGO stage IB1 tumors can be treated effectively with radical hysterectomy or combined EBRT and intracavitary irradiation; both have cure rates of 85% to 90%.¹⁶⁷

In a report of the only randomized trial comparing radical surgery (with or without postoperative RT) with RT alone, Landoni and colleagues¹⁶⁸ reported 5-year OS of 87% for patients with FIGO stage IB to IIA tumors of 4 cm or less in diameter treated with primary surgery compared with 90% for patients treated with definitive RT. Morbidity was somewhat greater in patients initially treated with surgery because many also received postoperative pelvic RT per the protocol for parametrial or lymph node involvement, positive tumor margins, or deep invasion into the stroma. In the same study, 5-year OS of patients with bulky FIGO stages IB2 and IIA tumors larger than 4 cm was similar for both treatments (70% for patients treated with surgery and 72% for patients treated with RT). However, 84% of patients with the larger lesions had the aforementioned high-risk features and received postoperative pelvic RT. As a result, morbidity was again greater in patients who had undergone surgery up front, as compared with those who had received definitive RT alone.¹⁶⁸ The equivalent survival results were obtained even though the combined dose of EBRT and LDR intracavitary irradiation used to treat patients in this study (median cumulative dose to point A was 76 Gy) was lower than that recommended by other clinicians.

Although some authors recommend radical surgical treatment for patients with FIGO stage IB2 carcinomas regardless of size, the risk of pelvic recurrence is high for most of these patients unless they also receive adjuvant postoperative RT or CT-based RT. To avoid exposing these patients to the combined risks of a radical hysterectomy and RT, concurrent chemoradiation is often preferred as the primary treatment. For the same reason, other findings that have been associated with an increased risk of pelvic lymph node metastasis and pelvic recurrence (extensive lymphovascular space invasion, deep stromal penetration) are considered by some clinicians to be contraindications to surgery as primary disease management. Unfortunately, the presence or absence of these factors cannot be reliably determined with conventional clinical staging. A recent cohort analysis suggested that elevated preoperative squamous cell carcinoma antigen levels predicted an increased likelihood of postoperative RT and cancer relapse.¹⁶⁹ Although intriguing, these observations should be validated with further studies.

In patients selected for primary RT for stage IB to IIA tumors, the use of concurrent chemotherapy should be based on tumor size and/or the presence of retroperitoneal lymphadenopathy. In small-volume disease (IB1) with no clinical evidence of pelvic nodal disease, RT alone provides excellent tumor control and cure rates. Similar to patients with stage IA tumors, many of these cases are referred for irradiation based on medical conditions that render primary surgery less desirable. However, with increased tumor size (i.e., stage IB2 disease) or the presence of pelvic nodal metastases, present evidence indicates the benefit of concurrent cisplatin-based chemoradiation.

Chemotherapy

Cisplatin has long been considered the most active single chemotherapy agent for the treatment of cervical carcinoma.²¹² Phase III studies comparing cisplatin 50 mg/m² administered as a short infusion with other regimens have not confirmed an advantage with either higher doses or alternative infusion schedules.^213,214 Furthermore, a phase II study conducted by the GOG suggested inferior response rates with the platinum analogs carboplatin and iproplatin.²¹⁵ Subsequent phase II studies have identified a number of drugs with limited single-agent activity against cervical carcinoma, including mitolactol, ifosfamide, paclitaxel, topotecan, gemcitabine, vinorelbine, and bevacizumab^216–222 (see web-only Table 56-1).

In an attempt to improve therapeutic efficacy, a number of phase III trials have investigated the use of drug combinations with cisplatin.^223–227

Compared with cisplatin alone, Omura and colleagues²²³ showed a higher objective response rate and PFS with cisplatin plus ifosfamide; however, there was no improvement in OS, and toxicity rates with combination chemotherapy were significantly increased. Another GOG phase III trial demonstrated no advantage with the addition of bleomycin to the cisplatin plus ifosfamide combination.²²⁴ The GOG has compared single-agent cisplatin with a combination of cisplatin plus paclitaxel with quality-of-life assessments included among outcome measures. The combination of cisplatin plus paclitaxel resulted in a higher objective response rate, longer progression-free survival (PFS), and higher toxicity rate, with no apparent decrement in patient-reported quality of life.²²⁵ A prospective randomized trial comparing cisplatin with cisplatin plus topotecan demonstrated an improvement in OS with the combination regimen.²²⁶ Although statistically significant, many consider the gains clinically unimportant because they are of such short duration.

GOG 204 was a four-arm study comparing four cisplatin doublets with paclitaxel, topotecan, gemcitabine, and vinorelbine. After 513 patients were enrolled, a planned interim analysis recommended early closure of the trial based on the fact that none of the other arms would ever statistically show benefit over the control arm of cisplatin plus paclitaxel, demonstrating the challenge in achieving major progress for this patient population.²²⁷ PFS was as short as 4 to 6 months. Although multiagent systemic therapy remains an active area of investigation, the benefits of salvage chemotherapy remain modest at best (web-only Table 56-2).

It is now recognized that a majority of patients who recur after initial therapy are not platinum-naive, having received platinum-based chemoradiation as definitive or adjuvant therapy. Previous exposure to platinum clearly influences the potential response when platinum is used in a palliative setting. In an analysis of prognostic factors for response to cisplatin-based systemic chemotherapy for recurrent or metastatic disease, Moore and colleagues²²⁸ identified five factors as independent predictors of a poor response: African-American patient, Eastern Cooperative Oncology Group (ECOG) performance status score greater than 0, pelvic disease, prior radiosensitizer, and time interval from diagnosis to first recurrence of less than 1 year. They suggest that with a simple prognostic index, which combines the risk factors, a subgroup of patients can be identified who are very unlikely to benefit from cisplatin-containing regimens and who should be evaluated for other novel investigational agents or best supportive care.²²⁸

The design of the current GOG trial for patients with recurrent/metastatic cervical cancer (GOG 240) uses a 2 × 2 dual randomization scheme. Patients are randomized to cisplatin plus paclitaxel (control arm) versus paclitaxel plus topotecan (a nonplatinum doublet), with a secondary randomization to bevacizumab versus no bevacizumab. It is likely that future trials of salvage systemic therapy for recurrent or metastatic cervical cancer will take into account the prognostic index, such that this patient population will be separated into two or more subsets for clinical investigation, rather than including all patients unselectively in a single overarching study.

Irradiation

Radiation therapy can also play an important role in the palliation of patients with incurable advanced disease. Hypofractionated pelvic irradiation usually controls bleeding and frequently provides some relief of pelvic pain. There is a paucity of data and no randomized trials on optimal palliative irradiation regimens. A variety of fractionation schemes have been used. No standardized instruments for measuring symptom relief have been used.²²⁹ The choice of dose and fractionation schedule will be influenced by expected survival times, patient performance status, symptoms, site(s) and bulk of tumor involvement, adjacent normal tissue considerations, medical comorbidities, and logistic considerations.

The RTOG reported the results of a phase I/II study in which patients with advanced pelvic malignant disease were given up to three fractions of 10 Gy at 1-month intervals with misonidazole.²³⁰ The overall objective response rate was 57%, but the rate of grade 3 and 4 toxicities was high (45%), although it is unclear if some of the complications may have been due to tumor progression. Studies of the MDACC experience with this method have demonstrated a symptomatic response rate of approximately 75% with two fractions of 10 Gy but have also revealed an unacceptable rate of major complications when a third fraction of 10 Gy was given.^231,232

In a second RTOG study, accelerated split-course EBRT was used as palliative treatment for patients with advanced pelvic malignant disease. Patients received up to three courses of 14.8 Gy given in 3.7-Gy fractions twice daily over 2 days. A 3- to 6-week rest interval was given between courses. Patients who completed three courses of EBRT had an overall response rate of around 60%, with complete relief of pain achieved in 50% of patients.²³³

Other typically used fractionation schemes, such as 30 Gy in 10 fractions or 20 Gy in 5 fractions, have been used with some success. Prolonged fractionation is rarely indicated for palliation of patients with extraregional metastases from cervical cancer because the median life expectancy for these patients is very short. Above all, these patients benefit from close monitoring of their symptoms; prompt, aggressive treatment with analgesic drugs; and sensitive, supportive care. Anesthetic or neuroablative treatments may be helpful in selected cases, and prompt referral to a multidisciplinary pain service is warranted for patients with intractable pain.

Low-Dose-Rate Intracavitary Therapy

Historically, until the early 1980s, most intracavitary therapy was delivered using radioactive radium (radium-226 [²²⁶Ra]). Cesium-137 (¹³⁷Cs), an artificially produced isotope of similar average energy, gradually began to replace ²²⁶Ra in most practices. Because the half-life of ¹³⁷Cs is only about 30 years, the sources had to be replaced periodically. Commercially available cesium sources are usually slightly shorter (≤17 to 20 mm) than ²²⁶Ra sources. Therefore standard loadings designed for radium produce higher dose rates to critical structures if short cesium sources are used without spacers.

Many intracavitary applicator systems have been used to position sources in the uterus and vagina. All include a central uterine tandem; the major differences are in the design of the vaginal source holders. In the United States, most radiation oncologists use some variation of the Fletcher-Suit-Delclos applicator system that was first developed at the MDACC. The most characteristic feature of this system is the pair of cylindrical vaginal colpostats that are placed against the cervix on either side of the tandem. Ideally, these holders position the axis of the vaginal sources approximately perpendicular to the uterine tandem (Fig. 56-17). This positioning is designed to take advantage of the anisotropy of the sources, and, combined with the anterior and posterior tungsten shields incorporated in the design, to reduce the volume of bladder and rectum exposed to high doses of radiation while spreading the dose laterally to the parametria. For patients with a narrow vagina, unshielded miniovoids and Lucite cylinders of various sizes can be used to position the intravaginal sources. Another applicator system used successfully by a number of groups, including the Memorial Sloan-Kettering Cancer Center, is the Henschke applicator. With this system, the vaginal sources are positioned parallel to the axis of the intrauterine tandem.

Figure 56-17 Lateral views of Fletcher-Suit-Delclos intracavitary placements in a young woman with a FIGO IB2 endocervical tumor. A, The patient had a very pliable vagina, and aggressive packing pushed the uterus and the system high in the pelvis against the sacrum, potentially trapping bowel between the intracavitary system and the sacrum. B, The system was repacked using a suture slipped through the cervix to provide countertraction during packing. This kept the system lower in the pelvis, but the ovoids were allowed to fall posteriorly. This position can lead to overdosage of the rectum, particularly cephalad to the ovoids. C, A second repacking resulted in a good placement with acceptable positioning of the system midway between the sacrum and bladder. Ovoids are bisected by the tandem and are close to the cervical marker seeds; posterior packing protects the rectum. It is rare to need two adjustments of an intracavitary system, but the significant improvement achieved with this effort should improve the therapeutic ratio for this patient and underscores the importance of intraoperative radiographs in cervical cancer brachytherapy.

Today, all these systems are afterloading, to minimize personnel exposure to the radiation. Radiation exposure from LDR implants can be further reduced to negligible levels with computerized remote afterloading equipment that removes the cesium sources automatically when persons enter the room.

Successful intracavitary therapy requires experience, skill, some pragmatism, and a willingness to persist until an “optimal placement” has been achieved.²⁵⁹ Radiation sources must be positioned in the uterus and vagina in a way that avoids underdosing areas in the cervix and paracervical tissues, with a sensitivity to the limits of mucosal tolerance. Every tumor presents a somewhat different challenge because of the wide variations in tumors and patient anatomy encountered clinically. A thorough discussion of the methods that can be used to address these variations is beyond the scope of this chapter, but some basic principles apply to most common clinical situations.

Although there has been considerable debate regarding the “optimal” intracavitary brachytherapy system, and there is no doubt that brachytherapy requires technical skill and attention to detail, it is also apparent that whether intracavitary brachytherapy is used is more important than the details of how it is placed. In the United States, most radiation oncologists are familiar with some variation of the Fletcher-Suit-Delclos applicator system, but other systems are also used. A recent dosimetric evaluation of the Fletcher-Suit-Delclos applicator system compared with the Henschke shielded applicator suggested that the latter system provided a dose-distribution advantage.²⁶⁰ Other large institutions in North America reported a similar therapeutic ratio using linear intrauterine sources alone, without colpostats, provided that the tandem sources extended to 1 cm below the cervix or the inferiormost extent of vaginal disease.²⁶¹ What is clear is that the introduction of radioactive sources into the endocervical and endometrial canal permits a central tumor dose intensification that is unachievable by any EBRT technique, regardless of the nuances of source placement (Fig. 56-18). It is this very high radiation dose, placed in direct juxtaposition to the tumor, within a radiotolerant organ, that allows for control of even large cervical cancers.

Figure 56-18 Illustration of the central dose escalation achieved when combining intracavitary brachytherapy with external beam radiation therapy. Although the diagram is idealized, it is based on current GOG guidelines for radiation dosing in locally advanced cervical cancer: 45 Gy to the whole pelvis, intracavitary brachytherapy to an LDR equivalent dose of 85 Gy to point (pt) A, and an additional external beam parametrial boost of 4.5 to 9 Gy with central structures shielded. The x axis represents the distance from the centrally placed tandem toward each pelvic side wall, along the transaxial plane encompassing bilateral point As.

It is unclear, even with MRI guidance to define the degree of tumor extension, whether the entire uterine body should be treated. Conventionally for most cases, the highest sources in the tandem should extend superiorly at least 6 cm above the external os or, if the uterus is small, as high as possible in the uterine cavity. A relatively long line of sources will provide better lateral dose penetration and coverage of high endocervical tumor, as well as providing some incremental dose to pelvic side wall nodes. However, except in unusual circumstances, particularly where MRI appears to show that the entire uterine body is involved, the benefit of source loadings that extend more than 8 cm above the external os is probably outweighed by the additional radiation exposure to the small bowel and sigmoid colon. A tandem of 6.5 to 8 cm will accommodate 35 to 40 mgRaEq of cesium distributed in three linear sources spaced with their centers 22 to 25 mm apart. Typical loadings (cephalad to caudad) of LDR linear cesium sources would be 15-15-10 mgRaEq for relatively large tumors that still expand the endocervix at the time of intracavitary placement, or 15-10-10 mgRaEq for smaller tumors. The caudad source in the tandem should not protrude more than a couple of millimeters below the superior surface of the colpostats to avoid a hot spot in the adjacent bladder and rectum. Similar distributions can be achieved with remote afterloading units by distributing 5-mgRaEq point sources along the length of the tandem.

The choice of vaginal applicator is determined by the vaginal capacity and by the distribution of any vaginal disease. Vaginal cylinders are usually reserved for patients who have a very narrow vagina or significant vaginal mucosal disease where the dose needs to be delivered inferiorly in the vagina. In general, when colpostats are used, their medial surfaces should be separated by 1 cm or less to avoid a central cold spot. Instead, to maximize the dose deliverable from intravaginal sources and optimize the relative depth dose, the vagina should be fitted with the largest ovoids that can be placed snugly against the cervix. The anterior and posterior lips of the cervix should always be marked with radiopaque seeds (see Fig. 56-17) so the relationship between the cervix and vaginal applicators can be verified on intraoperative films. Significant caudad displacement of the colpostats will dramatically reduce the dose to the cervical tumor and lead to increased vaginal stenosis and probable fistula risk. The colpostats should be centered over the cervical portion; unless the anterior or posterior lip is disproportionately involved, the colpostats should be bisected by the tandem on the lateral view. Very posterior displacement of the colpostats usually results in an underdosage to anterior disease and an unacceptable overdosage to the rectum, particularly to the portion of the rectum that is superior to the colpostat. The standard loadings for Fletcher-Suit-Delclos ovoids are 10 or 15 mgRaEq for 2 cm (small); 15 or 20 mgRaEq for 2.5 cm (medium); 20 or, rarely, 25 mgRaEq for 3 cm (large); and 5 to 10 mgRaEq for miniovoids. These loadings will result in a dose rate at the lateral vaginal surface of 75 to 110 cGy/hr. The higher-activity sources are used when the placement is excellent or when the patient has bulky central disease. The lower activities tend to be used for patients with small tumors, for suboptimal (but acceptable) positioning, and to keep the total vaginal surface dose beneath the cumulative maximum of 120 to 140 Gy.

Placement of the system can be performed under intravenous sedation with monitored anesthesia care; general or regional anesthesia may be preferred, unless the patient is at increased risk for anesthetic complications, because it permits a good examination of the pelvis and provides maximal relaxation of the perineal musculature during placement and packing of the intracavitary applicator. The system should be packed in place with lubricated gauze, preferably a type that contains a radiopaque thread, while the vagina is retracted by an assistant. Packing should be carefully placed anteriorly and posteriorly, displacing the rectum and bladder away from the system. Care should be taken not to force the cervix away from the colpostats during the packing. Gradual withdrawal of the retractors during the procedure permits placement of additional packing in the space occupied by the retractors. With firm packing, the risk of displacement during a 48- to 72-hour placement is minimal. However, when vaginal cylinders are used instead of packing or when a remote afterloading device is used, a stitch should be placed in the labia and secured to the system to prevent displacement. The accuracy of the applicator position should be confirmed while the patient is still under sedation by anteroposterior and lateral radiographs. If the placement is unsatisfactory, the system should be repositioned and repacked (see Fig. 56-17). For patients undergoing LDR brachytherapy with prolonged immobilization, thromboprophylaxis with subcutaneous heparin and sequential compression devices should be initiated as early as during anesthesia for insertion, given the elevated risk for deep venous thrombosis in this setting.

Dose Specification

Several conventional standardized methods have been used to specify the radiation dose delivered by an intracavitary system. Today, most clinicians describe treatment using one of several variations of the Manchester system. With this approach, the dose and dose rate are specified to a paracentral point (point A) and to a point near the pelvic wall (point B) (Fig. 56-19). Point A is placed 2 cm lateral and superior to the external cervical os along the axis of the intrauterine tandem, although a number of methods have been used to identify the position of this reference point. Because point A lies in a region of steep dose gradient, relatively small variations in its position can result in substantial differences in the calculated dose rate. For this reason, the use of point A or similar reference points was criticized by the International Commission on Radiation Units and Measurements (ICRU) in its 1985 report on intracavitary dose and volume specification.²⁶² The commission recommended a system, used in some parts of Europe, in which the volume of tissue treated to a certain dose (usually, 60 Gy) and the reference air kerma (in micrograys [µGy] at 1 m) are specified. At the MDACC, a somewhat similar system is used, with additional emphasis on the vaginal surface dose, substituting mgRaEq hours for reference air kerma as a means of limiting pelvic integral dose and relying on a set of empirically derived rules concerning the position and activity of the radiation sources. When point A is used as a reference point for dosing and reporting, attention must also be given to the three-dimensional isodose distributions surrounding the entire implant.

Figure 56-19 Location of point A and point B using the method recommended in ICRU 38.

From International Commission on Radiation Units and Measurements: Dose and Volume Specifications for Reporting Intracavitary Therapy in Gynecology. Vol 38. Bethesda, Maryland, ICRU, 1985, pp 1-23.

The Manchester system was originally meant to be applied in the context of relatively standard intracavitary source arrangements and loadings. Unexpected results can occur when a standard dose is delivered to point A from a system that is poorly positioned or has very unusual source arrangements. For this reason, the use of point A to specify the dose from interstitial implants is probably particularly dangerous.

A well-placed LDR system loaded according to the preceding recommendations will produce a dose rate at point A of approximately 45 to 55 cGy/hr. Somewhat higher activity loadings have been recommended and used successfully. However, higher activity sources will result in higher dose rates and may have a somewhat greater biologic effect with the number of brachytherapy insertions limited to one or two; dose rates of more than 65 cGy/hr to point A should be used with caution. In a prospective randomized study, Haie-Meder and colleagues²⁶³ reported an increased rate of major complications when the dose rate to point A was increased from 40 to 80 cGy/hr.

Patients who have bulky central disease and favorable anatomy can usually be treated to a combined dose of “85 to 90 Gy” to point A (40 to 45 Gy with EBRT and 40 to 50 Gy with brachytherapy), with an acceptable risk of late complications. Higher doses of central EBRT tend to compromise the total paracentral dose that can be delivered. Somewhat lower doses (75 to 85 Gy) are usually recommended for smaller (IA to IB1) tumors. Adjustments to these doses and to the distribution of sources in the intracavitary applicators may be needed, however, taking into account the position of the system in relation to other pelvic structures and the distribution of tumor as determined by physical examination and imaging studies.

LDR brachytherapy has been used successfully in combination with EBRT since the 1950s to treat thousands of patients and to achieve high local control and cure rates with a low risk of complications. The radiobiologic advantages of delivering brachytherapy at a low dose rate have been emphasized by many, and a number of clinicians continue to express skepticism about the comparability of HDR therapy, particularly in the treatment of patients with unfavorable anatomy, for whom the dose to critical normal tissues may be similar to the paracentral dose.²⁶⁴ On the other hand, increased acceptance of, experience with, and training in HDR brachytherapy techniques have led many to adopt outpatient-based HDR brachytherapy. Whether using LDR or HDR therapy, the importance of attention to anatomic detail, an understanding of normal tissue tolerance, an appreciation of radiobiologic principles, and an adherence to guidelines for loading and fractionation cannot be overemphasized.

High-Dose-Rate Brachytherapy

Computerized remote afterloading technology has now made it possible to deliver intracavitary irradiation at very high doses in minutes instead of hours or days. Worldwide use of HDR brachytherapy as an alternative to LDR brachytherapy has increased rapidly in recent years. Because HDR treatment is always delivered with remote afterloading equipment, radiation exposure to personnel is eliminated. Patients do not have to be hospitalized for treatment, providing a possible economic advantage, and the delivery of treatment in several short fractions may permit greater control over the position of sources during treatment. The most important concern has been that treatment with large HDR fractions reduces the opportunity for recovery of sublethal normal tissue injury and therefore may narrow the therapeutic ratio between tumor control and complications. Other possible disadvantages include the labor intensity of the process and the opportunity for an irreversible error that is not discovered during a very short duration of exposure.

Investigators have been reporting their experiences with HDR brachytherapy for more than 20 years, describing thousands of patients with cervical cancer who were treated with this approach. The authors of numerous retrospective studies have demonstrated that HDR treatment is feasible, effective, and safe.²⁵⁴ In addition, there have been four randomized trials of HDR versus LDR brachytherapy^250–253 (Table 56-5). Although each study had flaws, the data would suggest, in total, that HDR brachytherapy, within carefully applied dosing and fractionation guidelines, provides therapeutic equivalency to traditional LDR approaches.

The biologic effect (particularly to normal tissues) of a nominal dose of radiation will be significantly greater when it is given with HDR as compared with LDR brachytherapy, and this depends on the fraction size. This factor leads to the need for increasing fraction numbers when using HDR versus LDR therapy. To select an HDR schedule that may be comparable with LDR treatment, it is helpful to consider the fractionation and dose-rate effects and, specifically, applications of the linear quadratic (LQ) model used to describe these effects.

The LQ model has been used to describe a biologically effective dose (BED), given as

where α/β describes the varying influence of fraction size on radiation effects in different tumors and normal tissues.

The use of the LQ equation allows one to calculate and approximate the biologic equivalency of HDR-based to traditional LDR-based dosing. Typically, an α/β ratio of 10 is used for tumor and acutely responding tissues and a ratio of 3 is used for late-responding normal tissues. Using the LQ equation, tumor doses of 80 to 85 Gy to point A in LDR equivalent would result in BEDs of 96 to 102 Gy₁₀. Conservatively accounting for late-responding normal tissue tolerances, LDR equivalent doses of 70 Gy to the rectum and 75 Gy to the bladder correspond to 120 Gy₃ and 125 Gy₃, respectively.

There is emerging evidence that small volumes of the rectum and bladder can tolerate a total of 130 to 140 Gy₃. Ogino and associates²⁶⁵ did not observe any severe grade 4 rectal complications with a dose equivalent of less than 147 Gy₃ to the rectum. Lower grade 2 to 3 rectal toxicity was reported in less than 5% of patients with a BED of less than 119 Gy₃ and in less than 10% with a BED of less than 146 Gy₃. Their current fractionation schedules are designed to keep the BED for late-responding tissues to less than 119 Gy₃ for early-stage disease and to less than 147 Gy₃ for locally advanced cancers, allowing a tailoring of dose to disease extent.²⁶⁵

HDR fractionation schedules reported in the literature vary markedly, with insertion numbers and point A dose fraction sizes ranging from 2 to 7 Gy and 3 to 14 Gy, respectively.²⁵⁴ Assuming an α/β ratio of 3 for late damage to normal tissues, Stitt and colleagues²⁶⁶ used the LQ model to predict how a dose of HDR brachytherapy would have to be divided so its effect on normal tissue was comparable to that of 70 Gy of LDR brachytherapy. According to their model, five or six fractions are sufficient if the dose to critical normal tissues is 80% or less of the dose to the paracentral reference point. If the anatomy is somewhat less favorable and the normal tissue dose is 90% of the tumor dose, however, more fractions may be considered.

A detailed analysis of 24 reported series studying HDR brachytherapy in locally advanced cervical cancer failed to identify a dose-response relationship for either tumor control or late tissue complications.²⁶⁷ Although this does not refute the importance of radiobiologic considerations and calculations in the implementation of HDR brachytherapy, it does underscore the complexity of patient- and treatment-related variables involved in the radiotherapeutic management of cervical cancer and the difficulty in reducing HDR dosing issues to a simple mathematical formula.

Viswanathan and colleagues²⁶⁸ reported on a recent survey of international HDR brachytherapy practice among members of the Gynecologic Cancer Intergroup (GCIG). The average EBRT dose to the pelvis approximated 45 Gy. For stage IB to IIA tumors, the three most common regimens were 6 Gy for five fractions, 6 Gy for four fractions, and 7 Gy for three fractions, with brachytherapy doses predominantly prescribed to point A. For stage IIB to IVA tumors, the three most common regimens were 6 Gy for five fractions, 7 Gy for four fractions, and 7 Gy for three fractions.^231a For its most recent protocols in locally advanced cervical cancer (where HDR therapy was permitted), the GOG had prescribed a whole-pelvic dose of 45 Gy, supplemented by an HDR boost of 6 Gy to point A for five fractions, as well as a 5.4- to 9-Gy parametrial boost to the involved side(s). This regimen, when converted using the LQ model, corresponded to a calculated LDR/conventional equivalent dose of 85 Gy to point A. However, it has recently been recognized that absolute adherence to inflexible guidelines does not take into consideration the uncertainties in assumptions and applications of the LQ model, nor the specific tumor geometry and patient factors associated with each case, leading to potential increased toxicity. Although the LQ model is a useful tool for comparing fractionation schemes, no mathematical formula can take the place of clinical judgment and observation. Going forward, the GOG has proposed modifications of its dosing parameters in locally advanced cervical cancer as follows: a whole-pelvis dose of 41.4 to 45 Gy, followed by HDR brachytherapy of 5.4 to 6 Gy for five fractions, with optional parametrial boosting based on tumor regression during EBRT. This new “scheme,” while seeking to maintain a minimal LDR equivalent dose of 80 Gy to point A, provides for flexibility in HDR application and allows for dose escalation to 85 Gy as clinically appropriate. To preserve biologic equivalency dosing to late-reacting normal tissues, the GOG has recommended that the ICRU rectal dose point receive no more than 4.1 Gy (68% of the point A dose) and the bladder dose point no more than 4.6 Gy (77% of the point A dose) per insertion. The increased flexibility in dose shaping with HDR brachytherapy may be useful in optimizing tumor-to-normal-tissue dose ratios.

As with LDR brachytherapy, the timing of HDR insertions depends on the stage and volume of disease and its response to EBRT. For small cervical cancers, brachytherapy may be initiated during the first 2 weeks of radiation therapy; for more locally advanced lesions, brachytherapy is performed near or at the end of EBRT. If most or all of the EBRT is to be given before brachytherapy, two, or even three, HDR fractions may be delivered per week to avoid unnecessarily protracting the overall treatment time (which should generally not exceed 8 weeks) EBRT can be inter-digitated with HDR brachytherapy—however, on days in which HDR brachytherapy is performed, EBRT to an overlapping treatment volume must not be given.

The literature describes a wide range of sedation methods (none involving spinal or general anesthesia) used during the administration of HDR brachytherapy. Most commonly, conscious sedation is used. This involves administration of intravenous midazolam and fentanyl by a trained nurse. To accommodate conscious sedation in the radiation oncology clinic, the patient must at least be continuously monitored by pulse oximetry and blood pressure measurements. The physician and nurse must be certified in conscious sedation procedures, be up to date on cardiopulmonary resuscitation measures, and have ready access to a resuscitation cart. In a review of 124 patients with cervical cancer treated at the University of Wisconsin with HDR brachytherapy, the median doses of midazolam and fentanyl given during each procedure were 8 mg (2 to 40 mg) and 200 µg (50 to 600 µg), respectively.²⁶⁹ After review of an MRI if available, the first HDR insertion in each patient may be facilitated with transabdominal ultrasound guidance for placement of the intrauterine tandem. If the endocervical card is difficult to negotiate for insertion of the tandem, an intrauterine Smit sleeve may be placed at the first implant to facilitate subsequent applications.

At present, most standard HDR loading schemes attempt to recapitulate the familiar and symmetric “pear-shaped” dose distribution typically used in LDR brachytherapy. This isodose distribution can be obtained by designating a series of dose points surrounding the tandem and colpostat and using the dosimetry program to calculate source dwell times in each source location to create the desired dose distribution (inverse planning). Alternatively, the physician may specify the relative weight of each selected dwell position in the brachytherapy apparatus, somewhat analogous to the loading of individual sources in an LDR system. Most HDR practitioners use tandem and ovoids that are based on the LDR Fletcher-Suit-Delclos applicator. Others, however, favor a tandem and ring system that has the advantage of having fixed geometry and potentially simplified dosimetric planning (Fig. 56-20).

Figure 56-20 Anterior (A) and lateral (B) radiographs of an intracavitary tandem and ring insertion for HDR afterloading brachytherapy. The source dwell positions selected for “loading” include those in the intrauterine tandem, as well as the lateral positions in the ring corresponding to the lateral vaginal fornices, thereby mimicking the dosimetry distribution of tandem and ovoids (C). Computerized brachytherapy dosimetry allows visualization of dose in the traditional planes of calculation (coronal, sagittal, and transverse) but also permits three-dimensional representation of dose distribution that may be exploited to conform better to unusual tumor geometries.

Although HDR brachytherapy has had a shorter history than LDR brachytherapy, the cumulative experience to date is not trivial. Results indicate that HDR brachytherapy has provided effective treatment for many patients with cervical cancer over the past three decades and is an acceptable alternative to LDR for intracavitary radiation implants. As with LDR, practitioners of HDR must be well trained and sufficiently experienced in the system of brachytherapy they ultimately choose to use.

A potential advantage of HDR brachytherapy that has yet to be fully exploited is the greater degree of dose optimization that may be achieved compared with LDR approaches. Extensive international efforts in three-dimensional image-guided and adaptive brachytherapy are leading, perhaps prematurely, to a shift from the present central symmetry of a classical “pear-shaped” distribution inherent in the point A system toward a more conformal and often asymmetric dose distribution biased toward residual tumor volume. Although CT imaging can help in delineating adjacent organs at risk, MRI-based brachytherapy is preferable for defining tumor target volumes.^270,271 It has been suggested that MRI image-guided brachytherapy allows customization that decreases the dose to adjacent organs at risk when treating small tumors, while permitting dose escalation in larger tumors to improve local control.^272–274 To further tailor the brachytherapy dose, investigators at the University of Vienna have developed an applicator that combines a tandem and ring with ring-templated parametrial interstitial needles, and have reported enhanced and effective brachytherapy coverage of asymmetric, bulky tumors.²⁷⁶ Although it is intriguing, the use of image-guided brachytherapy remains to be standardized and validated on a wide scale; this forms the basis for the ongoing IntErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer (EMBRACE) trial.²⁷³ Interobserver reproducibility of target definitions to published principles (such as the GEC-ESTRO guidelines)²⁷¹ and multi-institutional assessment of tumor control and complication rates will be evaluated. A clear danger would be underestimation of residual tumor volume for brachytherapy planning. Also of concern is that strict adherence to proposed dose volume constraints for organs at risk may result in tumor underdosage compared with that achieved with conventional dosing. Furthermore, there remain unanswered the issues of resource utilization and whether multiple MRI scans and complex planning are feasible for the majority of patients with cervical cancer. A recent survey of practice patterns by members of the American Brachytherapy Society showed that very few centers in the United States used MRI-based brachytherapy. Although the majority of physicians used CT postimplantation imaging rather than plain films for visualizing the gynecologic brachytherapy apparatus, most (76%) still prescribe to point A alone, indicating the need for further development and experience with three-dimensional image-guided brachytherapy dosimetry.²⁷⁷

Interstitial Brachytherapy

Interstitial brachytherapy has long been used to treat patients with vaginal disease recurrence after hysterectomy and to increase the dose of irradiation delivered to the distal vagina in the rare patient who presents with extensive vaginal disease. However, several groups have advocated a broader role for interstitial irradiation by reporting on the use of large interstitial implants, usually guided by a perineal template, for patients with a variety of clinical presentations, including poor anatomy, bulky disease, or extensive involvement in the parametrium or pelvic wall. Initial reports of this technique were enthusiastic, and high local control rates were reported^278–280 (see Chapter 14, Brachytherapy). Unfortunately, despite having more than 20 years of clinical experience, researchers have published few reports of long-term outcomes in patients with primary cervical carcinoma treated with this technique. A 1995 report²⁸¹ of the combined experiences of Stanford University and the Joint Center for Radiation Therapy at Harvard University was disappointing, with 3-year DFS of only 36% and 18% for patients with FIGO stages IIB and IIIB disease, respectively, and high rates of major complications. A review of 1992 to 1994 practice patterns from the Patterns of Care Study indicates that less than 6% of patients in the United States are treated with interstitial brachytherapy. Comparisons across series are rendered difficult by patient selection and the inherent case individualization in technique and dosimetry.

For selected patients with very difficult clinical presentations, this may, however, be a useful technique. Full understanding of its efficacy awaits further reports of mature clinical experiences, but its use should probably be limited to selected institutions with sufficient experience in using an interstitial approach. Because of the variability of interstitial approaches, the use of interstitial brachytherapy is currently not permitted in phase III randomized trials of irradiation or chemoradiation in cervical cancer. As noted earlier, a novel approach, using the Vienna applicator that combines both intracavitary and interstitial techniques, has been found effective in brachytherapy of selected patients with bulky, asymmetric tumors.²⁷⁶