K.S.Clifford Chao

A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results☆

OBJECTIVES In a prospective clinical study, we tested the hypothesis that sparing the parotid glands may result in significant objective and subjective improvement of xerostomia in patients with head-and-neck cancers. The functional outcome 6 months after the completion of radiation therapy is presented. METHODS AND MATERIALS From February 1997 to February 1999, 41 patients with head-and-neck cancers were enrolled in a prospective salivary function study. Inverse-planning intensity-modulated radiation therapy (IMRT) was used to treat 27 patients, and forward-planning three-dimensional radiation therapy in 14. To avoid potential bias in data interpretation, only patients whose submandibular glands received greater than 50 Gy were eligible. Attempts were made to spare the superficial lobe of the parotid glands to avoid underdosing tumor targets in the parapharyngeal space; however, the entire parotid volume was used to compute dose-volume histograms (DVHs) for this analysis. DVHs were computed for each gland separately. Parotid function was assessed objectively by measuring stimulated and unstimulated saliva flow before and 6 months after the completion of radiation therapy. Measurements were converted to flow rate (mL/min) and normalized relative to that before treatment. The corresponding quality-of-life (QOL) outcome was assessed by five questions regarding the patients oral discomfort and eating/speaking problems. RESULTS We observed a correlation between parotid mean dose and the fractional reduction of stimulated saliva output at 6 months after the completion of radiation therapy. We further examined whether the functional outcome could be modeled as a function of dose. Two models were found to describe the dose-response data well. The first model assumed that each parotid gland is comprised of multiple independent parallel functional subunits (corresponding to computed tomography voxels) and that each gland contributes equally to overall flow, and that saliva output decreases exponentially as a quadratic function of irradiation dose to each voxel. The second approach uses the equivalent uniform dose (EUD) metrics, which assumes loss of salivary function with increase in EUD for each parotid gland independently. The analysis suggested that the mean dose to each parotid gland is a reasonable indicator for the functional outcome of each gland. The corresponding exponential coefficient was 0.0428/Gy (95% confidence interval: 0.01, 0.09). The QOL questions on eating/speaking function were significantly correlated with stimulated and unstimulated saliva flow at 6 months. In a multivariate analysis, a toxicity score derived from the model based on radiation dose to the parotid gland was found to be the sole significant predictive factor for xerostomia. Neither radiation technique (IMRT vs. non-IMRT) nor chemotherapy (yes or no) independently influenced the functional outcome of the salivary glands. CONCLUSION Sparing of the parotid glands translates into objective and subjective improvement of both xerostomia and QOL scores in patients with head-and-neck cancers receiving radiation therapy. Modeling results suggest an exponential relationship between saliva flow reduction and mean parotid dose for each gland. We found that the stimulated saliva flow at 6 months after treatment is reduced exponentially, for each gland independently, at a rate of approximately 4% per Gy of mean parotid dose.

Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer.

PURPOSE To analyze the patterns of locoregional failure in patients with head-and-neck cancer treated with inverse planning intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Between February 1997 and December 2000, 165 patients with histologically confirmed head-and-neck cancer were treated using a parotid-sparing inverse planning IMRT protocol. Thirty-nine patients who received either palliative repeat irradiation or IMRT as a boost were excluded from this analysis, leaving 126 patients for this analysis. Of the 126 patients, 30 were women and 96 were men (median age 56 years, range 13-84). Fifty-two patients (41%) received definitive IMRT. Of the 52 patients, 17 were treated with RT alone and 35 with concurrent cisplatin-based chemotherapy regimens. Seventy-four patients (59%) received postoperative IMRT. The median follow-up was 26 months (range 12-55). IMRT was used only in the upper neck for salivary sparing. The lower neck was treated with a conventional AP low-neck port abutted to the inferior IMRT dose distribution border. The radiation dose was prescribed to the two clinical target volumes (CTVs) according to the assumed risk of containing disease. The mean dose for definitive IMRT patients was 72.64 +/- 4.83 Gy to CTV1 and 64.34 +/- 5.15 Gy to CTV2. The mean dose to CTV1 and CTV2 in postoperative cases was 68.53 +/- 4.71 Gy and 60.95 +/- 5.33 Gy, respectively. The locations of failure were analyzed. RESULTS Seventeen locoregional failures (persistent or recurrent disease) were found. Of these 17 failures, 9 (53%) were inside CTV1. One failure (6%) was marginal to CTV1 but inside CTV2. One failure (6%) occurred outside CTV1 but inside CTV2. Another failure was marginal to CTV2. Of the 17 failures, 5 (28%) were found outside of the IMRT field and in the lower neck. Dose-volume histogram analysis revealed that for all but 1 patient, the recurrent/persistent disease within the CTVs received comparable or superior dose coverage relative to the CTV. The 2-year actuarial locoregional control rate was 85%, and the ultimate locoregional control rate after surgical salvage was 89%. We observed no dermal failure and only one marginal failure in the region adjacent to the spared parotid glands. CONCLUSION We have shown that the target definition and coverage for patients treated with IMRT for parotid sparing is adequate. The predominant tumor failure within CTV1 may imply the need to identify patients with radioresistant tumor subvolumes (such as hypoxic regions) within the CTV. This information would assist in discriminating a subgroup of tumors for a more aggressive and target-specific therapeutic approach.

Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation.

PURPOSE The emergent use of combined modality approach (chemotherapy and radiation therapy) for the treatment of patients with cervical cancer is associated with significant gastrointestinal and genitourinary toxicity. Intensity-modulated radiation therapy (IMRT) has the potential to deliver adequate dose to the target structures while sparing the normal organs and could also allow for dose escalation to grossly enlarged metastatic lymph node in pelvic or para-aortic area without increasing gastrointestinal/genitourinary complications. We conducted a dosimetric analysis to determine if IMRT can meet these objectives in the treatment of cervical cancer. METHODS AND MATERIALS Computed tomography scan studies of 10 patients with cervical cancer were retrieved and used as anatomic references for planning. Upon the completion of target and critical structure delineation, the imaging and contour data were transferred to both an IMRT planning system (Corvus, Nomos) and a three-dimensional planning system (Focus, CMS) on which IMRT as well as conventional planning with two- and four-field techniques were derived. Treatment planning was done on these two systems with uniform prescription, 45 Gy in 25 fractions to the uterus, the cervix, and the pelvic and para-aortic lymph nodes. Normalization was done to all IMRT plans to obtain a full coverage of the cervix with the 95% isodose curve. Dose-volume histograms were obtained for all the plans. A Students t test was performed to compute the statistical significance. RESULTS The volume of small bowel receiving the prescribed dose (45 Gy) with IMRT technique was as follows: four fields, 11.01 +/- 5.67%; seven fields, 15.05 +/- 6.76%; and nine fields, 13.56 +/- 5.30%. These were all significantly better than with two-field (35.58 +/- 13.84%) and four-field (34.24 +/- 17.82%) conventional techniques (p < 0.05). The fraction of rectal volume receiving a dose greater than the prescribed dose was as follows: four fields, 8.55 +/- 4.64%; seven fields, 6.37 +/- 5.19%; nine fields, 3.34 +/- 3.0%; in contrast to 84.01 +/- 18.37% with two-field and 46.37 +/- 24.97% with four-field conventional technique (p < 0.001). The fractional volume of bladder receiving the prescribed dose and higher was as follows: four fields, 30.29 +/- 4.64%; seven fields, 31.66 +/- 8.26%; and nine fields, 26.91 +/- 5.57%. It was significantly worse with the two-field (92.89 +/- 35.26%) and with the four-field (60.48 +/- 31.80%) techniques (p < 0.05). CONCLUSION In this dosimetric study, we demonstrated that with similar target coverage, normal tissue sparing is superior with IMRT in the treatment of cervical cancer.

Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques

BACKGROUND AND PURPOSE Intensity-modulated radiation therapy (IMRT) offers superior dosimetric conformity for normal tissue sparing in patients with oropharyngeal cancer. In this study, acute and late toxicity, and tumor control were compared between conventional beam arrangement (CRT) and IMRT. MATERIALS AND METHODS Between January 1970 and December 1999, 430 patients with carcinoma of the oropharynx were treated at the Mallinckrodt Institute of Radiology. There were 260 patients with tonsil primary tumors and 170 patients with tumors arising from the base of the tongue. Twenty-four (6%) patients had stage I disease, 88 (20%) had stage II, 128 (30%) had stage III, and 190 (44%) had stage IV disease. Patients were divided into five treatment groups. Group I consisted of 109 patients who received preoperative CRT. Group II consisted of 142 patients who received postoperative CRT. Group III consisted of 153 patients who received definitive CRT. Inverse planning IMRT (Peacock, NOMOS) was used to treat 14 patients postoperatively (Group IV) and 12 patients definitively without surgery (Group V). Acute and late normal tissue side-effects were scored according to the Radiation Therapy Oncology Group radiation morbidity criteria. The median follow-up was 3.9 years. RESULTS The 2-year local-regional control values for the five studied groups were 78, 76, 68, 100 and 88%, respectively. The 2-year disease-free survival values for the five studied groups were 68, 74, 58, 92 and 80%, respectively. IMRT significantly reduced the incidence of late xerostomia. CONCLUSIONS When IMRT was compared with conventional techniques, the dosimetric advantage of IMRT did translate into a significant reduction of late salivary toxicity in patients with oropharyngeal carcinoma. No adverse impact on tumor control and disease-free survival was observed in patients treated with IMRT.

Radiotherapy Dose–Volume Effects on Salivary Gland Function

Publications relating parotid dose-volume characteristics to radiotherapy-induced salivary toxicity were reviewed. Late salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia (defined as long-term salivary function of <25% of baseline) is usually avoided if at least one parotid gland is spared to a mean dose of less than approximately 20 Gy or if both glands are spared to less than approximately 25 Gy (mean dose). For complex, partial-volume RT patterns (e.g., intensity-modulated radiotherapy), each parotid mean dose should be kept as low as possible, consistent with the desired clinical target volume coverage. A lower parotid mean dose usually results in better function. Submandibular gland sparing also significantly decreases the risk of xerostomia. The currently available predictive models are imprecise, and additional study is required to identify more accurate models of xerostomia risk.

Delayed Regional Metastases, Distant Metastases, and Second Primary Malignancies in Squamous Cell Carcinomas of the Larynx and Hypopharynx†

Objective To determine the impact of delayed regional metastases, distant metastases, and second primary tumors on the therapeutic outcomes in squamous cell carcinomas of the larynx and hypopharynx.

DETERMINATION AND DELINEATION OF NODAL TARGET VOLUMES FOR HEAD-AND-NECK CANCER BASED ON PATTERNS OF FAILURE IN PATIENTS RECEIVING DEFINITIVE AND POSTOPERATIVE IMRT

PURPOSE We present the guidelines for target volume determination and delineation of head-and-neck lymph nodes based on the analysis of the patterns of nodal failure in patients treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Data pertaining to the natural course of nodal metastasis for each head-and-neck cancer subsite were reviewed. A system was established to provide guidance for nodal target volume determination and delineation. Following these guidelines, 126 patients (52 definitive, 74 postoperative) were treated between February 1997 and December 2000 with IMRT for head-and-neck cancer. The median follow-up was 26 months (range 12-55), and the patterns of nodal failure were analyzed. RESULTS These guidelines define the nodal target volume based on the location of the primary tumor and the probability of microscopic metastasis to the ipsilateral and contralateral (Level I-V) nodal regions. Following these guidelines, persistent or recurrent nodal disease was found in 6 (12%) of 52 patients receiving definitive IMRT, and 7 (9%) of 74 patients receiving postoperative IMRT had failure in the nodal region. CONCLUSION On the basis of our clinical experience in implementing inverse-planning IMRT for head-and-neck cancer, we present guidelines using a simplified, but clinically relevant, method for nodal target volume determination and delineation. The intention was to provide a foundation that enables different institutions to exchange clinical experiences in head-and-neck IMRT. These guidelines will be subject to future refinement when the clinical experience in head-and-neck IMRT advances.

Tumor Size, Irradiation Dose, and Long-Term Outcome of Carcinoma of Uterine Cervix

PURPOSE To assess the impact of tumor size and extent, and dose of irradiation on pelvic tumor control, incidence of distant metastases, and disease-free survival in carcinoma of the uterine cervix. METHODS AND MATERIALS Records were reviewed of 1499 patients (Stages IA-IVA) treated with definitive irradiation (combination of external beam plus two intracavitary insertions to deliver doses of 65-95 Gy to point A, depending on stage and tumor volume). Follow-up was obtained in 98% of patients (median 11 years, minimum 3 years, maximum 30 years). The relationship between outcome and tumor size was analyzed in each stage. Pelvic tumor control was correlated with total doses to point A and to the lateral pelvic wall. RESULTS The 10-year actuarial pelvic failure rate in Stage IB was 5% for tumors <2 cm, 15% for 2.1-5 cm, and 35% for tumors >5 cm (p = 0.01); in Stage IIA, the rates were 0%, 28%, and 25%, respectively (p = 0.12). Stage IIB unilateral or bilateral nonbulky tumors <5 cm had a 23% pelvic failure rate compared with 34% for unilateral or bilateral bulky tumors >5 cm (p = 0.13). In Stage IIB, pelvic failures were 18% with medial parametrial involvement only, compared with 28% when tumor extended into the lateral parametrium (p = 0.05). In Stage III, unilateral parametrial involvement was associated with a 32% pelvic failure rate versus 50% for bilateral extension (p < 0.01). Ten-year disease-free survival rates were 90% for IB tumors <2 cm, 76% for 2.1-4 cm, 61% for 4.1-5 cm, and 47% for >5 cm (p = 0.01); in Stage IIA, the rates were 93%, 63%, 39%, and 59%, respectively (p < or = 0.01). Patients with Stage IIB medial parametrial involvement had better 10-year disease-free survival (67%) than those with lateral parametrial extension (56%) (p = 0.02). Stage III patients with unilateral tumor extension had a 48% 10-year disease-free survival rate compared with 32% for bilateral parametrial involvement (p < or = 0.01). The presence of endometrial extension or tumor only in the endometrial curettings had no significant impact on pelvic failure. However, in patients with Stage IB disease, the incidence of distant metastases was 31% with positive curettings, 15% with negative curettings, and 22% with admixture (p < or = 0.01). In Stage IIA, the corresponding values were 51%, 33%, and 18% (p = 0.05). The 10-year disease-free survival rates in Stage IB were 67% with positive curettings, 81% for negative curettings, and 77% for admixture (p = 0.02); in Stage IIA, the rates were 45%, 66%, and 67%, respectively (p = 0.14). Because this is not a prospective Phase II dose-escalation study, the correlation of doses of irradiation with pelvic tumor control in the various stages and tumor size groups is not consistent. Nevertheless, with Stage IB and IIA tumors <2 cm in diameter, the pelvic failure rate was under 10% with doses of 70-80 Gy to point A, whereas for larger lesions even doses of 85-90 Gy resulted in 25% to 37% pelvic failure rates. In Stage IIB with doses of 70 Gy to point A, the pelvic failure rate was about 50% compared with about 20% in nonbulky and 30% in bulky tumors with doses > 80 Gy. In Stage III unilateral lesions, the pelvic failure rate was about 50% with < or =70 Gy to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses. CONCLUSIONS Clinical stage and size of tumor are critical factors in prognosis, therapy efficacy, and evaluation of results in carcinoma of the uterine cervix. The doses to point A suggest that for lesions <2 cm, doses of 75 Gy result in < or =10% pelvic failures, whereas in more extensive lesions, even with doses of 85 Gy, the pelvic failure rate is about 30%; and in Stage IIB-III tumors, doses of 85 Gy result in 35-50% pelvic failures. Refinements in brachytherapy techniques and/or use of agents to selectively sensitize the tumors to irradiation will be necessary to improve the present results in invasive carcinoma of t

Radiation therapy morbidity in carcinoma of the uterine cervix: dosimetric and clinical correlation

PURPOSE To quantitate the impact of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in patients treated with irradiation alone for cervical cancer. METHODS AND MATERIALS Records were reviewed of 1456 patients (Stages IB-IVA) treated with external-beam irradiation plus two low-dose rate intracavitary insertions to deliver 70 to 90 Gy to point A. Follow-up was obtained in 98% of patients (median, 11 years; minimum, 3 years; maximum, 30 years). The relationships among various dosimetry parameters and Grade 2 or 3 sequelae were analyzed. RESULTS In Stage IB, the frequency of patients developing Grade 2 morbidity was 9%, and Grade 3 morbidity, 5%; in Stages IIA, IIB, III, and IVA, Grade 2 morbidity was 10% to 12% and Grade 3 was 10%. The most frequent Grade 2 sequelae were cystitis and proctitis (0.7% to 3%). The most common Grade 3 sequelae were vesicovaginal fistula (0.6% to 2% in patients with Stage I-III tumors), rectovaginal fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In the bladder, doses below 80 Gy correlated with less than 3% incidence of morbidity and 5% with higher doses (p = 0.31). In the rectosigmoid, the incidence of significant morbidity was less than 4% with doses below 75 Gy and increased to 9% with higher doses. For the small intestine, the incidence of morbidity was less than 1% with 50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall (p = 0.04). When the ratio of dose to the bladder or rectum in relation to point A was 0.8 or less, the incidence of rectal morbidity was 2.5% (8 of 320) vs. 7.3% (80 of 1095) with higher ratios (p < or = 0.01); bladder morbidity was 2.3% (7 of 305) and 5.8% (64 of 1110), respectively (p = 0.02). The incidence of Grade 2 and 3 bladder morbidity was 2.9% (10 of 336) when the dose rate was less than 0.80 Gy/h, in contrast to 6.1% (62 of 1010) with higher dose rates (p = 0.07). Rectal morbidity was 2% to 5% in Stage IB, regardless of dose rate to the rectum; in Stages IIA-B and III, morbidity was 5.2% (28 of 539) with a dose rate of 0.80 Gy or less and 10.7% (37 of 347) with higher dose rates (p < 0.01). Multivariate analysis showed that dose to the rectal point was the only factor influencing rectosigmoid sequelae, and dose to the bladder point affected bladder morbidity. CONCLUSIONS Various dosimetric parameters correlate closely with the incidence of significant morbidity in patients treated with definitive irradiation for carcinoma of the uterine cervix. Careful dosimetry and special attention to related factors will reduce morbidity to the lowest possible level without compromising pelvic tumor control.

Intensity-modulated radiation therapy in head and neck cancers: an update.

Intensity‐modulated radiation therapy (IMRT), an advent of three‐dimensional conformal radiotherapy (3D CRT), has excited the profession of radiation oncology more than any other new invention since the introduction of the linear accelerator. Approximately 1000 articles have been published on this topic to date, more than 200 of which focus on head and neck cancer. IMRT is based on computer‐optimized treatment planning and a computer‐controlled treatment delivery system. The computer‐driven technology generates dose distributions that sharply conform to the tumor target while minimizing the dose delivered to the surrounding normal tissues. The high dose volume that tailors to the 3D configuration of the tumor along with the ability to spare the nearby normal tissues allows the option of tumor dose escalation.