The use of planned neck dissection (ND) in patients with advanced nodal disease in head and neck squamous cell carcinoma (HNSCC) after treatment with chemoradiotherapy is controversial. The purpose of this study is to clarify the role for neck dissection in patients treated with combined chemoradiotherapy (CRT) on 2 similar organ preservation protocols at our institution. The records of 90 patients with N2-N3 neck nodes who were treated between 1991 and 2001 at Stanford University on two organ preservation CRT protocols (OSP2 and OSP3) were reviewed. All patients received 2 cycles of cisplatin and 5-Fluorouracil (5-FU) induction chemotherapy, followed by concurrent CRT with similar chemotherapeutic agents. Patients on OSP3 were randomized to receive either CRT alone versus CRT and Tirapazamine for 8 doses. Radiotherapy was delivered at conventional fractionation at 2 Gy/fraction to a total dose of 66–70 Gy to the gross target volume. Patients with persistent neck nodes either clinically or radiographically at a planned evaluation at 50 Gy proceeded to a neck dissection following completion of CRT. Patients treated on the OSP3 protocol (n = 54) also received a single dose of 5 Gy delivered via 9–16 MeV electrons to the largest nodal mass prior to treatment for the comet study. The median follow up was 3.6 years. Overall, 63% (n = 57) of the patients attained a clinical complete response (cCR) in the neck; of these, 8 patients had a ND and all 8 had a pathologic complete response (pCR). Of the remaining 49 cCR patients whose necks were observed, 13 relapsed and 2 had a neck relapse without a recurrence at the primary site (1 with an isolated neck recurrence, 1 with a neck and distant failure). Of the 33 patients (37%) with < cCR in the neck, 2 had progressive disease and died. The remaining 31 patients had NDs with a pCR rate of 52% (n = 16). Outcomes of the 3 groups: (1) cCR, (2) < cCR/pCR and (3) < cCR/< pCR are summarized in table 1. The cCR rates were similar for the 2 OSP protocols (61% and 65%). There was a trend for higher pCR rate patients who underwent ND in OSP3 group (58% vs. 42%, p = 0.3, χ2 Test) Based on our experience, in patients with N2-N3 neck nodes who have achieved a clinical and radiographic cCR in the neck following CRT, planned ND benefited only 4% (2/49) and is therefore not routinely recommended. Patients with a

Purpose: Despite the well-known fact that intensity-modulation could significantly improve the dose distributions in breast irradiation, its clinical implementation has been hindered by deficiencies in the current inverse planning systems and by the lack of a comprehensive procedure. The aim of this work was to develop a general scheme of intensity-modulated breast treatment using MSRT and to demonstrate its superiority over IMRT as well as standard tangential-field (TF) technique using 20 clinical cases of various breast sizes.Methods: The patient setup and target definition were the same as that used in the TF treatment. Two planning methods were studied: (1)manual forward planning, and (2)computer MSRT optimization. A 3D planning system with a trial-and-error was used in the manual MSRT planning to stack MLC segments on top of the standard TFs to get a sensible MSRT plan. The underlying reason for the approach to be a viable choice is that the initial TFs have already brought the system to the vicinity of optimal solution. As a result, it is often sufficient to add 1∼3 segments to greatly improve the dose distribution. MSRT optimization was also developed using a gradient method. The DVH-based score function depended on both segment weights and shapes. MLC constraints were included to prevent unphysical MLC configurations. The target volume, defined at the patient setup based on the palpable breast tissue, was used by the algorithm for calculation.The segmented fields were concatenated to form a step-and-shoot delivery. An algebraic method was devised to determine the segmented MU to optimally compensate the MLC transmission. The fluence map and MU were independently checked. 20 patients were planned and the results were compared with the standard TF plans, as well as the TF and multiple-field IMRT plans.Results: The MSRT significantly improved target dose uniformity. Figure 1 shows a manual plan. It was also possible to reduce the lung/heart dose with a slight deterioration of target dose. Optimization yielded consistent beam apertures and weights and became advantageous for complicated cases. Our results revealed that MSRT could easily reduce the dose uniformity from 105∼120% (prescription was at 90%) to 100∼112%. The results were comparable or even more favorable than the conventional TF IMRT plans. It was noticed that IMRT with 3∼7 beams was inferior in that more normal tissues were irradiated.Conclusion: IMRT deviates from the conventional approach and requires additional steps in the treatment process. MSRT bridges the gap between conventional and IMRT treatments. For breast cancer, MSRT is a natural extension of standard procedure and improves the treatment without paying the excessive overhead associated with current IMRT. Purpose: Despite the well-known fact that intensity-modulation could significantly improve the dose distributions in breast irradiation, its clinical implementation has been hindered by deficiencies in the current inverse planning systems and by the lack of a comprehensive procedure. The aim of this work was to develop a general scheme of intensity-modulated breast treatment using MSRT and to demonstrate its superiority over IMRT as well as standard tangential-field (TF) technique using 20 clinical cases of various breast sizes. Methods: The patient setup and target definition were the same as that used in the TF treatment. Two planning methods were studied: (1)manual forward planning, and (2)computer MSRT optimization. A 3D planning system with a trial-and-error was used in the manual MSRT planning to stack MLC segments on top of the standard TFs to get a sensible MSRT plan. The underlying reason for the approach to be a viable choice is that the initial TFs have already brought the system to the vicinity of optimal solution. As a result, it is often sufficient to add 1∼3 segments to greatly improve the dose distribution. MSRT optimization was also developed using a gradient method. The DVH-based score function depended on both segment weights and shapes. MLC constraints were included to prevent unphysical MLC configurations. The target volume, defined at the patient setup based on the palpable breast tissue, was used by the algorithm for calculation. The segmented fields were concatenated to form a step-and-shoot delivery. An algebraic method was devised to determine the segmented MU to optimally compensate the MLC transmission. The fluence map and MU were independently checked. 20 patients were planned and the results were compared with the standard TF plans, as well as the TF and multiple-field IMRT plans. Results: The MSRT significantly improved target dose uniformity. Figure 1 shows a manual plan. It was also possible to reduce the lung/heart dose with a slight deterioration of target dose. Optimization yielded consistent beam apertures and weights and became advantageous for complicated cases. Our results revealed that MSRT could easily reduce the dose uniformity from 105∼120% (prescription was at 90%) to 100∼112%. The results were comparable or even more favorable than the conventional TF IMRT plans. It was noticed that IMRT with 3∼7 beams was inferior in that more normal tissues were irradiated. Conclusion: IMRT deviates from the conventional approach and requires additional steps in the treatment process. MSRT bridges the gap between conventional and IMRT treatments. For breast cancer, MSRT is a natural extension of standard procedure and improves the treatment without paying the excessive overhead associated with current IMRT.

Purpose: Recently, energy- and intensity-modulated electron radiotherapy (MERT) has garnered growing interest for the treatment of superficial targets. In MERT, small electron beams (beamlets) of different angles, energies and intensities are optimized to achieve dose conformity both laterally and in the depth direction. The potential of MERT for breast cancer is to improve dose uniformity in the treatment volume while reducing dose to normal tissues such as the lung, heart and contralateral breast. In this work, we carried out a comparative dosimetry study to evaluate MERT, photon beam intensity-modulated radiation therapy (IMRT) and conventional tangential photon beams for the treatment of breast cancer. We also included the effects of respiration (organ motion) on each treatment modality. Materials and methods: A MERT system has been investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. A prototype electron multileaf collimator (eMLC) for accurate MERT beam delivery has also been developed. For this study, we have compared breast treatment plans (with and without nodal involvement) generated using MERT, IMRT and conventional tangential photon beams. The MERT plans were derived using our own treatment optimization software with up to 3 gantry angles and 5 nominal energies (6, 9, 12, 16, 20 MeV beams from a Varian Clinac 2100C accelerator). The tangential photon treatment plans were derived using the CMS FOCUS 3D treatment planning system with 6 MV wedged photon beams. A 6 MV anterior-posterior field was also used if there was nodal involvement. The IMRT plans were derived using the NOMOS CORVUS treatment optimization system with the same tangential beam angles of 6 MV x-rays. To remove any inconsistencies between the dose calculation algorithms used in the treatment planning system, all the plans were recalculated using the Monte Carlo method. Our Monte Carlo code system also took into account the effects of organ motion due to respiration and the effects of photon and electron leakage through the MLC and scattering off the MLC leaves. Results: In general, MERT provides better or similar target dose coverage compared with conventional wedged tangential photon beams and intensity-modulated tangential beams. Our results confirmed the findings of previous investigators that IMRT could reduce the dose to the lung, heart and contralateral breast compared to conventional tangential wedged beams (up to 5 Gy in the maximum dose). However, MERT reduces the maximum dose to the lung by up to 20 Gy and to the heart by up to 35 Gy compared to conventional tangential wedged beams. When respiration motion was considered with a 1 cm chest wall movement significant dose heterogeneities were found in regions where the tangential photon beams abut the anterior-posterior supraclav photon beams. The effect of respiratory motion on MERT dose distributions was very small since the modulated electron beams were incident normally or at relatively small oblique angles. Conclusion: Because of its superior capabilities to achieve dose conformity both laterally and in the depth direction, MERT can be developed into a useful modality for superficial targets, especially for the treatment of breast cancer. The advantages of MERT over the currently used treatment techniques include uniform target coverage and significantly reduced normal tissue toxicity. Software and hardware development is ongoing with the hope for clinical testing of this new beam modality in early 2002. Further investigations are being carried out for other treatment sites such as head and neck, lung (mesothelioma), and palliative spine cases. This work was supported in part by NIH: CA78331 and by DOD US Army Breast Cancer Research Program: BC971292.

Purpose: RT/CCT in advanced HNC improves anti-tumor efficacy but also exacerbates treatment-associated morbidity. rHuKGF, a member of the fibroblast growth factor family (FGF-7), is a potent mitogen that stimulates the proliferation of epithelial tissues including the mucosa of the aerodigestive tract. Preclinical studies have shown that rHuKGF reduces the severity of RT and CT induced mucositis. We performed a multi-institutional double blind phase I/II trial to define the safety of several dose levels of rHuKGF in advanced HNC patients receiving RT/CCT.Materials and Methods: Patients with non-metastatic, previously untreated, AJCC stage 3 or 4 squamous cell HNC received hyperfractionated RT (1.25 Gy bid to a total dose of 72.5 Gy over < 7 weeks) and continuous infusion 5-fluorouracil (1000 mg/m2 /day for 4 days) and bolus cisplatin (100 mg/m2 during weeks 1 and 5). A planned break in RT occurred at week 4. Patients underwent a 3:1 randomization to receive intravenous rHuKGF (20, 40, 60, 80 μg/kg) or placebo, respectively, for 3 days immediately prior to the initiation of RT/CT (first 3 cohorts) or once on the Friday before RT/CT (last cohort), and then weekly for a total of 10 doses. There was no stratification for T stage, N stage, performance status, or disease site. Minimum cohort size was 12 patients. Study endpoints included KGF-associated toxicity and the incidence and duration of severe mucositis (RTOG grade ≥ 3 ), acute pharyngitis and salivary gland toxicity (RTOG grade ≥ 2).Results: Of the 60 patients enrolled (14 placebo, 46 KGF), 87% had T3/T4 primaries and 67% had N+ necks. AJCC Stage IV disease was present in 75%. Primary tumor sites included oral cavity (23%), oropharynx (44%), hypopharynx (20%), and larynx (13%). The only adverse effects attributable to KGF were facial and upper thoracic skin flushing (9 patients) and excess salivation (1 patient, 20 μg/kg) that occurred during the initial 3 day dosing period. Skin events were generally mild to moderate and increased with higher doses; one severe skin reaction occurred at the 60 μg/kg dose. Transient, asymptomatic elevations in serum lipase and amylase were observed at all KGF dose levels with three consecutive days of dosing. Median duration in days (25-75 percentile range) of RT/CT-related toxicities of the mucosal membranes (mucositis), pharynx/esophagus (dysphagia) and salivary glands (acute xerostomia) are listed below:There were no significant differences in 1-year actuarial local-regional control, failure-free survival, & survival for placebo and KGF patients. Longer term followup is ongoing and will be presented.Conclusion: Weekly KGF administration during RT/CCT was safe and well-tolerated at the dose levels given in this study. A larger scale phase II study in which all patients receive doses of 60 μg/kg is ongoing to evaluate more thoroughly the efficacy of rHuKGF. Tabled 1MucosaPharynx/EsophagusSalivary GlandsRTOG Grade 3, 4RTOG Grade 2–4RTOG Grade 2,4Placebo11.0 (6–27)40.0 (15–58)42.5 (23–56)RHuKGF6.5 (4–23)22.8 (8–45)21.3 (0.40) Open table in a new tab Purpose: RT/CCT in advanced HNC improves anti-tumor efficacy but also exacerbates treatment-associated morbidity. rHuKGF, a member of the fibroblast growth factor family (FGF-7), is a potent mitogen that stimulates the proliferation of epithelial tissues including the mucosa of the aerodigestive tract. Preclinical studies have shown that rHuKGF reduces the severity of RT and CT induced mucositis. We performed a multi-institutional double blind phase I/II trial to define the safety of several dose levels of rHuKGF in advanced HNC patients receiving RT/CCT. Materials and Methods: Patients with non-metastatic, previously untreated, AJCC stage 3 or 4 squamous cell HNC received hyperfractionated RT (1.25 Gy bid to a total dose of 72.5 Gy over < 7 weeks) and continuous infusion 5-fluorouracil (1000 mg/m2 /day for 4 days) and bolus cisplatin (100 mg/m2 during weeks 1 and 5). A planned break in RT occurred at week 4. Patients underwent a 3:1 randomization to receive intravenous rHuKGF (20, 40, 60, 80 μg/kg) or placebo, respectively, for 3 days immediately prior to the initiation of RT/CT (first 3 cohorts) or once on the Friday before RT/CT (last cohort), and then weekly for a total of 10 doses. There was no stratification for T stage, N stage, performance status, or disease site. Minimum cohort size was 12 patients. Study endpoints included KGF-associated toxicity and the incidence and duration of severe mucositis (RTOG grade ≥ 3 ), acute pharyngitis and salivary gland toxicity (RTOG grade ≥ 2). Results: Of the 60 patients enrolled (14 placebo, 46 KGF), 87% had T3/T4 primaries and 67% had N+ necks. AJCC Stage IV disease was present in 75%. Primary tumor sites included oral cavity (23%), oropharynx (44%), hypopharynx (20%), and larynx (13%). The only adverse effects attributable to KGF were facial and upper thoracic skin flushing (9 patients) and excess salivation (1 patient, 20 μg/kg) that occurred during the initial 3 day dosing period. Skin events were generally mild to moderate and increased with higher doses; one severe skin reaction occurred at the 60 μg/kg dose. Transient, asymptomatic elevations in serum lipase and amylase were observed at all KGF dose levels with three consecutive days of dosing. Median duration in days (25-75 percentile range) of RT/CT-related toxicities of the mucosal membranes (mucositis), pharynx/esophagus (dysphagia) and salivary glands (acute xerostomia) are listed below: There were no significant differences in 1-year actuarial local-regional control, failure-free survival, & survival for placebo and KGF patients. Longer term followup is ongoing and will be presented. Conclusion: Weekly KGF administration during RT/CCT was safe and well-tolerated at the dose levels given in this study. A larger scale phase II study in which all patients receive doses of 60 μg/kg is ongoing to evaluate more thoroughly the efficacy of rHuKGF. Tabled 1MucosaPharynx/EsophagusSalivary GlandsRTOG Grade 3, 4RTOG Grade 2–4RTOG Grade 2,4Placebo11.0 (6–27)40.0 (15–58)42.5 (23–56)RHuKGF6.5 (4–23)22.8 (8–45)21.3 (0.40) Open table in a new tab

Purpose: Recent data suggests that adjuvant locoregional radiotherapy may improve survival in women with node positive breast cancer.Concerns have been raised, however, regarding toxicities associated with comprehensive locoregional treatment including the chestwall (CW).supraclavicular fossa (SCF), and internal mammary nodes (IMN).This study compares seven commonly used comprehensive treatment techniques using NTCP predictions for pneumonitis and ischemic heart disease (IHD) and DVH analyses for normal and target tissues.Methods: Twenty representative left-sided post-mastectomy cases were selected.All had contrast enhanced CT scans with clinical delineation of standard field borders using radio-opaque catheters.CW, IMN (interspaces one through three), lung and heart structures were defined in three dimensions.Seven commonly used techniques were implemented for each case, assuming a prescription of 50 Gy in 25 fractions.All techniques included an AP field to the SCF.Techniques were standard tangents to CW only; electron fields to IMN and CW: cobalt fields using an AP IMN field and lateral tangents to CW; reverse hockey stick (RHS) with an AP IMN electron held and lateral AP/PA photon fields to CW; two variations of angled and mixed photon/electron beams (30/70 and 20/80) to IMN with lateral tangents to CW; and partly wide tangent fields (PWTF) to IMN and CW.One hundred forty dose distributions were calculated and nearly 6000 data points were tabulated.NTCP mode1 metrics (Lyman-Kutcher-Burma" NTCP method for lung and Relative Seriality for lung and heart) were used to quantify the risks of pneumonitis and IHD, while dose-volume metrics were used to assess target coverage (CW and IMN) and normal tissue doses.Mean values.standard deviations (SD), and repeated measures analysis of variance (an expansion of a pair-comparison t-test) were used to rank techniques. Results:The twenty cases showed a wide spectrum of body habitus characteristics.The CW was treated most uniformly by standard tangents [mean dose (Dmean) 49.6 Gy (SD 18 Gy)], p = 0.0003, although the other techniques (except the cobalt and electron plans) provided excellent coverage as well.IMN coverage was superior for both the 30/70 photon/electron mix [Dmean 50.0 Gy (3.8 Gy)], p < 0.0001, and PWTF [Dmean 49.3 Gy (3.6 Gy)], p < 0.0001 Pneumonitis predictions for standard tangents [NTCP 0.4% (O.S%)], cobalt [NTCP 0.8% (lo%)], and PWTF [NTCP 2.3% (2.5%)] were lower than values for the 20/80 mix [NTCP 6.0% (8.7%) and 30/70 mix [NTCP 6.8% (114%)], p = 0.0078.The NTCP for IHD was signiticantly lower for PWTF versus all other techniques, with [NTCP 0.0% (O.l%)] for PWTF versus values ranging from [NTCP 0.5% (1 I%)] for RHS to [NTCP 4.4% ( 17%)] for cobalt, p < 0.000 1 Of interest, the NTCP for IHD [ 11% (1 S%)] was significantly greater using standard tangents compared to the NTCP for PWTF.p = 0.0041.Conclusion: No one technique studied combines the best CW and IMN coverage with minimal lung and heart complication probabilities.The choice of technique should be based upon clinical discretion and the technical expertise available to implement these complex plans.Of the techniques studied, our analysis supports PWTF as the most appropriate technique for irradiation of the CW and IMN.

I-125 sources are being used in temporary interstitial implants of various sites. Radiation safety considerations favor its use over other available radioisotopes. Cost containment is achieved by using the same sources for a number of patients. Loading I-125 seeds into implant catheters at our institutions permit customized source arrangement to optimize the implant dose patterns. Clinical examples are given for which the dose distributions achieved with customized source loading are superior to those achievable with standard Ir-192 ribbons.

The squamous cell carcinomas of 119 patients treated between 1958 and 1980 were retrospectively reclassified according to the 1977 American Joint Committee for Cancer Staging-End Results Reporting guidelines. Analysis of the information was performed with an interactive computer program that allows the analysis of a large number of medical factors with numerous variables. The following factors show the statistically significant improved survival rates: well-differentiated histopathologic findings, small T-stage lesions, and clinically negative neck disease. Although the survival curve was similar in the planned combined therapy and radiation therapy groups, local control was statistically superior in the combined therapy group. A similar trend is seen in those patients who receive interstitial implants in addition to external beam therapy. A randomized prospective study is needed to determine the optimum mode of therapy.

Between March 1973 and December 1980, 76 patients with Stage I or II breast carcinoma were treated by biopsy and definitive radiation therapy at Stanford University Medical Center. There were 78 treated breasts since two patients had bilateral carcinomas at presentation. During a median follow-up period of 29 months, eight patients developed discrete masses in the treated breast. In four of these patients biopsied tissue revealed recurrent carcinoma yielding a local control rate of 95%. Four additional patients had lesions which were clinically indistinguishable from recurrent cancer. Biopsy specimens, however, revealed fat necrosis of the breast. The clinical and pathologic features of this entity are described. It is imperative that clinicians be aware of this treatment sequelae so that conservative diagnostic procedures may be used and breast deformity minimized. If postirradiation fat necrosis is considered, mastectomy for suspected persistent or recurrent disease may be avoided.

The locoregional control of 60 to 61 patients supports the results published by other centers and compares favorably with results of any surgical series. The cosmetic results are excellent with only three of 61 patients having severe fibrosis of the breast develop. No rib fractures, skin ulcerations, symptomatic radiation pneumonitis, edema of the arm or limitation of arm movement have been observed as complications. Ten of the 28 patients who have had axillary dissection had transient edema of the breast develop. Results of numerous studies suggest that primary radiotherapy without mastectomy is appropriate treatment for early carcinoma of the breast. The accessibility of the breast makes it relatively easy to deliver curative doses of radiation with minimal damage to surrounding normal tissues. The cumulative radiotherapy experience has demonstrated the gratifying results of not only maintaining a rather normal breast but also avoiding the negative physical and psychologic repercussions of the mastectomy. Radiation therapy is an alternative to Halsted's radical mastectomy.

The use of absorbable Vicryl sutures containing 125 Iodine seeds intra-operatively as an adjuvant to surgery and external beam radiotherapy is an attractive technique for implanting patients with locally advanced cancer.

I‐125 seeds in Vicryl suture have been used as a radioactive suture in 24 cases of advanced malignancy of the head and neck. Twelve cases had metastatic carcinoma attached to the internal or common carotid artery. The goal was to excise surgically as much tumor as possible, then implant any residual tumor with this radioactive suture which remains as a permanent implant (half‐life of 60 days)

Between 1950 and 1978, 27 cases of Kaposi's sarcoma were diagnosed.Sixteen of these 27 patients received radiation therapy, of whom 15 are evaluakle for radiation response, with median follow-up of 5 years.Treatment modalities include superficial, orthovoltage, megavoltage photons, and superficial electrons.Small field techniques with protracted fractionation were utilized for treatment in the majority of the cases.A total of 92 anatomic sites were irradiated with 85 located within the skin of the lower extremities.Each site was analyzed with regards to treatment modality, response in tumor size, bleeding, pain, local pigmentation and duration of relief.Of the 85 evalwable individual lesions (15 patients), a complete response was noted in 62%, relief of pain in 88% and recession of bleeding in 94%.A ret dose of 1000 or greater is associated with a higher rate of local tumor control as compared,to lower time-dose fractionation schemes.Poor local response appears to be predictive of later regrowth.A higher failure rate seems associated with the use of electron beam therapy.Although several patients have survived for periods of up to 20 years without manifesting visceral involvement, half of the cases developed lymphedema, presumably by sarcomatous engorgement of deep lymphatic channels, causing serious morbidity and responding poorly to systemic chemotherapy.

Sixteen patients with advanced head and neck carcinomas were treated with cis-diaminedichloro platinum chemotherapy; seven preoperatively and nine for recurrent disease. Cis-platinum was given by 24-hour infusions of 80 mg/m2 every three weeks. There was 50% regression in 38% (6) of the patients; another 38% (6) had 25% to 50% regression. Toxicity was minimal, with vomiting occurring in 75% (12) of the courses, renal toxicity in 6% (2), leukopenia in 13% (4), thrombocytopenia in 9% (3), and anemia in 31% (10). Of the seven patients who had serial audiograms, only one experienced ototoxicity. Cis-platinum, given by 24-hour infusion, was effective in reducing tumor bulk in 75% (12) of the patients, with advanced head and neck carcinomas, without undue morbidity.