Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk, locally advanced/inflammatory, and metastatic breast cancer.

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies.

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.

Resection with external beam and intraoperative radiotherapy for recurrent colon cancer.

OBJECTIVE: To review treatment outcomes for patients with locoregional recurrent colon cancer who underwent resection, intraoperative radiotherapy (IORT), and external beam radiotherapy (EBRT). DESIGN: Retrospective study of patients treated between January 1990 and June 1994. SETTING: Tertiary care cancer center. PATIENTS: Eleven patients with bulky recurrent colon cancer extending to adjacent organs or structures signed informed consent forms to receive IORT. INTERVENTION: Of 10 patients who underwent exploratory laparotomy, 5 had no metastatic disease and underwent resection, IORT, and EBRT. Complete resection was accomplished in 4 patients. Doses of IORT ranged from 13 to 20 Gy depending on residual tumor burden; EBRT was typically delivered postoperatively to a dose of 45 Gy. MAIN OUTCOME MEASURES: Survival and locoregional tumor control. RESULTS: All 4 patients who underwent complete resection, IORT, and EBRT are alive without locoregional recurrence 53 to 77 months after treatment. Of these, only 1 patient developed distant metastases. The fifth patient, who had gross residual tumor, developed local recurrence 5 months after IORT. One patient developed an IORT complication-ureteral fibrosis leading to ipsilateral nephrectomy. CONCLUSION: Long-term disease-free survival can be achieved in selected patients with bulky regional recurrence of colon cancer with complete tumor resection, IORT, and EBRT.

High-dose therapy and autologous bone marrow transplantation for Hodgkin's disease patients with relapses potentially treatable by radical radiation therapy.

PURPOSE: A retrospective review evaluated the results of autologous bone marrow transplantation (A-BMT) for patients with relapsed Hodgkin's disease (HD) who were potentially treatable by radical radiation therapy (RRT). METHODS AND MATERIALS: Evaluated patient cases met the following criteria: initial treatment with chemotherapy (with or without involved field radiation therapy < 25 Gy); no history of bone marrow or extensive lung involvement; no current or previous evidence of systemic metastases except liver; radiation therapy used with salvage chemotherapy for prior relapse would not preclude use of RRT (e.g., > 20 Gy to spinal cord); HD at time of salvage therapy limited to lymph nodes, Waldeyer's ring, liver, spleen, direct extension sites, and/or one lung. RESULTS: There were 23 A-BMT patients treated between 1986 and 1991 who fulfilled the criteria. Three (13%) patients died from treatment-related complications and eight (35%) developed nonfatal Grade 3-4 complications. The 3-year actuarial disease-free survival rate was 61%. The 3-year disease-free survival rate was 55% for the nine patients with at least one prior disease-free interval (DFI) > 12 months, 67% for nine patients with DFI < 12 months, and 60% for five induction failure patients (p > 0.10). These results are comparable to retrospective studies of RRT results in selected relapsed HD patients. CONCLUSIONS: Long-term disease-free survival is frequently possible with either A-BMT or RRT in appropriately selected relapsed HD patients. In considering treatment options, important prognostic factors include initial stage of disease, number of prior relapses, DFI, and extent of relapsed disease.

Pathophysiology of irradiated skin and breast.

The evolution, time course, and dose response of gross and histologic changes associated with the acute and late changes of the skin are noted and a composite pathophysiologic operational model given. This model focuses the selection of the observations to be "scored" to assess the tolerance and cosmetic response of the skin and breast to different dose and combined therapy studies. Skin scoring, Late effects skin, Late effects breast, Skin irradiation response, Breast radiation response, Pathophysiology of irradiated skin, Dose tolerance of skin, Dose tolerance of breast, Skin functional unit, Microvessel response to irradiation.

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens.

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin's disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose 5-7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (> 5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30-40 Gy at 1.8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease.

Abutment of adjacent intraoperative radiotherapy electron fields to treat large tumor volumes.

Abutment of unmodified Intraoperative Radiotherapy (IORT) electron fields to irradiate large volumes can lead to dose inhomogeneities at the junction site of the matched fields. Although precise field matching is difficult to achieve in the IORT setting, we have fabricated special cones and dosimetrically evaluated their use. Based on these results, we have established guidelines for the routine use of multiple IORT fields that require field matching. This study examines the abutment of adjacent IORT electron fields for various cone sizes and beam energy combinations, using film dosimetry and a scanning densitometer. Results indicate that for abutting two adjacent 9 x 9 cm square cones, an optimum field separation at the depth of the 90% isodose line (d90) can be obtained as follows: For 6, 9, and 12-MeV electron beams, abut the inner wall of the second IORT cone to the inner wall of the first IORT cone. For 16- and 20-MeV electron beams, abut the inner wall of the second IORT cone to outer wall of the first IORT cone.

Radical radiotherapy as salvage treatment for relapse of Hodgkin's disease initially treated by chemotherapy alone: prognostic significance of the disease-free interval.

PURPOSE: A study was performed to determine the effectiveness of radical radiation therapy (RT) in the treatment of patients with Hodgkin's disease who relapsed following initial treatment with chemotherapy alone. METHODS AND MATERIALS: A retrospective review of patients treated at City of Hope National Medical Center between 1970 and 1987 revealed a total of 10 patients who received radical RT with curative intent as salvage therapy. RESULTS: Complete remission was achieved in eight of the ten patients. Patients had an overall 5-year actual survival of 60% and 10-year actuarial survival of 38%. Relapse-free survival was 30% at 5 years and at 10 years. For the five patients with a disease-free interval (DFI) of at least 12 months prior to radical RT, overall actual survival at 5 years was 100% and relapse-free survival was 60%. Three of the ten patients, all with a DFI > 12 months and in first relapse when undergoing radical RT, were long-term relapse-free survivors. CONCLUSION: Radical RT is an effective salvage regimen for select patients with advanced stage Hodgkin's disease who relapse following initial treatment with chemotherapy alone provided that relapse is limited to sites which can be encompassed by radical RT fields and the DFI is greater than 12 months. Review of other published series supports DFI > 12 months as a favorable prognostic factor. Comparison to other salvage regimens such as autologous bone marrow transplantation is limited. Reviews of other treatment modalities should perform subset analysis on patients with similar presentations to compare the relative effectiveness of various salvage approaches.

Breast conservation therapy: local tumor control in patients with pathologically clear margins who receive 5000 cGy breast irradiation without local boost.

A retrospective study was performed to determine the value of pathological evaluation of inked primary tumor specimen margins in the local control of patients with stage I and II breast cancer. In 150 patients with 153 invasive breast cancers, treatment involved surgical resection of the primary tumor, pathological determination of tumor-free inked specimen margins, and 5000 cGy whole breast radiation therapy (RT) without tumor bed RT local boost. This approach yielded an actuarial five-year local control rate of 95%. The local control rate was 96% for T-1 cases and 93% for T-2 cases. The local control rate was 96% for patients with clear margins achieved at initial resection and 94% for patients with clear margins achieved at re-excision. Among patients with clear margins at re-excision, the local control rate was 97% for those with no residual cancer and 88% for those with residual cancer. Patients with surgical margins clear by 3 mm or less had a local control rate of 92% at five years. Local control rates appear to be comparable to other breast conservation approaches which routinely employ local RT boosts. In omitting the local RT boost in patients with clear margins, the overall RT course will be briefer and the cosmetic changes associated with high-dose, large volume local RT boosts can be avoided.

Wound-healing complications following biopsy of the irradiated breast.

A retrospective review evaluated results of 38 posttreatment biopsies (with resulting benign pathologic findings) that were performed on 32 irradiated breasts or axillae in 31 of 232 patients who underwent conservation treatment of early-stage breast cancer. Postbiopsy wound-healing complications developed in eight (30%) of 27 patients who were undergoing open biopsies but in none of 11 who underwent only needle biopsies. Wound-healing complications occurred in two of five patients who underwent incisional skin biopsy, three of five who underwent mammographic needle-localized excisional biopsy, and three of 17 who underwent other types of open biopsies. Frequency of wound-healing complications following open biopsy was not related to patient age, diabetes mellitus, cigarette smoking, or use of chemotherapy. Wound-healing complications were related to breast size, developing in four (67%) of six patients with large breasts (brassiere cup size D or DD) as compared with that in only four (19%) of 21 patients with smaller breasts. Significant worsening of cosmetic breast retraction was frequently associated with wound-healing complications, especially wounds that took more than 1 month to heal.

Factors affecting cosmetic outcome in breast-conserving cancer treatment--objective quantitative assessment.

A battery of objective measurements of cosmetic outcome was performed on 114 patients who had been treated by breast-preservation techniques for breast cancer. Cosmetic breast retraction, as determined by Breast Retraction Assessment (BRA) measurements, was significantly greater in patients who underwent extensive primary tumor resection, were more than 60 years old, weighed more than 150 lbs, or had a primary tumor in an upper breast quadrant. While use of a local RT boost, per se, was not a significant factor, those patients with high dose and/or large volume local boosts more frequently had marked retraction. Breast telangiectasia and depigmentation (T/D) was related to use of a local RT boost, patient age greater than 60 years, and use of separate nodal RT fields. Breast T/D was significantly more frequent with use of electron beam local RT boost which delivered a boost skin dose exceeding 1600 cGy. Objective quantitative assessments, such as BRA and T/D area measurements, provide data to determine factors related to each type of cosmetic change and thus provide guidelines for optimizing cosmetic outcome. Limiting the extent of primary tumor resection may minimize the amount of breast retraction. Omitting the local RT boost, particularly large volume, high dose boosts, may reduce the frequency of marked cosmetic retraction and skin T/D.

Spontaneous pneumothorax in patients irradiated for Hodgkin's disease and other malignant lymphomas.

A retrospective review of patients treated for Hodgkin's disease or other malignant lymphomas between 1953 and 1988 revealed 10 cases of spontaneous pneumothorax. Nine had Hodgkin's disease whereas one had diffuse histiocytic lymphoma. Ages of the 10 patients ranged from 11 to 54 years, although nine were less than 30-years old. Spontaneous pneumothorax was observed only in patients who had received mantle or mini-mantle radiation therapy (RT). Five patients had concurrent severe parenchymal pulmonary disease including chemotherapy-induced interstitial fibrosis, Varicella pneumonia and severe radiation pneumonitis. Pneumothorax in these patients tended to be severe, bilateral and/or recurrent. All five required chest tube placement. Three of the five also required thoracotomy. RT dose ranged from 3000-7500 cGy, exceeding 4700 cGy in three patients who required a second course of RT which included the involved lung apex. In comparison, the five who did not have concurrent severe lung disease had milder episodes of pneumothorax. Only one required chest tube placement, whereas none required thoracotomy. Pulmonary apex RT dose ranged from 3672-4257 cGy. For Hodgkin's disease patients treated by RT, the frequency of spontaneous pneumothorax in the absence of concurrent pulmonary disease was 2.2%. Limiting analysis to patients in the peak age population of 10-30 years raised the frequency to 3.0%. No RT dose-response effect could be demonstrated, although spontaneous pneumothorax was not observed in patients who received less than 3000 cGy. Spontaneous pneumothorax was not more frequent among patients who also received chemotherapy as compared to those treated only by RT. Exploratory thoracotomy in three cases with severe pulmonary disease revealed subpleural apical blebs and/or dense pleural fibrosis. Unusual aspects in the medical histories of other cases suggest the possibility that patients who develop pneumothorax may have unusually dense pulmonary and/or pleural fibrosis compared to the majority of patients who receive RT for Hodgkin's disease or other malignant lymphomas.

The reverse hockey stick technique: postmastectomy radiation therapy for breast cancer patients with locally advanced tumor presentation or extensive loco-regional recurrence.

A combination of photon and electron radiation therapy (RT) fields was devised to treat patients with initial or recurrent breast cancer presentations which extensively involved the chest wall (CW) and/or the axilla. The ipsilateral supraclavicular, infraclavicular, axillary, and lateral CW regions are treated in continuity by anterior and posterior opposed photon beam "reverse hockey stick" fields. The internal mammary and medial chest wall regions are treated by an anterior electron beam field which is tightly junctioned to the photon beam fields. Electron beam energy and thickness of applied bolus are selected so that the electron beam 80% depth isodose curve matches the anterior pleural surface and/or deepest extent of tumor. The goal of treatment is to deliver 4400-5000 cGy to regions at risk of microscopic tumor with local boosts to 6000-7500 cGy to sites of gross disease. Between January 1977, and June 1985, this technique was selectively used in 46 patients, 31 patients with loco-regional tumor recurrence and 15 post-mastectomy patients who initially presented with locally advanced disease. A minimum tumor dose of 4400 cGy was delivered in all except five patients. A diffuse moist skin reaction developed in 31 of the 44 (70%) patients who received at least 3800 cGy. This healed in less than 1 month in all except seven. Frequency of CW diffuse moist skin reaction within the electron beam field was related to the daily applied RT dose. Diffuse moist skin reactions were also noted to be more frequent among patients who had received prior or concurrent Adriamycin. Significant complications included symptomatic arm lymphedema in seven; CW ulcer in two; and acute radiation pneumonitis; steroid-withdrawal radiation pneumonitis, pleuritis, and marked thrombocytopenia in one patient each. With a follow-up of 36-100 months, there was no evidence of loco-regional tumor relapse in 55% of patients treated for recurrent disease and in 73% treated following mastectomy for locally advanced presentations. In summary, we find the reverse hockey stick technique to be a simple, highly reproducible and effective RT approach for postmastectomy breast cancer patients with extensive initial presentation or recurrent disease.

Total skin electron irradiation for mycosis fungoides: relationship between acute toxicities and measured dose at different anatomic sites.

From June 1978 to June 1986, 50 patients with primary and recurrent mycosis fungoides were treated with total skin electron irradiation (TSEI), using the Stanford technique, to a total dose of 3600 cGy. TSEI was used alone, or in combination with low dose total body photon irradiation, or MOPP. Thermoluminescent dosimeter (TLD) measurements of the prescribed skin dose were obtained on twenty patients. The dorsum of the foot was 24% higher. The axillae, the bottom, and the arch of the foot were significantly underdosed. Frequencies of acute toxicities noted at 2000 cGy were: Skin, Grade I-II (RTOG) 80%. Partial epilation: scalp, 100%; eyebrows and at eyelashes, 20%. Nail dystrophy, 48%. Edema: hands and feet, 44%. Bullae: dorsum of feet, 8%; hands, 4%; and 3600 cGy: Skin, grade III 22%. Total epilation: scalp, 66%; eyebrows and eyelashes, 56%. Nail loss, 38%. Edema: hands and feet, 76%. Bullae: dorsum of feet, 34%; hands, 12%. Conjunctivitis, 4%. Large bullae, were more significant on the dorsum of the feet. Severe moist desquamation occurred in eight patients who had ulcerated lesions on initial presentation. Three patients were hospitalized due to ulceration and skin infection. All patients completed treatment after a short to moderate break. No patient developed skin necrosis, or corneal ulceration. No correlation exists between dose level, degree and onset of toxicity with previous chemotherapy or TBI. We conclude that the overall toxicity of TSEI is well tolerated.

Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx, and pharynx: preliminary report of a prospective randomized trial.

A prospective randomized trial was performed in patients with advanced squamous cell carcinomas (SCC) of the oral cavity, larynx, and pharynx to examine the effect of adjuvant postoperative radiation therapy on locoregional recurrence and survival following "curative" resection. Fifty-one patients with stage III or IV SCC treated from 1981 through 1984 were randomized to receive either surgery alone (n = 27) or surgery with postoperative radiation (n = 24). Five patients were excluded from the study after randomization because of ineligibility or protocol violations. Overall recurrence rates of 55.6% and 36.8% were noted in the surgery and surgery with adjuvant radiotherapy arms, respectively (p = NS). This trend towards a higher recurrence rate in the surgery only arm was in part due to the development of lymph node metastases in the contralateral, nonoperated neck. Thus far, no significant differences in either locoregional or overall survival have been noted between the two treatment arms. In this preliminary analysis, adjuvant postoperative radiotherapy does not appear to improve disease-free or overall survival.

To boost or not to boost: decreasing radiation therapy in conservative breast cancer treatment when "inked" tumor resection margins are pathologically free of cancer.

A retrospective study was performed to compare local treatment approaches for 108 treated breasts in 105 patients with Stage I or II breast cancer. Six cases with intraductal carcinoma have shown no evidence of recurrence. The other 102 cases had invasive cancer. In 54 treated breasts in 53 patients, the treatment approach involved surgical resection of the primary tumor, pathological determination of tumor-free "inked" specimen margins and 5000 cGy to the whole breast. Local radiation therapy (RT) boosts to the primary site were not given. This approach produced a 100% local control rate (mean follow-up of 38 months). In 28 treated breasts in 27 patients, the treatment approach involved tumor excision without evaluation of specimen margins followed by RT which included a local boost by either interstitial Iridium-192 implant or electron beam. This approach yielded an actuarial local control rate of 87% at 48 months (mean follow-up of 47 months). The difference in local control rate between the two groups was statistically significant (p less than 0.03). Among patients with clear surgical margins who received a local RT boost, 1 of 9 developed a local recurrence. Among those with tumor involving specimen margins who received a local boost, 1 of 8 developed local recurrence. Local recurrence developed more frequently among patients with poorly differentiated cancers (2 of 11 cases) than among those with other invasive cancers (3 of 91 cases). Comparison of treatment approaches was limited since poorly differentiated cancer was present in 25% of cases with unknown specimen margins, as compared with only 2% of those with clear surgical margins who did not receive a local RT boost. Our preliminary findings suggest that when "inked" primary tumor resection margins are pathologically free of cancer, 5000 cGy whole breast RT appears to be highly effective for local tumor control in patients with Stage I or II disease. Our results are inconclusive as to whether patients with poorly differentiated cancers should receive a local RT boost even when surgical margins are clear.