Results of a pooled analysis of IOERT containing multimodality treatment for locally recurrent rectal cancer: Results of 565 patients of two major treatment centres.

OBJECTIVE: Aim of this study is analysing the pooled results of Intra-Operative Electron beam Radiotherapy (IOERT) containing multimodality treatment of locally recurrent rectal cancer (LRRC) of two major treatment centres. METHODS AND MATERIALS: Five hundred sixty five patients with LRRC who underwent multimodality-treatment up to 2010 were studied. The preferred treatment was preoperative chemo-radiotherapy, surgery and IOERT. In uni- and multivariate analyses risk factors for local re-recurrence, distant metastasis free survival, relapse free survival, cancer-specific survival and overall survival were studied. RESULTS: Two hundred fifty one patients (44%) underwent a radical (R0) resection. In patients who had no preoperative treatment the R0 resection rate was 26%, and this was 43% and 50% for patients who respectively received preoperative re-(chemo)-irradiation or full-course radiotherapy (p < 0.0001). After uni- and multivariate analysis it was found that all oncologic parameters were influenced by preoperative treatment and radicality of the resection. Patients who were re-irradiated had a similar outcome compared to patients, who were radiotherapy naive and could undergo full-course treatment, except the chance of local re-recurrence was higher for re-irradiated patients. Waiting-time between preoperative radiotherapy and IOERT was inversely correlated with the chance of local re-recurrence, and positively correlated with the chance of a R0 resection. CONCLUSIONS: R0 resection is the most important factor influencing oncologic parameters in treatment of LRRC. Preoperative (chemo)-radiotherapy increases the chance of achieving radical resections and improves oncologic outcomes. Short waiting-times between preoperative treatment and IOERT improves the effectiveness of IOERT to reduce the chance of a local re-recurrence.

Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group.

PURPOSE: To develop a tolerable regimen of fluorouracil (5-FU), low-dose leucovorin, and radiation, and to obtain an early estimate of therapeutic effectiveness. PATIENTS AND METHODS: Forty patients with locally unresectable or recurrent gastrointestinal carcinoma were studied (pancreas, n = 22; rectum and sigmoid, n = 10; gastric, n = 6; other, n = 2). Irradiation therapy was administered in 1.8-Gy fractions 5 days per week, with total doses ranging from 45 to 54 Gy. 5-FU 400 mg/m2/d plus leucovorin 20 mg/m2/d, both by rapid intravenous injection, were administered for 3 or 4 days during the first and fifth weeks of radiation. 5-FU 425 mg/m2/d plus leucovorin 20 mg/m2/d were administered for 4 days at 4 weeks following radiation and for 5 days at 9 weeks. RESULTS: Major toxicities with upper abdominal treatment were nausea, vomiting, weight loss, and leukopenia. A tolerable dosage regimen was radiation at 45 Gy with 4 days of 5-FU plus leucovorin during the first week and 3 days during the last week with postradiation chemotherapy. Major toxicities with pelvic radiation were diarrhea and leukopenia. A tolerable regimen was 54 Gy with 4 days of 5-FU plus leucovorin during the first and fifth week followed by the postradiation chemotherapy. Median survival durations for pancreatic and rectal/sigmoid carcinomas are 13 months and 31 months, respectively. Five patients have no evidence of disease from 38 to 50 months after the onset of therapy (rectal, n = 2; stomach, n = 2; pancreas, n = 1). CONCLUSION: We have developed patient-tolerable regimens for combined 5-FU plus leucovorin followed by radiation to the abdomen and to the pelvis. The favorable results observed in locally unresectable disease allow cautious optimism for possible effectiveness in the surgical adjuvant setting, a possibility currently being tested in national trials of rectal and gastric carcinoma.

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.

Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114.

PURPOSE: The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor. We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and/or levamisole. METHODS: A total of 1,696 patients were randomized and eligible for treatment with one of four treatment schemes. All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy. Chemotherapy was either 5-FU alone, 5-FU with leucovorin, 5-FU with levamisole, or 5-FU with leucovorin and levamisole. RESULTS: With a median follow-up duration of 48 months, there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone. There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone. Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation. CONCLUSION: There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer. Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation.

Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma.

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Current issues in the treatment of colorectal cancer.

For colorectal cancers that are confined to the bowel wall with uninvolved nodes, surgery alone is curative in most patients, and adjuvant treatment is usually not indicated. A combined modality approach for the initial treatment of many rectal and selected colonic carcinomas is based on data that "radical" operations do not necessarily prevent either local regrowth or distant failures and acceptance of a significant palliative but infrequent curative role for irradiation and chemotherapy when such failures occur. Published data for rectal cancer indicates that local recurrence can be markedly reduced by moderate to high dose pre- and post-operative irradiation +/- chemotherapy. For colon cancer, data from pilot trials suggest that post-operative irradiation may reduce local recurrence by stage when compared with surgery alone analyses, but randomized trials are needed. With locally advanced disease, aggressive treatment combinations appear to increase both local control and survival, but much interaction is required between involved physicians.

The current role of radiotherapy in colorectal cancer.

During the last two decades, radiotherapy has become an integral part of the multidisciplinary approach in the treatment of patients with colorectal cancer. Currently, radiotherapy is seen mainly as an adjuvant therapy, sometimes in combination with chemotherapy, in a pre- or postoperative setting. Adjuvant radiotherapy alone leads to a significant reduction of local recurrence rates, but an impact on survival is seen only in subset analyses. Combined modality treatment can reduce local recurrence rates even further, and can also reduce the rate of distant relapses and increase survival. The acute toxicity of combined modality is considerably higher. Local radiation can also be use as a component of organ conserving local treatment for selected early lesions. Radiotherapy has been an important palliative treatment modality, diminishing symptoms in cases of inoperable primary rectal cancers or pelvic recurrences. The timing of radiation, surgery and chemotherapy has been under evaluation for years. For patients with locally advanced primary or recurrent malignancies (unresectable due to fixation), the preferred sequence is pre-operative irradiation with or without chemotherapy, followed by surgical resection. For mobile resectable lesions, sequencing issues are being tested in phase III randomised trials.

Surgical adjuvant therapy of rectal cancer.

Surgery is the preferred method of curative therapy for carcinoma of the rectum. However, in spite of complete gross tumor resection, many patients with locally advanced tumors will experience recurrence of malignant disease in the pelvis and/or distant metastases. This article summarizes the roles of radiotherapy and chemotherapy, administered alone and in combination, as surgical adjuvant treatment for patients with resectable rectal cancer. A biostatistical overview is presented. It is concluded that strong evidence exists supporting the efficacy of combined postoperative radiotherapy and chemotherapy. Further clinical trials are indicated to determine the optimum chemotherapy regimen, sequence, and duration of the therapy.

Intraoperative irradiation: current and future status.

Intraoperative radiation therapy (IORT) in its broadest sense refers to the delivery of irradiation at the time of an operation. This article will discusses the rationale for and results of both intraoperative electron radiation therapy and intraoperative high dose rate brachytherapy when used in conjunction with surgical exploration and resection and external beam radiation therapy and chemotherapy. Both IORT methods evolved with similar philosophies as an attempt to achieve higher effective doses of irradiation while dose limiting structures are surgically displaced.

Radiation therapy for small bowel carcinoma: report of three patients and review of the literature.

The potential role of radiation therapy in the management of localized small bowel carcinoma is reviewed based upon three patients irradiated at a major referral center and seven previously reported patients in the literature. The one patient irradiated postoperatively for gross residual disease has had local-regional disease control for 1.5 years. The two patients irradiated postoperatively in an adjuvant setting are alive disease at 3.8 and 0.5 years, respectively. Patients with unresectable disease (initially or at recurrence) have fared poorly. Patterns of tumor spread are reviewed, and recommendations on irradiation dose and volume are suggested.

Adenocarcinoma of the stomach: areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy.

Following initial "curative" operative procedures for gastric carcinoma, 107 patients had planned single or multiple re-operations at the University of Minnesota. Later evidence of cancer was found in 86 patients at re-operation and/or other follow-up. Initial operative-pathologic extent of disease was correlated with incidence and patterns of failure. Distant metastasis (DM) alone was uncommon, but was found as a new component in 25.6% of the failure group. Nearly half of the peritoneal failures (PS) were localized, and when diffuse, were usually accompanied by a moderate sized local-regional failure. Local recurrence and/or regional lymph node metastasis (LF-RF) occurred as the only failure in 53.7% of the failure group if localized peritoneal failures were included, and as any component of failure in 87.8% (67.3% of the total 107 patients). Operation alone yields inadequate results for the majority of patients with gastric carcinoma. The rationale of adjuvant radiation and systemic therapy alone or in combination is discussed.

Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy.

A total of 230 patients had planned single or multiple reoperative procedures following "curative" resection of colorectal cancer at the University of Minnesota. The site of the primary lesion was extrapelvic in 91, and later evidence of cancer was found in 58 patients (64%) at re-operation and/or other follow-up. Eight of the 58 (14%) were converted to disease-free status. Incidence and patterns of failure were correlated with initial operative-pathologic extent of disease (87 of the 91 at risk had initial tumor extension beyond the bowel wall, involved nodes or both) and comparisons were made with the previously analyzed rectal reoperation patients. While a component of local-regional failure was more common with rectal lesions (48/74 at risk, 65%), it was not uncommon with extrapelvic primaries (44/91-48%). The incidence of hematogenous metastasis (DM) was equal, but the pattern of initial DM differed (extrapelvic colon--primarily liver; rectum--liver and lung). Peritoneal seeding was a more common component of failure with the extrapelvic primaries (19/91--21% vs 3/74-4%). Since surgery alone is inadequate treatment for many patients with colon as well as rectal cancer, the rationale of adjuvant radiation and systemic therapy, alone or in combination, is discussed.

Endocavitary radiotherapy of rectal cancer.

PURPOSE: This analysis was performed to evaluate the results of endocavitary radiotherapy (RT) administered for early rectal cancer at our institution. METHODS AND MATERIALS: Patient charts were retrospectively reviewed to determine the results of endocavitary RT regarding survival, local control, and complications. Between 1987 and 1994, 25 patients were treated with endocavitary RT for early rectal cancer. Twenty had early, low grade tumors and met the criteria for treatment with curative intent. Five had more advanced, high grade, or multiple recurrent tumors and were treated with palliative intent. The tumors were treated to between 20 and 155 Gy in one to four fractions with 50 KV x-rays given through a specialized proctoscope. Patients were followed for 5 to 84 months (median = 55 months) after therapy. Local control and survival were determined using the Kaplan-Meier method. RESULTS: Local control was achieved in 18 of the 20 patients treated with curative intent and 4 of 5 treated with palliative intent. For those patients treated with curative intent, the 5-year local control rate was 89% and the 5-year survival rate was 76%. The most significant toxicity was ulceration that occurred in 5 of the 25 patients. The ulcers were asymptomatic in three cases and associated with bleeding in one case. The fifth patient had pain. One ulcer was biopsied, resulting in perforation that was treated with an abdominal perineal resection (APR). There was no tumor found upon pathologic evaluation. CONCLUSIONS: Endocavitary RT can be used to treat patients with early, low-grade rectal cancers and will yield a high level of disease control and a low risk of serious complications. Major advantages of this treatment technique are that it requires neither general anesthesia nor hospitalization.

Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies.

We have devised a single after-loading applicator, the Martinez Universal Perineal Interstitial Template (MUPIT), which has been used in combination with external beam irradiation to treat 104 patients with either locally advanced or recurrent malignancies of the cervix, vagina, female urethra, prostate, or anorectal region. Twenty-six patients treated for prostate cancer are excluded because of their short follow-up. Local failure developed in 13 of the 78 remaining patients (16.6%)--major complications developed in 4 patients (5.1%). Follow-up has been 1 year to 7 1/2 years; 60/78 patients have been followed for more than 2 years. All local recurrences and complications occurred before 18 months. The device consists of two acrylic cylinders, an acrylic template with an array of holes that serve as guides for trocars, and a cover plate. In use, the cylinders are placed in the vagina and/or rectum or both and then fastened to the template so that a fixed geometric relationship among the tumor volume, normal structures, and source placement is preserved throughout the course of the implantation. Appropriate computer programs have been developed to calculate the dose from these implants. The advantages of the system are (a) greater control of the placement of sources relative to the tumor volume and critical structures, as a result of the fixed geometry provided by the template and cylinders, and (b) improved dose-rate distributions obtained by means of computerized optimization of the source placement and strength during the planning phase. We conclude that the local control rate (83.4%) with low morbidity (5.1%) achieved with the combination of external beam irradiation and MUPIT applicator in these patients with locally advanced malignancies represents an improvement over previous published results with other applicators.

Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films.

For colorectal cancer, the adjuvant radiation dose levels required to achieve a high incidence of local control closely parallel the radiation tolerance of small bowel (4500-5000 rad), and for patients with partially resected or unresected disease, the dose levels exceed tolerance (6000-7000 rad). Therefore, both the surgeon and the radiation oncologist should use techniques that localize tumor volumes and decrease the amount of small intestine within the irradiation field. Surgical options include pelvic reconstruction (reperitonealization, omental flaps, retroversion of uterus, etc.) and clip placement. Radiation options include the use of radiographs to define small bowel location and mobility combined with treatment techniques using multiple fields, bladder distention, shrinking or boost fields, and/or patient position changes (prone, decubitus, etc.). When both specialties interact in optimum fashion, local control can be increased with minimal risks to achieve a suitable therapeutic ratio.

A pilot study to determine clinical tolerability of intensive combined modality therapy for locally unresectable gastric cancer.

Eighteen patients with unresectable carcinoma of the stomach whose known malignant disease was confined to structures immediately adjacent to the primary tumor and could be encompassed within a radiotherapy field were treated with an intensive sequential combined modality regimen. The regimen consisted of 5-FU plus adriamycin chemotherapy, followed by high dose megavoltage radiation therapy with 5-FU given as a radiation sensitizer, followed by maintenance chemotherapy with 5-FU plus adriamycin plus methyl CCNU (FAMe). Our primary objective was to determine patient tolerability. Severe and prolonged anorexia, nausea, and decreased performance status occurred during and after high dose radiotherapy given twice daily in 150-170 cGy (rad) fractions when given with 5-FU. Lengthening intervals between treatment segments, and the use of one daily dose of radiation therapy combined with 5-FU or two fractions daily without 5-FU seemed to decrease nutritional complications. Control of tumor at the primary site appeared to be achieved in most patients. Distant metastases represented the predominant mode of treatment failure with only two patients currently without progression of malignant disease. Our treatment regimen as initially conceived was too toxic for general use. Improved therapeutic results in locally unresectable gastric cancer will require the development of more effective therapy for occult distant metastases.

Matching intraoperative electron-beam fields: dosimetric and clinical considerations.

In the setting of a large or irregularly shaped tumor, adjacent or intentionally overlapped intraoperative electron fields may be required to give adequate coverage of the intraoperative target volume. The matching of such intraoperative electron fields present special dosimetric problems because of the divergence of electron isodose curves with depth. In the intraoperative setting, where large, single-fraction doses are delivered, the low- and high dose areas which result from gaps or overlaps between the diverging isodose curves of electron fields matched at depth or the surface may translate into decreased local tumor control or excessive normal tissue toxicity. This study examines the dosimetry of gapped, adjacent, and overlapped 8 X 9 cm2 rectangular intraoperative fields, for 9 to 18 MeV electrons, using film densitometry. "Ideal" methods of matching rectangular intraoperative electron fields are presented, and include: 1) a 2-mm gap plus surface bolus for adjacent fields, and 2) placing a tenth-value layer shaped lead cutout in the overlap region for intentionally overlapped fields.

Postoperative radiation therapy for incompletely resected colorectal carcinoma.

The efficacy of high-dose post-operative radiation therapy was evaluated in 56 patients with pathologically proven or suspected residual disease after surgical resection of colon or rectal carcinoma. Patients had either microscopic or gross residual. They were treated with pelvic or abdominal irradiation to a dose of 4500 cGy followed by boost therapy to as much as 6000 to 7000 cGy if small bowel could be moved from the radiation field. Patients with microscopic residual had a local failure rate of 30% compared to 57% in those with gross residual disease. Five-year disease-free survival was 45% in patients with microscopic versus 10.6% for those with gross residual tumor. There was a trend toward a dose response curve for those with microscopic disease, but none was noted with gross residual. In view of the limited results obtained with current external beam techniques, it is recommended that newer avenues, such as high-dose preoperative therapy combined with intraoperative radiation, be investigated in this poor prognosis group.

Long-term survival and patterns of failure after postoperative radiation therapy for subtotally resected rectal adenocarcinoma.

Between 1977 and 1984, 17 patients received external beam irradiation after subtotal resection of rectal carcinoma. Ten patients had microscopic residual disease and 7 had gross residual disease. In the group with microscopic residual disease, 4 had tumor cut through with pathologically involved margins, 5 had adjacent unresected structures that were biopsy positive, and 1 had tumor spillage into the pelvis. The patients with gross residual disease were noted by the surgeon to have visible tumor after maximal debulking. Nine of 17 cases had involved pelvic lymph nodes. Radiation was administered to the pelvis with 4, 6, or 10 MV photons. Doses ranged from 40 to 60 Gy, with a median dose of 50 Gy given at 1.8 to 2.0 Gy per fraction, 5 days per week. Three patients received bacillus Calmette-Guérin (BCG), 2 received 5-fluorouracil (5-FU), and 1 received hycanthone. Thirteen of the 17 patients (76%) experienced local failure and, of these, 10 also developed distant disease. No patients developed distant metastasis in the absence of local failure. Local control was achieved in 3 of 10 patients (30%) with microscopic residual and 1 of 7 (14%) with gross residual. Four of the 17 patients (24%) have remained free of disease for greater than 5 years. External beam irradiation is capable of producing long-term survival and local control in a minority of patients with rectal cancer after subtotal resection. Investigation of more aggressive forms of therapy such as the addition of intraoperative irradiation, brachytherapy, radiation dose modifiers, and chemotherapy is warranted.

The treatment of locally advanced colon cancer.

PURPOSE: The results of therapy for 103 patients with locally advanced colon cancer who received radiotherapy were analyzed to determine the outcome and tolerance of therapy. METHODS AND MATERIALS: Between 1974 and 1994, 103 patients received radiotherapy and maximal resection of locally advanced colon cancers. Following resection, 50 patients had no residual disease, 18 patients had microscopic residual disease, and 35 patients had gross residual disease. External beam radiotherapy was initiated 1 to 4 months following resection except in two patients who received preoperative radiotherapy. Treatment was delivered to the tumor bed and adjacent lymph nodes using 4 to 18 MV X-rays with doses ranging from 16.2 to 60 Gy. Intraoperative electron radiotherapy (IOERT) was also administered to 11 of the patients with doses ranging from 10 to 20 Gy. Chemotherapy was administered to 77 patients. Follow-up in survivors ranged from 0.5 to 17 years (median: 5.8 years). RESULTS: The 5-year actuarial local failure rate was 10% for patients with no residual disease, 54% for patients with microscopic residual disease, and 79% for patients with gross residual disease (p < 0.0001). For patients with residual disease, local failure occurred in 11% of patients receiving IOERT compared with 82% of patients receiving only external beam therapy (p = 0.02). The 5-year actuarial survival rate was 66% for patients with no residual disease, 47% for patients with microscopic residual disease, and 23% for patients with gross residual disease (p = 0.0009). The 5-year survival rate in patients with residual disease was 76% for patients receiving IOERT and 26% for patients receiving external beam therapy alone (p = 0.04). CONCLUSIONS: Patients with locally advanced colon cancer who have had a complete resection have a high probability of local control after external beam irradiation +/- 5 fluorouracil (5FU)-based systemic therapy. The toxicity of therapy can be minimized with attention to treatment technique and dose. Local control and survival rates in patients with residual disease who received IOERT appear to be significantly greater than for those patients who received external beam radiotherapy therapy alone.