Local-regional Failure Rate Research Articles

Importance of radiation therapy for breast cancer patients treated with high-dose chemotherapy and stem cell transplant

Purpose: To determine local-regional failure rates in breast cancer patients treated with surgery and high-dose chemotherapy with stem cell transplant and to relate local-regional failure to the use and timing of radiation treatment. Methods and Materials: We retrospectively reviewed the records of 165 breast cancer patients treated on institutional protocols with surgery and high-dose chemotherapy with stem cell transplant. All patients had either Stage III disease, 10 or more positive axillary lymph nodes, or 4 or more positive axillary lymph nodes following neoadjuvant chemotherapy. Twelve patients had inflammatory breast cancer. Thirteen patients treated with breast preservation and 5 patients who died from toxicity within 30 days of transplant were excluded from the analyses of local-regional recurrences. In the remaining 147 patients, 108 were treated with adjuvant radiation and 39 were not. The disease stage distribution for these two groups was comparable. The median follow-up for surviving patients was 35 months. Results: The 3- and 5-year actuarial disease-free survival (DFS) for the entire group was 60% and 51%, respectively. The 5-year rates of freedom from isolated local-regional recurrence were 95% in the patients treated with adjuvant radiation and 86% in the patients who did not receive radiation ( p = 0.014, log rank comparison). The 5-year rates of any local-regional recurrence as a first event (isolated recurrences plus those with simultaneous local-regional and distant recurrences) were 92% versus 82%, respectively for patients whose treatment did and did not include radiation ( p = 0.038). We could not demonstrate a correlation of the timing of radiation with the risk of local-regional recurrence. Conclusions: These data indicate that high-dose chemotherapy does not negate the importance of radiation in optimizing local-regional control in patients with high-risk breast cancer. Given the results of recent randomized trials studying postmastectomy radiation, which show that improving local-regional control improves overall survival (OS), we believe that all breast cancer patients with high-risk primary breast cancer who are treated with high-dose chemotherapy with stem cell transplant should receive radiation as a component of their treatment.

Overexpression of p53 Protein Does Not Predict Local-Regional Control or Survival in Patients With Early-Stage Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiotherapy

Purpose: Nonfunctional or mutated p53 protein (m-p53) is found in a myriad of solid tumors in humans. m-p53 is believed to confer radioresistance through inhibition of radiation-induced apoptosis. This study was carried out to determine if the overexpression of p53 in squamous cell carcinomas (SCC) of the glottic larynx treated with radiation therapy alone carried a poorer prognosis than normal wild-type p53 (w-p53) and could, therefore, be used as a marker of radioresistance in glottic SCC. Methods & Materials: Eighty-six patients with early-stage glottic SCC (64 T1N0, 25 T2N0 by TMN stage) treated with contemporary radiotherapy techniques to doses of 50–70 Gy were analyzed. Aberrant p53 protein was detected by immunohistochemical (IHC) staining on archival tissue samples containing original tumor specimens. Analysis of prognostic factors and treatment outcome to expression of p53 was performed. All patients were carefully selected to have comparable sites of disease, histology, early-stage disease, and treatment delivered, thus increasing the power of this study by controlling for other independent factors affecting outcome. Results: Sixty percent of patients demonstrated overexpression of p53 in tissue samples. Accumulation of p53 was not predictive of tumor grade, stage, or smoking status prior to diagnosis. p53 status was not predictive of treatment outcome parameters including local-regional failure rate and disease-free survival rate. Factors significantly affecting treatment outcome were stage and dose of radiotherapy in T2 patients (50 Gy vs. > 62 Gy). Conclusion: m-p53 protein detected by IHC staining was not predictive as a prognostic factor for clinical outcome following radiation therapy for early-stage glottic SCC. This is in general agreement with other recently published studies of laryngeal carcinoma patients treated with radiation or surgery. At the present time, p53 status should not be used as a marker for prognosis and clinical outcome in laryngeal SCC.

Advanced carcinoma of the larynx: Results of surgery and radiotherapy without induction chemotherapy (1980–1985): A multivariate analysis

Purpose: Induction chemotherapy has been proposed in the case of advanced laryngeal cancer in order to preserve laryngeal function in those patietns who are complete responders. To clarify the treatment policies, a restrospective multicentric analysis of 116 patients with advanced carcinoma of the larynx treated by radical surgery and postoperative radiotherapy was carried out in order to evaluate prognostic factors for local control and survival.Methods and Materials: Between 1980 and 1985, 116 patients with Stage III squamous cell carcinoma of the larynx underwent radical surgery and postoperative radiotherapy with a curative intent. Treatments were very homogenous, and doses delivered were in the range of 50–65 Gy according to nodal involvement and surgical margins status.Results: The local recurrence rate and the local disease-free survival rate at 5 years were 22.5% and 76.3%, respectively. Actuarial survival at 5 years was 68.3% with 44 patients stil alive who no evidence of disease (NED) with more than 5 years follow-up. For both overall survival and relapse-free survival, cervical node involvement with capsular rupture was found to be the only significant adverse pronostic factor in univariate and multivariate analysis. No other parameter was predictive either for local recurrence or for survival.Conclusions: Local prognosis and survival depend largely on nodal involvement and capsular rupture while increasing doses of radiation strategy is likely to reduce the risk of local and nodal recurrence. Preservation of functional larynx is certainly an important goal to achieve when treating advanced carcinoma of the larynx, provided that local failure rate and survival be similar. In the unique randomized study previously published in the literature comparing radical surgery and postoperative radiotherapy to induction chemotherapy and radiotherapy, the local-regional failure rate was drastically increased in the chemotherapy arm. Other results from well-designed controlled studies are awaited before recommending systemic induction chemotherapy and larynx preservation in complete responders. On the other hand, testing synchronous or alternated chemotherapy vs. induction chemotherapy may address the pending questions about the optimal treatment of advanced laryngeal carcinoma.

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

Treatment of locally advanced noninflammatory breast cancer has changed markedly over the past 50 years. Haagensen's description of the clinical signs that define inoperable and operable tumors was the first realization that radical surgery alone could not cure the majority of women with locally advanced disease. Studies of the use of local therapy alone (surgery or radiation therapy) confirmed that most patients developed both distant metastatic disease and a high rate of local-regional failure. Combination surgery and radiation therapy regimens improved local control but did not influence long-term survival. The advent of successful multimodal regimens incorporating systemic treatment (chemotherapy or chemohormonal therapy) as well as local therapy (surgery and radiation) has significantly improved disease-free and overall survival as well as local-regional control. The benefits of neoadjuvant and adjuvant chemotherapy regimens have been debated. Neoadjuvant therapy allows clinical and pathologic assessment of tumor response to the chemotherapy regimen. In addition, local-regional control seems to be improved, and reductions in the size of the primary tumor allow breast-preserving procedures, even in patients initially not believed to be candidates for resection. Longer follow-up of these conservatively treated patients will be needed, however, to determine whether local-regional control is preserved.

Randomized phase [formula omitted] trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88-09

To establish the feasibility of performing split-course accelerated hyperfractionation (AHFX-S) and concomitant boost accelerated fractionation radiotherapy (AFX-C) for advanced head and neck cancer in a multi-institutional cooperative trial setting and to evaluate the tumor clearance rate and acute and late toxicity of these fractionation schedules. Between February 1989 and January 1990, 75 patients with Stage III or IV squamous cell carcinoma of the head and neck were randomized to receive: (a) AHFX-S: 1.6 Gy/fraction, twice daily (6-h interval), 5 days/week, to a total dose of 67.2 Gy/42 fractions/6 weeks, with a 2-week rest after 38.4 Gy; or (b) AFX-C: 1.8 Gy/fraction/day, 5 daily fractions/week to 54 Gy/30 fractions/6 weeks to a large field and 1.5 Gy/fraction/day to a boost field, 6 h after large field treatment during the last 11 treatment days, to a total dose of 70.5 Gy/41 fractions/6 weeks. Acute and late toxicities were scored according to the RTOG normal tissue reaction scales and tumor clearance was evaluated at completion of therapy and at regular intervals thereafter. Of the 70 analyzable patients, 38 received AHFX-S and 32 received AFX-C. The two arms were balanced with respect to sex, age, T-stage, and Karnofsky Performance Status (KPS). However, the AHFX-S arm had a higher proportion of oropharyngeal primaries (63% vs. 44%), and Stage IV disease (82% vs. 50%) and lower proportion of oral cavity lesions (3% vs. 22%) and N0 disease (16% vs. 31%) than the AFX-C arm. The median follow-up was 2 years (range: 0.03-4.87 years). Tolerance of both variants of accelerated fractionated radiotherapy was satisfactory. There was no significant difference in local-regional control, disease-free survival, or survival between the two arms. The 2-year local-regional failure rate, survival, and disease-free survival was 50, 50, and 40%, respectively, for the entire group of patients. Acute radiation mucositis was increased in both arms. There was no significant difference in the incidence of grade 3 acute toxicities (63% vs. 56%) and grade 3 (14% vs. 14%) or grade 4 (6% vs. 17%) late toxicities. Permanent grade 4 late toxicity was observed in 6 and 7% of the patients, respectively. Results of this randomized Phase I/II trial showed that the two accelerated fractionated schedules studied can be successfully given in a multi-institutional cooperative trial. There was no significant difference in acute or late toxicities, local-regional control, disease-free survival, or survival in this small scale study. Therefore, a Phase III trial comparing the relative efficacy of these two accelerated fractionation schedules against standard fractionation and hyperfractionation has been activated.

Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: Results of a randomized prospective trial

Purpose : To evaluate the effectiveness of fast neutron radiation therapy in treatment of locally advanced carcinomas of the prostate. Methods and Materials : From April 1986 to October 1990, 178 patients were entered on a prospective, multi-institutional randomized study of the NCI-sponsored Neutron Therapy Collaborative Working Group. This trial compared external beam photon irradiation (7000–7020 cGy) with external beam neutron irradiation (2040 ncGy) for patients with high-grade T 2 or T 3–4, N 0−1, M 0 adenocarcinomas of the prostate. Eighty-nine patients were randomized to each treatment. Six patients were subsequently judged to be ineligible, leaving 85 photon and 87 neutron randomized patients eligible for analysis. Results : With a follow-up time ranging from 40 to 86 months (68 months median follow-up) the 5-year actuarial clinical local-regional failure rate for patients treated with neutrons was 11%, vs. 32% for photons ( p < 0.01). Incorporating the results of routine posttreatment prostate biopsies, the resulting “histological” local-regional tumor failure rates were 13% for neutrons vs. 32% for photons ( p = 0.01). To date, actuarial survival and causes-pecific survival rates are statistically indistinguishable for the two patient cohorts, with 32% of the neutron-treated patient deaths and 41% of the photon-treated patient deaths caused by prostate cancer ( p = n.s.). Prostate specific antigen (PSA) values were elevated in 17% of neutron-treated patients and 45% of photon-treated patients at 5 years ( p < 0.001). Severe late complications of treatment were higher for the neutron-treated patients (11% vs. 3%), and were inversely correlated with the degree of neutron beam shaping available at the participating institutions. Neutron treatment delivery utilizing a fully rotational gantry and multileaf collimator did not result in an increase in severe late effects when compared to photon treatment. Conclusion : High energy fast neutron radiotherapy is safe and effective when adequate beam delivery systems and collimation are available, and it is significantly superior to external beam photon radiotherapy in the local-regional treatment of large prostate tumors.

Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: phase I-II study.

From June 1988 to July 1991, 20 patients with locally advanced rectal or rectosigmoid cancer were treated prospectively with a strategy of combining preoperative irradiation and fluorouracil chemotherapy before surgical resection. The preoperative radiation dose was 5,000 cGy, and fluorouracil chemotherapy was administered on the first and last 3 days of irradiation in an intravenous bolus dose of 500 mg/m2. In a median follow-up of 25 months, the local regional failure rate was 10%. The 3-year actuarial overall survival and disease-free survival were 92% and 82%, respectively. Twenty percent of the surgical specimens showed no residual tumor, and only 10% showed positive lymph nodes. Significant leukopenia occurred in 10% of patients. Preoperative irradiation and fluorouracil chemotherapy increased surgical downstaging and improved local regional control. The overall toxicity was acceptable. The results of this particular multimodality approach was encouraging and warrant further investigation in phase III trials.

The effect of systemic therapy on local-regional control in locally advanced breast cancer

One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical partial response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer ( p = .02), and local-regional failure as any component of first failure 12% versus 36% ( p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5 31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2 53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy ( p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not, however, significantly affect either relapse-free or overall survival.

Patterns of failure following curative resection of gastric carcinoma

To identify patterns of failure following curative resection of gastric carcinoma, the records of 130 patients undergoing resection with curative intent at the Massachusetts General Hospital were rreviewed. The total local-regional failure rate was 38% (49130 patients), with 21 patients having local-regional failure alone and 28 patients having local-regional failure and distant metastases. The incidence of local failure rose with the more advanced stages of disease. Tumors staged B2, B3, C2, and C3 had local-regional failure rates in excess of 35%. This group of patients might benefit from adjuvant radiation therapy to the tumor bed and regional lymphatics. Local-regional failure rate was highest in the anastomosis or stump 33130 (25%), followed by the stomach bed 27130 (21%). The overall incidence of distant metastases was 52% (67130 patients) and rose in the more advanced disease stages. Tumors staged B2, B3, C2, and C3 had rates of distant metastases greater than 50%. Sixty-one patients (77%) had failure in the abdomen (liver, peritoneal surface, adrenal, kidney, and spleen, but excluding tumor bed, anastomosis, or regional nodes). Patients with Stage B2, B3, C2, and C3 tumors had total abdominal failure rates greater than 40%. The highest failure rates in the liver were in Stages B3 and C3, in which the subsequent development of liver metastasis was 40% and 47%, respectively. Peritoneal seeding occurred in 30130 (23%) of patients and was highest in Stages C2 and C3, with rates of 27% and 41%, respectively.

Primary radiotherapy in the treatment of stage I and II oral tongue cancers: Importance of the proportion of therapy delivered with interstitial therapy

From January 1963 through December 1979, 103 patients with Stage T 1N 0 and T 2N 0 squamous cell carcinomas of the oral tongue were treated with definitive radiotherapy. The primary was Stage T 1 in 18 patients and T 2 in 85 patients. Therapy to the primary consisted of interstitial therapy only in 18 patients, 16–37 Gy in 2.4–4.0 Gy fractions followed by interstitial therapy to doses of 38–55 Gy in 31 patients, external therapy of 40–50 Gy with interstitial therapy of 20–40 Gy in 46 patients, and external beam only to doses of 45–82 Gy in 8 patients. Follow-up ranged from 2 to 290 months (median 159 months). Five of the 8 patients treated with external therapy alone and 6 of the 18 patients treated with interstitial therapy failed at the primary site. In those patients treated with a combination of external and interstitial therapy the 2-year local control rate was 92% for patients treated with external therapy to doses of <40 Gy combined with a moderately high dose of brachytherapy, compared with 65% for patients who received external therapy to doses of ≥40 Gy with lower brachytherapy doses ( p = .01). Conversely the risk of failure in the neck was directly related to the dose delivered by external beam therapy. In field recurrence occurred in 44% of patients receiving no therapy to the neck, 27% in those receiving <40 Gy, and 11% in those patients with neck treatment to ≥40 Gy. Eleven of 87 (13%) of patients who were at risk for complications for ≥24 months developed severe complications; severe complications were more likely to occur in the group who received most of their therapy with external beam irradiation. These data show that a high dose of interstitial therapy is necessary to secure optimum local control of early primary tongue cancer. Because of the high frequency of moderate to severe late complications in this series we have adopted a policy of initial surgery for most oral tongue cancers with postoperative radiotherapy if indicated by pathological features predictive of a high rate of local-regional failure.

Radiobiological analysis of human tumors from patients with known clinical outcome

This data show that a high dose of interstitial therapy is necessary to secure optimum local control of oral tongue cancer. However, a large brachytherapy component of treatment compromises adequate neck irradiation. For this reason along with the frequency of severe complications encountered in this series with primary radiotherapy, we have adopted a policy of initial surgery for most oral tongue cancers with postoperative radiotherapy if indicated by pathological features predictive of a high rate of local-regional failure.

Definitive irradiation for early stage breast cancer: The University of Pennsylvania experience

From 1977 to 1984, 552 breast cancers in 548 women were treated with definitive irradiation following breast-conserving surgery at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. All patients had invasive carcinoma and were AJC clinical Stage I or 11. Pathologic axillary lymph node staging was known for all cases. The 5-year actuarial survival for the entire group was 93% with an NED survival of 81%. The 5-year survival for clinical Stage I and 11 patients was 97 and 87%, respectively, with a corresponding NED survival of 87 and 73%, respectively. For pathologic Stage I and II patients, the corresponding survival figures were 97 and 89%, respectively, with NED survival rates of 86 and 76%, respectively. The overall 5-year actuarial local failure rate was 6%, and the rate of local only as the first failure was 3%. The overall local-regional failure rate was 13% with a local-regional only first failure rate of 8%. These results compare favorably with other reported series and contribute a substantial number of patients to the increasing experience with definitive irradiation following breast-conserving procedures. The relatively low incidence of breast recurrence may be related to the emphasis on integrating the surgical, pathologic, and radiotherapeutic aspects of treatment, as well as the emergence of a re-excision policy for patients at high risk to have residual tumor.

Local-regional failure in patients treated with adjuvant chemotherapy for breast cancer.

Risk factors for local-regional recurrence of breast cancer were analyzed in a retrospective review of 117 patients treated with adjuvant CMF (Cytoxan [Mead Johnson & Co, Evansville, Ind], methotrexate, 5-fluorouracil) after radical or modified radical mastectomy at the Vincent T. Lombardi Comprehensive Cancer Center (Washington, DC). The median follow-up time was 50 months after mastectomy. The median time to recurrence was 23 months. The actuarial local-regional failure rate was 19% at five years. Risk of local failure correlated with size of primary (27% for T3 v 15% for T1) and axillary node status (36% for four or more positive nodes v 9% for three or fewer positive nodes). These findings suggest a rationale for the addition of postoperative radiation therapy in high-risk patients treated with adjuvant chemotherapy.

Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma: Implications for adjuvant therapy

Curative resection was accomplished in 28 of 82 patients with biopsy-proven carcinoma of the extra-bepstic bile ducts, gallbladder, and ampulla of Vater seen initially at the Massachusetts General Hospital from 1962 through 1978. None of the 28 had adjuvant radiation therapy nor chemotherapy. Later evidence of cancer (failure) was found in 16 of 25 patients who were post-op survivors. Local-regional recurrence ± distant metastases (documented at re-exploration, autopsy, or clinically) occurred in 13 16 , and only 3 developed distant disease only. Local-regional failure rates varied with anatomic location: 4 10 ampulla of Vater, 7 11 gallbladder, 1 3 common bile duct, land 1 1 hepatic duct (“Klatskin”) The time to local-regional recurrence ranged from 2 to 100 months post-operatively with a median of 17 months. Only 5 patients of the 28 are presently alive NED. The prognostic significance of tumor grade, lymph node involvement, perineural-lymphatic-venous invasion, and extension through the waq relative to patterns of failure are presented, and the implications for adjuvant therapy are discussed.