Mohammed Mohiuddin

Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial

BACKGROUND The standard treatment for spinal cord compression caused by metastatic cancer is corticosteroids and radiotherapy. The role of surgery has not been established. We assessed the efficacy of direct decompressive surgery. METHODS In this randomised, multi-institutional, non-blinded trial, we randomly assigned patients with spinal cord compression caused by metastatic cancer to either surgery followed by radiotherapy (n=50) or radiotherapy alone (n=51). Radiotherapy for both treatment groups was given in ten 3 Gy fractions. The primary endpoint was the ability to walk. Secondary endpoints were urinary continence, muscle strength and functional status, the need for corticosteroids and opioid analgesics, and survival time. All analyses were by intention to treat. FINDINGS After an interim analysis the study was stopped because the criterion of a predetermined early stopping rule was met. Thus, 123 patients were assessed for eligibility before the study closed and 101 were randomised. Significantly more patients in the surgery group (42/50, 84%) than in the radiotherapy group (29/51, 57%) were able to walk after treatment (odds ratio 6.2 [95% CI 2.0-19.8] p=0.001). Patients treated with surgery also retained the ability to walk significantly longer than did those with radiotherapy alone (median 122 days vs 13 days, p=0.003). 32 patients entered the study unable to walk; significantly more patients in the surgery group regained the ability to walk than patients in the radiation group (10/16 [62%] vs 3/16 [19%], p=0.01). The need for corticosteroids and opioid analgesics was significantly reduced in the surgical group. INTERPRETATION Direct decompressive surgery plus postoperative radiotherapy is superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer.

Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data

BACKGROUND Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15-27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR. METHODS In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test. FINDINGS 484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0-277). 5-year crude disease-free survival was 83.3% (95% CI 78.8-87.0) for patients with pCR (61/419 patients had disease recurrence) and 65.6% (63.6-68.0) for those without pCR (747/2263; HR 0.44, 95% CI 0.34-0.57; p<0.0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0.54 (95% CI 0.40-0.73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0.91 (95% CI 0.73-1.12). The effect of pCR on disease-free survival was not modified by other prognostic factors. INTERPRETATION Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival. FUNDING None.

Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy: report by the radiation therapy oncology group

This report details the patterns of tumor recurrence in two prospective randomized studies involving 551 patients with histologically proven unresectable or medically inoperable non‐oat cell carcinoma of the lung treated with definitive radiotherapy. Patients were treated according to two protocols, depending on the stage of the tumor: (1) Patients with T1, 2, 3‐NO, 1, 2 tumors were randomized to four different regimens: 4000 cGy split course (2000 cGy in five fractions, per 1 week, 2 weeks rest and additional 2000 cGy in five fractions, per 1 week) or 4000, 5000, or 6000 cGy continuous courses, five fractions per week. (2) Patients with T4, any N or N3, any T stage tumors were randomized to be treated with 3000 cGy tumor dose (TD), ten fractions in 2 weeks, 4000 cGy split course (described above), or 4000 cGy continuous course. In the patients with less advanced tumors (Study 1) the intrathoracic failure rate within the irradiated volume was 48% with 4000 cGy continuous, 38% with 4000 cGy split course or 5000 cGy continuous, and 27% for patients receiving 6000 cGy continuous course. The failure rate in the nonirradiated lung ranged from 25% to 30% in the various groups. Patients with adenocarcinoma or large cell undifferentiated carcinoma had better intrathoracic tumor control (35%) than those with squamous cell carcinoma (20%). The incidence of distant metastases was 75% to 80% in all histologic groups. Distant metastases appeared sooner after therapy in the patients with adenocarcinoma or large cell undifferentiated carcinoma. The initial failure rate in the brain was 7% in patients with squamous cell carcinoma, 19% with adenocarcinoma, and 13% in patients with large cell carcinoma. The ultimate incidence of brain metastases was 16% in squamous cell carcinoma, and 30% for adenocarcinoma or large cell undifferentiated carcinoma. Higher doses of irradiation will be necessary in order to improve the intrathoracic tumor control. Clinical trials by the Radiation Therapy Oncology Group, some of them involving multiple daily fractionation, are in progress. Furthermore, because of the high incidence of distant metastases, effective systemic cytotoxic agents are critically needed to improve survival of lung cancer patients. The high frequency of brain metastases suggests that, as in small cell carcinoma of the lung, elective irradiation of the brain may be necessary, if not to improve survival to enhance the quality of life of patients with adenocarcinoma and large cell carcinoma.

Randomized Phase II Study of Neoadjuvant Combined-Modality Chemoradiation for Distal Rectal Cancer: Radiation Therapy Oncology Group Trial 0012

PURPOSE To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a randomized phase II study PATIENTS AND METHODS Patients with clinical T3/T4 distal rectal cancers were randomly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection. Patients were randomly assigned to receive continuous venous infusion (CVI) fluorouracil (FU) 225 mg/m2 per day, 7 days per week, plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid (arm 1) or CVI FU 225 mg/m2 per day Monday to Friday, 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day (arm 2). Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy. The primary end point of this study was pathologic complete response (pCR). Secondary end points included acute and late normal tissue morbidity. RESULTS A total of 106 patients were entered onto the study, with 103 assessable for response. The overall resectability rate was 93%. The median time to surgery was 7 weeks. Tumor downstaging was observed in 78% of patients in both arms. The pCR rate for all assessable patients was 26% in each arm. For patients who had surgery, the pCR rate was also the same (28%) in both arms. Acute and late toxicity was also similar. Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13% and 38% in arm 1 and 12% and 45% in arm 2, respectively. CONCLUSION Although the overall complete response rate and toxicity seems similar in both arms, this is the first multi-institutional study to establish a relatively high (28%) pCR rate after neoadjuvant therapy.

The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: Results of an analysis from the RTOG head and neck database☆

A retrospective analysis of the effect of local control on the development of distant metastases was performed in 2648 patients with carcinoma of the head and neck selected from the RTOG database. The 5-year time-adjusted incidence of distant metastases was 21% for patients who were in local-regional control at 6 months after the start of treatment, compared to 38% for local-regional failure patients (p less than 0.001). The incidence of distant metastases detected between the interval of 6 months to 2.5 years after treatment was significantly increased in patients with tumors of the oral cavity, oropharynx, supraglottic larynx, and glottis who developed local-regional failure within this time period, compared to those who remained locally controlled (19% distant metastases for local-regional failure vs 7% for local-regional control (p less than 0.001)). In contrast, there as no difference in the incidence of distant metastases in patients with carcinoma of the nasopharynx or hypopharynx regardless of the local-regional disease status. A Cox proportional hazards regression analysis demonstrated that local-regional control was the most significant variable affecting the development of distant metastases, followed by tumor site, N-stage, and T-stage. For all tumor sites, except for the hypopharynx and nasopharynx, improvements in local-regional control are likely to improve survival. Tumors of the hypopharynx and nasopharynx have a higher probability of micro-metastatic dissemination at the time of initial diagnosis, and until effective methods to treat disseminated disease are developed, the effect of local control on survival will not be readily discerned.

Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation

PURPOSE To assess the potential downstaging of advanced rectal cancer with combined preoperative chemoradiation. METHODS AND MATERIALS Thirty-one patients with fixed rectal cancers (stage > or = cT3) were treated with concomitant preoperative chemotherapy and high-dose radiation in an effort to improve resectability. Three (10%) patients had partially fixed low rectal cancers, 24 (77%) patients had fixed tumors, and 4 (13%) had advanced fixation with pelvic sidewall invasion. Radiation was delivered to the whole pelvis using shaped anterior and posterior and lateral fields to 45 Gy followed by a boost to the tumor. Median total radiation dose was 55.8 Gy. Chemotherapy consisted of low dose continuous infusion of 5-FU (200-300 mg/m2/day) for the duration of radiation treatment. All 31 patients underwent surgical resection of tumor 6-8 weeks following treatment. Median follow up is 24 months (range 9-60). RESULTS Twenty-three (74%) of the tumors were clinically downstaged following preoperative treatment. Of 24 fixed cancers, 11 (46%) became mobile, 6 (25%) became partially fixed, and 7 remained fixed. Of the four tumors with advanced fixation, two (50%) became mobile and two (50%) no longer had tumor extension to the pelvic sidewall. Two of the three initially partially fixed cancers became mobile and one remained partially fixed. Following surgery, the pathologic postradiation T-stages were as follows: T0: 10%, T1: 0%, T2: 32%, T3: 42%, and T4:16%. Seven patients (23%) were also node-positive (T0-2: 2, T3: 4, T4: 1), and two patients (6%) had liver metastases at surgery. Preoperative chemoradiation was well tolerated. There was no significant hematological toxicity. Acute grade 3 gastrointestinal toxicity was seen in six patients requiring a short hospitalization for dehydration and/or abdominal discomfort. No patient developed grade 4 toxicity. Five patients (16%) developed local recurrence of disease (T0-2: 0/13, T3: 1/13, and T4: 4/5). The actuarial 3-year survival is 68%. CONCLUSIONS Concomitant preoperative chemoradiation using low dose continuous infusional 5-FU for advanced rectal cancer is relatively safe with acceptable morbidity. This approach is associated with considerable clinical and pathologic downstaging of cancer. Tumor resectability is improved with potential for improved local control of disease and survival.

Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors: Final radiation therapy oncology group report

This is the final analysis of Protocol #78–10 which explored increasing single‐doses of half‐body irradiation (HBI) in patients with multiple (symptomatic) osseous metastases. When given as palliation, HBI was found to relieve pain in 73% of the patients. In 20% of the patients the pain relief was complete; over two thirds of all patients achieved better than 50% pain relief. The HBI pain relief was dramatic with nearly 50% of all responding patients doing so within 48 hours and 80% within one week from HBI treatment. Furthermore, the pain relief was long‐lasting and continued without need of retreatment for at least 50% of the remaining patients life. These results compare favorably with those obtained by the Radiation Therapy Oncology Group (RTOG) using several conventional daily fractionated schemes on similar patients in a prior study (RTOG #74–02). HBI achieves pain relief sooner and with less evidence of pain recurrence in the irradiated area than conventionally treated patients. The most effective and safest of the HBI doses tested were 600 rad for the upper HBI and 800 rad for the lower or mid‐HBI. Increasing doses beyond these levels did not increase pain relief, duration of relief, or achieved a faster response; however, the increase in dose was associated with a definite increase in toxicity. Single‐dose HBI was well tolerated with no fatalities seen among 168 treated patients. A comprehensive premedication program has proven to decrease the acute radiation syndrome to very acceptable levels. There were excellent responses found in practically all tumors treated, but especially breast and prostate among which over 80% of all patients experienced pain relief, 30% in a complete fashion. Single‐dose HBI emerges as one of the safest, fastest, and more effective palliative tools for intractable cancer pain in modern radiation oncology. Cancer 58:29–39, 1986.

Prognostic significance of postchemoradiation stage following preoperative chemotherapy and radiation for advanced/recurrent rectal cancers

PURPOSE To evaluate the prognostic significance of postchemoradiation pathologic stage and implications for further therapy following preoperative chemoradiation and surgery for advanced/recurrent rectal cancer. METHODS AND MATERIALS Seventy-seven patients with advanced (fixed or tethered T4) or recurrent rectal cancer were treated with preoperative chemoradation followed by surgical resection of disease. Chemotherapy consisted of either of bolus 5-FU 500 mg/m(2) per day or continuous venous infusion 225 mg/m(2) per day for the duration of radiation. Radiation therapy was planned to be delivered to the whole pelvis to a dose of 45 Gy followed by a boost to the area of the tumor of 5-15 Gy. Total radiation doses ranged from 40 to 63 Gy with a median of 55.8 Gy. Surgical resection was then carried out 6-10 weeks following the completion of treatment (median, 7 weeks). Twenty-eight patients underwent abdominoperineal resection and and 49 patients had sphincter-sparing surgical procedures. None of the patients received postoperative chemotherapy. Follow-up in these patients ranges from 1 year to 8 years with a median of 3 years. RESULTS Significant downstaging of disease was observed with 12/77 (16%) having no residual disease(pT0) and 13% (10/77) found to have pT1-2, N0 disease, 31% (24/77) with pT3-4, N0 and 40% (31/77) for pT0-4, N1-2 cancers. Survival by pathologic stage was 100% for pT0-2, N0 cancers, 80% for pT3-4, N0 and 73% for pTx, N1-2. Local recurrence of disease was observed in 0% of patients with pT0-2, N0 as compared with 13% (3/24) in pT3-4, N0 and 16% (5/31) in pT0-4, N1-2 patients. CONCLUSION Downstaging following preoperative chemoradiation is a significant prognostic factor. Patients with pT0, T1, or T2 disease have an excellent prognosis and are unlikely to fail locally or with systemic disease. However, patient with T3/T4 or N+ disease may benefit from further adjuvant chemotherapy.

Concomitant Cisplatin Chemotherapy and Radiotherapy in Advanced Mucosal Squamous Cell Carcinoma of the Head and Neck Long-Term Results of the Radiation Therapy Oncology Group Study 81-17

One hundred twenty‐four eligible patients with advanced mucosal squamous cell carcinoma of the head and neck were entered into a pilot study of concomitant cisplatin (100 mg/m2 given every 3 weeks for three doses) and standard irradiation. The initial complete response (CR) was 71% with an additional two cases salvaged by surgery for an overall 73% CR. When no keratin was identified in the histologic specimen (41 patients) the CR was 90%. The nasopharynx showed the best CR (89%) among the sites. At 4 years after treatment, the estimated locoregional tumor control rate was 43% and the survival, 34%. When no keratin was present in the specimen, the estimated locoregional control of tumor was superior (56% versus 38% with keratin identified, P = 0.02) and the estimated survival was also superior (48% versus 26%, P = 0.008). Acute treatment‐related toxicities included one death due to renal damage and two patients with life‐threatening renal damage. The delivery of radiotherapy was not altered. Late toxicity included necrosis −3%, fibrosis −4%, and one fistula. The results of this study justify a randomized trial for the comparison of this combination of cisplatin and radiotherapy versus radiotherapy alone in advanced mucosal carcinomas of the head and neck.

Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response

PURPOSE Preoperative chemoradiation is being utilized extensively in the treatment of rectal cancer. However, a variety of dose time factors in both delivery of chemotherapy and irradiation remain to be established. This study was undertaken to examine the impact of dose time factors on pathological complete response (pCR) rates following preoperative chemoradiation for fixed rectal cancer. METHODS AND MATERIALS Thirty-three patients with fixed rectal cancers were treated with combined 5-fluorouracil (5-FU) chemotherapy and pelvic radiation. Twenty-one patients received bolus 5-FU during the first 3-5 days of radiation and repeated on days 28-33 of their radiation treatment. Twelve patients were treated with continuous infusion (CI) 5-FU, 225 mg/m(2) for the duration of the pelvic radiation. Fifteen patients received a planned total radiation dose of 45 to 50 Gy and 18 patients received a dose of 55 to 60 Gy. Surgical resection was then carried out 6-8 weeks after completion of treatment. RESULTS Diarrhea was the most frequent acute toxicity. Grade 3 diarrhea was observed in 6 patients requiring treatment interruption and was not related to the chemotherapy regimen. There was no Grade 4 or 5 toxicity. pCR was observed in 2 of 21 (10%) patients treated with bolus 5-FU as compared to 8 of 12 (67%) for patients treated with CI (p = 0.002). pCR were observed in 8 of 18 (44%) patients receiving radiation dose > or = 5500 cGy as compared to 2 of 15 (13%) patients treated to a dose < or = 5000 cGy (p = 0.05). In the high-dose radiation (> or = 5500 cGy) group, a significant difference in pCR rate was observed in patients treated with CI, 8 of 12 (67%) (p = 0.017) as compared with bolus 5-FU (0 of 6). There was no significant difference in operative morbidity or in wound healing between patients treated with bolus 5-FU or CI or within the groups treated with low or high doses of radiation. Three patients have developed local recurrence at 14 and 24 months, two in the low-dose group treated with bolus 5-FU and one patient in the CVI group. The overall 5-year survival for the whole group is 71%. CONCLUSION Dose intensity of 5-FU and dose of radiation correlate significantly with the likelihood of achieving a pCR. Continuous infusion 5-FU (CI) and a preoperative radiation dose of 5500 cGy or higher can achieve pCR rates of approximately 50%, even in fixed cancers of the rectum.