Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

BACKGROUND: Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. METHODS/DESIGN: SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. DISCUSSION: To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial. TRIAL REGISTRATION: controlled-trials.com ISRCTN13029788.

Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Erratum to: The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

[This corrects the article DOI: 10.1186/s40814-016-0046-2.].

Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma.

BACKGROUND: Objectively measured circulating biomarkers of prognosis complementing existing clinicopathological models are needed in renal cell carcinoma (RCC). METHODS: Blood samples collected from 216 RCC patients in Leeds before nephrectomy (median follow-up 7 years) were analysed for C-reactive protein (CRP), osteopontin (OPN) and carbonic anhydrase IX (CA9) and prognostic significance determined. RESULTS: CA9, OPN and CRP were univariately prognostic for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) with CRP and CA9 being independently prognostic for OS/CSS and OS, respectively. Including CA9, OPN and CRP with other conventional prognostic factors gave a superior predictive capacity when compared with a previously published pre-operative clinical nomogram (Karakiewicz et al, 2009). Osteopontin outperformed this nomogram and the post-operative SSIGN score for OS but not for CSS, being significantly predictive for non-cancer deaths. Osteopontin, CRP and CA9 outperformed stage (c-index 76% compared with 70% for stage) and OPN or CA9 identified several subsets of poor prognosis patients including in T1 patients, who may benefit from adjuvant therapy and increased surveillance. CONCLUSION: Circulating CA9, OPN and CRP add value to existing clinicopathological prognostic factors/models and support further studies to investigate their potential use in improving the clinical management of RCC.

A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial.

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.

Designing phase II trials in cancer: a systematic review and guidance.

BACKGROUND: Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design. METHODS: A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration. RESULTS: A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design. CONCLUSION: The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.

Meta-analysis to evaluate the role of interferon in follicular lymphoma.

PURPOSE: To determine whether interferon (IFN) -alpha2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma. PATIENTS AND METHODS: Ten phase III studies evaluating the role of IFN-alpha2 in 1,922 newly diagnosed patients with follicular lymphoma were analyzed. Updated individual patient data were used to perform meta-analyses for response, survival, and remission duration. RESULTS: The addition of IFN-alpha2 to initial chemotherapy did not significantly influence response rate. An overall meta-analysis for survival showed a significant difference in favor of IFN-alpha2, but also showed significant heterogeneity between studies. Further analyses were carried out in order to explain this heterogeneity, and to define the circumstances in which IFN-alpha2 prolonged survival. The survival advantage was seen when IFN-alpha2 was given: (1) in conjunction with relatively intensive initial chemotherapy (2P = .00005), (2) at a dose >/= 5 million units (2P = .000002), (3) at a cumulative dose >/= 36 million units per month (2P = .000008), and (4) with chemotherapy rather than as maintenance therapy (P = .004). With regard to remission duration, there was also a significant difference in favor of IFN-alpha2, irrespective of the intensity of chemotherapy used, IFN dose, or whether IFN was given as a maintenance strategy or with chemotherapy. CONCLUSION: When given in the context of relatively intensive initial chemotherapy, and at a dose >/= 5 million units (>/= 36 x 10(6) units per month), IFN-alpha2 prolongs survival and remission duration in patients with follicular lymphoma.

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Long-term survival in 463 women treated with platinum analogs for advanced epithelial carcinoma of the ovary: life expectancy compared to women of an age-matched normal population.

The objective was to assess the long-term survival (5-15 years) in 463 women, with stages IIb-IV epithelial carcinoma of the ovary and to compare their survival with that of a normal population matched for age and sex. Statistical analysis of 463 women, with stages IIb-IV epithelial cancer of the ovary, who were participants in two consecutive North Thames Ovary Group randomized trials, which took place between 1985 and 1994, was performed. The median follow-up period was 10.5 years. The women were treated with debulking surgery, where possible, and adjuvant platinum chemotherapy. One of the randomized groups in the first North Thames trial also received total abdominal radiotherapy. Survival rates at 5, 10, and 15 years were assessed. Prognostic factors for long-term survival were determined using a mathematical model to separate early effects from late effects. The ratio of observed to expected deaths compared to the normal population was calculated. Overall survival at 5 years was 21% (95% confidence intervals 17.5-25%), at 10 years was 13.5% (95% confidence intervals 10.5-17%), and at 15 years was 12% (95% confidence intervals 9-16%). The important prognostic factors for long-term survival were disease-free or minimal residual disease (a single remaining deposit <2 cm) at initial surgery with tumor grade 1 and good performance status. Compared with the normal population (1995 data), the ratio of observed to expected deaths after start of chemotherapy at 5 years was 14.1 (P < 0.001 Fisher's exact test), at 9-10 years 4.9 (P = 0.0033, Fisher's exact test), while in the 11- to 15-year period it had dropped to 2.75 (P = 0.090, Fisher's exact test), which was not significantly different. Patients with advanced cancer of the ovary, who survive 11 years or longer, have a life expectancy which is very similar to that of a normal population of women of the same age. Women with advanced ovarian cancer have an improved chance of long-term survival following treatment if they present with minimal residual disease after primary surgical debulking, grade 1 tumors, and good performance status.

ChlVPP alternating with PABlOE is superior to PABlOE alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial.

The purpose of this randomized trial was to compare the efficacy of 6 cycles of prednisolone, Adriamycin (doxorubicin), bleomycin, vincristine (Oncovin) and etoposide (PABlOE) with 3 cycles of PABIOE that alternate with 3 cycles of chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) in patients with advanced Hodgkin's disease. Between October 1992 and April 1996, 679 patients were entered onto the study. 41 of these did not match the protocol requirements on review and were excluded from further analysis, most of these being reclassified as NHL on histological review. Of the remaining 638 patients, 319 were allocated to receive PABIOE and 319 were allocated to receive ChlVPP/PABlOE. The complete remission (CR) rates were 78% and 64%, for ChlVPP/PABlOE and PABIOE respectively after initial chemotherapy (P< 0.0001). 124 patients were re-evaluated subsequently following radiotherapy to residual masses. The CR rates changed from 78% to 88% for ChlVPP/PABlOE and from 64% to 77% for PABlOE when re-evaluated in this manner (treatment difference still significant, P = 0.0002). The treatment associated mortality in the PABlOE arm was 2.2% (7 deaths), while there were no such deaths in the ChlVPP/PABlOE arm (P = 0.015). The failure-free survival was significantly greater in the ChlVPP/PABlOE arm (P< 0.0001) as was the overall survival (P = 0.01). The failure-free and overall survival rates at 3 years were 77% and 91% in the ChlVPP/PABlOE arm, compared with 58% and 85% in the PABIOE arm, respectively. These results indicate that ChlVPP alternating with PABIOE is superior to PABIOE alone as initial treatment for advanced Hodgkin's disease.

Applied kinesiology for treatment of women with mastalgia.

To determine whether an applied kinesiology technique was of benefit to women with breast pain, an open pilot study was conducted in which 88 newly presenting women with self-rated moderate or severe mastalgia were treated by applied kinesiology. This involved a hands-on technique consisting of rubbing a series of 'lymphatic reflex points' while touching painful areas of the breasts. The women were predominantly pre-menopausal, and patients with both cyclical and non-cyclical pain were included in the study. Patients' self-rated pain scores, both before and immediately after applied kinesiology were compared, together with a further score 2 months later. Immediately after treatment there was considerable reduction in breast pain in 60% of patients with complete resolution in 18%. At the visit after 2 months, there was a reduction in severity, duration and frequency of pain of 50% or more in about 60% of cases (P<0.0001). This preliminary study suggests that applied kinesiology may be an effective treatment for mastalgia, without side-effects and merits testing against standard drug therapies.

Identification of long-term survivors in primary breast cancer by dynamic modelling of tumour response.

Although clinical response to primary chemotherapy in stage II and III breast cancer is associated with a survival advantage, it is the degree of pathological response in the breast and ipsilateral axilla that best identifies patients with a good long-term outcome. A mathematical model of the initial response of 39 locally advanced tumours to anthracycline-based primary chemotherapy has been previously shown to predict subsequent clinical tumour size. This model allows for the possibility of primary resistant disease, the presence of which should therefore be associated with a worse outcome. This study reports the application of this model to an additional five patients with locally advanced breast cancer, as well as to 63 patients with operable breast cancer, and confirms the biological reality of the model parameters for these 100 breast cancers treated with primary anthracycline-based chemotherapy. The tumours that responded to chemotherapy had higher cell-kill (P < 0.0005), lower resistance (P < 0.0001) and slower tumour regrowth (P < 0.002). Furthermore, ER-negative tumours had higher cell-kill (P < 0.05), as compared with ER-positive tumours. All patients with a pathological complete response had zero resistance according to the model. Furthermore, the long-term implication of chemo-resistant disease was demonstrated by survival analysis of these two groups of patients. At a median follow-up of 3.7 years, there was a statistically significantly worse survival for the 37 patients with locally advanced breast cancer identified by the model to have more than 8% primary resistant tumour (P < 0.003). The specificity of this putative prognostic indicator was confirmed in the 63 patients presenting with operable disease where, at a median follow-up of 7.7 years, those women with a resistant fraction of greater than 8% had a significantly worse survival (P < 0.05). Application of this model to patients treated with neoadjuvant chemotherapy may allow earlier identification of clinically significant resistance and permit intervention with alternative non-cross-resistant therapies such as taxoids.

A randomized British National Lymphoma Investigation trial of CHOP vs. a weekly multi-agent regimen (PACEBOM) in patients with histologically aggressive non-Hodgkin's lymphoma.

BACKGROUND: Between 1987 and 1991, the British National Lymphoma Investigation randomized 459 patients with non-Hodgkin's lymphoma with a large-cell component to either CHOP or the PACEBOM regimen. PATIENTS AND METHODS: Four hundred fifty-nine eligible patients were included in this trial, four hundred one with diffuse large-cell lymphoma and fifty-eight with diffuse mixed-cell lymphoma according to the Working Formulation. Two hundred twenty-six patients were randomized to receive CHOP and two hundred thirty-three to receive PACEBOM. The two arms of the trial were well balanced for all potential prognostic factors. RESULTS: The complete remission rate with PACEBOM was 64% and with CHOP 57% (NS). At eight years, the actuarial cause specific survival (CSS) in the PACEBOM arm is 59% compared to 49% in the CHOP arm (P = 0.09). Patients < 50 years of age fared significantly better in the PACEBOM arm both for CSS and overall survival (P = 0.002) and the CSS was also significantly improved in stage IV disease (P = 0.02). CONCLUSIONS: The mature data from this trial suggest that an etoposide-containing multi-agent weekly regimen can be superior to CHOP.

A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study.

BACKGROUND: There is no clear data on the optimum number of courses of platinum chemotherapy required for treating advanced ovarian cancer. A prospective randomised trial was performed to compare five with eight courses of either carboplatin 400 mg/m2 or cisplatin 75 mg/m2 given four-weekly to patients with stage IC-IV ovarian cancer. PATIENTS AND METHODS: 225 patients were entered into the study and 233 were eligible for randomisation: 118 to five courses and 115 to eight courses. In each randomisation, half the patients received carboplatin and half received cisplatin. RESULTS: The mean number of courses received on the five arm was 4.74 and on the eight arm, 6.42, an increase of 35%. The median survival for all patients was 24 months with the median survival for the 156 patients with stage 3 disease being 21 months. No difference was detected in survival (P = 0.53) or time to progression from initial surgery (P = 0.29) between the two arms of the trial. False-negative calculations based on a multivariate analysis show that the trial currently has 95% power for excluding a difference of 10% in favour of the eight course arm at three years. CONCLUSION: There is insufficient evidence at the present time to justify more than five courses of first-line single agent platinum chemotherapy in the management of advanced ovarian cancer.

Body weight and vascular invasion in post-menopausal women with breast cancer.

To examine the relationship between body weight and vascular invasion (VI) around tumours in post-menopausal women with operable breast cancer, a retrospective study was conducted of 393 patients treated in a breast unit between 1987 and 1991. Weight was measured at the time of diagnosis. Vascular invasion was recorded as being present or absent. Vascular invasion was seen in slightly more of the 50 perimenopausal patients than in the 343 post-menopausal women (44% vs 36%). In the tumour specimens from post-menopausal patients weighing <50 kg, VI was observed in 11% compared with 45% of those weighing more than 80 kg (P= 0.02). Furthermore, the 5-year survival of those with VI was 74% compared with 91% for those without (P < 0.0001). Menopausal status and body weight may influence survival in patients with breast cancer, possibly as a result of the presence of unopposed circulating oestrogens at the time of surgery. Oestrogens may alter cohesiveness of breast cancer cells and modulate secretion of proteases, thereby influencing invasive potential. Excision of tumours in such an environment may have a deleterious impact on survival.

Cautionary tales of survival analysis: conflicting analyses from a clinical trial in breast cancer.

Data from a completed randomized trial in breast cancer are used to demonstrate and quantify the variation in estimated survival curves and log-rank statistics at different times throughout a trial. False 'plateaux' are common, as are wide fluctuations in chi2 values obtained from the log-rank test when there are few events. We show how analyses conducted at different times can demonstrate different effects. Long follow-up is often necessary to allow correct interpretation of results. We discuss the assumption of proportional hazards and the consequences of making that assumption inappropriately. We show how checking whether hazards are proportional can help in avoiding erroneous conclusions.

A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report.

A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkin's lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis.

Mathematical modelling of tumour response in primary breast cancer.

Although breast cancer is perceived to be relatively chemosensitive, cytotoxic drug therapy only leads to cure in the adjuvant setting. In advanced disease, primary resistance and inadequate cell kill may be important in determining the lack of a durable response to cytotoxics, but for an individual patient's tumour there is no consistent way of determining the importance of these two factors. An adaptation of Skipper's log cell kill model of tumour response to chemotherapy was applied to serial tumour measurements of 46 locally advanced primary breast carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal distribution of errors in the clinically measured volumes, the model produced, for each tumour separately, in vivo estimates of proportional cell kill, initial resistance and tumour doubling times during therapy. After 4 weeks' treatment, these data could then be used to predict subsequent tumour volumes with good accuracy. In addition, for the 13 tumours that became operable after the neoadjuvant chemotherapy, there was a significant association between the final volume as predicted by the model and the final pathological volume (P < 0.05). This approach could be usefully employed to determine those tumours that are primarily resistant to the treatment regimen, permitting changes of therapy to more effective drugs at a time when the tumour is clinically responding but destined to progress.