Komel Khabra

Clinical Activity and Tolerability of a 14-Day Infusional Ifosfamide Schedule in Soft-Tissue Sarcoma

Background. Soft-tissue sarcomas (STS) are a heterogeneous group of diseases with lack of effective treatments in most cases. Previous data suggest that continuous infusional ifosfamide regimens might improve cytotoxicity and tolerability compared to standard schedules. Methods. We retrospectively report the outcome of 35 patients affected by STS treated with a 14-day infusional ifosfamide regimen (1000 mg/m2/day) in our institution. Predictive factors for toxicity were also explored. Results. Median age was 53 years. There were 16 males and 19 females. Classification by histology was dedifferentiated liposarcoma (DDLPS): 22 (62.8%), synovial sarcoma: 7 (20%), myxoid/round-cell liposarcoma: 3 (8.5%), and others: 3 (8.5%). Overall, 7 patients (20%) achieved partial response (PR) and 10 patients (29%) achieved stable disease (SD). DDLPS showed special sensitivity: 5 patients (22.7%) had PR, 7 patients (31.8%) had SD, and disease control rate was 54.5%. Median progression-free survival and overall survival were 4.2 and 11.2 months, respectively. The most common toxicities were fatigue, nausea, and vomiting (all grades: 85.7%, 83%, and 54.3%, resp.). Neither hypoalbuminaemia nor gender was found to predict toxicity, although encephalopathy predominantly affected females. Conclusion. Ifosfamide administered as a 14-day continuous infusion is a safe regimen in STS with notable activity in DDLPS.

Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia.

Abstract Patients with childhood relapsed and refractory mature B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukemia (B-ALL) are rare and have a dismal prognosis. The previous UK national analysis of 26 children over a 7-year period prior to 1996 had highlighted the poor outcome, with only three survivors. This 10-year multicenter study evaluated recent data, since 2000. Of 33 children, nine survived (27.3%), with a median follow-up of 4.3 years. On exclusion of six children treated with palliative intent, the survival was one-third (nine of 27; 33.3%). All patients with primary refractory disease (n = 7) and all except one with early relapse (n = 11) died. Administration of four doses of 375 mg/m2 of rituximab was associated with a longer survival (p = 0.006). Response to reinduction (p < 0.001) and autologous hematopoietic stem cell transplant (auto-HSCT) (p = 0.003) were significant on multivariate analysis. Patients with a time to relapse of at least 6 months are potentially curable and must be offered intensive treatment with salvage chemotherapy, rituximab and auto-HSCT.

Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Here, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600‐mutant metastatic melanoma for organ‐specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system (CNS) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression.

Observation as a treatment strategy for advanced renal cell carcinoma—a call for prospective validation

A number of cancers can follow an indolent clinical course, even when the disease is at an advanced stage. For example, this pattern can be observed in some patients with renal cell carcinoma (RCC), breast cancer, and low grade non-Hodgkin lymphoma (NHL). When systemic treatments for these conditions are palliative, chronic and often toxic, there is an argument for deferring therapy until there is a clinically relevant burden of disease, at which time the side effects of treatment are counter-balanced by relief of symptoms and disease control. A randomized trial of “watchful waiting” compared to immediate chemotherapy treatment in asymptomatic patients with low-grade NHL found that overall survival between these two groups was the same, and the authors proposed that this approach might be particularly useful in elderly patients (Ardeshna et al., 2003). Furthermore, preliminary results of a randomized trial of immediate rituximab (an anti-CD20 monoclonal antibody) versus a watch and wait strategy in patients with asymptomatic follicular lymphoma were presented and indicate that rituximab significantly delays the time to initiation of new therapy such as chemotherapy or radiotherapy (Ardeshna et al., 2010). It is important to note that rituximab has a favorable side effect profile, and the most powerful argument for a watchful waiting approach is freedom from debilitating side effects and preservation of quality of life for patients. Prospective evidence for an initial observational strategy in other solid tumor types is limited, even though it is common in clinical practice. It is well recognized that a subgroup of patients with advanced RCC has slowly progressive metastatic disease over a number of years. Metastatic RCC (mRCC) was considered refractory to systemic therapy for many years, but there are now seven so called “targeted” agents approved for this condition, which target the critical vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, leading to inhibition of angiogenesis and cell survival and proliferation. All seven drugs have been shown in randomized clinical trials to significantly improve clinical outcomes for patients with mRCC, but they are non-curative and associated in general with moderate toxicity. Up to 20% of patients appear to be primarily refractory to these treatments (Rini and Flaherty, 2008), and almost all patients will eventually become resistant to an individual drug, necessitating sequential, chronic therapy. Because of the potential for substantial toxicity, a key question in this field is the optimal time to start treatment. It has been inferred from a number of sources, including a randomized discontinuation trial of sorafenib (Ratain et al., 2006), that treatment delays do not have an adverse impact but there are no published data to support this contention. Recently, we conducted a retrospective cohort study of patients treated at two centers to evaluate the clinical outcomes of those patients with metastatic renal cell cancer treated in the “targeted therapy era,” in who first line systemic therapy was deliberately deferred. Sixty-two patients with mRCC who had a planned period of observation prior to starting first line therapy, because of asymptomatic or slowly progressive disease, were included and the primary objective was to determine the progression free survival (PFS) of patients on deferred first line systemic therapy. All but one patient had favorable or intermediate risk disease (63% and 36% respectively), as defined by Heng et al. (2009). On average, patients with mRCC were observed for 18.7 months (95% CI 14.5–22.0 months). After a period of observation, 39 patients were treated with sunitinib, 18 with interferon, and 5 with other agents such as mTOR inhibitors. Overall, the median PFS for patients on first line therapy was 9 months (95% CI 8.1–10.1 months). Patients treated with sunitinib after observation also had a median PFS of 9 months (95% CI 8.1–9.9 months), and those treated with interferon had a median PFS of 6.7 months (95% CI 0.7–12.7 months). Median overall survival, defined as the time from starting first line treatment to death, was 25.2 months for all patients (95% CI 8.0–42.4 months), 17.4 months (95% CI 11.6–23.2 months) in the sunitinib group, and 37.6 months (95% CI 2.6–72.5 months) in the interferon group. Thus, in this cohort of patients with indolent, favorable or intermediate prognosis mRCC, first line systemic therapy was deferred by an average of more than 18 months and median PFS and overall survival times were comparable to those observed in the pivotal phase III and expanded access trials of sunitinib (Motzer et al., 2007; Gore et al., 2009). Retrospective data such as these are limited and clearly reflect selection bias. However, they suggest that this practice in mRCC is reasonable and does not compromise outcome, and in our view, there are compelling reasons for observational strategies to be prospectively, rigorously studied in this and other tumor types. This would provide an opportunity to evaluate longitudional quality of life data using tools such as Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST), which incorporates duration of survival and quality of life experienced into a single endpoint (Cole et al., 2004). It is possible that surveillance only for advanced cancer results in increased patient anxiety, and thus harms quality of life, but this should be prospectively assessed. Routine collection of tumor tissue from these patients would enable investigation and validation of biomarkers predictive of an indolent clinical course, and importantly, this information could be extrapolated for use in the non-metastatic disease setting. For example, observation may also be appropriate in those patients with incidental small renal masses, particularly in the presence of co-morbidities. Finally, an observational strategy might result in more efficient use of limited financial resources, a problem which is now faced by almost all developed countries.

Hemicerebellitis: Report of three paediatric cases and review of the literature

Acute inflammation of a single cerebellar hemisphere (hemicerebellitis) is a rare disorder of unknown origin. The clinical presentation is mainly characterized by headache, ataxia, dysmetria, and vomiting. In addition, some children may develop severe intracranial hypertension. The neuroimaging of hemicerebellitis raises a challenging differential diagnosis, particularly with posterior fossa tumours. Although there is no standard treatment for hemicerebellitis, its outcome is usually favourable. However, ipsilateral hemicerebellar atrophy develops in up to half of cases, and a minority of children may show persisting fine motor and/or neurocognitive sequelae. In this article, we contribute with three new reports and review a total of 35 cases of hemicerebellitis.

Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib

The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2–3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.

Development and responses of brain metastases during treatment with trastuzumab emtansine (T-DM1) for HER2 positive advanced breast cancer: A single institution experience

Ado‐trastuzumab emtansine (T‐DM1) is an antibody‐drug conjugate that does not cross an intact blood‐brain barrier. In the EMILIA trial of T‐DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T‐DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T‐DM1 at the Royal Marsden Hospital from 2011 to 2016. Data collected included baseline characteristics, previous treatment for advanced breast cancer, sites of metastatic disease, duration of T‐DM1, sites of progression, and treatment of CNS progression. Fifty‐five patients were identified who had received a median of two prior lines of treatment (range 0‐5). All were HER2 positive; 45 patients had IHC 3+ tumors and 10 were ISH positive. Patients received a median of 12 cycles of T‐DM1 (range 1‐34), and six remain on treatment at the time of analysis. Before commencing T‐DM1, 16/55 (29%) had known brain metastases (treated with whole brain [9] stereotactic radiotherapy [6] or both [1]). Brain was the first site of progression in 56% (9/16) patients, with a median time to brain progression of 9.9 months (95% CI 3.9‐12.2). In patients without known baseline brain metastases, 17.9% (7/39) developed new symptomatic brain disease during T‐DM1, after a median of 7.5 months (95%CI 3.8‐9.6). Brain progression was isolated, with control of extra‐cranial disease in 4/7 patients. Only one patient was suitable for stereotactic radiotherapy. Median time to extra‐cranial progression in all patients was 11.5 months (95% CI 9.1‐17.7), and median OS in all patients was 17.8 months (95% CI 14.2‐22). In patients not screened for brain metastases at baseline, the brain was the first site of progression in a significant proportion. Baseline brain imaging may have a role in standard practice for patients commencing T‐DM1 therapy.

Pazopanib-Induced Alopecia, an Underestimated Toxicity?

Pazopanib and sunitinib are treatment options for metastatic renal cell cancer (mRCC), with similar efficacy, and minor differences in their toxicity profile. Our experience has suggested that pazopanib-induced alopecia may be a potentially significant but previously under-reported toxicity. For this reason, we performed a retrospective review of the clinical records of all patients with mRCC treated with pazopanib at the Royal Marsden Hospital from European licensing until June 2013, and all patients treated with sunitinib over the same period. We found that 36 patients with mRCC were treated with pazopanib and 85 patients with sunitinib. Four of the 36 (11%) patients treated with pazopanib developed alopecia severe enough to warrant a wig versus none of 85 patients treated with sunitinib (p = 0.007). In conclusion, grade 2 pazopanib-induced alopecia was reported at significantly higher rates when compared to sunitinib-induced alopecia. Hence, in our view, patients should be informed about this potential toxicity when discussing the treatment options for mRCC.

Abstract P3-11-05: Neoadjuvant chemotherapy in invasive lobular breast carcinoma: Comparison of response, surgery and disease free survival with invasive ductal carcinoma

Background Lobular breast cancer (ILC) has been reported to be associated with a lower rate of pathologic complete response (pCR) and breast conserving surgery following neoadjuvant chemotherapy compared with ductal carcinoma (IDC). ILC is predominantly oestrogen receptor positive, HER-2-ve and histologic grade 1 or 2. Oestrogen receptor positive breast cancer has been shown to have poorer responses to neoadjuvant chemotherapy. HER-2 positivity is associated with better responses to anthracycline based neoadjuvant chemotherapy than HER-2 negative, and substantially improved pathological complete response (pCR) rates relative to HER-2 negative disease with the use of HER-2 targeted agents in this patient group. This study investigates response and disease free survival of ILC compared with IDC. Methods Patients with ILC and IDC treated with neoadjuvant chemotherapy were identified from the prospectively collated breast unit database at the Royal Marsden Hospital. Demographic, tumour, treatment and outcome data was obtained from the database and hospital electronic patient record system. Statistical analysis was undertaken comparing IDC and ILC. Clinical response rates, pCR rates, breast conserving surgery rates, and disease free survival were analysed. Clinical response was defined as those with partial response (≥50% reduction in the product of breast tumour size from baseline measurement), or complete clinical response (no clinically palpable breast tumour). Subgroup analysis was performed on ER+ve, HER-2–ve and HER-2 unknown cases. Results A total of 1017 patients were identified. Of these, there were 920 IDC and 97 ILC cases. Median age at commencement of neoadjuvant chemotherapy was 47.9 years (range 23.6-74.9). Median follow-up was 7.6 years (range 0.2-26.5). Pathologic response rates were available for 717 patients. 119 (19%) IDC had pCR, and 1 (1.1%) ILC (p Within the ER+ve, HER2-ve/unknown group there were 403 IDC and 82 lobular patients. pCR results were available for 148 (30%) of the patients. 41 (15.8%) in the IDC and 1 (1.3%) in the ILC group had pCR (p=0.001). 335 (83.1%) in the IDC group and 64 (78.0%) in the ILC group had a clinical response (p 0.27). Breast conserving surgery rates were 212 (57.6%) in the ductal group and 30 (39.0%) in the lobular group (p 0.003). Conclusion Within the cohort entire rates of pCR and of breast conserving surgery were lower for those with ILC compared with IDC. Despite lower rates of pCR and breast conserving surgery in ILC, there was no difference in clinical response rates or in disease free survival compared with IDC. Significant differences in pCR and breast conserving surgery rates between ILC and IDC persisted on subgroup analysis of those with ER+ve HER2-ve/unknown breast cancer. Citation Format: Hilary L Martin, Geraldine Walsh, Komel Khabra, Tabitha Skinner, Ian E Smith. Neoadjuvant chemotherapy in invasive lobular breast carcinoma: Comparison of response, surgery and disease free survival with invasive ductal carcinoma [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-05.

Low‐cost Kinect Version 2 imaging system for breath hold monitoring and gating: Proof of concept study for breast cancer VMAT radiotherapy

Abstract Voluntary inspiration breath hold (VIBH) for left breast cancer patients has been shown to be a safe and effective method of reducing radiation dose to the heart. Currently, VIBH protocol compliance is monitored visually. In this work, we establish whether it is possible to gate the delivery of radiation from an Elekta linac using the Microsoft Kinect version 2 (Kinect v2) depth sensor to measure a patient breathing signal. This would allow contactless monitoring during VMAT treatment, as an alternative to equipment–assisted methods such as active breathing control (ABC). Breathing traces were acquired from six left breast radiotherapy patients during VIBH. We developed a gating interface to an Elekta linac, using the depth signal from a Kinect v2 to control radiation delivery to a programmable motion platform following patient breathing patterns. Radiation dose to a moving phantom with gating was verified using point dose measurements and a Delta4 verification phantom. 60 breathing traces were obtained with an acquisition success rate of 100%. Point dose measurements for gated deliveries to a moving phantom agreed to within 0.5% of ungated delivery to a static phantom using both a conventional and VMAT treatment plan. Dose measurements with the verification phantom showed that there was a median dose difference of better than 0.5% and a mean (3% 3 mm) gamma index of 92.6% for gated deliveries when using static phantom data as a reference. It is possible to use a Kinect v2 device to monitor voluntary breath hold protocol compliance in a cohort of left breast radiotherapy patients. Furthermore, it is possible to use the signal from a Kinect v2 to gate an Elekta linac to deliver radiation only during the peak inhale VIBH phase.